glomerulo Flashcards
sindrome nefritica
has, hematuria, proteinuria
sindrome nefritica
-LES
-GNPE
-ANCA vasculite :
Wegener’s Granulomatosis
Microscopic Polyangiitis
Renal-limited vasculitis
Anti-Glomerular Basement Membrane (Anti-GBM):
Antibody disease
Goodpasture’s disease (if associated with pulmonary hemorrhage)
IgA Nephritis
Henoch-Schonlein Purpura
Endocarditis-associated glomerulonephritis
Cryoglobulinemic glomerulonephritis
investigacao sindrome nefritica
Anti-nuclear antibody (ANA)
C3 and C4 (complements)
P-ANCA (perinuclear ANCA)
C-ANCA (cytoplasmic ANCA)
Anti-GBM (glomerular basement membrane) antibody
Cryoglobulins
Hepatitis C antibody
lupus investigacao
biopsia
se exames indicando lupus ou flare =creatinina,eas,razao proteina/creatinina
sorologia com anti dna e complemento
. Depressed complement levels (of C3 and C4) and elevated anti-DNA antibody titers also suggest active disease
Renal involvement in sle
persistent proteinuria > 500 mg/dL/day, 3+ on dipstick, cellular urinary casts
proteinuria between 500 and 1000 mg/day is already associated with significant kidney damage and also that “low-grade” proteinuria does not exclude significant kidney injury in LN
early management of LN improves the prognosis of the disease [, an additional argument in favor of an early biopsy.
The most common lesion observed in LN is glomerulonephritis with immune deposits.
kidney biopsy l goals: (i) to characterize the type of glomerular involvement and thereby guide immunosuppression; (ii) to consider other mechanisms of renal injury such as thrombotic microangiopathy or podocytopathy, which require a different therapeutic approach; and (iii) to assess the chronicity and therefore the irreversibility of the lesions.
discovery of tubulointerstitial nephritis is not exceptional and is also associated with a worse prognosis, independent of glomerular lesions
Fisiopatologia LES
e nefrite lupica
linfócitos B -> plasmócitos -> produção de auto-anticorpos e com a deposição de complexos imunes, os quais resultam em inflamação crônica e lesão dos tecidos.
. It is primarily caused by a type-3, hypersensitivity reaction, which results in the formation of immune complexes.
Anti-double-stranded DNA (anti-dsDNA) binds to DNA, which forms an anti-dsDNA immune complex.
immune complexes deposit on the mesangium, subendothelial, and/or subepithelial space near the glomerular basement membrane of the kidney. This leads to an inflammatory response with the onset of lupus nephritis, in which the complement pathway is activated with a resultant influx of neutrophils and other inflammatory cells.
polymorphisms in the allele coding for the immunoglobulin receptors on macrophages and APOL1 gene variations found exclusively in African American populations with SLE were found to be associated with predisposition to lupus nephritis
[Antibodies also cross-react with glomerular antigens in particular from the basement membrane
The location of IC deposits explains the clinical phenotype.
Subendothelial IC induce endothelial dysfunction and recruitment of macrophages and T cells into crescents, which also contain proliferating cells from the parietal layer of Bowman’s capsule, thereby causing the so-called “proliferative” variants.
Subepithelial IC cause damage to podocytes, but pro-inflammatory cell recruitment is more limited because the glomerular basement membrane prevents contact with the intravascular space. There is less glomerular inflammation, By contrast, the enlargement of basement membrane pores explains the (usually massive) proteinuria.
proliferative variants with subendothelial immune deposits correspond to class III/IV LN,
while subepithelial immune deposits correspond to class V LN.
, LN is also characterized by tubulointerstitial lesions which do not result from passive deposition of IC but are part of an adaptive immune response
.
Biópsia na nefrite lupica
all forms of LN can be adequately treated with corticosteroids plus mycophenolate mofetil (MMF)
the biopsy is important to define the nature of renal involvement.
Although immune-complex–mediated GN is the most common cause of kidney disease in SLE, there are other mechanisms that result in renal injury which can only be diagnosed with a biopsy, and require a different approach
Ex: thrombotic microangiopathy and lupus podocytopathy (defined as nephrotic syndrome in SLE that on kidney biopsy shows diffuse foot process effacement and no subendothelial or subepithelial immune deposits)
The find- ing of isolated tubulointerstitial nephritis is rare
.biopsy provides important information that guides management, including activity versus chronicity, the latter affecting prognosis and susceptibility to treatment toxicities, and concomitant abnormalities, such as thrombotic microangiopathy or membranous feature, which have implications on the natural history and choice of therapy
Indicação bx lúpus
Alteração não justificada da fc renal
Ptnuria > 500mg/dia
Sedimento ativo : hematuria ou leucocituria estéril
Ou cilindros celulares ( hematicos ou leucocitarios)
Electron microscopy, extent and severity of podocyte injury and the loci of immune deposits
Because clinical findings do not always correlate with the extent or severity of kidney involvement, a kidney biopsy is useful to confirm the diagnosis and for the assessment of activity and chronicity features that inform treatment decisions and prognosis
hipocomplementenemia
consumo de complemento
LES
GNPE
endocardite
shunt
GNMP
GN crioglobulinemica
dc renal ateroembolica
shu e ptt
Quadro clínico e Dx da nefrite lúpica:
Monitoring for the development of lupus nephritis is done with serial creatinine, urine albumin-to-creatine ratio, and urinalysis
Critério diagn Les
Eular 2019
Fan>1:80
+ descartar outras causas+ 10 pontos de critério e pelo menos 1 domínio clínico
Tipos histológicos renais do LES:
no man faces difuse menstrual situation
Class I = nefrite lupica mesangial minima. MO=normal, IF complexos imunes mesangiais
classe II-mesangial proliferativa hipercelularidade mesangial ou expansao da matriz mesangial com deposicao de imunocomplexos subepi e subendo,
Hematuria, low-grade proteinuria; renal insufficiency, nephrotic syndrome not expected
classe III-NL FOCAL= glomerulonefrite endo/extracapilar, focal ativa ou inativa, segmentar ou global que acometa menos de 50%dos glomerulos pode ter lesoes ativas, inativas cronicas c cicatrizes gloemrulares ou ambas.Class III is further subdivided into A, A/C or C depending on the activity or chronicity of the lesions noted
segmental endocapillary proliferation in <50% of glomeruli
Lesions can be active, chronic, or have elements of both
Hematuria, proteinuria seen in most patients; renal insufficiency, nephrotic syndrome not unusual
classe iv=Diffuse LN forma mais severa=sclerotic or global=glomerulonefrite endo/extracapilar, difusa ativa ou inativa, segmentar ou global que acometa > 50%dos glomerulos.
Depósitos imunes subendoteliais difusos com ou sem alteracoes mesangiais sao comuns. categoria dividida em segmentardifusa ou global difusa
wire loop lesions in sle and hyaline thrombi Mesangial and subendothelial immune complexes/
Proliferative, necrotizing and crescentic lesions may all be present. Wire loops may be seen. Immunofluorescence will reveal the typical ‘full house’ pattern of immunoglobulin/ complement deposition. Subendothelial deposits may be seen on electron microscopy. Class IV is similarly divided into segmental (S), global (G), active (A) or chronic (C) based on pathology findings
Mesangial and subendothelial immune complexes/
segmental or global endocapillary proliferation in >50% of glomeruli
Lesions can be active, chronic, or have elements of both
Hematuria, proteinuria seen in most patients; renal insufficiency, nephrotic syndrome not unusual
classe v=Membranous LN =Class V=subepithelial deposits producing membranous patter= Numerous subepithelial immune complexes in >50%
of glomerular capillaries
Proteinuria, often nephrotic range; hematuria possible; usually no renal insufficiency
Advanced sclerosing LN=Class 6, > 90% globally sclerosed without residual activity
6 Glomerulosclerosis in >90% of glomeruli
Renal insufficiency; proteinuria and hematuria often present
Classificação biópsia nefrite lupica
classe 1 mesangial minima Normal light microscopy; complexos imunes mesangiais detectaveis na IF
classe 2-mesangial proliferativa hipercelularidade mesangial com deposicao de imunocomplexos , expansao mesangial
Hematuria, low-grade proteinuria; renal insufficiency, nephrotic syndrome not expected
3 Mesangial and subendothelial immune complexes/
segmental endocapillary proliferation in <50% of glomeruli
Lesions can be active, chronic, or have elements of both
Hematuria, proteinuria seen in most patients; renal insufficiency, nephrotic syndrome not unusual
4 Mesangial and subendothelial immune complexes/
segmental or global endocapillary proliferation in >50% of glomeruli
Lesions can be active, chronic, or have elements of both
Hematuria, proteinuria seen in most patients; renal insufficiency, nephrotic syndrome not unusual
5 Numerous subepithelial immune complexes in >50%
of glomerular capillaries
Proteinuria, often nephrotic range; hematuria possible; usually no renal insufficiency
6 Glomerulosclerosis in >90% of glomeruli
Renal insufficiency; proteinuria and hematuria often present
Role of anti-malarials in lupus nephritis
hcq para todo mundo a nao ser q tenha ci
Reduce the risk of lupus nephritis (LN) in patients with Systemic Lupus Erythematosus (SLE), reduce the risk of development of ESRD in patients with LN, and increase the odds of complete remission in patients with lupus nephritis.
(including lower rates of disease flares, progressive kidney damage, and vascular complications)
higher response rates to therapy, lower incidence of CV and thrombotic events in patients with antiphospholipid antibodies, less organ damage, improved lipid profile, and better preservation of bone mass.
e use in pregnancy has been associated with a decrease in lupus activity and a satisfactory safety profile in both the mother and the fetus
****Hydroxychloroquine may accumulate in lysosomes and cause a form of phospholipidosis with accumulation of multilamellar zebra bodies in podocytes that can mimic the appearance of Fabry disease
- Anti-malarials significantly reduce the risk of lupus nephritis (LN) in patients with Systemic Lupus Erythematosus (SLE), reduce the risk of development of ESRD in patients with LN, and increase the odds of complete remission in patients with lupus nephritis.
- Most common side effect: retinal toxicity, which necessitates annual dilated eye exam
- Less risk of retinal toxicity if the dose of hydroxychloroquine is less than 6 mg/kg/day
induction and maintenance treatment choices for proliferative lupus nephritis.
high-dose corticosteroids for rapid control of inflammation and either MMF or cyclophosphamide to control inflammation and autoimmunity
lack of antimalarial use may be associated with an increase in LN treatment failures
Cyclophosphamide can be given orally or intravenously, and if intravenous in either standard-dose ( NIH regimen) or low- dose (low-dose or Euro-lupus regimen).
High intensity immunosuppression is given for the first 3–6 months and then replaced by MMF (or a lower dose of MMF if it was used for induction) or azathioprine to maintain suppression of autoimmunity and inflammation, and thereby prevent flare.
Standard-dose cyclophosphamide (either oral or NIH) improved the long-term kidney survival compared with corticosteroids alone and set the standard-of-care for LN treatment
Because of toxicity concerns surrounding cyclophosphamide, MMF and NIH cyclophosphamide were directly compared in a large randomized controlled trial and found to be equivalent for the induction of renal responses after 6 months of treatment
MMF has replaced cyclophosphamide as first-line induction therapy for LN in many areas.
Typical regimens often start with
methylprednisolone at 0.5–1.0 g/d intravenously for 2–3 days followed by daily oral glucocorticoid with progressive tapering. Mycophenolate mofetil at around 2 g/d in divided doses in Asian or Caucasian patients or up to 3 g/d in others is used for 6–12 months followed by gradual tapering.
Measurement of mycophenolic acid blood level may be useful in select patients who show unsatisfactory treatment response or treatment-associated adverse effects
. Reduced-dose cyclophosphamide (500 mg intravenously fortnightly for 3 months; the Euro-Lupus regimen) is recommended, although the modified NIH regimen at 0.5–1 g/m2 intravenously monthly for up to 6 months can be considered in patients with low cumulative drug exposure and severe disease, such as those with extensive crescents, especially in “high-risk” groups (for example, patients of African descent)
. Potential adverse effects such as marrow or gonadal toxicity, alopecia, and malignancy predisposition, and also the inconvenience and cost of intravenous infusions, are the disadvantages of cyclophosphamide.
The choice between mycophenolate and cyclophosphamide also takes into consideration the response and tolerance to treatments in previous flares, cumulative lifetime cyclophosphamide exposure, treatment adherence, and patient preference.
abatacept and cyclophosphamide combination efficacy and safety study (ACCESS) trial which studied the effect of blocking the CD28/CD80 costimula- tory pathway in LN with abatacept, a CTLA4-Ig construct. Although abatacept did not offer any benefit for induction of remission when added to low-dose cyclophosphamide, patients in the abatacept arm that reached a complete renal remission at 6 months were followed for another 6 months without any maintenance immunosuppressive therapy. At 12 months the patients in the abatacept arm had fewer SLE flares than patients in the placebo arm who did receive aza.
calcineurin inhibitors (CNIs) cyclosporine A and tacro- limus have been tested extensively in LN, especially in Asia, with very encouraging results. CNIs attenuate inflamma- tion by preventing release of inflammatory cytokines from leukocytes, and also block T cell activation (96), and there- fore could have an effect to maintain remission. CNIs have been used as part of a multitarget approach to treating LN, added to a regimen of MMF and corticosteroids, and have been shown to be superior to cyclophosphamide in induc- ing remission by 6 months (97). A multitarget approach is appealing as the pathogenesis of SLE involves several im- mune pathways. CNIs plus corticosteroids alone have also been used for LN induction and found to be as effective as MMF for proliferative LN
Nefrite lupica kdigo 2021
Hcq para todos 5mg/kg/dia max 400mg
Classe I E II
Se proteinúria IECA/BRA Para todos
Proteinúria níveis baixos: imunossupressão guiado por manifest extra renais
Se sind nefrotica: avaliar podicitopatia na ME = tto DLM,
corticoide dose baixa+ outra imunossupressão AAMF, aza, icn
geralmente resp bem ao corticoide=over 90% of patients given glucocorticoid monotherapy achieved remission within a median time of 4 week
The proliferative classes (3 and 4) are often treated with potent immunosup- pression, whereas nonproliferative,
membranous LN (class 5) may be managed conservatively (antiproteinuric therapy) if patients have subnephrotic proteinuria, or with immunosuppression if patients have nephrotic range proteinuria.
Tratamento classe i , ii e vi
tto = controle pressorico
ieca/bra se tiver proteinuria
hidroxicloroquina
O EXTRA RENAL QUE DEFINE O TTO
podocitopatias tratar com lesao minima ;prednisona1mg/kg/dia se houver sind nefrotica
desmame em até 6 meses
Considerar terapia de manutencao com glicocorticoide e mais um agente para imunossupressao PREFERENCIA MICOFENOLATO
Nefrite lupica tto classe iii e iv
1) acessar atividde e cronicidade=
classe III/IV +/- V ATIVA
corticoide +metilprednisolona .nao exceder 80mg mes
+ cni, micofenolato +ciclofosfamida
PREFERENCIA MICOFENOLATO OU CFF
Class III and Class IV LN are often very severe, and without treatment, they are associated with significant patient morbidity and mortality and a very high risk of kidney loss.
SE ja tiver lesoes cronicas= tto de suporte
mas se tiver a classe v ai trata a classe v
Tto nefrite lupica classe iii e iv
Current treatment strategy in patients with severe proliferative lupus nephritis:
- Induction with IV methylprednisolone followed by oral prednisone, taper over weeks plus one of the four options:
- IV cyclophosphamide once a month for six months (high dose cyclophosphamide or NIH protocol)
- PO cyclophosphamide for 2-4 months
- IV cyclophosphamide 500 mg every two weeks for the doses (EURO-Lupus protocol)
- Mycophenolate for six months
- Maintenance with low dose prednisone along with one of the following options:
- Mycophenolate
- Azathioprine (if intolerant to mycophenolate or plans for pregnancy)
- Cyclosporine (if intolerant to mycophenolate or azathioprine)
alternativas
nao deu certo ,faz outra droga
nao respondeu = ttos alternativos
considerar repetir bx
multitarget
Nefrite lupica classe iii ou iv
Com ou sem componente de nefropatia membranosa (classe v)
Corticoide + CFF I.V. em dose baixa ou associado ao MMF
Indução por 6m: pulso de metil 250-500g dia por 3 dias + pred 0,6- 1mg /kg/ dia com desmame progressivo
+
CFF IV 0,5-1g/m2 1x mês por 6 meses
Ou
CFF IV 0,5g 15/15 dias por 3meses-6 pulsos
Ou
AAMF- MMF 2-3g /dia
Ou MFS 1440-2160mg/dia por pelo menos 6 meses
Ou
TAC OU CSA. + MMF DOSE REDUZIDA
MANUTENÇÃO
CORTICOIDE + MMF
Ou aza ou Tac/csa
Nefrite lupica
Esquema NIH 1986
Ciclofosfamida I.V. 0,5-1g/m2 1x mês por 6 meses + pulso de metilprednisolona por 3 dias
efeitos CFF = leukopenia, infertility, and future cancers
Considerar
Pacs com NL GRAVE: GNRP, creat >3,presença de crescentes ou necrose fibrinoide
Não responderam ao eurolupus
Não aderem ao tto oral
Physicians may choose an i.v. regimen if suboptimal adherence is anticipated. Age is an important factor with respect to preservation of fertility, as susceptibility to gonadal failure after cyclophosphamide use increases with age. Susceptibility to future malignancies increases with higher lifetime cyclophosphamide exposure, so a detailed knowledge of prior therapies is important. Despite these considerations for cyclophosphamide, many physicians would initially choose standard-dose cyclophosphamide for patients in whom kidney function is rapidly deteriorating and whose biopsy shows severe activity (e.g., capillary necrosis, an abundance of crescents). It should be noted that there are sparse data on this group of patients who present with aggressive disease, as their clinical characteristics precluded them from inclusion in clinical trials. Physicians caring for patients of mixed ethnic background or Hispanic ethnicity may choose MPAA over cyclophosphamide as there are some post hoc analysis data suggesting it has higher efficacy,731,732 whereas physicians caring for Chinese patients may want to choose MPAA and glucocorticoids, or triple immunosuppression with glucocorticoids plus low-dose MPAA plus low-dose CNI, as opposed to a cyclophosphamide-based regimen.6
Eurolupus=2002
Alta dose= nih clássico
Baixa dose: pulso mp 3 dias +
Ciclofosfamida I.V. dose fixa 0,5g 6 pulsos de 15/15 dias por 3 meses
Eficácia similar
GCs adm intravenously (IV) (total dose of 500 to 2500 mg of IV methylprednisolone) and then orally (prednisolone 0.3–0.5mg/ kg/d until week 4, reduced to ≤5–10 mg/d at month 3), in combination with either mycophenolate mofetil (MMF; target dose 2 g/d) or IV cyclophosphamide (CY), according to the Euro-Lupus regimen (EL; 6 fortnightly doses of 500 mg IV CY) [21]. An alternative is a combination of MMF (dose of 1 g) with a calcineurin inhibitor (CNI; tacrolimus 4 mg/day). In case of acute kidney injury, cellular crescents, and/or fibrinoid necrosis, the aforementioned regimens are also recommended, but higher doses of IV CY can also be proposed according to the National Institutes of Health (NIH) regimen [22].
ALMS - aspreva - nefrite lúpica
Comparou MMF + pred. Vs ciclofosfamida I.V. mensal 0,5-1g /m2 + pred
Eficácia semelhante em pacs c fc renal normal e proteinúria moderada
MULTITARGET=corticoide +mmf +cni equiparou a cff obs= nao foi estudado em varias populacaoes
lupus ttoo
Nefrite lupica
Tto classe v
NEFRITE LUPICA CLASSE v=
5-10%dos casos de nefrite lupica,
10-30% IRAO PROGREDIR ESKD,
proteinuria não costuma resolver espontaneamente.
Proteinuria = aumenta o risco cv e predispõe a trombose.
Tratamento= antipreoteinuricos IECA usa micofenolato de mofetil como primeira opção
proteinuria baixa = ieca/bra
imunossupressao guiada por sintomas extrarrenais
hidroxicloroquina
se a proteinuria piora e /ou outras complicacoes= considerar imunossupressao
PROTEINURIA NEFROTICA
bloq SRAA
Imunossupressao com corticoide + outro agente = MICOFENOLATO ou cni ou rituximab ou aza
hcq
Inibidores da calcineurina na nefrite lupica
Esquema de indução alternativo para quem n tolera ou n responde ao mmf o cff
Grávidas com NL
Estudo AURORA
Voclosporina - inibidor de calcineurina 4x mais potente, não precisar fazer dosagem sérica
Recent evidence showed that adding voclosporin or belimumab to standard dual immunosuppression increased treatment efficacy. The immunosuppressive action on T lymphocytes and the stabilizing effect on the podocyte cytoskeleton account for the efficacy of calcineurin inhibitors (CNIs).
Nefrite lupica
Estudo multi target
Mp+ Tac + mmf = mais efetivo que cff
Rituximab anticd20
anticd20
Lise linfócito b e depressão linfócito b
Nefrite lupica
LUNAR
Rituximab
Resposta parcial foi maior c o rituximab porém resposta completa não
Não atingiu o end point
Obinutuzumab
Nefrite lupica
Depleção maior e mantida de linfócitos b
Estudo mobility
Estudo BLISS LN
Belimumab - inibe BAFF ( baff estimula linfócitos b)
I.V. 1x ao mês
Estudo bliss bom resultado
. When added to standard therapy, the efficacy of belimumab was evident within 6 months and was sustained for at least 2 years (5). Post hoc analysis showed that belimumab treatment was associated with reduced rates of flares and adverse kidney outcomes
Secuquinumab
e novos estudos
Inibe a IL17a
Sc 1x mês
Nefrite lupica : o aumento da expressão de IL17 = mais grave
Níveis de IL17 se correlacionam c atividade da NL
Currently active lupus nephritis trials:
- Proteasome inhibitors in LN: block NF-KB activation and with this decrease cytokine release and immune activation.
-
Obinutuzumab: Humanized type II anti-CD20 monoclonal antibody. Compared to rituximab, it is more potent (among others, it is less reliance on complement-dependent cytotoxicity).
- NOBILITY study: Phase II study
- Obinutuzumab + MMF + steroids arm had superior complete remission rates (40%), when compared to placebo + mycophenolate + steroids (18%, p<0.01 at week 76)
- B-cell depletion better maintained over one year as compared to rituximab.
-
Belimumab: Antibody against BLYS (survival factor for B-cells): prevents the reconstitution of B-cells and may help sustain a renal response
- Phase II open-label randomized controlled trial
- Induction with steroids + cyclophosphamide + rituximab at weeks 0 and 2 and then randomized to placebo or belimumab at week 4
- At week 24 no difference between the two arms
- BLISS LN study with belimumab + standard therapy: results pending
- Antifrolumab: anti-IFN-alpha receptor monoclonal antibody that inhibits activation of B-cells, T-cells, and maturation of plasma cells. It was studied in seropositive moderate-severe non-renal systemic lupus with favorable results. The results of an ongoing study in patients with LN are pending.
- Multi-target therapy: Phase II trial with low dose corticosteroids (with aggressive steroid taper) + low dose mycophenolate + voclosporin. Patients assigned to volcosporin arm had better complete renal response as compared to control arm (both groups received steroids and mycophenolate). Phase III trial results are pending.
Qual é o tipo de nefropatia lúpica mais comum?
Nefropatia proliferativa difusa.
indices de atividade
IF in lupus nephritis
full house - IgG, IgA, IgM, C1q and C3
features of activity index in sle
endocapillary hypercellularity
glomerular neutrophil infiltration
wire loop deposits
fibrinoid necrosis
cellular and or fibrocellular crescents
interstitial inflammation
Acima de 3 cels espaço mesangial
Acúmulo de matriz e expansão mesangial
Nefrite lupica classe V
Proteinúria baixa: bloq SRAA e controle Pa
HQC
TTO imunossupressor guiado por manifest extra renal
Síndrome nefrótica
Corticoide + MMF
OU ICN, ou cff ou aza ou rituximab
Ou cff+ Tac + mff
Nefrite lúpica classe IV –
– é a manifestação mais comum e grave do lúpus no rim e tem, como uma das principais marcas, a hematúria,além de freqüente alteração da função renal e de hipertensão arterial ;
Consumo de C4 no lúpus associa a via…,
Clássica.
Quando não realizar a Bx na nefrite lúpica?
tratamento atual para pacs com nefrite lupica proliferativa severa
Induction with IV methylprednisolone followed by oral prednisone, taper
over weeks plus one of the four options:
o IV cyclophosphamide once a month for six months (high dose
cyclophosphamide or NIH protocol)
o PO cyclophosphamide for 2-4 months
o IV cyclophosphamide 500 mg every two weeks for the $doses
(EURO-Lupus protocol)
o Mycophenolate for six months
Maintenance with low dose prednisone along with one of the following
options:
o Mycophenolate
o Azathioprine (if intolerant to mycophenolate or plans for
pregnancy)
o Cyclosporine (if intolerant to mycophenolate or azathioprine)
Currently active lupus nephritis trials
Proteasome inhibitors (Velcade (bortezomib), Kyprolis (carfilzomib), and Ninlaro (ixazomib).)in LN: block NF-KB activation and with this decrease cytokine release and immune activation.
Obinutuzumab: Humanized type II anti-CD20 monoclonal antibody.Compared to rituximab, it is more potent (among others, it is less reliance on complement-dependent cytotoxicity).
o NOBILITY study: Phase II study
o Obinutuzumab + MMF + steroids arm had superior complete remission rates (40%), when compared to placebo +mycophenolate + steroids
o B-cell depletion better maintained over one year as compared to rituximab.
Belimumab:&Antibody against BLYS (survival factor for B-cells):prevents the reconstitution of B-cells and may help sustain a renal response
o Phase II open-label randomized controlled trial
o Induction with steroids + cyclophosphamide + rituximab at weeks
0 and 2 and then randomized to placebo or belimumab at week 4
o At week 24 no difference between the two arms
o BLISS LN study with belimumab + standard therapy: results
pending
$
Antifrolumab: anti-IFN-alpha receptor monoclonal antibody that inhibits
activation of B-cells, T-cells, and maturation of plasma cells. It was
studied in seropositive moderate-severe non-renal systemic lupus with
favorable results. The results of an ongoing study in patients with LN are
pending.
$
$Multi-target therapy: Phase II trial with low dose corticosteroids (with
aggressive steroid taper) + low dose mycophenolate + voclosporin.
Patients assigned to volcosporin arm had better complete renal response
. In this context, the Membranous Nephropathy Trial of Rituximab (MENTOR) study investigates whether B-cell depletion with rituximab, which has a more tolerable side effect profile than alkylating agents, is noninferior to calcineurin inhibition with cyclosporine in inducing and maintaining remission of PMN.
To understand the rationale for and significance of MENTOR, one must first understand the history behind our understanding of PMN pathophysiology.
In 1957, pathologist David Jones first identified membranous GN as a separate entity from other lesions associated with nephrotic syndrome. Using a special periodic acid–silver methenamine stain, now known as the Jones stain, Dr. Jones reported the unique features of MN not shared by what is now known as membranoproliferative GN, minimal change disease, and focal segmental glomerulosclerosis (FSGS). In his report, he wrote: “In the present investigation it has become apparent that this lesion is the result of a peculiar modification of the epithelial basement membrane of the glomerulus. With the periodic acid silver methenamine stain this thickened membrane resolves itself into a much less thick epithelial membrane from which protrudes externally innumerable short silver-positive projections of club or mushroom shape. Between these projections is a silver-negative hyaline material which is in droplet form (Fig. 10).”
From Jones DB, American Journal of Pathology, 1957.
Here is another example of silver staining.
Courtesy of Arkana Labs.
In the 1957 manuscript, Dr. Jones also states, “An auto-antibody formation similar to that of acute glomerulonephritis appears to be present but its mechanism is still unknown.” This concept of autoimmunity in nephrosis extended into experimental science in 1959 with the development of a rat experimental model subsequently known as Heymann nephritis, where intraperitoneal injection of rat proximal tubular homogenates into other rats induced clinical and histopathological features similar to human MN. In other words, injecting rats into their peritoneal space with ground up proximal tubules of other rats induced an inflammatory reaction leading to subepithelial deposits akin to those seen in human MN. Because the antigen(s) from the ground up kidneys did not cross the peritoneal space, those immune complexes in the subepithelial deposits formed from an auto-antigen. Until the 1970s, nephrologists believed these autoimmune complexes were circulating immune complexes passively trapped by glomeruli. Then, in the late 1970s additional seminal studies (including one from Dr. David Salant) established that subepithelial deposits can be induced by in situ immune complex formation rather than circulating immune complex deposition. In other words, the subepithelial deposits seen in MN could be induced by antibodies binding to an antigen residing on the glomerular capillary wall, potentially originating from the podocyte. This concept is best illustrated by the figure below, where panel A is a representation of circulating immune complex deposition while panel B is a representation of how in situ immune complex formation works, with the antigen originating from the visceral epithelial podocyte.
From Glassock RJ, NEJM, 2009.
During the 1980s, scientists attempted to identify this podocyte-intrinsic antigen, and from the Heymann nephritis model they believed it was megalin, a member of the low-density lipoprotein (LDL) receptor family, that in rats is expressed on both podocyte foot processes and the proximal tubule. However, in humans, podocytes do not express megalin, and a search for anti-megalin antibodies in PMN patients turned up empty. Enthusiasm for the paradigm-shifting in situ immune complex hypothesis began to wane until a 2002 report in the NEJM attributed a case of neonatal MN to transplacental passage of maternal antibodies against neutrophil endopeptidase on the baby’s podocytes.
Several years later (50 years after the first description of the Heymann nephritis model), Drs. Larry Beck (@LaurenceHBeckJ1) and David Salant reported in a landmark NEJM study that the M-Type phospholipase A2 receptor (PLA2R) is a major target antigen in human PMN. Years of experimentation exposing extracts of healthy human glomeruli to PMN patient sera led to this discovery through a combination of Western blotting (to assess whether PMN sera binds to any glomerular proteins), mass spectrometry (to identify what this bound glomerular protein is), and immunoprecipitation with anti-PLA2R antibody (to validate the target antigen). They found that the majority of sera from sampled PMN patients reacted with PLA2R but that sera from patients with FSGS, diabetic nephropathy, or no kidney disease did not. Three decades after the initial in situ immune complex hypothesis for PMN emerged, a specific causal antigen and causal biomarker (circulating antibody) were finally identified. The excitement in the nephrology world was palpable, as evident in the late Dr. Nate Hellman’s Renal Fellow Network posts on the initial unveiling of unpublished results and on the NEJM report almost exactly 10 years ago.
Courtesy of Arkana Labs. Strong anti-PLA2R staining on IF of a PMN biopsy.
In addition, the presence of anti-PLA2R in the serum of a PMN patient correlated with disease activity, as shown in Figure 6 of the 2009 report below. The red box in panel B highlights the presence of anti-PLA2R activity (2 dark bands in the box) in December 2005, prior to the patient’s initiation of immunosuppressive treatment (charted in panel A). Of note, the antibody disappears by April 2006, prior to full remission of proteinuria. We will return to this detail later.
From Beck LH et al., NEJM, 2009.
Salant’s group also identified another putative antigen in a small number of anti-PLA2R negative cases that ended up being thrombospondin type 1 domain-containing 7A (THSD7A).
Courtesy of Arkana Labs. Strong anti-THSD7A staining on IF of a PMN biopsy.
So what does this scientific history lesson tell us? Decades of research have informed us that PMN is an autoimmune disease with podocyte-intrinsic antigens that form in situ subepithelial immune complexes with auto-antibodies against these antigens. We now have disease-specific, causal biomarkers of PMN, meaning that we have biomarkers (anti-PLA2R and anti-THSD7A) that directly contribute to disease pathogenesis and are not found in other glomerular diseases. Because the antibody is causal, why not treat PMN by eliminating production of the disease-causing antibody? Because the antibody is causal, why not track disease status by circulating antibody levels?
Let’s start with the first question. Yes, it would make sense that immunosuppressive therapy works by decreasing production of the disease-causing antibody, but not all immunosuppressive therapies are equal. Nephrologists have been investigating the role of rituximab in treating PMN because rituximab targets CD20 on B cells and depletes B-cell lineages that would later mature into antibody-producing cells as illustrated in the adapted figure below.
Adapted from Ruggenenti et al., Nature Reviews Nephrology, 2017. The left panel shows the rituximab binding site on the large loop of the CD20 molecule of a B cell. The right panel shows which types of cells would be targeted by rituximab: CD20 positive pre-B cells, immature B cells, mature B cells, and activated B cells. Plasma cells and long-lived memory cells would not be targeted due to absence of CD20.
With a more specific mechanism of action than the current first-line alkylating agents, rituximab also has a more mild side effect profile, making it a more attractive therapeutic option should RCT data support its efficacy. Prior to the MENTOR study, clinical trials investigating the effect on rituximab and PMN remission have been small but promising. In the GEMRITUX study that initially enrolled 80 patients, rituximab failed to meet the primary end point of complete or partial remission of nephrotic syndrome at 6 months, although remission was achieved in the post randomized control trial (RCT) period. The study did find that compared to conservative therapy alone, rituximab significantly decreased circulating anti-PLA2R antibody levels within 3 months. In retrospect, this lag time between depletion of circulating anti-PLA2R antibody and remission of proteinuria would have been expected based on Beck’s initial 2009 NEJM report, which presented a more rapid decline in serum antibodies prior to substantial decrease in proteinuria (see brief summary of that report above). Indeed, this phenomenon was confirmed in a subsequent report. For the “negative” GEMRITUX study, was 6 months a reasonable primary outcome time point for remission of proteinuria, and are anti-PLA2R levels a more optimal functional biomarker for trial outcomes? People were still willing to bet on rituximab, and the trial provided a lesson in restrategizing how to run an RCT in PMN.
As mentioned above, alkylating agents such as cyclophosphamide have historically been part of the gold standard for treating PMN patients with persistent nephrotic-range proteinuria not responsive to conservative therapy. However, due to its blunt mechanism of action, which involves inducing DNA damage in all proliferating cells and inhibiting B cell function, cyclophosphamide has an unfavorable side effect profile that gives many physicians pause before prescribing it for PMN. Rituximab, with its more specific mechanism of action targeting B cells rather than all proliferating cells, has a less severe side effect profile. Indeed, the two agents were compared in a prospective observational cohort study in terms of safety profile and remission rates, and patients receiving rituximab were found to have fewer adverse events while experiencing similar complete disease remission rates. At the moment, alkylating agents, not rituximab, are still indicated by KDIGO as first-line treatment for the subset of PMN patients with persistent nephrotic range proteinuria as we await more RCT data on rituximab, but could the MENTOR study help change that?
Meanwhile, calcineurin inhibitors (CNIs), which have significant although less severe side effects than cyclophosphamide, have become an increasingly popular therapeutic option for PMN among nephrologists in the United States and elsewhere. Cyclosporine and tacrolimus have comparable efficacy when compared against each other. Like cyclophosphamide, their main mechanism of action (reviewed here and here) is not B-cell specific, but compared to cyclophosphamide, CNIs have higher rates of relapse after drug withdrawal.
So now 60 years after the first description of Heymann nephritis and 10 years after the published discovery of PLA2R, we have the MENTOR study, which compares CNI cyclosporine with the B-cell depletion strategy of rituximab in the treatment of PMN. The MENTOR investigators set out to ask whether rituximab is noninferior to cyclosporine in inducing and maintaining remission of proteinuria for up to 24 months in patients with PMN. Below we will discuss the study design, results, and implications for future PMN studies and management.
For more background on PMN, we recommend checking out this CJASN review by Couser; CJASN review (more cautious about rituximab) by Ponticelli and @GlassockJ; AJKD retrospective by @GlassockJ; AJKD review by Francis, Beck, and Salant; RFN post by @Slatts_1 ; most recent KDIGO statement, and this GlomCon lecture.
The Study
The MENTOR study set out to answer the following question: Is rituximab therapy noninferior to cyclosporine therapy in inducing and maintaining remission of proteinuria, regardless of baseline anti-PLA2R status, for up to 24 months in patients with PMN?
Trial Design
To answer this question, the investigators designed an investigator-initiated, open-label, multicenter, randomized noninferiority trial. The purpose of a noninferiority trial is to evaluate whether a new treatment (rituximab) has similar efficacy to that of an established treatment (cyclosporine, per KDIGO GN guidelines). Noninferiority trials (reviewed here) have become prevalent because treatment with a placebo or no-treatment arm, especially for a disease such as PMN, is not ethical when an effective treatment already exists. For MENTOR, the null hypothesis is that in PMN, rituximab induces and maintains remission of proteinuria at a lower rate than cyclosporine does. Rejection of this null hypothesis by a noninferiority margin of 15% on an absolute risk-difference scale would support that rituximab is noninferior to cyclosporine in the treatment of PMN for the predetermined primary outcome. All participants were either already on conservative therapy (ACEI or ARB) or were placed on conservative therapy during the run-in phase prior to being randomized to either the rituximab arm or the cyclosporine arm. \
Funding Source
Genentech (maker of rituximab) supported the study, although the authors state the company did not influence the planning, data collection, interpretation, or writing of the study.
Figure S1: Overview of Trial Design. NR = non-response, CR = complete remission
Study Participants
Broadly speaking, the participants were adults with biopsy-proven PMN already on conservative management but not on other immunosuppressive agents. The inclusion and exclusion criteria are stated in detail in the supplemental section of the manuscript.
Inclusion Criteria:
PMN diagnosed by kidney biopsy demonstrating subepithelial spikes along capillary walls by silver stain, granular IgG and C3 along capillary walls on IF, and subepithelial deposits seen on EM. All three components were required, and pathology was adjudicated by a study PI prior to randomization.
Age: 18 to 80 years
If female, not pregnant; if not post-menopausal or surgically sterile, must be practicing medically approved contraceptive method
Not exposed to prednisone or mycophenolate mofetil for > 1 month, not exposed to alkylating agents for > 6 months
Treatment with RAS blockade and/or ARB for ≥ 3 months prior to randomization, BP < 140/80 in > 75% readings.
Participants with more than 5g per 24-hours were able to enter the study’s treatment phase without the run-in period
Estimated GFR (by MDRD) ≥ 40 mL/min/1.73m2 or quantified creatinine clearance ≥ 40 mL/min
Exclusion Criteria:
Active infection
Secondary cause of MN (hepatitis B, SLE, medications, malignancy)
Type 1 or type 2 diabetes mellitus to exclude proteinuria due to diabetic nephropathy
Pregnancy or breast feeding
History of resistance to CNIs, rituximab, or alkylating agents (although relapse after 3 months for CNI and 6 months for rituximab and alkylating agents was still accepted for eligibility)
Intervention:
Eligible participants were randomized to either the rituximab arm or the cyclosporine arm and observed for 6 months.
Rituximab dosing: 1000 mg intravenous (donated by Genentech) on days 1 and 15
Cyclosporine dosing: 3.5 mg per kg per day every 12 hours (purchased from Novartis), with target serum trough levels 125 to 175 ng/mL as assessed every 2 weeks until target trough obtained. Dose reduction was performed for participants with a persistent and unexplained increase in serum creatinine of more than 30% (if creatinine did not fall in response to this dose decrease the participant was considered to have experienced treatment failure).
If at 6 months into the study complete remission was observed in either arm, treatment was stopped. In the cyclosporine arm, the drug was then tapered over an additional 2-month period. For both arms, if non-response was observed (reduction in proteinuria by less than 25%), treatment was stopped, and in the cyclosporine arm a 2-month taper was initiated.
At the 6-month mark, partial responders continued for an additional 6 months, with treatment then stopping at the 12-month mark (with relevant taper for cyclosporine). Note how this additional step for months 6-12 differs from the absolute stop at the 6-month mark of the GEMRITUX trial (discussed in our introduction). Additional follow up in MENTOR was performed until month 24.
Sample Size and Stats
130 participants were enrolled and randomized, with n = 65 in each arm. The investigators calculated that they would need 63 participants in each arm to achieve 80% power to detect noninferiority at a one-sided alpha of 0.025 corresponding to a two-sided alpha of 0.05 and a noninferiority margin of 15% on an absolute risk difference scale. In other words, this study was powered for the desired, preset outcome. As a side note, one major limitation of approximately half of noninferiority trial is the failure to state the a priori noninferiority margin, so the explicit statement of the proposed margin in the main text and supplement is already a strength. However, the best practice for defining such a margin is less clear. It is generally recommended that the margin “be defined based on statistical considerations and clinical judgement” where a margin can be defined based on a pooled estimate of effect size from historical placebo-controlled RCTs or based on the limit of the confidence interval (CI) closest to the null effect. For the MENTOR study, the 15% corresponded to half of the risk difference of approximately 30% expected at month 24 compared with placebo, according to a prior cyclosporine RCT. The margin was also determined by the rationale that benefits of rituximab–tolerability, less nephrotoxicity, greater compliance, and lower cumulative cost of discrete injections over daily medications–would justify a 15% inferiority margin for efficacy. To run the statistics on whether rituximab was noninferior, standard error for Z tests comparing differences between groups was calculated using a generalized linear model with binomial distribution and identity link function. The test was considered significant if the one-sided p value was < 0.025. If noninferiority was established, then superiority was tested. Rituximab was considered superior to rituximab if a two-sided p value was < 0.05. Other comparisons (Kaplan Meier curves and hazard ratios from Cox regression models) were performed using 95% CI. Sensitivity analyses were also executed to see whether different statistical approaches would yield the same result.
Outcomes
The primary endpoint was assessed in an intention to treat analysis and was defined as a composite of complete remission or partial remission of proteinuria at 24 months after randomization.
Complete remission was defined as ≤ 0.3 g/24 hours proteinuria and serum albumin ≥ 3.5 g/dL. Partial remission was defined as a reduction in baseline proteinuria of ≥ 50% and final proteinuria between 0.3 and 3.5 g/24 hours (regardless of serum albumin). Neither of these endpoints were defined by eGFR.
Treatment failures consisted of any of the following:
< 25% reduction of baseline proteinuria at 6 months
Relapse
Premature termination before 12 months due to disease activity or adverse event
Patients requiring additional immunosuppressive medications not on the study protocol
Not meeting criteria of complete or partial remission by 24 months
Loss to follow-up
The investigators also examined many secondary outcomes, including:
Different time points for proteinuria remission
Time to remission
Relapse
Treatment failure at different time points
Time to treatment failure
Anti-PLA2R levels at various time points (see potential rationale here)
Quality of life as assessed by the Kidney Disease Quality of Life Short Form (KDQOL-SF)
Decrease in creatinine clearance
ESKD at 24 months
Adverse events
Results
As shown below in Figure S2 of the study, a total of 182 patients were screened, and 130 were enrolled (n=65 in each arm). Out of the 52 excluded, the vast majority did not meet inclusion criteria. After randomization, the rituximab arm had incomplete follow-up on only two participants (considered treatment failure), and in the cyclosporine arm only four participants had incomplete data (considered treatment failure). No participants were excluded from the final analysis.
Figure S2. Overview of recruitment and follow-up.
Participants in each study arm were fairly evenly matched in terms of baseline characteristics, listed in Table 1. They were primarily middle-aged, majority male, with heavy proteinuria (median 8.9 g/24 hours in each arm) and relatively high creatinine clearance (> 80 mL/min in each arm). There was no mention of race or ethnicity, although given the epidemiology of PMN the cohort participants were most likely of primarily European ancestry.
When baseline characteristics were further broken down by sex and randomization arm, median baseline anti-PLA2R levels were 179 u/mL among females in the rituximab arm, compared to 382 u/mL among males in the same arm and 535 u/mL among females in the cyclosporine arm.
So how did rituximab fare against cyclosporine in this study? At the end of 12 months, rituximab was noninferior to cyclosporine in terms of the composite primary outcome of complete or partial remission of proteinuria (60% achieved the composite outcome in the rituximab arm vs. 52% for cyclosporine, P = 0.004). Figure 1 below shows the range (blue line) of risk difference never crossed the dashed noninferiority margin line. Remarkably and perhaps more excitingly, at 24 months, rituximab was superior to cyclosporine in maintaining the composite outcome, remaining at 60% vs cyclosporine’s drop down to 20% with a risk difference (blue line) of 40% (P < 0.001 for both superiority and noninferiority).
Figure 1. The primary outcome: composite of complete or partial remission of proteinuria at 12 and 24 months.
Similar results were seen at month 18 as well (Table 2), and in terms of complete remission at 24 months none in the cyclosporine group had it whereas 35% did in the rituximab group (Table S7). For participants meeting the composite outcome, proteinuria levels (median and interquartile range) were plotted on a log scale in Figure S8 according to treatment arm and time.
The rituximab advantage was consistent across subgroups, although an interaction for sex in the rituximab group disappeared after adjustment for baseline anti-PLA2R (see Table S5 above for different baselines, Figure S5 below for the subgroup data).
As a secondary outcome of measuring disease activity, anti-PLA2R data were concordant with the proteinuria data, and anti-PLA2R levels decreased to a greater extent and on a steeper slope in the rituximab group compared to the cyclosporine group among participants who achieved the composite outcome (Figure S10).
Looking at the other side of the coin, by 24 months a greater proportion of patients had treatment failure in the cyclosporine group (80%) compared to the rituximab group (40%), with time to treatment failure plotted in Figure 2 below.
Figure 2. Time to treatment failure.
In terms of adverse events, the incidence was similar between treatment arms, although the adverse events for rituximab were infusion-related symptoms, compared to elevations in serum creatinine and gastrointestinal symptoms in the cyclosporine group (Table 3). Finally, for quality of life metrics, little difference was seen between groups.
Discussion
In patients with nephrotic-range proteinuria while on conservative therapy, rituximab was non inferior at 12 months and superior at 24 months to cyclosporine in terms of maintaining proteinuria remission up to 24 months. In short, the trial was adequately powered with a clear design that seems to circumvent the timing limitations of GEMRITUX.
Limitations and unanswered questions to consider:
The trial was not blinded to the patients and treating physicians, although objective laboratory data that formed the primary outcome were blinded to those measuring and analyzing.
Would the risk difference change if the non-responders in both arms at 6 months had continued with therapy? Would the cyclosporine arm have had more remission cases with that subgroup? What was happening to anti-PLA2R levels in non-responders?
Would we have seen fewer treatment failures (serum creatinine, adverse events requiring discontinuation) in the CNI arm if tacrolimus had been used instead?
Would we see the same results in patients of black, Asian, or Hispanic ethnicities?
How was the “positive” threshold for anti-PLA2R determined, and for future trials is there a standardized approach to measuring this analyte?
Are we missing differences among responders, non-responders, and treatment failures in terms of subtype of PMN and potentially even the different antigen epitopes of PLA2R and THSD7A?
Given the results of this trial, a portion of the nephrology community might consider moving on from CNIs and use rituximab as initial therapy. For some nephrologists, the superiority in maintaining remission would be a reason to switch to B-cell strategies. For patients, temporary adverse effects related to the infusion might be more tolerable than daily gastrointestinal upset or worry about CNI-induced nephrotoxicity. Do the results of MENTOR provide enough of an impetus to initiate immunosuppressive therapy earlier, or perhaps even in patients with disease but who are still hovering in the sub-nephrotic range, patients in whom the risk/benefit ratio of cyclophosphamide was suboptimal?
For KDIGO GN to release new guidelines, anticipated results of the STARMEN trial (tacrolimus-rituximab vs methylprednisolone-cyclophosphamide) and RI-CYCLO (rituximab vs steroids and cyclophosphamide) might need to be considered first.
This study does not provide data to make decisions about rituximab vs the modified Ponticelli protocol.
Despite some limitations and open-ended questions, the MENTOR study does seem to provide some momentum to steer the nephrology community in a B-cell centric direction for approaching PMN therapy. However, our work is not done. At the moment, one could view our available therapies as relatively blunt tools, with rituximab being an improvement but still not as sophisticated and precise as it should be.
Work remains to be completed on understanding the different subtypes of PMN further for precision medicine, linking the genetic and environmental risk factors that may trigger PMN, and engineering more specific therapies so that not all B-cells are necessarily depleted while remaining plasma cells (not expressing CD20 and thus not depleted by rituximab) producing anti-PLA2R can also be targeted. Certainly the past decade has been exciting in terms of translational developments for PMN, kick-started with the identification of PLA2R as a causal glomerular in situ antigen, and it will be even more exciting to see what these upcoming trials and future research will bring in advancing the field.
Summary prepared by Jennie Lin, Northwestern University.
Pathology slides contributed by Tiffany Caza, Arkana Laboratory
Tagged: mentor, membranous, glomerulonephritis, trial, rct, nejm, jennie lin, tiff caza, rituximab, cyclosporine, non inferiority
as compared to control arm (both groups received steroids and
mycophenolate). Phase III trial results are pending.
$
BMS 986165: selective tyrosine kinase-2 inhibitor that inhibits activation
of Janus Kinase that subsequently decreases cellular effects such as T-
cells/ B-cells response and autoantibody production.
o PAISLEY LN Study: Ongoing Phase II trial of BMS 986165 as an
add-on therapy to mycophenolate in patients with proliferative
lupus nephritis, who do not adequately respond to mycophenolatein the run-in period. The primary efficacy endpoint is partial renalresponse at week 24 (>50% reduction of proteinuria from baseline). The secondary endpoint includes, among others, a complete renal response by weeks 24 and 52, as defined by proteinuria <0.7 g/g
Classe I.V. nefrite lupica
Hipercelularidade
Depósitos imunes dentro das alças capilares alça em arame ou wide loop
Nefrite lúpica classe V
a glomerulonefrite membranosa do LES pode se manifestar como uma síndrome nefrótica pura, sem hipertensão e com todas as características clínicas que a nossa paciente apresenta.
Nefrite lupica
Black individuals are also more likely to have positive anti-Ro, anti-Sm, and anti-RNP anti- bodies, which have a high association with LN
LN is a major risk factor for morbidity and mortality
in SLE and 10% of patients with LN will develop ESRD The risk of ESRD is higher in certain sub- sets of LN.
For example, in class 4 LN the risk may be as high as 44% over 15 years
Qual o padrão da imunofluorescência sugestivo de LES?
contracepcao e gravidez lupus
Pregnancy in patients with LN is associated with increased maternal complications and inferior fetal outcomes compared with the occurrence in healthy individuals, and the risks are higher when LN is active. Some of the frequently used medications in patients with lupus are contraindicated during pregnancy, such as MMF, cyclophosphamide, and warfarin. Counseling with regard to contraception and pregnancy should be done early in patients of childbearing age. Patients should be seen by a gynecologist to discuss the choice of methods for contraception. For patients who prefer oral hormonal contraception, estrogen–progestin contraceptives with ethinyl estradiol dose at not higher than 30 mg may be used in patients who are negative for antiphospholipid antibodies and with stable low disease activity, whereas progestin-only contraceptives are preferable in patients with a moderate or high level of disease activity. Estrogen-containing contraceptives should be avoided in patients with antiphospholipid antibodies or a history of thrombosis, in view of the risk of thromboembolism.678 Data from women exposed to chemotherapy showed efficacy of gonadotrophin-releasing hormone (GnRH) analogues in reducing the rate of premature ovarian failure, whereas the putative gonadal protective effect of oral contraceptive pills appeared variable.679 Fertility protection with GnRH agonists, or sperm and oocyte cryopreservation, should be considered in patients treated with cyclophosphamide, especially in patients with high cumulative exposure.
Índice de atividade e cronicidade nefrite lupica
Glomerular Diseases That Cause Nephrotic Syndrome
Non–Immune Complex :
Minimal Change Disease
Congenital Nephrotic Syndrome of Finnish Type
Diffuse Mesangial Sclerosis
Focal Segmental Glomerulosclerosis (FSGS), Not Otherwise Specified (NOS) and Variants:
FSGS, NOS
Collapsing Glomerulopathy
Tip Lesion Variant of FSGS
Cellular Variant of FSGS
Hilar Variant of FSGS
C1q Nephropathy
Immune Complex:
Membranous Nephropathy
Membranoproliferative Glomerulonephritis (GN)
C3 Glomerulopathies:
Dense Deposit Disease
GN With Dominant C3
Fibrillary GN
Immunotactoid Glomerulopathy
sindrome nefrotica
Heavy proteinuria (>3.5 g/24 hours)
Hypoalbuminemia
Peripheral edema
Hyperlipidemia
CLINICAL CONDITIONS ASSOCIATED WITH MINIMAL CHANGE DISEASE
Idiopathic minimal change disease (lipoid nephrosis, nil disease)
subgroup with acute renal failure
Secondary forms of diffuse epithelial cell disease:
- associated with drug use, with or without AIN
- early stage of HIV-associated nephropathy, collapsing glomerulopathy, and heroin nephropathy
- associated with Hodgkin’s disease, lymphoma, CLL, and other lymphoproliferative disorders
- associated with insect bites, immunizations, etc.
- associated with IgA nephropathy, diabetes mellitus, SLE, and other glomerulopathies
sindrome nefrotica causas primarias
- DLM
- GESF
- GNMembranosa
manifestacoes glomerulares de doenca sistemicas
associadas com sindrome nefrotica
Diseases Associated With Nephrotic Syndrome
Non–Immune Complex Mediated
Monoclonal Immunoglobulin Deposition Disease:
AL Amyloidosis
Light Chain Deposition Disease
Light and Heavy Chain Deposition Disease
Heavy Chain Deposition Disease
Hereditary and Other Non-AL Amyloidoses
HIV-Associated Nephropathy
Sickle Cell Nephropathy
Fabry Nephropathy
Lecithin–Cholesterol Acyltransferase (LCAT) Deficiency
Type III Collagen Glomerulopathy
Fibronectin Glomerulopathy
Immune Complex Mediated
Membranous Lupus Nephritis, ISN/RPS Class V
DLM RESP a terapia
REMISSAO COMPLETA = reducao da proteinuria para <0,3g/dia ou
RPC<300mg/g ,creat serica estavel e albumina>3,5 g/dl
REMISSAO PARCIAL = reducao da proteinuria para 0,3-3,5g/dia ou
RPC<300-3500mg/g e uma diminuiçao de 50% da linha de base
RECAIDA=proteinuria> 3,5g/dia ou RPC>3500mg/g apos a remissao completa
DLM resistente a corticosteroides= persistencia da proteinuria >3,5g/dia ou RPC >3500mg/g com reducao de <50% da linha de base apesar da prednisona 1mg/kg/dia ou 2mg/kg em dias alternados por 16 semanas.
DLM recorrente = Duas ou + recaidas por 6 meses ou 4 ou mais em 12 meses
DLM dependente de corticoide= Recidiva que ocorre durante ou dentro de 2 semanas da conclusao do tto com corticoide
causas 2arias de DLM
Drogas: AINES, ampicilina, litio
Cancer: Hodgkin’s lymphoma, other lymphoproliferative diseases
Toxins: mercury, lead, bee stings
Infection: mononucleosis, HIV, immunizations
dlm
glomérulo de aparência normal.
• achatamento, retracção e hipertrofia dos pedicelos – típico da doença das lesões mínimas
Síndrome nefrótico (1 - Proteinúria maciça, 2 - hipoalbuminuremia, 3 - Edema generalizado – anasarca, 4 - hiperlipidemia e lipidúria
- O que esperava observar no exame de imunofluorescência? Nada (ausência de depósitos de imunoglobulinas ou componentes do S. Complemento).
- Qual é o seu diagnóstico? Doença das lesões mínimas (nefrose lipóide é um termo mais antigo a evitar). É a causa mais comum de doença glomerular na criança.
aines
lesao minima e nia
A associação de nefrite intersticial aguda a doença de Lesão Mínimas é muito relacionada a DLM por uso de AINES.
Pensa-se que o bloqueio da COX-2 mediado pelo AINES, pode abrir a possibilidade da reação inflamatória mediada por leucotrienos, o que justificaria tais achados. A imagem em si evidencia que em região tubulointersticial é evidente que há separação dos túbulos entre si, tanto por edema, como pela própria infiltração.
dlm tto
relapso frequente ou esteroide dependente OU cortico refratario
se nao usou ciclofosfamida = CFF
se ja usou CFF ou o paciente nao quer usar= RITUXIMAB
CNI OU MMF
DLM NO ADULTO
1 OPCAO- corticoide
se tiver contraindicacao
2 opcao CICLOFOSFAMIDA
pode ser tb
CNI
MICOFENOLATO + corticoide
rituximab?
CONDITIONS ASSOCIATED WITH MEMBRANOUS NEPHROPATHY
MEMBRANOUS NEPHROPATHY
1.- “Idiopathic” Membranous Nephropathy
- M type phospholipase A2 receptor (PLA2r)
- Thrombospondin Type-1 Domain-Containing 7A
[THSD7A]
- α enolase
- cationic milk proteins (children)
Congenital Membranous Nephropathy - neutral endopeptidase
2.- Autoimmune Diseases
- SLE and RA, Hashimoto’s disease, Grave’s disease, MCTD, Sjögren’s syndrome, IgG4-related disease, primary biliary cirrhosis, bullous pemphigoid, dermatitis herpetiformis, ankylosing spondylitis, small bowel enteropathies
3.- (Triggered by) Infectious or Parasitic Diseases Hepatitis B and C
Syphilis
Filariasis, hydatidic cyst, schistosomiasis, malaria, leprosy, enterococcal endocarditis
4.- (Triggered by the use of) Drugs
MEMBRANOUS NEPHROPATHY
5.- Associated with Tumors
carcinomas, lymphomas, CLL
6.- (Assoc. to) Miscellaneous conditions
sarcoidosis, de novo MGN in kidney allograft, sickle cell disease, Fanconi’s syndrome, Kimura’s disease, Crohn’s disease, HUS, alpha-1-antitrypsin deficiency,
Guillain-Barre syndrome, angiofollicular lymph node hyperplasia, Weber-Christian panniculitis
Au, Hg, Penicillamine, Captopril,
NSAIDs, Hydrochlorothiazide, Hydralazine, Trimethadione, Chlormethiazole
CLINICAL CONDITIONS ASSOCIATED WITH GLOMERULAR BASEMENT MEMBRANE ABNORMALITIES
Hereditary nephritis (Collagen type IV): Classical Alport syndrome
Autosomal recessive hereditary nephritis Autosomal dominant hereditary nephritis
Thin basement membrane disease (TBMD) Epstein and Fechtner syndromes (myosin HC IIA) Pierson Syndrome (laminin β2) (CNS+eye abn.) Nail-patella syndrome or hereditary osteo-
onychodysplasia (LMX1B, LIM homeodomain
transcription factor)
Collagen III glomerulopathy, Fibronectin glomerulopathy Lecithin-cholesterol acyltranferase deficiency (Resolving immune complex mediated GN)
Thin Basement Membrane Nephropathy
Population prevalence 5-9%; clinically seen in <1%
• 30-50% have +FHx hematuria; often dominant pattern
• No FHx hearing/visual impairment or ESKD
• Mutations in genes encoding α-3 and α-4 chains of Type IV collagen; ‘carrier state’ for recessive Alport
• Presentation: microscopic hematuria on routine u/a
• Frank hematuria, loin pain, AKI 2/2 heavy hematuria
• Dx: GBM thickness 150-225nM vs 300-400nM (nl)
• Prognosis: Generally excellent. Some association with development of proteinuria & FSGS
Alport syndrome
• MutationsingenesencodingTypeIVcollagen
• α-3,α-4&α-5chainscodistributedwithinGBM,
cochlea & eye
• 80%:Xlinkedinheritance
– Mutations in COL4A5 gene (α-5 chain) – No father to son transmission
– Females variably affected (lyonization)
• 15%:Autosomalrecessiveinheritance
– Mutations in COL4A3 or COL4A4 genes (α-3 or
-4 chains)
• 5%:Autosomaldominantinheritance
– Mutations in COL4A3 or COL4A4 genes – Slower progression than X-linked Alport
Alport Syndrome: Clinical manifestations
- Up to 15% have no FHx
- Hematuria: macroscopic, recurrent and temporally linked with respiratory infections in childhood
- Progressive CKD with hypertension & proteinuria
- Ocular abnormalities include anterior lenticonus
- Sensorineural hearing loss – rate of progression similar to CKD
- +FHx hematuria with CKD and deafness
- ESKD by age 16-35 in X-linked or recessive forms; later in dominant (45-60 yrs)
Diagnosis
Renal biopsy: Immunostaining reveals absence/abnormality of α-3, -4,-5 chains in GBM
Skin biopsy: Immunostaining with antibody against α-5 chain
Alport Syndrome: Management
Treatment:
• ACEi:DelaysprogressiontoESKDinproteinuric pts with normal GFR (European Alport Registry)
• Cyclosporine:Conflictingdata Renal Transplantation:
• Excellent outcomes
• 3% incidence of anti-GBM disease, M>>F
• Diagnosis:IFofallograftbiopsyessential
• Serologicaltestingforanti-GBMmaybenegative
(Ab against Goodpasture antigen vs α-5 chain)
THE SPECTRUM OF KIDNEY DISEASES ASSOCIATED WITH PARAPROTEINS
AL Amyloidosis AH Amyloidosis AHL Amyloidosis
Light chain deposition disease (LCDD)
Heavy chain deposition disease (HCDD)
Monoclonal Ig deposition disease (LHCDD)
Cryoglobulinemia type I
Direct infiltration of the
kidney by B cells or plasma cells
Light chain cast nephropathy (Myeloma Kidney)
Toxic tubulopathy with acute tubular injury and kidney failure
Crystal storage tubulopathy (Fanconi syndrome)
Thrombotic angiopathies Hyperviscosity syndrome
Fibrillary glomerulonephritis Immunotactoid
glomerulopathy
Non-Ig paraproteinemia
IgA Nephropathy
• Defined by IgA deposition in glomerular mesangium
• Presents- Young – gross hematuria
Adults – Proteinuria + hematuria
• Not benign hematuria ( Berger’s Disease )
• ESRD in 15-20% by 10 yrs from onset and 30-40 % by 20 yrs.
• Risk Factors for Progression.
• Rx – Changing Views but clearly NO SINGAL Therapy for Everyone – Must customize therapy in 2018.
MEST-Oxford Classification System
IgA
• Mesangial hypercellularity 0 = <50%;
1 = >50% glomeruli involved
• Endocapillary proliferation
0 = Absent
1 = Present
• Segmental glomerulosclerosis
0 = Absent
1 = Present
• Tubulo-Interstitial fibrosis
0 = <25%
1 = 25-50% 2 = >50%
Serologic markers of immune
complex vasculitis and. (IF GRANULAR)
glomerulonephritis
if granular =lima
low complement
lupus
infecciosas
Membranosa , membranoproliferativa
igA
granular = imunocomplexos
• Postinfectious
– low complement
– anti-streptococcal antibodies, blood cultures
• Cryoglobulinemia
– low complement
– cryoglobulins, hepatitis C
• Systemic lupus erythematosus
– low complement – ANA, anti-dsDNA
• Membranoproliferative GN
– low complement
No good serologic marker for Henoch-Schoenlein purpura
IgA nephropathy
• Complements usually normal
• Serum IgA level may be elevated but not a
sensitive or specific marker
• May be a low grade, smoldering process or may be rapidly progressive
• Skin lesions may also have IgA deposits
• Renal biopsy is standard for diagnosis
Spectrum of Vasculitis Associated with ANCA
Granulomatosis with polyangiitis =Wegener’s granulomatosis
Microscopic polyangiitis
• Including the syndrome of alveolar hemorrhage and nephritis
Renal limited variant
• Pauci-immune necrotizing and crescentic glomerulonephritis
Churg Strauss Syndrome - EGPA Primary pulmonary fibrosis Subglottic tracheal stenosis
ANCA vasculitis
Autoantibodies (typically IgG class) against lysosomal components of in neutrophils and monocytes
Specificity for myeloperoxidase (MPO) or proteinase 3 (PR3)
Pathogenesis
ANCAs are thought to be pathogenic: neutrophil priming by cytokines (e.g. TNF,C5a) à translocation of cytoplasmic antigens (MPO, PR3) à binding with ANCA Ab
à neutrophil activation leading to endothelial injury and complement system activation
Triggers for ANCA production: environmental (infection and molecular mimicry),genetic predisposition (HLA Class II), defective neutrophil apoptosis, certain drugs
Drug-induced: propylthiouracil, hydralazine, minocycline, anti-TNF alpha,levamisole
Idiosyncratic, younger patients, better renal survival, high MPO titers
Diagnosis of ANCA vasculitis should specify the serotype and clinicopathological variant
Pathology
Does not discriminate between various clinicopathology conditions caused by ANCA
Glomeruli will show fibrinoid necrosis with crescents
Cellular (days-weeks, potentially reversible), fibrocellular (weeks) and fibrous (weeks-months)
Vasculature
Renal vasculitis in 5-35% of cases
Involves small arteries (interlobular > arcuate), arterioles, capillaries and venules with fibrinoid necrotizing lesions
Medullary angiitis: inflammation of the medullary vasa recta
Suggests the presence of systemic vasculitis but is not specific for ANCA GN (i.e.IgAN, cryoglobulinemic GN)
Granulomatous inflammation: rare in the kidney but seen more in the lung/upper respiratory tract
Histopathological Classification: allows for uniform reporting, prognostication and guiding treatment
Focal (> 50% with normal glomeruli, best renal prognosis), Crescentic (> 50% with cellular crescents), Sclerotic (> 50% globally sclerotic, worse renal prognosis)),
Mixed (< 50 normal, < 50 crescents, < 50 globally sclerotic)
ANCA GN can be superimposed/co-existing in other diseases (i.e. LN, anti-GBM)
Crescents/necrosis out of proportion to immune complex deposition
Temporal heterogeneity of crescents/level of chronicity (i.e. anti-GBM)
o Clinical Aspects
Granulomatosis with polyangiitis (formerly Wegener’s)
-Necrotizing granulomatous inflammation primarily of lungs and nasal sinuses (saddle-nose deformity). 70% tem envolv da va superior, 48% va inferior, rim, pele e olhos, 20-13-15% CFF
Eosinophilic granulomatosis with polyangiitis (previously Churg-Strauss): Asthma, peripheral eosinophilia
Microscopic polyangiitis: Necrotizing vasculitis mostly affecting multiple sites
Type of ANCA does NOT permit specific diagnosis but ANCA antigen specificity is
associated with disease phenotype/prognosis
PR3-ANCA: most often granulomatous inflammation, systemic features, higher
relapse rate
MPO-ANCA: most often renal-limited, worse renal prognosis
Rough correlation of ANCA titers with response and relapse
75% will achieve remission but 40% may relapse
Poor prognostic factors
Age >65, higher SCr or dialysis dependency at onset, proteinuria, higher chronic
histologic indices
sindrome pulmao rim
ira + hemorragia alveolar
sindrome de good pasture= anticorpos anti MBG
Vasculite ANCA positiva= poliangeite microscopica, wegener,churg strauss
.
The majority of cases of pulmonary-renal syndromes are associated with ANCAs. The antigen targets in ANCA-associated disease are proteinase-3 and myeloperoxidase.
The antigen target in Goodpasture’s syndrome is the alpha-3 chain of type IV collagen.
Disease spectrum associated with ANCA
- All the diseases associated with ANCA are associated with the identical renal histologic lesion
- ie, the lesion of necrotizing and crescentic glomerulonephritis with scant or no immune complexes
Only two specific types of ANCA have been shown to be
of diagnositic value
Antigen recognized
1) Proteinase 3. C-ANCA
2) Myeloperoxidase. P-ANCA
Pauci-immune glomerulonephritis (GN)
Pauci-immune glomerulonephritis (GN)is defined histologically by the presence of necrotizing and crescentic GN with few or no immune deposits on IF or EM
o Most common cause of rapidly progressive GN (RPGN) especially in adults and elderly patients
o 80-90% of pauci-immune GN cases are Anti-neutrophil cytoplasmic antibody (ANCA) positive
10-20% are ANCA negative
Not detected in current assays; IgA ANCAs
Younger age, fewer extrarenal symptoms, poorer renal survival
Summary of Serologic Evaluation of Vasculitis
Linear =Anti-GBM ELISA or Western blot
• Granular – immune complex
– C3,C4
– ANA, Anti-dsDNA, cryoglobulins, hep C, hepatitis B, anti-DNAase B/ASLO, blood cultures
• Pauci-immune – ANCA
• Immunofluorescence
• ELISAforanti-proteinase3andanti-myeloperoxidase
• Other
– LDH, platelets, reticulocytes, anticardiolipin antibodies – HIV
– SPEP
Pathophysiology of ANCA Vasculitis
Pathophysiology of ANCA Vasculitis
(Mostly) Unknown trigger(s)
stimulate
ANCA specific circulating B-Cells
become
Plasma cells
produce
Circulating ANCA
bind to
Primed neutrophils and monocytes
activate
Neutrophils and monocytes
via surface binding and Fc receptors release
Complement activators, proteases and
O2 radicals
cause
Tissue destruction Complement activation (C5a) Amplification of inflammation
Characterization of Drug-induced ANCA vasculitis
PANCA+ CANCA+ anticorpo antiMPO
Apparent drug-induced ANCA cases have:
long exposures to culprit drugs
higher rates of MPO positivity and lower rates of PR3
higher MPO-ANCA titers
higher propensity for double-positive ANCA
higher rates of other autoantibodies
ANCA associado a drogas
Certain drugs implicated occasionally
Hydralazine
Propylthiouracil
Penicillamine
Minocycline
Cocaine / levamisole
Allopurinol
Possibly INH, sulfasalazine
Silicone exposure Stone workers
Treatments of ANCA vasculitis
Clear circulating B-cells
Pulse steroids
Cytotoxic agents
Cyclophosphamide
Azathioprine, methotrexate
Anti-B-cell monoclonals Rituximab
Remove circulating ANCA
Adsorbtion of ANCA
Myeloperoxidase or proteinase 3 column Not currently available
Plasmaphoresis / plasma exchange EUVAS – MEPEX
Appeared valuable in severe, acute settings Pexivas trial
Recent release (2018) reported no benefit overall
.Pulsed methylprednisolone and do plasma exchange followed by ivcyclophosphamide.This Patient has double positive vasculitis. had a benecial effect on renal and patient outcomes comparedwith treatment without plasma exchange. Anti-GBM antibody titers shouldbe monitored regularly and apheresis should be stopped when none aredetectable, typically after 10–14 treatments.Double positive patients show similar outcome to anti-GBM disease, but mayrelapse like AAV (ANCA associated vasculitis)
Treatment options
Induction: Corticosteroids with Rituximab OR Cyclophosphamide
Maintenance: Azathioprine OR Rituximab
Plasmapheresis: can be considered in severe/refractory cases however role may
change with upcoming trial data (PEXIVAS)
Novel therapy under investigation: C5a receptor blockers
ANCA TTO
Glomerulonefrite crescêntica
Tipo I (anti-membrana basal)=Síndrome de Goodpasture
Tipo II (imunocomplexos)Infecciosa SLE Púrpura Henoch-Schölein
Tipo III (Pauci-Imune)Associada a ANCAS Granulomatose de Wegener Panarterite nodosa
Rituximab for AAV
Estudo RAVE Conclusion
Rituximab not inferior to cyclophosphamide for induction of remission at 6 months
Rituximab for AAV RAVE
197patientsrandomized
Primaryendpoint-
Remissionat6months Offsteroids
Results
Rituximab64%achievedtheprimaryendpoint
Cyclophosphamide55%achievedtheprimaryendpoint
Adverseevents
Nosignificantdifferences
Relapses
GNPE
Hipercelularidade (infiltrado inflamatório – polimorfonucleares; proliferação de células endoteliais e mesangiais).
HIPERCELULARIDADE ENDOCAPILAR GLOBAL COM NEUTROFILOS FREQUENTES
Obliteração de alças capilares.
depósitos de imunocomplexos na membrana basal.
depósito de imunocomplexos em localização sub-epitelial depósitos em dorso de camelo (“humps”) surgem normalmente em glomerulonefrites pósinfecciosas (geralmente estreptocócicas)
IF= CEU ESTRELADO /GUIRLANDA
C3 E IGG
deposicao de c3 e igg na parede do capilar e mesangial , irregular, mas raro de iga
GNPE
Estreptococos beta hemolítico do grupo A
Incubação pós faringoamigdate 1-3 semanas média 10 dias
Ac relacionado a piodermite: AntiDNaseB
IF: depósito de imunocomplexos padrao granular
Indicação de bx: SOPHHHIA
glomerulonefrite por outras infeccoes
endocardite subaguda bacteriana
nefrite por shunt
infeccao por cateter central
abscessos viscerais
glomerulonefrite pos infeccao STAPHYLOCOCCUS
associada ao S.aureus e S.epidermidis
infeccao geralmente esta ativa quando a glomerulonefrite desenvolve
imunossupressao contraindicada na presenca de infeccao
THE MEMBRANOPROLIFERATIVE PATTERN OF INJURY
STRUCTURAL CHANGES:
HYPERCELLULARITY
CAPILLARY WALL THICKENING (double contours)
CONDITIONS ASSOCIATED WITH THE MPGN PATTERN:
- IMMUNE COMPLEX DISEASES-
- ABNORMALITIES OF COMPLEMENT-
- (PARAPROTEIN) DEPOSITION DISEASE
- REGULATORY PROTEINS
- THROMBOTIC ANGIOPATHIES
- (PARAPROTEIN) DEPOSITION DISEASE
CONDITIONS ASSOCIATED WITH A MEMBRANOPROLIFERATIVE PATTERN OF INJURY
1. IMMUNE COMPLEX-MEDIATED DISEASES
- IMMUNE COMPLEX-MEDIATED DISEASES
Chronic infections:
Viral: hepatitis B, hepatitis C and essential mixed cryoglobulinemia
Bacterial: endocarditis, infected ventriculo-atrial (or jugular) shunt, central line infection, multiple visceral abscesses, leprosy, meningococcal meningitis
Protozoa: malaria, schistosomiasis
Other infections: mycoplasma, Borreliosis, Leishmaniasis; Strongyloides stercoralis, other parasites
Autoimmune diseases:
SLE, Sjögren syndrome, Rheumatoid arthritis, Inherited complement deficiencies, in particular C2 deficiency
MEMBRANOPROLIFERATIVE PATTERN
OF INJURY
2. DEFECTS IN COMPLEMENT- REGULATORY PROTEINS:
MEMBRANOPROLIFERATIVE PATTERN
OF INJURY
- DEFECTS IN COMPLEMENT- REGULATORY PROTEINS:
Spectrum of diseases
Dense Deposit Disease (DDD) (MPGN type II)
Glomerulonephritis C3 (GN-C3) Atypical HUS (d-HUS)
CONDITIONS ASSOCIATED WITH A MEMBRANOPROLIFERATIVE PATTERN OF INJURY
3. CHRONIC AND HEALED THROMBOTIC ANGIOPATHIES
Healing phase of HUS and TTP
The syndrome of circulating anti-phospholipid
(anti-cardiolipin) antibodies Post-partum ARF, preeclampsia, HELLP, POEMS syndrome, paraproteinemia Radiation nephritis
Nephropathy associated with bone marrow
transplantation
Drug-associated thrombotic angiopathies
Sickle cell anemia and polycythemia Dysfibrinogenemia and other pro-thrombotic states Transplant glomerulopathy
GNMP
baseada na microscopia eletronica
tipo 1 = GNMP SUBENDOTELIAL - IF GNMP mediada por imunocomplexos imunoglobulinas e complemento na IF=paraproteinas, virus, autoimune
tipo2= deposito denso subendotelial DDD=GNMP mediada por complemento C3 predomina na IF
tipo3= gnmp subendotelial com depositos intramembranosos e subepiteliais-if negativa , sem relacao com complemento ou complexos imunes
if negativa = mat
GNMP
GNMP
1) IF POSITIVA PARA IMUNOGLOBULINAS COM + OU NAO DE C3= infeccoes, gamapatia monoclonal, doencas autoimunes
2) if complemento dominante -complemento mediada- glomerulopatia por c3- ddd c3 ou gn c3
complemento mediada -glomerulopatia por c4 =c4ddd ou gn por c4
3)if negativa=
SAF
shu/mat
anemia falciforme
policitemia
GNMP
gnmp tipo 1 imunoglobulinas complexos ig/ic
auto imune:LES, SJOGREN, AR, doenca mista do tec conjun
infeccoes=hep b, hep c , endocardite, shunt, abscessos viscerais, leptospirose , malaria, esquistossomose, micoplasma
paraproteinemia=
gmsi
waldestroon
crio tipo1 e tipo 2 c4 consumido
imunotactoide , fibrilar
Glomerulonefrite membranoproliferativa
Proliferação de células mesangiais. • Espessamento da matriz extracelular.
proliferacao endocapilar
duplicidade de memb basal glomerular irregular
depositos subendoteliais
Tipo I primaria =Depósitos de imunocomplexos
Tipo I secundaria SLE (+ frequente) Infecção por VHB Endocardite Neoplasias malignas
Tipo II=Doença dos depósitos densos A membrana basal está muito densa
gnmp classificacao antiga pela ME
MESANGIOCAPILAR
lobular
glomerulos lobulados- mesangicapilar=proliferacao das cels endoteliais dos capilares= capilar espessado- prolif mesangial - mbg tram tracking devido a interposicao de cels mesangiais na mbg na prata
tipo1: GNMP subendotelial-celularidade mesangial aumentada e duplicaçao das alças capilares. Depositos subendoteliais e interposicao mesangial e depositos mesangiais
nova classificacao: IF
gnmp tipo 1- imunocomplexos= imunoglobulinas e complemento na IF (paraproteinas, virus e autoimune) C3 E Igs VARIADAS
DEPOSITOS GRANULARES =IgG,C3, C1q , C4
tipo2: deposito denso subendotelial=
gnmp tipo 2- complemento- IF C3 dominante - depositos densos intramembranosos na memb basal gloemrular e interposicao de cels mesangiais
tipo3: GNMP subendotelial com depositos intramembranosos e subepiteliais TIPO3 = 3 DEPOSITOS subepi,subendo,membranoso
gnmp 3- negativa if= nao é relacionada a complemento ou complexos imunes
if negativa mat
Diagnosis of Primary Membranous Nephropathy
Epi-membranous deposits of IgG, C3/C4, but not C1q
Anti-PLA2R antibody or anti-THSD7A antibody AND/OR positive staining for
PLA2R or THSD7A (but absence does not exclude a primary process)
Rule out secondary causes
OBRIGATORIO INVESTIGAR CAUSAS SECUNDARIAS
Treatment of Membranous Nephropathy
ESTUDO MENTOR
MENTOR Trial
Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy
Primary endpoint: Complete or partial remission of proteinuria at 24 months
o At the end of 12 months, RTX was noninferior to CsA.
o At the end of 24 months, RTX was superior to CsA in maintaining complete or partial proteinuria remission.
o RTX was more effective in reducing anti-PLA2R levels over time (faster and greater magnitude).
o Rituximab was also more effective in those with negative anti-PLA2R at baseline.
o Baseline titer of anti-PLA2R influences the immunological and clinical
response to both therapies (less response with higher baseline titers)
tratamento
baixo e moderado risco= espere e veja=chance de remissao espontanea ate 40%
moderado=pondere= risco d eprogressao ou complicacao, dificuldade de manejo sindrome nefrotica
se for tratar - rituximab ou cni
alto risco -rituximab, cff, cin+rituximab
mto alto risco =cff
membranosa risco
baixo risco= TFG normal, PTNuria <3,5 albumina >30g/l= manter tto conservador com bra ou ieca e controle da pa
risco moderado=TFG normal, proteinuria >4g/dia, sem queda >50% apos 6 meses de terapia conservadora c ieca ou bra
anti pla2r>50
moderada proteinuria de baixo peso molecular
indice de seletividade <0.15
igg urinaria <250mg/dia
nao imunossuprimir a menos q risco de progressao ou sintoma de sn com manejo dificil
risco alto=TFG<60, proteinuria>8g por 6 meses, antipla2r>150, proteinuria de baixo peso molecular alta igg urinaria>250
indice de seletividade >0,20
=imunossupressao
muito alto risco-= sindrome nefrotica q coloca a vida em risco
rapida deterioracao da fc renal
alta proteinuria de bx peso molecular em 2 eas coletados no intervalo de 6-12m
sindrome nefrotica
causas 2arias de gn MEMBRANOSA
-LES, artrite reumatoide
ca = pulmao , colon, mama
melanoma, leucemia, linfoma
hepatite b, sifilis e malaria
peniciliamina, ouro , captopril
diagn diferencia primaria e secundaria
primaria +igg4 secundaria +igg1
sem iga e igm pode ter iga e igm
subepitelia/mesangial raro subepi, subendo, mesangial
mesangial igg e c1q negativos mesangial igg e c1q positivo
calculo do indice de seletividade
indice de seletividade = igg urinaria x albumina serica/iig sericaxalb urinaria
AVALIACAO CAUSAS SECUNDARIA GN MEMBRANOSA
screening para malignidade
usg renal
HBV,HIV,HCV, SIFILIS,treponema
dçs sistemicas=reumatologicas, tireoide
rx de torax=sarcoidose
uso de drogas= aines, ouro, penicilamina
FAN
membranosa lupica pode acontecer antes da abertura do quadro de les
mulheres jovens
outros pontos para pensar em secundaria= HIPERCELULARIDADE MESANGIAL
IF RICA
IgG SUBCLASSE 1c(igg e c3)
Depositos sebepi, subendo e mesangial
anti PLA2R
nível sérico é relacionado ao diagnóstico da nefropatia membranosa (alguns centros já o utilizam para diagnóstico sem BX), para avaliação de atividade da doença, recidivas e remissões, e para avaliação da possibilidade de recidiva pós-TX.
niveis de antipla2r se correlacionam com proteinuria =quanto mais alto =mens provavel a remissao espontanea
a curva é importante
se inicamos o tto conservador e depois de 3meses o antipla2r esta subindo, provavelmente proteinuria vai aumentar
nível sérico do anticorpo no tecido, bem como o quadro clínico do paciente podem estar em remissão e ainda existir a sua positividade tecidual.
A interpretação do resultado do Anti-PLA2r é esperado na nefropatia membranosa primária, mas tem sensibilidade de aproximadamente 70%,-80% ou seja, podem existir falsos-negativos. Mesmo raramente, pode ser positivo também em causas secundárias, tais como lúpus, câncer e infeccões (mesmo não passando de 20% dos casos na maioria das causas secundárias).
membranosa tto
esquema com cff sao os unicos com evidencia em desfecho solido reduzir drct
mais efeitos colaterais
pac c alteracao da fc é o tto de escolha
niveis muito altos de antipla2r respondem melhor a cff
cff cíclico= metil1g iv 3 dias no comeco do mes 1,3,5
prednisona 0,5mg/kg nos meses 1,3,5
cff 2,5mg/kg/dia nos meses 2,4,6
cff continuo=
metil1g iv 3 dias no comeco do mes 1,3,5
prednisona 0,5mg/kg dia sim dia nao no meses 1-6
cff 1,5mg/kg/dia nos meses 1-6
rituximab= 1g 2x dentro de 2 semanas
375mg /m2 1-4 vezes em intervalos semanais
tacrolimus= 0.05-0.1mg/kg/dia, alvo nivel 3-8 por 12 meses
ciclosporina= 3,5mg/kg/dia alvo 125-225microgramas
MEMBRANOSA DEPOIS DO MENTOR
Dr. Glassock’s Recommendations for Initial Therapy after MENTOR:
First-line therapy: RTX or modified Ponticelli
o Cyclophosphamide (CYC) maybe preferred for very high titers of anti-PLA2R.
In a retrospective study, CYC was more effective in reducing anti-PLA2R than RTX in those with very high baseline titers.
o RCT in Europe (RI-CYCLO): RTX vs. modified Ponticelli.$ Results in late 2020 or early 2021
Second-line therapy: calcineurin inhibitors
Expected Responses to RTX
26% CR + PR at 6 months, 60% at 12 months, 60% at 24 months
.$ However, anti-PLA2R levels were unknown.
$
What can be done to augment RTX treatment responses?
Higher doses of RTX when anti-PLA2R titers are very high?
o Dose does matter according to an analysis of data from NICE and
GEMRITUX cohorts
4
.
Higher remission rates, shorter time to remission and time to the
disappearance of anti-PLA2R antibody with higher doses of RTX
Combination of RTX and low-dose CYC for 3 months?$ Observational data only
5
o Oral cyclophosphamide x 8 weeks + RTX (1000 mg x2, then q 4months x 2
years )
o Almost 100% remission rate
RTX + sequential CsA (STARMEN Trial)
$
How do anti-PLA2R levels influence treatment (at baseline and follow-up)?
Declining anti-PLA2R levels predict remission (perhaps can determine treatment
duration based on levels)
Rising levels predict relapse (time lag of 3-9 months between rising level and
clinical relapse)
CsA is much less effective in lowering anti-PLA2R levels in MENTOR – the reason
for increased relapse?
$
Safety Issues with RTX
Short term: Fairly safe and well-tolerated in MENTOR
Long-term: less well known (Cytopenia, hypogammaglobulinemia, PML)
What CAN’T be learned from MENTOR?
Influence of spontaneous remission on results (no placebo control because
unethical)
Efficacy of RTX vs. cyclophosphamide
. In this context, the Membranous Nephropathy Trial of Rituximab (MENTOR) study investigates whether B-cell depletion with rituximab, which has a more tolerable side effect profile than alkylating agents, is noninferior to calcineurin inhibition with cyclosporine in inducing and maintaining remission of PMN.
During the 1980s, scientists attempted to identify this podocyte-intrinsic antigen, and from the Heymann nephritis model they believed it was megalin, a member of the low-density lipoprotein (LDL) receptor family, that in rats is expressed on both podocyte foot processes and the proximal tubule. However, in humans, podocytes do not express megalin, and a search for anti-megalin antibodies in PMN patients turned up empty.
, Drs. Larry Beck (@LaurenceHBeckJ1) and David Salant reported in a landmark NEJM study that the M-Type phospholipase A2 receptor (PLA2R) is a major target antigen in human PMN.
Courtesy of Arkana Labs. Strong anti-PLA2R staining on IF of a PMN biopsy.
In addition, the presence of anti-PLA2R in the serum of a PMN patient correlated with disease activity, as shown in Figure 6 of the 2009 report below. The red box in panel B highlights the presence of anti-PLA2R activity (2 dark bands in the box) in December 2005, prior to the patient’s initiation of immunosuppressive treatment (charted in panel A). Of note, the antibody disappears by April 2006, prior to full remission of proteinuria. We will return to this detail later.
From Beck LH et al., NEJM, 2009.
Salant’s group also identified another putative antigen in a small number of anti-PLA2R negative cases that ended up being thrombospondin type 1 domain-containing 7A (THSD7A).
Courtesy of Arkana Labs. Strong anti-THSD7A staining on IF of a PMN biopsy.
So what does this scientific history lesson tell us? Decades of research have informed us that PMN is an autoimmune disease with podocyte-intrinsic antigens that form in situ subepithelial immune complexes with auto-antibodies against these antigens. We now have disease-specific, causal biomarkers of PMN, meaning that we have biomarkers (anti-PLA2R and anti-THSD7A) that directly contribute to disease pathogenesis and are not found in other glomerular diseases. Because the antibody is causal, why not treat PMN by eliminating production of the disease-causing antibody? Because the antibody is causal, why not track disease status by circulating antibody levels?
Let’s start with the first question. Yes, it would make sense that immunosuppressive therapy works by decreasing production of the disease-causing antibody, but not all immunosuppressive therapies are equal. Nephrologists have been investigating the role of rituximab in treating PMN because rituximab targets CD20 on B cells and depletes B-cell lineages that would later mature into antibody-producing cells as illustrated in the adapted figure below.
Adapted from Ruggenenti et al., Nature Reviews Nephrology, 2017. The left panel shows the rituximab binding site on the large loop of the CD20 molecule of a B cell. The right panel shows which types of cells would be targeted by rituximab: CD20 positive pre-B cells, immature B cells, mature B cells, and activated B cells. Plasma cells and long-lived memory cells would not be targeted due to absence of CD20.
With a more specific mechanism of action than the current first-line alkylating agents, rituximab also has a more mild side effect profile, making it a more attractive therapeutic option should RCT data support its efficacy. Prior to the MENTOR study, clinical trials investigating the effect on rituximab and PMN remission have been small but promising. In the GEMRITUX study that initially enrolled 80 patients, rituximab failed to meet the primary end point of complete or partial remission of nephrotic syndrome at 6 months, although remission was achieved in the post randomized control trial (RCT) period. The study did find that compared to conservative therapy alone, rituximab significantly decreased circulating anti-PLA2R antibody levels within 3 months. In retrospect, this lag time between depletion of circulating anti-PLA2R antibody and remission of proteinuria would have been expected based on Beck’s initial 2009 NEJM report, which presented a more rapid decline in serum antibodies prior to substantial decrease in proteinuria (see brief summary of that report above). Indeed, this phenomenon was confirmed in a subsequent report. For the “negative” GEMRITUX study, was 6 months a reasonable primary outcome time point for remission of proteinuria, and are anti-PLA2R levels a more optimal functional biomarker for trial outcomes? People were still willing to bet on rituximab, and the trial provided a lesson in restrategizing how to run an RCT in PMN.
As mentioned above, alkylating agents such as cyclophosphamide have historically been part of the gold standard for treating PMN patients with persistent nephrotic-range proteinuria not responsive to conservative therapy. However, due to its blunt mechanism of action, which involves inducing DNA damage in all proliferating cells and inhibiting B cell function, cyclophosphamide has an unfavorable side effect profile that gives many physicians pause before prescribing it for PMN. Rituximab, with its more specific mechanism of action targeting B cells rather than all proliferating cells, has a less severe side effect profile. Indeed, the two agents were compared in a prospective observational cohort study in terms of safety profile and remission rates, and patients receiving rituximab were found to have fewer adverse events while experiencing similar complete disease remission rates. At the moment, alkylating agents, not rituximab, are still indicated by KDIGO as first-line treatment for the subset of PMN patients with persistent nephrotic range proteinuria as we await more RCT data on rituximab, but could the MENTOR study help change that?
Meanwhile, calcineurin inhibitors (CNIs), which have significant although less severe side effects than cyclophosphamide, have become an increasingly popular therapeutic option for PMN among nephrologists in the United States and elsewhere. Cyclosporine and tacrolimus have comparable efficacy when compared against each other. Like cyclophosphamide, their main mechanism of action (reviewed here and here) is not B-cell specific, but compared to cyclophosphamide, CNIs have higher rates of relapse after drug withdrawal.
So now 60 years after the first description of Heymann nephritis and 10 years after the published discovery of PLA2R, we have the MENTOR study, which compares CNI cyclosporine with the B-cell depletion strategy of rituximab in the treatment of PMN. The MENTOR investigators set out to ask whether rituximab is noninferior to cyclosporine in inducing and maintaining remission of proteinuria for up to 24 months in patients with PMN. Below we will discuss the study design, results, and implications for future PMN studies and management.
For more background on PMN, we recommend checking out this CJASN review by Couser; CJASN review (more cautious about rituximab) by Ponticelli and @GlassockJ; AJKD retrospective by @GlassockJ; AJKD review by Francis, Beck, and Salant; RFN post by @Slatts_1 ; most recent KDIGO statement, and this GlomCon lecture.
The Study
The MENTOR study set out to answer the following question: Is rituximab therapy noninferior to cyclosporine therapy in inducing and maintaining remission of proteinuria, regardless of baseline anti-PLA2R status, for up to 24 months in patients with PMN?
Trial Design
To answer this question, the investigators designed an investigator-initiated, open-label, multicenter, randomized noninferiority trial. The purpose of a noninferiority trial is to evaluate whether a new treatment (rituximab) has similar efficacy to that of an established treatment (cyclosporine, per KDIGO GN guidelines). Noninferiority trials (reviewed here) have become prevalent because treatment with a placebo or no-treatment arm, especially for a disease such as PMN, is not ethical when an effective treatment already exists. For MENTOR, the null hypothesis is that in PMN, rituximab induces and maintains remission of proteinuria at a lower rate than cyclosporine does. Rejection of this null hypothesis by a noninferiority margin of 15% on an absolute risk-difference scale would support that rituximab is noninferior to cyclosporine in the treatment of PMN for the predetermined primary outcome. All participants were either already on conservative therapy (ACEI or ARB) or were placed on conservative therapy during the run-in phase prior to being randomized to either the rituximab arm or the cyclosporine arm. \
Funding Source
Genentech (maker of rituximab) supported the study, although the authors state the company did not influence the planning, data collection, interpretation, or writing of the study.
Figure S1: Overview of Trial Design. NR = non-response, CR = complete remission
Study Participants
Broadly speaking, the participants were adults with biopsy-proven PMN already on conservative management but not on other immunosuppressive agents. The inclusion and exclusion criteria are stated in detail in the supplemental section of the manuscript.
Inclusion Criteria:
PMN diagnosed by kidney biopsy demonstrating subepithelial spikes along capillary walls by silver stain, granular IgG and C3 along capillary walls on IF, and subepithelial deposits seen on EM. All three components were required, and pathology was adjudicated by a study PI prior to randomization.
Age: 18 to 80 years
If female, not pregnant; if not post-menopausal or surgically sterile, must be practicing medically approved contraceptive method
Not exposed to prednisone or mycophenolate mofetil for > 1 month, not exposed to alkylating agents for > 6 months
Treatment with RAS blockade and/or ARB for ≥ 3 months prior to randomization, BP < 140/80 in > 75% readings.
Participants with more than 5g per 24-hours were able to enter the study’s treatment phase without the run-in period
Estimated GFR (by MDRD) ≥ 40 mL/min/1.73m2 or quantified creatinine clearance ≥ 40 mL/min
Exclusion Criteria:
Active infection
Secondary cause of MN (hepatitis B, SLE, medications, malignancy)
Type 1 or type 2 diabetes mellitus to exclude proteinuria due to diabetic nephropathy
Pregnancy or breast feeding
History of resistance to CNIs, rituximab, or alkylating agents (although relapse after 3 months for CNI and 6 months for rituximab and alkylating agents was still accepted for eligibility)
Intervention:
Eligible participants were randomized to either the rituximab arm or the cyclosporine arm and observed for 6 months.
Rituximab dosing: 1000 mg intravenous (donated by Genentech) on days 1 and 15
Cyclosporine dosing: 3.5 mg per kg per day every 12 hours (purchased from Novartis), with target serum trough levels 125 to 175 ng/mL as assessed every 2 weeks until target trough obtained. Dose reduction was performed for participants with a persistent and unexplained increase in serum creatinine of more than 30% (if creatinine did not fall in response to this dose decrease the participant was considered to have experienced treatment failure).
If at 6 months into the study complete remission was observed in either arm, treatment was stopped. In the cyclosporine arm, the drug was then tapered over an additional 2-month period. For both arms, if non-response was observed (reduction in proteinuria by less than 25%), treatment was stopped, and in the cyclosporine arm a 2-month taper was initiated.
At the 6-month mark, partial responders continued for an additional 6 months, with treatment then stopping at the 12-month mark (with relevant taper for cyclosporine). Note how this additional step for months 6-12 differs from the absolute stop at the 6-month mark of the GEMRITUX trial (discussed in our introduction). Additional follow up in MENTOR was performed until month 24.
Sample Size and Stats
130 participants were enrolled and randomized, with n = 65 in each arm. The investigators calculated that they would need 63 participants in each arm to achieve 80% power to detect noninferiority at a one-sided alpha of 0.025 corresponding to a two-sided alpha of 0.05 and a noninferiority margin of 15% on an absolute risk difference scale. In other words, this study was powered for the desired, preset outcome. As a side note, one major limitation of approximately half of noninferiority trial is the failure to state the a priori noninferiority margin, so the explicit statement of the proposed margin in the main text and supplement is already a strength. However, the best practice for defining such a margin is less clear. It is generally recommended that the margin “be defined based on statistical considerations and clinical judgement” where a margin can be defined based on a pooled estimate of effect size from historical placebo-controlled RCTs or based on the limit of the confidence interval (CI) closest to the null effect. For the MENTOR study, the 15% corresponded to half of the risk difference of approximately 30% expected at month 24 compared with placebo, according to a prior cyclosporine RCT. The margin was also determined by the rationale that benefits of rituximab–tolerability, less nephrotoxicity, greater compliance, and lower cumulative cost of discrete injections over daily medications–would justify a 15% inferiority margin for efficacy. To run the statistics on whether rituximab was noninferior, standard error for Z tests comparing differences between groups was calculated using a generalized linear model with binomial distribution and identity link function. The test was considered significant if the one-sided p value was < 0.025. If noninferiority was established, then superiority was tested. Rituximab was considered superior to rituximab if a two-sided p value was < 0.05. Other comparisons (Kaplan Meier curves and hazard ratios from Cox regression models) were performed using 95% CI. Sensitivity analyses were also executed to see whether different statistical approaches would yield the same result.
Outcomes
The primary endpoint was assessed in an intention to treat analysis and was defined as a composite of complete remission or partial remission of proteinuria at 24 months after randomization.
Complete remission was defined as ≤ 0.3 g/24 hours proteinuria and serum albumin ≥ 3.5 g/dL. Partial remission was defined as a reduction in baseline proteinuria of ≥ 50% and final proteinuria between 0.3 and 3.5 g/24 hours (regardless of serum albumin). Neither of these endpoints were defined by eGFR.
Treatment failures consisted of any of the following:
< 25% reduction of baseline proteinuria at 6 months
Relapse
Premature termination before 12 months due to disease activity or adverse event
Patients requiring additional immunosuppressive medications not on the study protocol
Not meeting criteria of complete or partial remission by 24 months
Loss to follow-up
The investigators also examined many secondary outcomes, including:
Different time points for proteinuria remission
Time to remission
Relapse
Treatment failure at different time points
Time to treatment failure
Anti-PLA2R levels at various time points (see potential rationale here)
Quality of life as assessed by the Kidney Disease Quality of Life Short Form (KDQOL-SF)
Decrease in creatinine clearance
ESKD at 24 months
Adverse events
Results
As shown below in Figure S2 of the study, a total of 182 patients were screened, and 130 were enrolled (n=65 in each arm). Out of the 52 excluded, the vast majority did not meet inclusion criteria. After randomization, the rituximab arm had incomplete follow-up on only two participants (considered treatment failure), and in the cyclosporine arm only four participants had incomplete data (considered treatment failure). No participants were excluded from the final analysis.
Figure S2. Overview of recruitment and follow-up.
Participants in each study arm were fairly evenly matched in terms of baseline characteristics, listed in Table 1. They were primarily middle-aged, majority male, with heavy proteinuria (median 8.9 g/24 hours in each arm) and relatively high creatinine clearance (> 80 mL/min in each arm). There was no mention of race or ethnicity, although given the epidemiology of PMN the cohort participants were most likely of primarily European ancestry.
When baseline characteristics were further broken down by sex and randomization arm, median baseline anti-PLA2R levels were 179 u/mL among females in the rituximab arm, compared to 382 u/mL among males in the same arm and 535 u/mL among females in the cyclosporine arm.
So how did rituximab fare against cyclosporine in this study? At the end of 12 months, rituximab was noninferior to cyclosporine in terms of the composite primary outcome of complete or partial remission of proteinuria (60% achieved the composite outcome in the rituximab arm vs. 52% for cyclosporine, P = 0.004). Figure 1 below shows the range (blue line) of risk difference never crossed the dashed noninferiority margin line. Remarkably and perhaps more excitingly, at 24 months, rituximab was superior to cyclosporine in maintaining the composite outcome, remaining at 60% vs cyclosporine’s drop down to 20% with a risk difference (blue line) of 40% (P < 0.001 for both superiority and noninferiority).
Figure 1. The primary outcome: composite of complete or partial remission of proteinuria at 12 and 24 months.
Similar results were seen at month 18 as well (Table 2), and in terms of complete remission at 24 months none in the cyclosporine group had it whereas 35% did in the rituximab group (Table S7). For participants meeting the composite outcome, proteinuria levels (median and interquartile range) were plotted on a log scale in Figure S8 according to treatment arm and time.
The rituximab advantage was consistent across subgroups, although an interaction for sex in the rituximab group disappeared after adjustment for baseline anti-PLA2R (see Table S5 above for different baselines, Figure S5 below for the subgroup data).
As a secondary outcome of measuring disease activity, anti-PLA2R data were concordant with the proteinuria data, and anti-PLA2R levels decreased to a greater extent and on a steeper slope in the rituximab group compared to the cyclosporine group among participants who achieved the composite outcome (Figure S10).
Looking at the other side of the coin, by 24 months a greater proportion of patients had treatment failure in the cyclosporine group (80%) compared to the rituximab group (40%), with time to treatment failure plotted in Figure 2 below.
Figure 2. Time to treatment failure.
In terms of adverse events, the incidence was similar between treatment arms, although the adverse events for rituximab were infusion-related symptoms, compared to elevations in serum creatinine and gastrointestinal symptoms in the cyclosporine group (Table 3). Finally, for quality of life metrics, little difference was seen between groups.
Discussion
In patients with nephrotic-range proteinuria while on conservative therapy, rituximab was non inferior at 12 months and superior at 24 months to cyclosporine in terms of maintaining proteinuria remission up to 24 months. In short, the trial was adequately powered with a clear design that seems to circumvent the timing limitations of GEMRITUX.
Limitations and unanswered questions to consider:
The trial was not blinded to the patients and treating physicians, although objective laboratory data that formed the primary outcome were blinded to those measuring and analyzing.
Would the risk difference change if the non-responders in both arms at 6 months had continued with therapy? Would the cyclosporine arm have had more remission cases with that subgroup? What was happening to anti-PLA2R levels in non-responders?
Would we have seen fewer treatment failures (serum creatinine, adverse events requiring discontinuation) in the CNI arm if tacrolimus had been used instead?
Would we see the same results in patients of black, Asian, or Hispanic ethnicities?
How was the “positive” threshold for anti-PLA2R determined, and for future trials is there a standardized approach to measuring this analyte?
Are we missing differences among responders, non-responders, and treatment failures in terms of subtype of PMN and potentially even the different antigen epitopes of PLA2R and THSD7A?
Given the results of this trial, a portion of the nephrology community might consider moving on from CNIs and use rituximab as initial therapy. For some nephrologists, the superiority in maintaining remission would be a reason to switch to B-cell strategies. For patients, temporary adverse effects related to the infusion might be more tolerable than daily gastrointestinal upset or worry about CNI-induced nephrotoxicity. Do the results of MENTOR provide enough of an impetus to initiate immunosuppressive therapy earlier, or perhaps even in patients with disease but who are still hovering in the sub-nephrotic range, patients in whom the risk/benefit ratio of cyclophosphamide was suboptimal?
For KDIGO GN to release new guidelines, anticipated results of the STARMEN trial (tacrolimus-rituximab vs methylprednisolone-cyclophosphamide) and RI-CYCLO (rituximab vs steroids and cyclophosphamide) might need to be considered first.
This study does not provide data to make decisions about rituximab vs the modified Ponticelli protocol.
Despite some limitations and open-ended questions, the MENTOR study does seem to provide some momentum to steer the nephrology community in a B-cell centric direction for approaching PMN therapy. However, our work is not done. At the moment, one could view our available therapies as relatively blunt tools, with rituximab being an improvement but still not as sophisticated and precise as it should be.
Work remains to be completed on understanding the different subtypes of PMN further for precision medicine, linking the genetic and environmental risk factors that may trigger PMN, and engineering more specific therapies so that not all B-cells are necessarily depleted while remaining plasma cells (not expressing CD20 and thus not depleted by rituximab) producing anti-PLA2R can also be targeted. Certainly the past decade has been exciting in terms of translational developments for PMN, kick-started with the identification of PLA2R as a causal glomerular in situ antigen, and it will be even more exciting to see what these upcoming trials and future research will bring in advancing the field.
ANTI PLA2R
Anti-PlA2R se relaciona ao diagnóstico de aproximadamente 70% de pacientes portadores de nefropatia membranosa primária. Por este motivo, alguns centros não realizam BX renal em pacientes com Anti-PLA2R positivo e síndrome nefrótica, atribuindo a estes pacientes o diagnóstico de nefropatia membranosa.
Mesmo após o resultado positivo, no entanto, ainda é recomendada a investigação de causas secundárias da membranosa (LES, HBV, sífilis, uso de medicações, neoplasias sólidas, sarcoidose).
membranosa secundaria
PROTEINURIA
Classification of proteinuriaClinical settingTypical level of proteinuria in adultsPredominant protein type
Transient proteinuriaFever, heavy exercise, vasopressor infusion, albumin infusion<1 g/dayAlbumin
Persistent proteinuria – orthostatic proteinuriaUncommon over age 30 years, may occur in 2 to 5% of adolescents<1 to 2 g/dayAlbumin
Persistent proteinuria – overflow proteinuriaMyeloma (monoclonal light chains), hemolysis (hemoglobinuria), rhabdomyolysis (myoglobinuria)Variable, could be nephrotic rangeNonalbumin
Persistent proteinuria – glomerular proteinuriaPrimary glomerular diseases, secondary glomerular diseases, diabetic nephropathy, hypertensive nephrosclerosisVariable, often nephrotic rangeAlbumin
Persistent proteinuria – tubulointerstitial proteinuriaHeavy metal intoxications, autoimmune or allergic interstitial inflammation, medication-induced interstitial injury<3 g/dayNonalbumin
Post-renal proteinuriaUrinary tract infections, nephrolithiasis, genitourinary tumor<1 g/dayNonalbumin
IF GRANULAR POR IMUNOCOMPLEXOS
CRESCENTE GNRP
deposicao de imunocomplexos = granular
=LIMA
Low complement
lupus
infeccao
membranosa.
membranoproliferativa
IgA
• Post infectious
– post streptococcal
– endocarditis, abdominal abscess
• Cryoglobulinemia
• Systemic lupus erythematosus
• Membranoproliferative GN
• IgA nephropathy/Hennoch Schoenlein Purpura
• Fibrillary glomerulonephritis
• C3 nephropathy
PROTEINURIA
Glomerular proteinuria – due to increased filtration of macromolecules (such as albumin) across the glomerular capillary wall.
This is a sensitive marker for the presence of glomerular disease. The proteinuria associated with diabetic nephropathy and other glomerular diseases, as well as more benign causes, such as orthostatic or exercise-induced proteinuria, fall into this category. Most patients with benign causes of isolated proteinuria excrete less than 1 to 2 g/day.
●Tubular proteinuria – Low-molecular-weight proteins, such as beta2-microglobulin, immunoglobulin light chains, retinol-binding protein, and polypeptides derived from the breakdown of albumin, have molecular weights that are generally under 25,000 Daltons in comparison to the 69,000 Daltons molecular weight of albumin. These smaller proteins can be filtered across the glomerulus and are then almost completely reabsorbed in the proximal tubule. Interference with proximal tubular reabsorption, due to a variety of tubulointerstitial diseases or even some primary glomerular diseases, can lead to increased excretion of these smaller proteins
Tubular proteinuria is often not diagnosed clinically, since the dipstick for protein is not highly sensitive for the detection of proteins other than albumin and because the quantity of non-albumin proteins excreted is relatively low. The increased excretion of immunoglobulin light chains (or Bence Jones proteins) in tubular proteinuria is mild, polyclonal (both kappa and lambda), and not injurious to the kidney. This is in contrast to the monoclonal and potentially nephrotoxic nature of the light chains in the overflow proteinuria seen in multiple myeloma.
●Overflow proteinuria – Increased excretion of low-molecular-weight proteins can occur with marked overproduction of a particular protein, leading to increased glomerular filtration and excretion. This is almost always due to immunoglobulin light chains in multiple myeloma but may also be due to lysozyme (in acute myelomonocytic leukemia), myoglobin (in rhabdomyolysis), or free hemoglobin (in intravascular hemolysis) that is not bound to haptoglobin [6]. In these settings, the filtered load is increased to a level that exceeds the normal proximal reabsorptive capacity. Patients with myeloma kidney also may develop a component of tubular proteinuria since the excreted light chains may be toxic to the tubules, leading to diminished reabsorption. (See “Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation”.)
●Postrenal proteinuria – Inflammation in the urinary tract, which can occur with urinary tract infection, can give rise to increases in urinary protein excretion, although the mechanism is unclear. The excreted proteins are often non-albumin (often IgA or IgG), and only small amounts are excreted. Leukocyturia is frequently present in such patients. Patients with nephrolithiasis or tumors of the urinary tract may also have proteinuria.
Amounts of proteinuria – The normal daily protein excretion (including all proteins) is less than 150 mg (usually 40 to 80 mg). The normal rate of albumin excretion is less than 20 mg/day (15 mcg/min); the rate is approximately 4 to 7 mg/day (3 to 5 mcg/min) in healthy young adults and increases with age and with an increase in body weight. Persistent albumin excretion between 30 and 300 mg/day (20 to 200 mcg/min) is called moderately increased albuminuria (formerly called “microalbuminuria”). Persistent albumin excretion above 300 mg/day (200 mcg/min) is considered overt proteinuria or severely increased albuminuria (formerly called “macroalbuminuria”), the level at which the standard dipstick becomes positive
HEMOPTISE + IRA
diagn diferenciais
3 primary glomerular diseases that cause nephrotic syndrome, and name 3 secondary causes of each
DLM, GESF, Nefropata membranosa
DLM=AINES
GESF= OBESIDADE, HIPERFILTRACAO, HIV
MEMBRANOSA= neoplasia, sifilis , hep b
Name 6 diseases that affect the kidney that are associated with hypocomplementemia.
Hypocomplementemia in glomerulonephritis is most often due to increased complement consumption. In these cases, immune deposits cause complement consumption at a greater rate than they can be synthesized. Other less common causes of hypocomplementemia are hereditary complement deficiency and the presence of circulating factors that promote complement activation.
Hypocomplementemia can occur with the following conditions:
Lupus nephritis
Subacute bacterial endocarditis
Membranoproliferative glomerulonephritis (MPGN)
Post-streptococcal glomerulonephritis
Cryoglobulinemic glomerulonephritis
Atheroembolic renal disease
Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura.
3 primary glomerular diseases that cause nephrotic syndrome, and name 3 secondary causes of each?
The term nephrotic syndrome refers to a distinct constellation of clinical and laboratory features of renal disease. It is specifically defined by the presence of:
Heavy proteinuria (>3.5 g/24 hours)
Hypoalbuminemia
Peripheral edema
Hyperlipidemia
Thrombotic disease may also be observed.
The classification is based on pathological findings:
minimal change disease
focal segmental sclerosis (FSGS)
membranous nephropathy
Sometimes there can be associated secondary diseases that may be causative in nature.
Minimal change:
Drugs: NSAIDs, ampicillin, lithium
Cancer: Hodgkin’s lymphoma, other lymphoproliferative diseases
Toxins: mercury, lead, bee stings
Infection: mononucleosis, HIV, immunizations
FSGS
Unilateral renal agenesis
Renal ablation – remnant kidney
Sickle cell disease
Morbid obesity
Heroin nephropathy
HIV nephropathy
Pamidronate
Vesicoureteral reflux
Membranous
Immunologic disorders eg. SLE, RA, MCD
Neoplasms e.g. Carcinoma (lung, colon, breast etc.), melanoma, leukemia, lymphoma
Infections e.g. Hepatitis B, syphilis, malaria
Medications e.g. Penicillamine, gold, captopril
A patient is scheduled for a renal biopsy. What are the risks that you would counsel them about?
At our institution, the following are the risk estimates:
The incidence of gross hematuria is approximately 5-10%
The incidence of significantly bleeding enough to delay discharge is approximately 1:100. This refers to persistent hematuria, or perinephric hematoma, which usually settles with conservative management
A transfusion is occasionally necessary
Serious bleeding complications sufficient to warrant interventions to stop bleeding are of the order of 1:1000
Kidney biopsy can be life threatening in 1:5000-1:10000
pulmonary-renal syndrome, which is a combination of acute glomerulonephritis with alveolar hemorrhage.
The pulmonary-renal syndrome can be caused by a variety of conditions, including Goodpasture’s syndrome which is associated with autoantibodies to the glomerular and alveolar basement membranes, and various forms of primary systemic vasculitis associated with serum positivity for antineutrophil cytoplasmic antibodies (ANCA), such as microscopic polyangiitis, Wegener’s granulomatosis and, less commonly, Churg-Strauss syndrome. This syndrome can be seen less commonly in association with systemic lupus erythematosus, systemic sclerosis, antiphospholipid syndrome, drugs (including propylthiouracil and hydralazine), Behçet’s disease, Henoch–Schönlein purpura, IgA nephropathy and mixed cryoglobulinaemia.
The majority of cases of pulmonary-renal syndromes are associated with ANCAs. The antigen targets in ANCA-associated disease are proteinase-3 and myeloperoxidase. The antigen target in Goodpasture’s syndrome is the alpha-3 chain of type IV collagen.
gn proliferativa
amiloidose
Amyloid deposition in the kidney can involve not only glomeruli and vessels, but also the interstitium and the tubular basement membranes, giving rise to several different morphological pictures.
There are cases of only minimal glomerular deposition, expressed by small mesangial nodules. Differential diagnosis has to be made from minimal change disease and some cases of IgA GN.
These very early cases need a careful demonstration of the few mesangial amyloid fibrils by electron microscopy.
When the deposits are massive, a nodular form is commonly found and has to be differentiated from other nodular glomerulonephritis, such as diabetic GS, light chain deposition disease and idiopathic MPGN. Amyloid specific stainings have to be performed in order to achieve a correct diagnosis
amyloidosis
deposition of an amorphous substance defined by the presence of a fibrillar structure by electron microscopy and a characteristic beta-pleated sheet structure by x-ray diffraction
Congo red staining. The material that accumulates in the extracellular compartment progressively destroys the involved organ.
Depending on peptide subunit deposition, the two most frequent types of amyloidosis have been defined, AL and AA, that can be differentiated using histochemistry and immuno-histochemistry techniques.
By light microscopy, amyloid appears as an amorphic, eosinophilic, PAS negative or scantly positive, extracellular substance.
Congo Red positivity is the most reliable staining in diagnosing amyloid deposition.
When stained with Congo Red, the sections show a typical apple-green birefringence under polarized light. Loss of Congo Red staining caused by pretreatment of the tissue with potassium permanganate is a useful tool for the diagnosis of amyloidosis AA.
IMMUNOHISTOCHEMICAL STAININGS
To differentiate amyloid AL and AA, specific antibodies can also be used.
Anti-immunoglobulin light chains (k e l) are useful for amyloid AL diagnosis.
nta
The distribution of the areas of necrosis is more segmental with ischemic injuries, while toxic injuries result in more diffuse proximal tubular injury. Urine output will drop precipitously. If life-threatening uremia can be treated, then recovery of the tubular epithelium can occur. As the tubular epithelium is regenerating, urine concentrating ability is impaired, and polyuria occurs.
glomerulopatias biopsia
glomerulopatias ingestao de proteinas
proteinuria 0,8-1,0g/kg/dia
adicionar 1g para cada g de proteina perdida ate 5g/dia
podocitopatias
Epidemiologia da GESF:
gesf
podocyte has a central role in the pathogenesis of FSGS.
Identification of products of mutated genes located in the podocyte and its slit diagram has resulted in the recognition of the hereditary forms of FSGS, and NPHS2; (Podocin), CD2AP (CD-associated protein), WT1; (Wilms’ tumor1), LAMß2; Laminin ß2 ACTN4 (Alfa-actinin4), TRPC6 (Transient receptor potential channel type6), PLCE1(Phospholipase Epsilon1), INF2(Inverted forming 2) and others are classified now genetic causes of FSGS and nephrotic syndrome
causas primarias vs secundarias
The underlying reason for the development of primary FSGS is unknown and suggested to be caused by an as yet unidentified circulating factor.INICIO ABRUPTO,FUSAO PODOCITARIA DIFUSA >70-80 PORCENTO,IMUNOSSUPRESSAO SO EM QUEM TEM SINDROME NEFROTICA
Secondary causes are typically due to hyperfiltration injuries in response to a reduction in nephron mass. FSGS can also occur due to a number of different genetic causes.
FSGS is usually thought to cause around 35% of cases of nephrotic syndrome in adults.
Distinction between primary and secondary causes of FSGS is important given the former are typically treated with immunosuppression, whereas the latter represents a maladaptive response to glomerular hyperfiltration and are treated with RAS blockade
classificacao daGESF
GESF PRIMARIA=provavelmente causada por um fator circulante ainda nao identificado que é toxico para o podocito que responde a imunossupressao. histopatologia com gesf e mais de 80% de fusoa dos podocitos e sem causa genetica ou secundaria identificavel.clinica com sindrome nefrotica
GESF DE CAUSA INDETERMINADA=sem causa genetica ou secundaria mas sem apagamento dos podocitos, sem SN=terapia de suporte
GESF genetica= considerar quando tiver forte historia familiar e corticoresistencia familiar , esporadica e sindromica
GESF secundaria= adultos sem SN, pensar em causa secundaria= nao deve ser feito imunossupressao.
mutacoes gesf
Autosomal dominant FSGS can be caused by mutations in the gene encoding alpha-actinin-4 (ACTN4) and transient receptor potential cation channel subfamily c member 6 (TRPC6).
Mutations in NPHS1 (Nephrin) cause the Finnish form of congenital nephrosis and mutations in the NPHS2(Podocin) cause steroid-resistant nephrotic syndrome. Both result in a clinical picture of congenital FSGS and are transmitted in recessive fashion. Other genes implicated in glomerulosclerosis with nephrotic range proteinuria include CD2-associated protein (CD2AP), Laminin Beta-2 (Lamb2), LIM Homeobox transcription factor 1 BETA (LMX1B) and WT1.
gesf
Forms of FSGS and collapsing glomerulopathy
Form of FSGS/CG Mechanisms or Features
Primary FSGS/CG-> Plasma factor suspected but remains unidentified; candidates include suPAR and CLC
adaptive FSGS-> Imbalance between glomerular load and glomerular capacity
APOL1 FSGS/CG -> APOL1 genetic variants seen in individuals of African descent
High-penetrance genetic FSGS/CG ->More than 50 nuclear and mitochondrial genes now associated
Virus-associated FSGS/CG-> Commonly seen in untreated HIV infection, largely as a result of APOL1 variants; also seen incytomegalovirus infection
Medication-associated FSGS/CG-> Lithium Interferon (primarily APOL1 high-risk individuals) Pamidronate
Fisiopatologia da GESF:
1) lesao podocitaria , levando ao colapso do capilar glomerular e cicatriz
gesf quadro clinico
: Primary FSGS classically presents with the constellation of features that encompass the nephrotic syndrome.
Secondary causes of FSGS however, are much more likely to present without edema, with non-nephrotic range proteinuria and normal serum albumin levels.
The noted exceptions to this are pamidronate induced FSGS or classical collapsing FSGS associated with human immunodeficiency virus (HIV) infection.
Histologically, FSGS is characterized into five different underlying lesions. There is some suggestion that differences in histology can be suggestive of prognosis, but the response to initial therapy with glucocorticoids is usually more predictive of the eventual outcome.
The differing types include; • FSGS not otherwise specified (NOS) • Collapsing • Tip • Perihilar • Cellular
FSGS NOS shows segmental areas of mesangial collapse and sclerosis in some, but not all, glomeruli. There is foot process effacement on electron microscopy. There may be weak and nonspecific binding of IgM, C3 or C1q in sclerotic areas. The sclerotic changes occur first in juxtamedullary glomeruli and can be missed with cortical biopsies (giving the classical misdiagnosis of MCD that subsequently does not respond as expected to glucocorticoid therapy).
The collapsing variant has collapse and sclerosis of the entire glomerular tuft. These patients often have rapid progression of their disease to kidney failure. It is classically associated with HIV and other viral infections such as COVID-19. Some have argued that collapsing variant should be considered a distinct entity away from FSGS. Treatment is directed at the underlying cause.
The tip variant shows injury at the tip of the glomerulus near the origin of the proximal tubule. These patients may be more likely to present abruptly with the nephrotic syndrome as well as being potentially more likely to respond to glucocorticoid therapy.
The perihilar variant has perihilar sclerosis and hyalinosis in more than 50% of segmentally sclerotic glomeruli
. The cellular variant is associated with segmental endocapillary hypercellularity that occludes the capillary lumen in at least one glomerulus.
it is important to exclude secondary causes that are treated in a markedly different way to primary causes of FSGS.
- Viral infections known to induce FSGS (HIV, parvovirus B19, HCV, cytomegalovirus and Epstein barr, SARS-CoV-2 virus) should be excluded
- A thorough family history should be taken to screen for familial FSGS
- A detailed drug history to exclude drug induced causes (ie bisphosphonates, heroin, interferon and anabolic steroids)
- Prior GN with subsequent FSGS changes in damaged glomeruli
- Factors that may have reduced nephron mass (nephrectomy, low birth weight / prematurity).
Patients who present with the nephrotic syndrome with no obvious causes of a secondary form of FSGS are likely to have primary FSGS. This may additionally be supported by features such as the degree of foot process effacement noted on electron microscopy: • Those with >80% foot process effacement are more likely to have primary FSGS.
- In contrast, < 60% foot process effacement with a segmental distribution are more likely to have a secondary form of FSGS.
- < 60% foot process effacement may also be seen in genetic causes of FSGS, although this is more variable (see below).
Those who fail to respond to therapy appropriately or have a suggestive family history may benefit from genetic testing to identify one of the genetic forms of FSGS. Genetic variants underlying FSGS are not uncommon and are beginning to be explored in more detail as genetic testing becomes more available. T
COLLAPSING GLOMERULOPATHY KNOWN ASSOCIATIONS
HIV infection – HIV-associated nephropathy
Other infections (parvovirus B19, CMV, HTLV,
polyomavirus, leishmaniasis, tuberculosis) Autoimmune disorders (SLE, Still’s disease, MCTD) Hemophagocytic syndrome (Macrophage Activating syndrome) Malignancy (MM, AMML, etc.)
Immunosuppression (recurrent and de novo
collapsing GN in the kidney allograft) Drug-induced (Interferon-α, Pamidronate,
Alendronate)
Genetic (APOL1 risk variants; familial collapsing GN,
action myoclonus- renal failure syndrome,
mitochondrial cytopathy, sickle cell disease) Idiopathic collapsing glomerulopathy
Secondary to ischemia and ESKD
IDIOPATHIC vs. ADAPTIVE FSGS
Idiopática
Sudden onset nephrotic syndrome (edema)
No history of prior kidney disease
Normal size glomeruli
Diffuse effacement of foot processes >80%
No significant parenchymal atrophy
Laboratory determinations at presentation Serum albumin often low
Response to immunosuppressive therapy Variable
Response to RAAS antagonism plus diuretic Usually responsive
Recurrence after kidney transplantation Sometimes
more likely to have has, hematuria, insuf renal e hipoalbuminemia
Adaptativa
ADAPTIVE FSGS
Slowly progressive proteinuria without edema
History of prior kidney disease (pregnancy) or vascular conditions
Glomerular hypertrophy
Response to RAAS antagonism plus diuretic Usually responsive and sometimes dramatically
Recurrence after kidney transplantation Rarely
Foot processes largely preserved
Pre-existing kidney injury
Many forms of genetic FSGS may present like adaptive FSGS. RAAS, renin-angiotensin-aldosterone system.
sindrome nefrotica
causas 2arias de GESF
Causes of adaptive FSGS
Reduced Glomerular Numbers: agenesia renal unilateral/ablaçao renal Prematurity Low birth weight (intrauterine growth retardation) Oligomeganephronia Vesicoureteral reflux Kidney transplantation donor–recipient size mismatch
Initially Increased GFR
anemia falciforme
obesidade morbida / Growth hormone excess / Anabolic steroid abuse
drogas
heroina
hiv
pamidronato
With regard to reduced nephron number, the pathophysiology involves a compensatory process to restore total kidney GFR toward normal, through an increase in single-nephron glomerular filtration. This is achieved by increasing intraglomerular pressure through constriction of the efferent glomerular arteriole
. Activation of the renin-angiotensin system is critical to the vascular pathophysiology, and production of aldosterone contributes to glomerular scarring. Increased pressures and flows in the glomerulus likely compromise podocyte structure and function.
Therapy for adaptive FSGS is directed at reducing activation of the renin-angiotensin system, by using angiotensin-converting–enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARB), or aldosteronereceptor antagonists, which are collectively referred to as renin-angiotensin-aldosterone system (RAAS) blockers.
Aldosterone blockers provide another option to reduce proteinuria and possibly slow progressive renal fibrosis. Two agents are available, spironolactone (which also has effects on the progesterone and testosterone receptors) and the more selective antagonist eplerenone, which has a much less off-target endocrine effect (
Principais causas secundárias de GESF:
Adults with FSGS who do not have nephrotic syndrome should be evaluated for a secondary cause
virus : hiv, parvovirus, cmv
drogas; litio, pamidronato, anabolizantes
Heroin-associated nephropathy, pamidronate, lithium, anabolic steroids
obesidade, rim unico
nefropatia do refluxo 4 mecanismos propostos=hiperfiltracao, deposicao de complexo antigeno anticorpo, injuria glomerular por imuno complexos circulantes e trapping macromolecular
Etiologia da GESF:
primaria= working with recurrent FSGS after renal transplantation, identified cardiotrophin-like cytokine factor 1 (CLCF1), an interleukin 6 family member
Primary FSGS/CG typically presents with nephrotic syndrome, especially in children, or with nephrotic proteinuria, defined as total urine protein >2 grams protein per gram creatinine, in the absence of other features of nephrotic syndrome, but it can present with subnephrotic proteinuria
The initial rationale for their use may have been that FSGS/CG was considered a disorder of the adaptive immune system
Most forms of high-penetrance genetic FSGS are refractory to steroids, whereas APOL1 FSGS can be steroid sensitive
gesf bx
trapping de IGM e IGG na IF
BIOPSIA:
CRITERIOS DE INCLUSAO=>The inclusion criterion is at least one glomerulus with a segmental scar (FSGS) or the presence of increased numbers of podocytes or epithelial cells in the Bowman space (CG)
For exclusion criteria, first, the biopsy specimen should lack evidence of immune deposits, other than IgM and C3; second, the patient should lack a systemic disease that can affect glomeruli, such as an inflammatory disease (lupus, systemic vasculitis) or a metabolic disease (diabetes)
gesf biopsia
is a clinicopathological entity which is histologically characterized by segmental glomerulosclerosis in some glomeruli, or tuft collapse, segmental hyalinosis, mostly negative or IgM staining on immunofluorescence and effacement of foot processes on electron microscopy.
It may be etiologically classified as primary, hereditary disease associated or secondary to infections, drugs/toxins, hyperfiltration, ischemia and as a renal involvement of mitochondrial disease
Glomerulosclerose focal e segmentar (atinge algumas porções de alguns glomérulos)
ME: perda e fusão dos podócitos (sinal de agressão epitelial) 2. Imunoflourescência: depósitos de IgM e C3.
Secundária=1. Associada a infecção por HIV, dependência de heroína, anemia falciforme e obesidade mórbida. 2. Como consequência da cicatrização dos glomérulos (ex.: Nefropatia por IgA) 3. Resposta adaptativa por perda de tecido renal (ex.: ablação renal) 4. Formas hereditárias de síndrome nefrótico (mutação de genes codificadores das proteínas do diafragma podocitário – nefrina, podocinα, α-actinina 4)
The lesions of FSGS are routinely subdivided into either primary (or often termed “idiopathic”) FSGS vs secondary FSGS forms.
Primary FSGS is thought to be due to an unknown circulating factor. Patients with primary FSGS usually present with nephrotic range proteinuria (>3.5g/day), serum albumin less than 3.5 g/dL, and will have have diffuse foot process effacement (>80%) on electron microscopy (EM).
Secondary FSGS is thought to be due to various different pathogenic mechanisms including via primary alterations of the glomerular epithelial cell, reduced nephron mass or glomerular adaptation, and secondary to focal proliferative glomerulonephritis. Patients with secondary FSGS typically present with non-nephrotic proteinuria, normal to low normal serum albumin >3.5 g/dL, and with segmental foot process effacement on EM. Common reported causes of secondary FSGS are:
Viral: HIV-associated nephropathy, Parvovirus B19, BK virus, Epstein-Barr virus
Drugs: Heroin-associated nephropathy, pamidronate, lithium, anabolic steroids
Systemic: Lupus, IgA nephropathy
Malignancy: Lymphoma, leukemia
Genetics: Familial FSGS, sporadic genetic mutations, APOL1
Reduced nephron mass / glomerular adaptation: Nephrectomy, reflux nephropathy, obesity-related
five recognized FSGS histologic subtypes:
- Not Otherwise Specified (NOS) variant
- Collapsing variant
- Tip variant
- Cellular variant
- Perihilar variant
Qual l achado a seguir?
gesf-PROGNOSTICO
Non-nephrotic FSGS patients have a better prognosis compared to their nephrotic FSGS counterparts.
Patients with massive proteinuria, >14 g/day, progress very rapidly to ESRD, sometimes termed as malignant FSGS.
Higher serum creatinine >1.3 mg/dL, interstitial fibrosis >20% and presence of cellular lesions >1% are predictors of progression to ESRD.
The APOL1 risk status has not been shown to influence response to initial treatment.
The identification of APOL1 polymorphic variants (namely G1 and G2 risk alleles) represented a revolution in understanding the racial difference in susceptibility to HIV infection-associated nephropathy, FSGS or ‘hypertensive nondiabetic kidney disease’ in patients of Black ancestry [9, 10]. In this view, HIV infection probably represents the ‘second hit’ required to develop glomerular injury and kidney disease in genetically predisposed subjects [11]. Low birth weight (LBW), prematurity, gestational and fetal distress, previous episodes of acute kidney injury (AKI) and nephrotoxins exposure, obesity, diabetes, highsalt diet and ageing represent other examples of risk factors
considerar causa genetica de gesf
Non-response to immunosuppression
- A suggestive family history
- FSGS and a potential syndromic presentation
- Pediatric steroid resistant nephrotic syndrome= Most forms of high-penetrance genetic FSGS are refractory to steroids, whereas APOL1 FSGS can be steroid sensitive
The documentation of a genetic cause of FSGS has a number of potential management implications. • Management decisions pertaining to choice of therapy (as immunosuppression is unlikely to be beneficial in these cases, with the notable exception of mutations in PLCE1, TRPC6, or WT1 that may be responsive). •
Prediction of recurrence post transplant, which is between 0 to 8% with genetic causes of FSGS compared to 30 to 70% with a primary cause. Common causative genes include: NPHS1 (nephrin, the classical congenital nephrotic syndrome of the Finnish type), NPHS2 (podocin, another cause of pediatric FSGS), TRPC6, ACTN4 and the collagen IV genes (COL4A3, COL4A4, COL4A5).
SIND NEFROTICA + fusao podocitaria difusa= corticoterapi=se responde é primaria
nao responde= resistencia = teste genetico
SEM SN + sfusao podoc deifusa= teste genetico
fusao podocitaria sem evidencia de causas secundarias=teste genetico
fusao podocitaria segmentar + evidencia de causa secundaria = adaptativa
tratamento gesf
Therapy is usually begun in those in whom the underlying cause is felt to be primary FSGS who present with the frank nephrotic syndrome.
We recommend that high-dose oral glucocorticoids be used as the first-line immunosuppressive treatment for primary FSGS
Initial high-dose glucocorticoids should be continued until complete remission is achieved, or as tolerated by patients up to a maximum of 16 weeks, whichever is earlier.
1mg/kg nao excedendo 80mg/dia
usar ate remitir e manter mais 2 semanas ate iniciar o desmame ou max 16 sems
Adults with primary FSGS who respond to glucocorticoid treatment should receive glucocorticoids for minimo 6 months para tentar diminuir recidiva
in adults with relative contraindications or intolerance to glucocorticoids, alternative immunosuppression with CNIs should be considered as the initial therapy in patients with primary FSGS ou opcao para coricoresistencia -a melhor
Additionally, patients who are expected to respond toglucocorticoids usually show at least some improvement inproteinuria within 4 a 8 weeks. In the setting of noindication of response and/or severe glucocorticoid sideeffects, it is prudent to move patients to second-linetherapy with a CNI. The overall duration of glucocorti-coids should be 6 months (high-dose period plus taper), and the overall duration of CNIs should be 12 months.
If patients have not responded to glucocorticoids or a CNI, the therapeutic choices for primary FSGS are limited.Several other immunosuppressive agents have been tried,but there are no high-quality data supporting their use
For adults with steroid-resistant primary FSGS, we recommend that cyclosporine or tacrolimus be given for 6 months rather than continuing with glucocorticoid monotherapy or not treating
Glucocorticoids alone are expected to produce at least a partial remission in 40 to 80% of those treated.
Adults with steroid-resistant primary FSGS who respond to CNI treatment should receive CNIs for a minimum of 12 months to minimize the risk of relapses
Patients resistant to or intolerant of CNIs Adults who have steroid-resistant primary FSGS with resistance to or intolerance of CNIs should be referred to specialized centers for consideration of rebiopsy, alternative treatment, or enrollment in a clinical trial
All patients should also be considered for standard risk reducing non-immunosuppressive therapies similar to that used for other forms of proteinuric CKD such as RAS inhibition and the identification and management of CVD risk factors such as treating hypercholesterolemia with statin therapy.
- Glucocorticoids are typically begun at a dose of prednisolone 1 mg/kg daily (to a maximum of 60 to 80 mg daily) as an oral formulation. • This initial dose is often continued for 8 to 12 weeks. • If a response is seen in that time period, this dose is typically continued for another 2 weeks before the dose is slowly tapered down over the ensuring 2 to 3 months, giving a total length of therapy of about 5 to 6 months. • If a partial response is seen this tapering is often done in a much slower fashion, extending out for around 9 total months of therapy.
- Patients who have a worsening of their proteinuria during glucocorticoid tapering typically have their dose reduction halted with consideration of starting another immunosuppressive agent (usually cyclosporine, but if there is significantly impaired kidney function (eGFR <30ml/min/ 1.73m2) then mycophenolate mofetil is often considered -Mycophenolate mofetil is typically used as a thirdline agent, after glucocorticoids and calcineurin inhibitors have been rejected
Those who have little response to prednisolone after 12 to 16 weeks of therapy are considered to be steroid resistant. If secondary or genetic causes have been excluded, then therapy usually consists of adding cyclosporine or mycophenolate if their kidney function is poor.
• Cyclosporine is typically begun at a dose of 2 to 4 mg/kg in two divided doses (usually around 75 to 100mg twice daily). The therapeutic drug level that should be aimed for (as a trough level) is about 100 to 175 ng/ml.
In contrast, tacrolimus may be used at a dose of 0.1mg/kg (2 to 4 mg twice daily) with trough levels between 5 to 10ng/ml aimed for. • It is unclear if prednisolone should be continued in these patients at a low dose. If it is used, the maximum dose is usually 15mg orally daily for approximately six months, followed by a reduction to 5 to 7.5mg orally daily for another six months afterwards. • Calcineurin inhibitors are typically continued for six months following an attainment of a complete remission and twelve months in cases of a partial remission. Non-responsiveness by six months should lead to consideration of an alternative therapy.
The dose of mycophenolate mofetil is usually 750 to 1000mg twice daily for six months. Low dose corticosteroids are often included in this regime. For those who suffer a relapse of their disease, glucocorticoids are often begun again at similar doses to those used for initial therapy, particularly if they had a good response to therapy in their initial course.
Those who relapse frequently or have side effects of glucocorticoids that make such therapy less advisable may benefit from the use of cyclosporine. FSGS is notorious for recurring in kidney allografts, and the rate of recurrence of primary FSGS may be as high as 30%. A full discussion of FSGS in the kidney allograft is outside the scope of this chapter, and the author invites the reader to appropriate topic reviews.
gesf remissao relapso
remissao completa= reducao da proteinuria para <0,3g/dia ou RPC <300mg/g ou <30mg/mmol,creat estavel e albumina >3,5
remissao parcial= reducao da proteinuria para 0.3-3,5g/d ou RPC300-3500mg/g e uma queda de 50% da proteinuria
RELAPSO=proteinuria >3,5g/d ou urina pcr >3500mg/g apos remissao completa ou um aumento na proteinuria de 50% durante a remissao parcial
Adults with previous steroid-sensitive primary FSGS who experience a relapse can be treated using the same approach as that for adults with relapsing MCD
Mutations in mitochondrial DNA (mtDNA) and mitochondrial dysfunction have been implicated in the pathogenesis of focal segmental glomerulosclerosis (FSGS).
manejo gesf
A low-sodium diet potentiates the antiproteinuric effect of RAAS blockers. The World Health Organization recommends a daily sodium intake of ,2 g/d, or approximately 50 mmol/d.
gesf colapsante em um unico glomerulo
Na definição histológica do tipo da GESF, mesmo discretas alterações segmentares, em um único glomérulo, que apresente a caracterização de hiperplasia/hipertrofia podocitária associada a colapso das alças é suficiente para o diagnóstico de glomerulopatia colapsante. Este padrão é o mais grave dos subtipos da GESF, chega a ser estudado a parte das demais outras apresentações, tem baixa resposta a corticoterapia isolada, e progride para ESRD em mais de 60% dos casos.
gesf tto
prognostico
The prognosis of untreated FSGS is generally unfavorable]
. The spontaneous remission rate is unknown, but is felt to be low and likely <10%.
Patients who respond to therapy have a better prognosis than those who do not. Other factors include; • A worsened outcome with a raised creatinine at presentation. • Nephrotic syndrome and heavy proteinuria predicts a worse outcome. • Response to therapy
variantes
“a classificação de Columbia” da GESF9 , com cinco variantes patológicas: colapsante (COL), celular (CEL), apical (TIP), peri-hilar (PHI) e usual (NOS).
PERIHILAR- polo tubulos- associada a hipergiltracao e gesf secundaria=esclerose perihilar secundaria?
TIP LESION=afets o polo vascular tem boa resp a corticoide-melhor prognostico
COLAPSANTE= colapso e esclerose de todo o tufo glomerular, nao proliferacao endocapilar,associado com cistos tubulares . associada a hivan-pior prognostico
CELULAR=hipercelularidade endocapilar com oclusao da alca capilar.lesao estagio inicial
NOS=sem esclerose perihilar, sem >50 de esclerose.aumento matriz, adesao da capsula de bowman
fatores de risco para progressao da gesf
proteinuria severa
elevacao da creat
negros
histologia -> colapsante,fibrose tubulo intersticial
falha ao alcancar remissao parcial ou total
quem n pode corticoide ou cni
gesf
micofenolato +dexametasona
acth
rituximabe
classificacao de columbia
A classificação de Columbia divide a GESF em seis tipos histológicos (Colapsante, perihilar, celular, variante usual - NOS, tip lesion, indeterminado), dentre os quais o de pior prognóstico é a forma colapsante. Nesta forma, há a proliferação de células podocitárias que promovem colapso das alças capilares.
CELULAR=proliferacao delular endocapilar-estagio inicial?
Alguns autores chegam a separa a Colapsante das outras GESFs, como uma doença à parte que merece maior cuidado e atenção. Isso se dá pela pior resposta terapêutica aos esquemas conhecidos de imunossupressores.
gesf peri hilar
Predominam nas alterações renais da obesidade os efeitos decorrentes da síndrome metabólica, como sua associação com nefropatia diabética ou hipertensiva, litíase urinária (cálculos de ácido úrico) e neoplasia renal (aumento da produção de IGF1). Mais raramente, um quadro de GESF é associado à obesidade, representando cerca de 25% das glomerulopatias em pacientes obesos mórbidos. Os principais fatores relacionados a essa glomerulopatia são o hiperfluxo e o processo inflamatório relacionado a produção de adipocinas e mudança da microbiota intestinal do indivíduo obeso. O padrão de GESF apresentado na classificação de Columbia é o padrão peri-hilar.
anemia falciforme
gesf secundaria e perihilar
Secondary SFGS often perihilar , with GBM ischemic corrugation and reduplication >Prominent hemosiderin deposition. >Sickled red blood cells > renal infarcts in vasooclusive episodes
gesf tto corticoresistencia
Para pacientes portadores de corticoresistência (manutenção do quadro nefrótico por um período superior a 16 semanas de corticóide na dose máxima), o desmame do corticóide a partir desta data deve ser realizada da maneira rápida, ao mesmo tempo que as evidências de imunossupressão em associação apontam para o tratamento associado com inibidores de calcineurina. No entanto, devemos ter a atenção, pois essas medicações podem agravar a progressão da fibrose tubular e piorar a insuficiência renal crônica.
tip lesion
Na classificação histológica da GESF (Classificação de Columbia), a variante tip lesion é a que apresenta melhor resposta a corticoterapia isolada. A medicação de primeira linha no tratamento da GESF primária em adultos, pelo KDIGO (2021), é o corticóide em dose imunossupressora (1 mg/kg/dia - máximo de 80 mg, ou pred 2mg/kg/Dias alternados - dose máxima 120 mg). Sua resposta clínica é muito favorável, semelhante a Doença de Lesões Mínimas.
gesf colapsante
Collapsing Glomerulopathy
CG is a podocytopathy whose pathologic picture is distinctly different from that of FSGS, with increased numbers of epithelial cells in the podocyte compartment along the external surface of the glomeruli, in the Bowman space, or both.
Entre os subtipos da GESF,
a colapsante é hierarquicamente a mais severa, sendo a que mais progride para DRC e que menos se relaciona a resposta isolada ao corticoide.
Foi inicialmentedescrita em associação ao vírus do HIV (HIVAN), sendo fatores de risco para essa associação a raça negra, Gene APOL1+, co-infecção com HCV, alta viremia, e baixa contagem de CD4.
Na biópsia renal do HIVAN, aos achados da GESF colapsante são associados microcistos no compartimento túbulo-intersticial.
colapso do tufo glomerular + microcistos tubulares ,atrofia tubular. sem proliferacao celular endocapilar
gesf colapsante e parvovirus
Um paciente pós-transplante renal, logo imunossuprimido, desenvolveu um quadro clínico de anemia aguda, sem evidências de doença sistêmica, associado a síndrome nefrótica. Esses achados podem ser relacionados à infecção pelo parvovírus B19, devido ao tropismo medular do vírus, e ao fato de sua infecção ser relacionada ao desenvolvimento de GESF colapsante.
APOL1
O gene da Apolipoproteína L1, derivado de seleção natural que ocorreu principalmente no continente africano, e mais prevalente em pacientes de raça negra é associado a HAS mais severa, Doença renal crônica, e podocitopatias, as quais incluem a GESF colapsante. Existem duas mutações desse gene, e os padrões homozigotos G1/G1 ou G1/G2, ou heterezigoto G1/G2 são associados a essas condições. Já pacientes homozigotos para o gene G1/_ podem desenvolver os quadros glomerulares após exposição a agentes (medicações: pamidronato, lítio), ou infecções virais (HIV, COVID, Parvovírus B19).
APOL1 G0 is the common variant and is the only variant seen in individuals of selfidentified European and Asian ancestry, with rare exceptions chiefly discovered in individuals who present with APOL1 glomerular disease and have African ancestry. Thus, the allelic combinations are G0/G0, two copies of the common or ancestral variant; G1/G0 and G2/G0, both having one risk allele; and G1/G1, G1/G2, and G2/G2, all having two APOL1 risk alleles. APOL1 low-risk status is considered to be zero alleles or one risk allele. APOL1 high-risk status is carriage of two risk
Recurrent Focal Segmental Glomerulosclerosis and Collapsing Glomerulopathy After Renal Transplantation
Recurrent FSGS/CG after renal transplantation is closely related to the primary diseases. Typically, these patients have the hallmarks of primary FSGS/CG, including nephrotic syndrome; they also tend to have experienced progression to ESRD) over a relatively short time, often less than 3 years. Recurrence rates after kidney transplantation have ranged from 10% to 30% in children and adults
Recurrence rates are higher among EuropeanAmericans than in African-Americans in the United States, likely because of the role of APOL1 FSGS in the latter population. In other countries, Asian and indigenous populations may be at high risk. Consistently, FSGS patients who undergo living related donor transplantation are at increased risk for recurrence, for reasons that are not clear
Recurrent FSGS/CG is typically suspected when proteinuria is discovered, or in some cases when serum creatinine rises, perhaps with only modest proteinuria. The renal biopsy specimen may show a minimal change in disease pattern. This is presumably because scarring has not occurred or because in early recurrent FSGS, as in any early form of FSGS, the glomerulosclerosis can be focal and missed on examination of a kidney biopsy specimen
Therapy for recurrent FSGS/CG has met with variable results. Glucocorticoids are often used, but the response rates are low. Many patients respond to plasma exchange or immunoadsorption procedures, but relapse is common
. A combination of plasma exchange plus cyclophosphamide had limited success, and there have been concerns about long-term toxicity
Abatacept has been used, loa but the most comprehensive report suggests lack of efficacy (32). Rituximab infusions are effective in some cases; factors predicting success include younger age, normal serum albumin at recurrence, and shorter time to the initiation of rituximab therapy (33). The mechanism by which rituximab may work is uncertain, but it may be relevant that a rituximab ligand, SMPDL, is expressed on the podocyte, as discussed above (34).
gesf colapsante e covid
Existem causas multifatoriais de lesão renal aguda na infecção pelo coronavírus, tais como choque, reação inflamatória, rabdomiólise, agressão viral direta, nefrite tubulointersticial (medicamentos?), agravamento das condições devido hipoxemia. No entanto, a questão direciona para uma lesão renal aguda, na qual foi evidenciada a associação com síndrome nefrótica (proteinúria e corpúsculos ovais graxos). Assim, a semelhança da nefropatia pelo HIV, foi descrito que o COVID-19 associou-se ao padrão de GESF colapsante, sendo mais uma causa para nos preocuparmos na associação com esta grave condição glomerular.
nefropatia membranosa + dç auto imune
Exostosinas com membranosas auto-imunes
A Glomerulopatia Membranosa é caracterizada pelo espessamento patológico da membrana basal glomerular.
A glomerulopatia membranosa é uma doença relacionada a deposição de complexos imunes subepiteliais (acima da membrana basal glomerular, e abaixo do podócito), com consequente repercussão desta deposição sobre a membrana basal glomerular, o que ocasiona a síndrome nefrótica. Isto é visto na análise da prata, sobre a forma de espículas (spikes), que são projeções da membrana na tentativa de envolver os complexos imunes. Em termos epidemiológicos, há predominância de sua ocorrência nos seguintes fatores: indivíduos de raça branca, homens e com idade superior a 40 anos. O anticorpo anti-PLA2r tem sido utilizado com implicações diagnósticas, prognósticas e terapêuticas, quando positivo, favorecendo ao diagnóstico da atividade dessa condição.
NEFROPATIA MEMBRANOSA TTO
Paciente apresenta diagnóstico de síndrome nefrótica associada a complicações clínicas (hipercolesterolemia severa e evento trombótico). Trata-se de uma nefropatia membranosa, já que a positividade do anticorpo anti-PLA2R positivo é suficiente para o diagnóstico desta condição, mesmo sem biópsia renal. Após afastadas causas secundárias, recomenda-se início de tratamento imunossupressor. Preenche critérios de uma síndrome nefrótica ameaçadora a vida, e é considerada uma nefropatia membranosa de muito alto risco (KDIGO 2021). O tratamento indicado envolve o esquema clássico de Ponticelli, em que há uma alternância do uso de corticoide (mês 1, 3 e 5) e ciclofosfamida oral (meses 2, 4 e 6).
nefropatia membranosa secundaria
A Nefropatia Membranosa pode ser relacionada a causas secundárias, o que permite ao nefrologista realizar uma série de investigações em busca de diagnósticos associados ao padrão membranoso, antes de indicar tratamento imunossupressor, que obterá boas repostas nas formas primárias. Devemos então conhecer as causas de nefropatia membranosa. O KDIGO (2021) recomenda a seguinte investigação:
1- Neoplasias sólidas (indica investigação em todos os pacientes com diagnóstico de nefropatia membranosa, inclusive os com ANTIPLA2R positivo); EX pulmao, colon, estomago e prostata
2- USG de rins e vias urinárias;
3- Infecções: Sífilis, HIV e hepatites;
3- Medicações: D-penicilamina, AINES, sais de ouro;
4- Sarcoidose (raro) - radiografia do tórax;
5- FAN: Lúpus classe 5;depositos imunes tb no mesangio e mbg
6- Exame físico e história clínica completa para: doenças sistêmicas e da tireoide, e exame físico articular e pele.
Outras características nos ajudam a diferenciar a nefropatia membranosa primária, da secundária, tais como:
A) Tipo da IgG identificada na IF ou IHQ - Na primária se identifica principalmente IgG4; nas secundárias podem ser identificadas IgG1, IgG2 e IgG3.
B) Na biópsia renal:
- microscopia óptica: pode ser identificada expansão e proliferação de mesângio;
- Na IF: associação com outras Ig´s que não a IgG - IgM, IgA, C1q;
- Na Microscopia eletrônica - Depósitos subepiteliais.
nefropatia membranosa
tratamento
Paciente apresenta um quadro de síndrome nefrótica após os 40 anos de idade, já sabemos que nessa idade, a principal causa primária de síndrome nefrótica é a nefropatia membranosa. O resultado da biópsia (presença de espículas na prata , imunofluorescência com depósitos granulares difusos de IgG e C3 nas alças capilares) é confirmatória desta condição. O uso do Anticorpo Anti-PLA2r tem efeitos diagnósticos, prognóstico e pode influenciar decisões terapêuticas nesta doença.
A respeito do tratamento da nefropatia membranosa, devemos considerar a seguinte divisão de risco do KDIGO (2021):
a) Baixo risco:
- TFG preservada, proteinúria < 3,5g/dia e albumina > 3,0g/dL
- TFG preservada + proteinúria < 3,5 g/dia ou uma redução superior a 50% da proteinúria/24h após uso de IECA/BRA (após 6 meses de terapia)
Tratamento -> tratamento conservador, apenas com o uso de IECA em dose máxima.
b) Moderado risco:
- TFG preservada + proteinúria 4-8 gramas/24h, com uma redução inferior a 50% com o uso de IECA/BRA (após 6 meses de terapia), mas sem preencher critérios de alto risco.
Tratamento -> Aguardar e observar - se piora clínica: Rituximab ou prednisona + inibidor de calcineurina
c) Alto risco:
- TFG < 60 ml/min/1,73 m2 e proteinúria > 8g/dia
- TFG preservada + proteinúria > 3,5 g, com uma redução inferior a 50% com o uso de IECA/BRA (após 6 meses de terapia) associado a:
- albumina sérica < 2,5 g/dL;
- nível sérico de anti-PLA2R > 50 RU/ml;
- alfa1-microglobulina urinária > 40 ug/min;
- IgG urinária > 1 ug/min;
- b2-microglobulina > 250 mg/dia;
- índice de seletividade > 0,2;
Tratamento -> Rituximab ou Ponticelli (alternância de corticoide e ciclofosfamida) ou inibidor de calcineurina + rituximab
Obs: devido ao perfil de efeitos adversos do tratamento com ciclofosfamida, a opção do KDIGO2021 é por tratamento com Rituximab.Calcineurin inhibitors such as cyclosporine and tacrolimus can also induce remission but the remission tends to be temporary with high rates of disease recurrence. Additionally calcineurin inhibitors have nephrotoxic side effects.
rituximab=
- Muito alto risco:
- Síndrome nefrótica ameaçadora de vida
- Piora rápida da função renal não explicada
Tratamento -> Ciclofosfamida alternado com corticoide
Neste caso, devido a evolução com insuficiência renal progressiva, não explicada e complicações graves da síndrome nefrótica, a opção foi o uso do esquema de Ponticelli, o qual alterna corticoide e ciclofosfamida por 6 meses.
corpusculo zebroides
Microscopia eletrônica evidenciando corpúsculos zebróides (zebra bodies). Tais achados podem ser relacionadas ao diagnóstico de doença de Fabry, e podem ser eventualmente identificados no uso crônico de cloroquina, medicação tradicionalmente utilizada no LES, e que teve grande evidência em 2020.
Doença de Hodgkin
. No entanto, na imagem apresentada evidenciamos: preservação das alças capilares, espaço urinário íntegro. Não há proliferação podocitária ou da cápsula de Bowman. No mesângio, identificamos apenas 3 ou menos células mesangiais, o conteúdo de matriz não ultrapassa o citoplasma dessa células. Qual a conclusão? Os glomérulos são normais. Na descrição do caso, temos a evidência de uma síndrome nefrótica clássica. Então, qual síndrome nefrótica se apresenta com histologia renal normal? Doença de lesões mínimas. Entre causas apontadas, qual será a provável causa do quadro clínico? Doença de Hodgkin, já que ela é altamente relacionada com este tipo histológico.
sirolimus =relacao com proteinuria
proteinuria
embolia por cristais de colesterol
A imagem apresentada evidencia a multilamelação do lúmen vascular (o que normalmente não ocorre), e é um achado sugestivo de ateroembolismo de colesterol, o qual sucede a realização dos procedimentos de angiografia cerca de 30 dias após a sua realização.
classificacoes
oxford
Classificação de Oxford (MEST-C) se relaciona ao diagnóstico anatomopatológico, com correlações clínicas estabelecidas por estudos, na nefropatia por IgA (Berger).
A título de conhecimento:
A classificação de Columbia divide o padrão histológico da GESF em 6 tipos (colapsante, tip lesion, celular, variante usual, variante indeterminada e peri-hilar).
EULAR é um grupo de estudos de reumatologia que, em 2019, atualizou os critérios clínicos de Lúpus.
A classificação de Cameron avalia a recidiva da GESF pós-TX: Imediata (<48h), precoce (<3 meses) ou tardia (>3 meses)
nefropatia por iga tto
No caso clínico, paciente apresenta apenar uma proteinúria > 1grama/24h, mas não nefrótica, já está em uso do IECA na dose máxima por 2 meses. O KDIGO define como paciente de alto risco de progressão para DRC, pacientes com nefropatia de IgA que apresentam proteinúria/24h > 750 mg, por um período superior a 3 meses. A recomendação pelo KDIGO (2021) para estes casos é manter o IECA em dose máxima por 6 meses, e avaliar resposta clínica. Caso persista superior a 1grama, pode-se tentar ciclo de corticoterapia.
O uso da imunossupressão em pacientes portadores da Nefropatia pela IgA tem sido discutido, sobretudo após estudos que questionaram seu real benefício, como o STOP-IGA. No entanto, são indicações formais do uso de corticóide em IgA pelo KDIGO 2021:
- pacientes que apresentam proteinúria em faixa nefrótica (associação com podocitopatia?);
- formas crescênticas.
Alterações cicatriciais, como a esclerose segmentar (S) e a atrofia tubular (T), nem sempre são relacionadas a boa resposta a imunossupressores. Caso o paciente apresente crescentes (C), deve receber esquema imunossupressor semelhante a vasculites (com corticóide + ciclofosfamida).
Indicações de imunossupressor fundamentadas em nefropatia de IgA no KDIGO (2021):
alguns estudos evidenciam que o há benefício de imunossupressão (corticóide isolado) ao esquema conservador de tratamento da Nefropatia da IgA (IECA, glifozina, estatina, etc) quando o paciente apresenta pontuações no componente “E” - proliferação endocapilar, pois esse padrão identifica uma forma de doença mais ativa (aguda).
Indicações de imunossupressor fundamentadas em nefropatia de IgA no KDIGO (2021):
- Síndrome nefrótica + Nefropatia por IgA: Corticóide 1mg/kg/d, em esquema semelhante a podocitopatia;
- Vasculite por IgA: corticóide + ciclofosfamida, em esquema semelhante a vasculites ANCA-relacionadas.
iga nao é hereditario
Poucos casos de nefropatia de IgA tem características de transmissão familiar, sendo também incomum o seu acometimento pediátrico. A incidência dessa doença predomina entre 20-30 anos de idade. O mecanismo fisiopatológico da nefropatia da IgA envolve pelo menos quatro “hits”: 1) Formação da IgA1 anômala; 2) presença de polimorfismo favorável; 3) polimerização da IgA1; 4) deposição tecidual com ativação local do complemento e produção da IgA no mesângio.
NEFROPATIA POR IGA-RESUMO
é uma glomerulopatia primária, de provável característica auto-imune, em que há uma anormalidade de polimerização da imunoglobulina A, associada à sua alta produção em mucosas, e
imunofluorescência, onde ocorre dominância ou codominância da IgA (podem existir outras Ig´s no mesângio) em mais de 90% dos glomérulos.
Sua apresentação clínica é variável e a maioria dos pacientes apresenta micro-hematúria e/ou proteinúria, outros desenvolvem síndrome nefrítica, rapidamente progressiva, glomerulonefrite crônica, e, raramente, pacientes apresentam síndrome nefrótica associada.
Quando associada a síndrome nefrótica, se pensa na associação da nefropatia da IgA e Lesões Mínimas, a qual, na manifestação nefrótica, é tratada com corticosteróide em esquema de imunossupressão.
Pacientes que não apresentam síndrome nefrótica (proteinúria < 3,5 g/24h), prejuízo de função renal ou crescentes, não necessariamente devem receber imunossupressão na IgA, podendo ser tratados com IECA ou BRA por 6 meses, para reavaliação do quadro clínico e proteinúria.
A nefropatia da IgA não é a glomerulopatia que mais recorre pós-transplante. A primeira posição é ocupada pela Glomerulonefrite Membranoproliferativa, sobretudo associada ao complemento (mais de 80% de recorrência pós-Tx). A nefropatia da IgA recorre em 30% dos pacientes pós transplante, mas a perda da função renal normalmente não ocorre pela sua recorrência, e sim por outras condições relacionadas ao Tx.
NEFROPATIA IGA BIOPSIA
CAUSAS PRIMARIA E SECUNDARIAS
O diagnóstico da nefropatia de IgA, continua sendo realizado através da biópsia renal, não havendo marcadores sorológicos
. Em geral, é observado uma dominância ou co-dominância da IgA difusa (>90% dos glomérulos tem que ser acometidos), na região mesangial, podendo ser positivo outras imunoglobulinas ou frações do sistema complemento.
No entanto, o diagnóstico de sua forma primária (Doença de Berger) ocorre quando são descartadas formas secundárias, que levam a deposição de IgA no mesângio, o que ocorre no(a):
- Etiologia viral (HIV, hepatite);
- Cirrose Hepática;
- Micose fungóide;
- Doenças Inflamatórias Intestinais;
- Doenças auto-imunes;
- Glomerulonefrite infecciosa IgA dominante (estafilococo).
São causas secundárias associadas a nefropatia pela IgA: cirrose hepática, micose fungóide, HIV, hepatites virais crônicas, doença inflamatória crônica, doenças auto-imunes e padrão de IgA dominante em processos infecciosos (sobretudo estafilococcia).
resposta a corticoterapia na DLM e GESF
A definição de cortico-dependência é relacionada a recidiva do quadro de síndrome nefrótica (proteinúria > 3,5 g/24h e albumina menor que 3,5 g/dL) após 2 semanas da retirada ou redução do corticóide em paciente portador de podocitopatia.
Cortico-resistência é diagnosticada quando não é obtida remissão clínica em paciente que utilizou o corticoide na dose máxima por um intervalo superior a 16 semanas.
Já recidiva frequente é definida quando ocorrem 2 recidivas em um intervalo de seis meses ou 4+ recidivas em um intervalo de um ano.
IgA E hematuria macro
A hematúria macroscópica pode se associar a dois quadros distintos na nefropatia da IgA: (a) uma glomerulonefrite crescêntica (C2 do MEST), com mais de 25% de glomérulos amostrados com crescentes; (b) sangramento glomerular - hematúria dismórfica - com piora de função renal relacionada à hematúria.
A diferenciação do caso será realizada através de Biópsia Renal, e o tratamento será determinado a partir da causa da piora da função renal. O “cenário a” requer início de corticóide e imunossupressão; já para o “cenário b” não é tão claro na literatura se a imunossupressão será benéfica, sendo o tratamento conservador suficiente para a remissão clínica em alguns casos.
O KDIGO (2021) ainda menciona que o diagnóstico de Glomerulonefrite Rapidamente Progressiva por Vasculite por IgA é estabelecido após descartar Vasculite Anca, Anticorpo Anti-MBG, e outras causas de IRA (nefrotoxidade, pré e pós-renal).
sindrome de alport
Além das alterações estruturais da membrana basal glomerular vista na eletrônica, o padrão de GESF secundária pode ser visto na MO
Feedback
A síndrome de Alport é uma doença hereditária, manifestada precocemente por hematúria, mas que tem as características de progressão para doença renal crônica. Apesar da maioria dos casos ser relacionada a mutações no cromossomo X ( o que leva ao padrão de herança ligada ao X - em que homens tendem a manifestar o quadro clínico mais grave, e mulheres apresentam um quadro mais brando), já existem casos de famílias que apresentaram o padrão autossômico de herança. A história natural de um menino com Alport, é de microhematúria na infância, progressão para albuminúria, DRC e entrada em hemodiálise antes dos 30 anos de idade. Apenas os IECA na fase proteinurica apresentaram alguma resposta em retardar a progressão desta doença, e devem ser iniciados ainda na infância. A realização de BX renal para o diagnóstico de Alport também é um desafio, e requer conhecimento do nefrologista e do patologista, já que os achados na microscopia óptica podem ser de uma GESF adaptativa, ausência de alterações na imunofluorescência, e achados de DRC nas formas mais avançadas. Na microscopia eletrônica é feito o diagnóstico, ao identificar alterações de forma, densidade e espessamento da membrana basal glomerular. Um padrão descrito é padrão lamelar das fibras colágenas da membrana basal, dando um aspecto “em rede” desta estrutura.
sindrome nefrotica secundaria
sorologias
Um jovem que apresenta síndrome nefrótica deve ser incialmente investigado de maneira não-invasiva, em busca de diagnósticos associados, tais como: diabetes melitus, doenças infecciosas crônicas e doenças auto-imunes.
A questão apresenta relações de sorologias positivas e padrões anatomopatológicos que justificariam a síndrome nefrótica, porém não há correta correlação entre as principais glomerulopatias associadas às sorologias positivas, as quais seriam :
HbsAg+ - membranosa
HCV+ - membranoproliferativa (com ou sem crioglobulinemia)
HIV + - GESF colapsante (SIDA) ou nefropatia do HIV associado a imunocomplexos (outras glomerulopatias - quando o paciente já apresentou a constituição imune devido ao uso de TARV).
Caso o paciente tenha sorologias negativas, ausência de provas de imunidade positiva, complementos normais, resta pensar que ele é portador de uma glomerulopatia primária. Entre as primárias, a principal causa de síndrome nefrótica na faixa de idade (até 30 anos) é a GESF.
biopsia na iga
Na análise da microscopia óptica foi visto um padrão proliferativo mesangial, o que pode ser comum a diversas patologias. Na análise de imunofluorescência, 100% dos glomérulos apresentaram depósitos mesangiais de IgA, a qual foi dominante sobre a IgG e IgM (a IgA reagiu em 3+, enquanto as outras Ig´s, +), fechando o diagnóstico anatomopatológico de doença de Berger (nefropatia da IgA).
Os achados de uma membranoproliferativa deveriam incluir um padrão de proliferação mesangial e celular, homogêneo, na microscopia óptica, que se projeta para as alças capilares, na prata, é visto tradicionalmente uma imagem em duplo contorno.
Na GESF, a descrição de uma região de esclerose, que ocupa menos de 50% da estrutura glomerular, e que pode formar aderências à cápsula de Bowman (sinéquias). Já na IF, o padrão associado é de “trapping” (aprisionamento) da IgM e C3 na região de esclerose.
A positividade das Ig´s em mesângio, associado ao padrão de proliferação mesangial lembra a descrição clássica do LES classe II (proliferativo mesangial). No entanto, no LES a dominância na imunofluorescência será de IgG, não de IgA., Além disso, o C1q (proteína do complemento mais relacionado à via clássica), é usualmente positivo no LES, levando ao padrão full house (positividade para IgG, IgM, IgA, C3 e C1q na IF, sendo a IgG dominante ou codominante).
DOENÇA DE FABRY
podocitos em espuma
avc, opacidades nas corneas, hve, proteinuria, isostenuria, insuf renal, parestesias, eritema palmar,angioceratomas no tronco,coxas, nadegas,
dor neuropatica, alteracoes tgi
altercoes psiquiatricas
MO= GESF
ME=corpos de zebra dentro dos podocitos
Depósitos podocitários podem ser evidenciados mesmo antes da progressão para insuficiência renal crônica.
doença rara, genética, necessariamente ligada ao X.
mutação genética que promove a deficiência da enzima alfa galactosidase,gene GLA esta deficiência se associa ao acúmulo de glicoesfingolípides (Gb3) que ocasiona dano tecidual e processo de isquemia orgânico.
apresentação mais grave ocorre em homens, em que podem ser evidenciados sinais cardinais: angioqueratomas, acroparestesias e córnea verticilata
. As formas tardias da doença normalmente acometem ambos os sexos, podendo ocasionar cardiopatia - miocardiopatia hipertrófica, quadro neurológico - AVC criptogênico e renal - Doença Renal Crônica.
Em homens, o exame de triagem pode ser a dosagem da atividade da enzima alga-galactosidase, mas em mulheres apenas o teste genético é utilizado até o momento para a realização de triagem.
REPOSICAO ENZIMATICA PRECOCE
A Nefropatia da IgA (NIgA) é a mais comum das doenças glomerulares no mundo. Sua taxa de progressão de 30-40% em 20-30 anos
O defeito primordial reside na produção de moléculas de IgA1 aberrantes, que são deficientes em galactose, polimerizando-se e acumulando em região mesangial, com ativação do sistema complemento.
Feedback
A fisiopatologia da nefropatia pela IgA envolve a produção anômala de IgA1 em mucosas, características genéticas (que não seguem o padrão mendeliano, possivelmente características poligenéticas), polimerização da IgA aberrante, seu acúmulo em nível do tecido renal, e ativação do sistema complemento pela via lecitina. Esse processo se associa ao desenvolvimento de diversos padrões anatomopatológicos renais, tais como glomeruloesclerose, proliferação endocapilar, crescentes, necrose de tufo glomerular. Um escore clínico foi validado para apresentar os critérios prognósticos da nefropatia pela IgA - VALIGA study. A manifestação clínica também é variável, e sua resposta clínica a corticóide também não segue padrão homogêneo, sobretudo respondem pacientes que apresentam proliferação endocapilar.
achados anatomopatologicos da nefropatia diabetica
Hipertrofia podocitária com expansão mesangial
Glomeruloesclerose nodular intercapilar (lesão acelular de Kimmelstiel-Wilson)
Glomeruloesclerose difusa de etiologia isquêmica
vasculite por iga
púrpura de Henoch Shonlein, hoje denominada Vasculite por IgA, é uma doença sistêmica na qual a manifestação renal é a Nefropatia pela IgA. Trata-se de uma vasculite de pequenos vasos, que tem sua prevalência aumentada em crianças. Associa-se ao quadro renal a dor abdominal, acometimento articular e púrpuras. Raramente acomete pulmão e SNC. Diante do envolvimento renal desta condição, faz-se necessário o tratamento imunossupressor à semelhança dos quadros de vasculites, em que são utilizados corticosteróides e ciclofosfamida em pulsoterapia por 6 meses.
O KDIGO (2021) propõe o diagnóstico por biópsia renal em crianças que apresentem achados consistentes de PHS e nefrite significante, proteinúria > 1grama e/ou prejuízo de função renal. Recomenda descartar as causas secundárias para IgA em adultos(infecções virais, doenças imunes, cirrose, doença inflamatória intestinal, micose fungóide, infecções com predomínio de IgA e neoplasias). E também menciona que a imunossupressão deve ser direcionada ao acometimento renal, não havendo recomendação de uso de corticoide como profilaxia de acometimento renal em pacientes que apresentam o acometimento extra-renal exclusivo.
glomerulonefrite estafilococica
Nos últimos anos tem sido descrita a associação de glomerulonefrites e diversos agentes infecciosos (de vírus a fungo, sendo a lista imensa). O padrão de acometimento varia de hematúria/proteinúrias assintomáticas, classes proliferativas focais ou difusas, e até mesmo GNRP. Em relação ao complemento, vários padrões de consumo (C3 isolado, C3 e C4 associados) também são vistos. No que se diz em relação a glomerulonefrite estafilocócica, que acomete preferencialmente idosos e diabéticos, na realização da biópsia renal pode ser encontrado a predominância de IgA, o que faz diagnóstico diferencial com o Berger. Em geral surge em conjunto com a infecção, e seu prognóstico é ruim, progredindo para estágios finais de DRC. Púrpuras também são comuns.
sindrome nefrotica
Nephrotic Syndrome § Nephrotic range proteinuria ( > 3 – 3.5 g/24 hrs) § Anasarca § Hypoalbuminemia § Hyperlipidemia, lipiduria § Fatty oval bodies in urine § Hypercoagulable state
primarias
DLM
GESF
MEMBRANOSA
OUTRAS:• IgA nephropathy • Fibrillary glomerulopathy (fibrils 16 – 24 nm) • Immunotactoid glomerulopathy (fibrils > 30 nm) • Smoking-associated nodular glomerulosclerosis
biopsia lesoes agudas vs cronicas
Active lesions includes cellular proliferation, crescents, edema, necrosis and acute inflammation while chronic lesions represent fibrosing conditions such as fibrous crescents, interstitial fibrosis, glomerulosclerosis, tubular atrophy or vascular sclerosis.
lesoes glomerulares
sindrome nefrotica
Glomerular lesions : No or minimal hypercellularity
No or minimal hypercellularity offers usually a limited differential diagnosis.further investigations with immunofluorescence (IF) and electron microscopy(EM) are needed along with a detailed clinical history.
If glomerular capillaries are abnormal three main categories are defined; glomerular capillary wall thickening, sclerosis/capillary wall collapse and luminal occlusion
. If the patient has nephrotic syndrome three main diagnosis are considered ; minimal change disease, membranous GN(early stage ) and also amyloidosis in which amyloid deposits can be very subtle to detect on light microscopy. However, these disorders can be easily differentiated by immunofluorescence and ultrastructural microscopic findings.
Minimal change diseases(MCD) is the most common cause of idiopathic nephrotic syndrome and characterized by absence of pathologic changes by light microscopy but diffuse effacement of foot processes of podocytes by EM.
It is usually a primary disease but it may be secondary to malignant diseases and nonsteroidal anti-inflammatory drugs
Proteinuria is generally massive, selective and mostly of abrupt onset.
podocitopatias tratamento
De acordo com o KDIGO (2021), em podocitopatias a dose máxima de corticóide deve ser mantida até 16 semanas, caso o paciente não apresente remissão clínica ou efeitos adversos da terapia. Esse seria o momento no qual o paciente receberia o diagnóstico de corticoresistência. Após esse diagnóstico, ou caso necessitasse retirar o corticóide anteriormente devido efeitos adversos, a medicação a ser associada seria os inibidores de calcineurina (tacrolimus ou ciclosporina).
lesoes glomerulares sindrome nefrotica
biopsia
sindrome nefrotica, sem proliferacao celular/hypercelularidade e SEM achados na microscopia otica
=
DLM
amiloidose
membranosa estagio inicial
biopsia
sem hipercelularidade, sem achados na microscopia otica e com hematuria
ALPORT
MEMBRANA FINA
LES CLASSE I E II
IgA
Microscopia optica: -avalia a estrutura e a celularidade
Pas=celularidade
Prata de Jones=membrana basal glomerular
Microscopia eletrônica: avaliação da ultraestrutura glomerular
Medir espessura d amembrana, porcentagem de apagamento dos processos podocitarios
Imunofluorescência: -depósitos imunes- forma , tamanho e distribuição desses depoistos
biopsia
sem hipercelularidade e com alteracoes capilares
If glomerular capillaries are abnormal three main categories are defined; glomerular capillary wall thickening, sclerosis/capillary wall collapse and luminal occlusion
1) COLAPSO OU ESCLEROSE CAPILAR GLOMERULAR
GESF E COLAPSO GLOBAL
2)ESPESSAMENTO DA PAREDE CAPILAR
=gn membranosa, diabetes,glomerulopatia fibrilar e amiloidose
three processes that can result in the glomerular capillary wall appearing thickened. One of these three is membranous glomerulonephritis (GN). immune complexes diffusely deposit in the subepithelial space (between the glomerular basement membrane and the podocyte)With time, the deposits invoke a reaction resulting in the formation of additional membrane material that first grows up between the deposits (“spikes”) and then extends on top of and surrounding the deposits (“holes”). These stages will result in membrane thickening that can be appreciated by light microscopy.
A thickened GBM can be detected as a major feature in several glomerular diseases including membranous GN, membranoproliferative(mesangiocapillary) GN , fibrillary GN and diabetic nephropathy, thrombotic microangiopathy, Alport syndrome or transplant glomerulopathy. Aforementioned first three disorders have typical immunofluorescence microscopic findings while IF is expected to be negative in the others
3) OCLUSAO LUMINAL
MAT, Crio, amiloidose,lesoes embolicas, lesoes endoteliais
hematuria and glomerular basement membrane(GBM) thinning
In cases with hematuria and glomerular basement membrane(GBM) thinning one should consider first Alport syndrome (AS) or thin basement membrane nephropathy (TBMN).
Diagnosis of thinning should be made by comparison of age-matched controls. A cut-off value has been reported 250 nm in adults in most series. However, care must be taken to diagnose TBMN in children since GBM thickening increases with age.
. A thinned GBM may be an early lesion in Alport syndrome. Children with Alport syndrome may show only diffuse GBM attenuation, making differentiation from TBMN a challenge. However, in full-blown cases with AS there is also characteristic thickening of the glomerular basement membrane with splitting of the lamina densa, electron lucent areas and electron dense particles detected by EM. (Figs. 4,5)A progressive, high-frequency sensorineural deafness frequently detectable by audiometry in later childhood in boys with X-linked AS and both boys and girls with autosomal recessive AS and anterior lenticonus or perimacular retinal flecks are other characteristics of AS
Thinning of lamina densa of GBM can be seen in normal children, IgA nephropathy, minimal change disease and in some forms of lupus nephritis. However, thinning in these disorders is mostly segmental whereas there is a diffuse involvement in patients with TBMN.
glomerulo
filtracao
Desse modo, a barreira de filtração é composta por três camadas: a camada de células endoteliais fenestradas, que reveste as alças capilares; a MBG propriamente dita;
e a camada de células epiteliais glomerulares viscerais (podócitos)
. As cargas negativas presentes na superfície das células endoteliais e podócitos, bem como na MBG, conferem uma barreira carga-seletiva contra a passagem de moléculas aniônicas (p. ex., albumina).
fenda do diafragma, uma junção intercelular especializada situada entre os podócitos, forma a barreira tamanho-seletiva final contra a passagem das proteínas plasmáticas.
A fenestrated endothelium forms the inner glomerular layer, followed by a layer composed of various extracellular proteins called the glomerular basement membrane (GBM). The outer layer has visceral epithelial cells, podocytes, and mesangial cells. The intricate arrangement provides the basis for continuous plasma volume filtration at the glomerular level.
nefritica vs nefrotica
Nephrotic Glomerulonephritis
Minimal change disease
Focal segmental glomerulosclerosis
Membranoproliferative glomerulonephritis
Membranous nephropathy
HIV associated nephropathy
Diabetic nephropathy
Amyloidosis
Nephritic Glomerulonephritis
IgA nephropathy/Henoch Schonlein purpura (HSP)[7]
Post streptococcal glomerulonephritis.
Anti-glomerular basement membrane disease
Rapidly progressive glomerulonephritis
Granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis
Polyarteritis nodosa
Idiopathic crescentic glomerulonephritis
Goodpasture syndrome
Lupus nephritis
Hepatitis C infection[8]
Membranoproliferative glomerulonephritis (typical presentation is with acute nephritic syndrome, however, sometimes features resembling nephrotic syndrome may occur, additionally)[9]
A more modern and widely accepted way to classify glomerulonephritis is to divide it into five forms of glomerulonephritis based on underlying immune processes.
The following is the modern classification of glomerulonephritis, including pathogenic type and the disease entity associated with it:
Immune-complex GN - IgA nephropathy, IgA vasculitis, infection-related GN, lupus nephritis, and fibrillary GN with polyclonal Ig deposits
Pauci-immune GN - PR3-ANCA GN, MPO-ANCA GN, and ANCA-negative GN
Anti-glomerular basement membrane (GBM) GN - Anti-GBM GN
Monoclonal Ig GN - Proliferative GN with monoclonal Ig deposits, monoclonal Ig deposition disease, fibrillary GN with monoclonal Ig deposits, and immunotactoid glomerulopathy
C3 glomerulopathy - C3 glomerulonephritis, dense deposit disease[10]
fisiopatologia glomerulonefrites
The underlying pathogenetic mechanism common to all of these different varieties of glomerulonephritis (GN) is immune-mediated, in which both humoral as well as cell-mediated pathways are active. The consequent inflammatory response, in many cases, paves the way for fibrotic events that follow.
The targets of immune-mediated damage vary according to the type of GN.
For instance, glomerulonephritis associated with staphylococcus shows IgA and C3 complement deposits.[3]
One of the targets is the glomerular basement membrane itself or some antigen trapped within it, as in post-streptococcal disease.
Such antigen-antibody reactions can be systemic, with glomerulonephritis occurring as one of the components of the disease process, such as in systemic lupus erythematosus (SLE) or IgA nephropathy.[17] On the other hand, in small vessel vasculitis, cell-mediated immune reactions are the main culprit instead of antigen-antibody reactions. Here, T lymphocytes and macrophages flood the glomeruli with resultant damage.[18]
These initiating events activate common inflammatory pathways, i.e., the complement system and coagulation cascade. The generation of pro-inflammatory cytokines and complement products, in turn, results in the proliferation of glomerular cells. Cytokines such as platelet-derived growth factor (PDGF) are also released, ultimately causing glomerulosclerosis. This event is seen in those situations where the antigen is present for longer periods, for example, in hepatitis C viral infection. When the antigen is rapidly cleared, as in post-streptococcal GN, the resolution of inflammation is more likely.[19]
Structural Changes
Structurally, cellular proliferation causes an increase in the cellularity of the glomerular tuft due to the excess of endothelial, mesangial, and epithelial cells.[5] The proliferation may be of two types:
Endocapillary - within the glomerular capillary tufts
Extracapillary - in the Bowman space, including the epithelial cells
In extra-capillary proliferation, parietal epithelial cells proliferate to cause the formation of crescents, characteristic of some forms of rapidly progressive glomerulonephritis.
Thickening of glomerular basement membrane appears as thickened capillary walls on light microscopy. However, on electron microscopy, this may look like a consequence of the thickening of the basement membrane proper, for instance, diabetes or electron-dense deposits either on the epithelial or endothelial side of the basement membrane. There can be various types of electron-dense deposits corresponding to an area of immune complex deposition, such as subendothelial, subepithelial, intramembranous, and mesangial. (See the images below)
Features of irreversible injury include hyalinization or sclerosis that can be focal, diffuse, segmental, or global.
Functional Changes
Functional changes include the following:
Proteinuria
Hematuria[20]
Reduction in creatinine clearance, oliguria, or anuria
Active urine sediments, such as RBCs and RBC casts
This leads to intravascular volume expansion, edema, and systemic hypertension.
glomerulonefrites
We distinguish three main categories of glomerular diseases:
(i) immune-mediated glomerulopathies that encompass distinct histopathological patterns [e.g. immunoglobulin A (IgA) nephropathy, membranous nephropathy (MN), C3 glomerulopathy, etc.], all showing immune deposits on kidney biopsy;
(ii) systemic diseases with glomerular involvement [e.g. lupus nephritis (LN),monoclonal gammopathies,metabolic storage diseases, etc.], with a wide spectrum of histologic findings;
and (iii) podocytopathies, with a typical pathological picture of diffuse mesangial sclerosis (DMS), minimal-changes (MC), focal segmental glomerulosclerosis (FSGS) or collapsing glomerulopathy (CG) [
RITUXIMAB
ANTICORPO MONOCLONAL ANTI CD20 na supeerficie dos linfocitos B
uso=
nefropatia membranosa primaria
podocitopatias corticodependentes ou recidivantes
vasculite ANCA
nefrite lupica
rejeicao
doenca linfoproliferativa pos tx
dessensibilizacao
mecan de acao=citotoxicidade mediada por complemento e citotoxicidade mediada por cels dependentes de anticorpos , apoptose de cels B, estabilizador de citoesqueleto dos podocitos
infusao e monitorizacao= triagem para hep b, c e hiv, tuberculoseprofilaxias e vacinacoes
risco de anafilaxia
complicacoes e ef adv= reacoes infusionais, reativacao de hep b, sintomas resp, infeccoes, neutropenia, ev cardiovasc, hipogamglobulinemia, angioedema, neuropatia
NEFROPATIA POR C1Q
Deposito imune mesangial, IF COM 2+ IGG 2+ igm 2+c3 e 4+ c4 +c1q
Nefropatia por ciq= variantes da gesf ou membranosa=predomínio de c1q na IF onde não HÁ EVIDENCIA DE NEFRITE LUPICA.maioria na microscopia optica padrão de GESF
VARIANTES DA LESAO MINIMA =NEFROPATIA POR IGM
is a pattern of glomerulonephritis characterized by predominant mesangial C1q deposition but with other histological features resembling lupus nephritis, although no extrarenal disease.
dominant or co-dominant immunofluorescence staining for C1q, mesangial electron dense deposits, and no clinical or serologic evidence of systemic lupus erythematosus (SLE)
It is characterized clinically by heavy proteinuria or nephrotic syndrome and resistance to steroids. Up to 40% of patients have hematuria. The majority of patients are young (from <1 year to >30 years), with a median age in the teens.
C1q nephropathy does not appear to be associated to extrarrenal disease.
Most C1q nephropathy patients had focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD), the majority of them presenting with corticosteroid-dependent or corticosteroid-resistant nephrotic syndrome. Many show a very poor response to immunosuppressive therapy and high risk for progressive renal insufficiency
Many cases of C1q nephropathy have been described as “seronegative lupus nephritis” in patients with renal histology typical of lupus nephritis who have no clinical or serological evidence of SLE. Many had histological features typical of lupus nephritis with “wire loop” appearances on light microscopy, “full house” immunoglobulin and complement deposition by immunoperoxidase, and electron-dense deposits in at least two glomerular locations
described this nephropaty as “a variant of focal segmental glomerulosclerosis”, and they stated that “C1q nephropathy falls within the clinical-pathologic spectrum of MCD/FSGS”. Tubules and interstitium show no abnormalities other than resorption droplets. In some cases, frequently those with FSGS, atrophic tubules and fibrosis may be present, and this feature have pronostic implicationes (chronic renal damage).
Staining for C1q is present in all glomeruli and it is intense; staining is predominantly mesangial, altough scattered capillary wall deposits may be seen in a few glomeruli in some cases. Virtually all described cases have staining for IgG, and many cases IgM and C3. IgA is frequently present.
In patients with FSGS appear to have a more aggressive course. The nephropathy is frequently resistant to steroids or there are relapses.
C1q nephropathy encompasses a range of biopsy findings that share deposition of dominant C1q, with varied clinical presentation. Patients are usually children or young adults who present with marked proteinuria, but may also have active urine sediment with red blood cells. Those with nephrotic syndrome typically have nonspecific light microscopy findings, with extensive foot process effacement and mesangial deposit shown by electron microscopy, identified as C1q by immunofluorescence. About 77% of these respond to immunosuppression. In contrast, patients with sclerosing or proliferative lesions revealed by light microscopy, the latter associated with subendothelial deposits, have worse prognosis, with stable kidney disease in about half of those with proliferative lesions.
Immunofluorescence microscopy: C1q dominant mesangial deposits, which may extend to subendothelial areas.
Electron microscopy: Extensive foot process effacement and mesangial deposits in those with unremarkable light microscopic findings, or lesser foot process effacement and subendothelial extension of deposits in those with proliferative lesions. There are no reticular aggregates.
Differential Diagnosis
The presence of deposits shown by electron microscopy, with dominant C1q staining, rule out minimal change disease and primary focal segmental glomerulosclerosis. Deposits with C1q could suggest lupus nephritis. However, the absence of immunoglobulin G dominant/codominant deposits or reticular aggregates, and lack of clinical history of systemic lupus erythematosus, are against this diagnosis.
- C1q staining and mesangial deposits shown by electron microscopy
- Extensive foot process effacement in cases without proliferative lesions
- Lesser foot process effacement in cases with proliferative lesions
- No reticular aggregates, and lack of immunoglobulin G dominant deposits
IgM Nephropathy (IgMN) is a podocytopathy
is a podocytopathy that is often considered a variant of Minimal Change disease (MCD) or FSGS.
Like C1QN, it is also a controversial entity with a lack of uniformity from a diagnostic point of view.
This undoubtedly leads to under-reporting with some pathologists calling a case IgMN what others would call MCD/FSGS/Mesangial Proflierative GN with low level IgM staining.
First descriptions of IgMN reported mesangial hypercellularity on light microscopy, granular IgM and C3 mesangial deposits on immunofluorescence with electron dense deposits in about half of cases.
Podocyte foot process effacement was also evident consistent with the presentation of nephrotic syndrome. The incidence has been reported to be 2-18% of renal biopsy series and age at presentation appears to be bimodal with a peak in childhood and again later in life, 6-7th decades.
The incidence of IgMN may be higher in the developing world and most recent reports come from developing nations
The accurate diagnosis of IgMN is important from a prognostic and therapeutic point of view. Overall, IgMN does not respond to steroids as well as MCD with a higher proportion of patient with steroid-dependent and resistant disease. Furthermore, assessment of children with steroid-dependent and resistant MCD revealed a high proportion of IgMN, which appeared to respond better to cyclosporin than to cyclophosphamide. Rituximab (as ever!) may be another alternative therapeutic choice, although evidence remains at case report level, i
Similar to C1QN, the severity is likely dependent on the light microscopic changes with MCD patterns reporting an excellent remission rate and an FSGS pattern of injury having a worse prognosis (ref). Most cases however may have mesangial proliferative changes evident. There is even a report of IgMN presenting with crescentic lesions.
IgM deposition may be seen in many other glomerular disorders and its role is unclear. Is it an innocent bystander, reflecting natural IgM binding to exposed epitopes on injured glomerular cells? There is some evidence that IgM deposition may activate complement and that efforts to prevent IgM antibody deposition may prevent complement activation and slow the progression of glomerular injury. IgMN is another glomerular disease that we have an unclear understanding of pathogenesis and etiology where we rely on crude pathological descriptions. Hopefully the future will bring clarity to these diseases and facilitate precise molecular diagnosis of entities such as IgMN.
kdigo 2021
quando tratar sem bx
dlm em ccas <12 anos
gnpe
tratamento pode ser considerado sem bx
sindrome nefrotica +antipla2r positivo
mpo+ ou pr3 + anca vasculite
anti mbg doenca
alport
fabry
gesf familiar
les
contraindicacao a bx
GNRP
.
RPGN is broadly classified based on the histopathology and immune complex deposition as follow:
A. Linear antibody deposition.
B. Granular immune complex deposition disorders.
C. Pauci-immune (absence of deposition) disorders.
GNRP=crescentes em mais de 50% da amostra hipercelularidade
Rapid loss of renal function over a very short period (days to weeks) +Nephritic urine analysis: proteinuria, micro or macroscopic hematuria, dysmorphic red blood cells (RBC), RBC casts+ Histopathological characteristic on renal biopsy finding; cellular crescent formation in the glomeruli; which is proliferative cellular response seen outside the glomerular tuft within Bowman’s capsule and because of its crescentic shape called crescentic glomerulonephritis.
Crescentes= proliferação de células epiteliais parietais entremeadas por monócitos e macrófagos
Ruptura de alça capilar
Classificacao –imunofluorescencia (fisiopatologia)
TIPO1- anticorpo antI MBG :doenca da membrana basal ou goodpasture- DEPÓSITO LINEAR pq se deposita ao longo da membrana basal
Tipo2= depósitos de imunocomplexos –imunoglobulina e complememto=GRANULAR-LIMA
LES,NIgA, associada a infecção e membranoproliferativas
Tipo3= pauci-imune
- ausencia ou poucos depósitos na IF
- vasculites ANCA associadas (vasculite necrotizante de pequenos vasos)
RPGN is broadly classified based on the histopathology and immune complex deposition as follow:
A. Linear antibody deposition.
B. Granular immune complex deposition disorders.
C. Pauci-immune (absence of deposition) disorders.
gnrp
etiologia
Small-sized vessels: Smaller vessels within the kidneys (interlobar artery, arcuate artery, interlobar artery, arterioles)
Immune complex deposits in vessel walls:
Cryoglobulins: cryoglobulin deposits often affecting both skin and glomeruli
IgA-dominant deposits (HSP): vasculitis involving skin, gut, and glomeruli, with associated arthritis/arthralgias
Systemic lupus erythematosus (SLE) or rheumatoid arthritis
Others: postinfectious, hypocomplementemic urticarial (anti-C1q) vasculitis
Circulating ANCA with paucity of vascular or glomerular immunoglobulin staining:
Granulomas and no asthma: granulomatous polyangiitis (Wegener’s)
Eosinophilia, asthma, and granuloma: eosinophilic granulomatosus with polyangiitis (Churg–Strauss)
No asthma or granulomas: microscopic polyangiitis
classified based on the histopathology and immune complex deposition as follows:
A) Linear antibody deposition, anti-glomerular basement membrane (GBM) disease: it is circulating antibodies IgG directed against an antigen normally present in the GBM and/or alveolar basement membrane, specifically the non-collagenous domain of alpha-3 chain of type IV collagen. It is approximately 10% to 15% of all diffuse crescentic GN. It can be presented as one of the following features:
- Crescentic glomerulonephritis alone (renal limited variant)
- or with pulmonary hemorrhage; The combination of glomerulonephritis and pulmonary hemorrhage referred to as Goodpasture syndrome
- or associated with the positive anti-neutrophil cytoplasmic antibody (ANCA), sometimes called “dual antibody disease” or “double positive; in which patient has crescentic GN and positive for both ANCA and anti-GBM antibody, some literature showed 10% to 50% of patients with the anti-GBM disease have detectable ANCA (usually recognizing myeloperoxidase [MPO]), and up to 10% of patients with ANCA also have circulating anti-GBM antibodies.
B) Granular immune complex disorder: it can be idiopathic or secondary to the following: LIMA
- Postinfectious GN, especially after a Streptococcus infection
- Collagen vascular disease
- Lupus nephritis
- Henoch-Schönlein purpura – there is immunoglobulin A deposits and associated systemic vasculitis
- Immunoglobulin A nephropathy without vasculitis
- Mixed cryoglobulinemia
- Membranoproliferative glomerulonephritis
- Fibrillary glomerulonephritis
- Idiopathic
C) Pauci-immune disorder: almost 80 to 90% of cases are positive for ANCA.
- Granulomatosis with polyangiitis [GPA], previously called Wegener granulomatosis
- Microscopic polyangiitis -MPA
- Eosinophilic granulomatosis with polyangiitis – EGPA, Churg-Strauss syndrome
- There are various drugs associated with the GN (renal limited or systemic)
Hydralazine
Levamisole contaminated cocaine
Propylthiouracil and methimazole
Allopurinol
Sulfasalazine
Minocycline
Penicillamine
Rifampicin
Aminoguanidine
Sofosbuvir
Anti-TNF alfa therapy for rheumatoid arthritis and ankylosing spondylitis
D) Idiopathic pauci-immune necrotizing and crescentic GN: with negative anti-GBM antibody and negative ANCA, and it is approximately 5 to 10% of the cases.
gnrp fiopatologia
1) rupture of the basement membrane followed by extra capillary fibrin precipitate, followed by the proliferation of parietal cells and formed capsular proliferate in a crescent shape.
Each disease leads to this pathway in different ways:
In anti-GBM disorder, there are circulating antibodies; usually, IgG directed against an antigen present in the GBM and/or alveolar basement membrane, specifically the non-collagenous domain of alpha-3 chain of type IV collagen.
These antibodies will cause glomerular capillary wall injury by local complement activation and polymorphonuclear leukocytes. There is also the role of the T-cell-independent of this mechanism.[2] some precipitating factors are environmental triggers for the formation of these antibodies, like smoking, hydrocarbons. Also, there is a genetic association in which HLA-DR15 increases the risk of anti-GBM.
In another 10 to 15% of cases are associated with the immune complex deposition in the glomerular capillary tufts. The mechanism is either by the formation of the immune complex in the circulation and getting deposited at the glomerular capillary tuft or production of this immune complex in situ in the glomerular capillary wall. The antigen associated with the immune complex formation is heterogeneous, either exogenous (virus/bacteria) or autogenous (nuclear antigens/tumor antigens). Immune complex-mediated glomerulonephritis is often due to multisystem disease (lupus), or it can arise as a complication of another primary glomerulonephritis (membranous GN/C3 GN).[
Fifty to 80% of cases are involved with the anti-nuclear cytoplasmic antibody (ANCA). The ANCA is either directed against myeloperoxidase (MPO), proteinase 3 (PR3), or both. When MPO and PR3 are both involved, it usually suggests drug-induced pathogenesis. The precise mechanism by which ANCA arises is not clear, but it is evident that autoantibodies activate neutrophils to injure the glomerular capillary wall. There is the activation of local as well as systemic complement, mainly through an alternative pathway. Cytokines, including tumor necrosis factor alfa, also play a significant role in the pathogenesis. Also, there are the production of anti-plasminogen and plasminogen activator autoantibodies, which can inhibit fibrinolysis and predispose to fibrinoid necrosis and thrombophilia.[8]
Ultimately, there is the proliferation of parietal and visceral epithelial cells, polymerization of fibrin, infiltration of monocyte/macrophages and t-cells, and myofibroblast cell invasion from the interstitium forming glomerular crescents. The interleukin-1 (IL-1), TNF- alfa, macrophage chemotactic protein-1 (MCP-1), macrophage inflammatory factor (MIF), Tumor growth factor-beta production play a role in the whole process.
Anti-Glomerular Basement Membrane Diseases
In anti-GBM disease, the autoantibody targets the non-collagenous 1 domain of the a3 subunit of type 4 collagen
ANCA positivity was found in 15% of this cohort. Most patients (68%) required dialysis within the first month of identification, and the median serum creatinine concentration was 637 mmol/L. Treatment consisted of plasma exchange, corticosteroids, and cyclophosphamide (84%).
As many as one third of patients with antiGBM disease will have ANCA positivity.
the diagnosis of anti-GBM disease was based on the kidney biopsy showing crescentic GN with linear GBM staining for IgG in the absence of other reasons for linear GBM immunofluorescence such as diabetes mellitus
gnrp histopatologia
The primary lesion of crescentic GN is the destruction of a glomerular capillary wall along with the accumulation of parietal and visceral epithelial cells in Bowmen’s space, forming a crescent. There is an accompanying accumulation of lymphocytes, macrophages, and myofibroblasts with the proliferation of podocytes. That leads to diffuse, proliferative, necrotizing glomerulonephritis with crescent formation.
ANCA lesions can be found in various stages of crescents (cellular, fibrocellular, or fibrous) at the time of the biopsy, whereas all lesions in anti-GBM disease are in the same GN stage.
Interstitial inflammation is also found mainly in the periglomerular region. In the later stage, fibrosis developed rapidly over a few days to weeks manifesting as glomerular sclerosis and obliteration.
The immunofluorescence of the anti-GBM disease would show linear IgG deposition along the capillary wall and lesions on the same stage. While in immune complex deposition disease, there is the granular deposition of IgG, IgM, or IgA along the capillary wall, and lesions are in different stages. Pauci-immune disorder: There are no deposits, or very scant deposits of IgG or IgM or C3 is seen on immunofluorescent; the ANCA-associated GN lesions are also in various stages, and sometimes fibrinoid necrosis is found along with the other lesions
GNRP prognostico
Various histopathologic lesions are indicative of the prognosis. The extent of crescentic involvement on microscopic findings is indicative of the prognosis. Usually, a focal lesion with more than 50% normal glomeruli has a more favorable prognosis, almost 90% or more renal survival after 5 years follow up after treatment. Whereas more than 50% of glomeruli with cellular crescent has a less favorable prognosis of around 75% renal recovery at 5 years follow up. When more than 50% of glomeruli are globally sclerosed, the renal recovery is less than 25% up to 5 years follow-up period. Variants include cellular, fibrocellular, and fibrous crescent. The extent of chronic tubule-interstitial fibrosis lesions can also impact the prognosis inversely. The disruption of Bowmen’s capsule is associated with poor outcomes.[21]
The time of initiation of the treatment is very crucial for stopping the rapidly progressive irreversible damage. The early the treatment initiated, the better is the outcome.
Age and gender do not affect the overall prognosis greatly. Children usually tend to do well after the treatment as compared to the elderly.[21]
The magnitude of proteinuria has not been shown to affect short-term prognosis, but persistent proteinuria despite treatment is indicative of poor long-term outcomes.
Renal function at the presentation is reflecting the severity of the disease, and the higher serum creatinine, anuria, requirement of dialysis is associated with the poor outcome after the treatment and progression to renal failure.[21]
The pretreatment antibody level affects the prognosis. The higher the anti-GBM Ab level at the time of diagnosis is associated with the poor renal outcome. Whereas the ANCA level has a complex association with the renal outcome.[21]
DRB 1* 15 allele is a risk factor for Anti -PR3 ANCA vasculitis. HLA DR-2 and/or B-7 has a possible association with the severity of the disease and the outcome.[22]
RPGN associated with drugs and infection is associated with a better outcome.
anti MBG
A) Linear antibody deposition, anti-glomerular basement membrane (GBM) disease: it is circulating antibodies IgG directed against an antigen normally present in the GBM and/or alveolar basement membrane, specifically the non-collagenous domain of alpha-3 chain of type IV collagen. It is approximately 10% to 15% of all diffuse crescentic GN. It can be presented as one of the following features:
- Crescentic glomerulonephritis alone (renal limited variant)
- or with pulmonary hemorrhage; The combination of glomerulonephritis and pulmonary hemorrhage referred to as Goodpasture syndrome
- or associated with the positive anti-neutrophil cytoplasmic antibody (ANCA), sometimes called “dual antibody disease” or “double positive; in which patient has crescentic GN and positive for both ANCA and anti-GBM antibody, some literature showed 10% to 50% of patients with the anti-GBM disease have detectable ANCA (usually recognizing myeloperoxidase [MPO]), and up to 10% of patients with ANCA also have circulating anti-GBM antibodies.
GRANULAR
GNRP
LIMA
LUPUS
INFECCAO
MEMBRANOPROLIF
IGA
B) Granular immune complex disorder: it can be idiopathic or secondary to the following:
- Postinfectious GN, especially after a Streptococcus infection
- Collagen vascular disease
- Lupus nephritis
- Henoch-Schönlein purpura – there is immunoglobulin A deposits and associated systemic vasculitis
- Immunoglobulin A nephropathy without vasculitis
- Mixed cryoglobulinemia
- Membranoproliferative glomerulonephritis
- Fibrillary glomerulonephritis
- Idiopathic
FOCAL NECROTIZING AND CRESCENTIC GLOMERULONEPHRITIS
Idiopathic or primary crescentic glomerulonephritis: Type I, anti-GBM disease
Type II, immune complex-mediated
Type III, pauci immune polyangiitides (SVV);
(often ANCA-associated)
- Microscopic polyangiitis
- Granulomatosis with polyangiitis
- Eosinophilic granulomatosis with polyangiitis - Drug-induced vasculitides
Other primary or secondary glomerulonephritides: post-infectious GN, IgA nephropathy, MPGN, etc.
Systemic diseases (SLE, RA, H-S purpura)
Granulomatosis with polyangiitis (Wegener’s), also known as GPA,
Respiratory and kidney involvement
• Commonly presents with the syndrome rapidly progressive
glomerulonephritis (RPGN)
• Associated with ANCA
Glomerulopatia c crescentes
Síndrome nefritica + GNRP
MO:>50% dos glomerulos c crescentes
IF
Granular immune complex deposition:
GNRP E GNINFECCIOSA, les, igA
Linear antibody deposition: anti mbg e goodpasture
“Pauci immune” - absence of deposition
Vasculite ANCA +
Crescentic Glomerulonephritis (GN)
o Histological marker for severe glomerular injury
Cellular proliferation (> 2 layers of parietal epithelial cells (=podocytes)) and inflammation within Bowman’s space
Disruption of the glomerular basement membranes (GBM) with fibrinoid necrosis
o Major etiologies include: Immune complex mediated GN, Anti-GBM and Pauci-immune GN
Drug-induced ANCA:
hydralazine, propylthiouracil,
minocycline, penicillamine, cocaine
gn crioglobulinemia
A Crioglobulinemia é definida pela presença de imunoglobulinas circulantes que precipitam em temperaturas menores do que 37°C e dissolvem com o reaquecimento.
crioglobulinemia se classifica em três tipos:
Tipo I (composta por uma Ig monoclonal geralmente associada com doença hematológica), Tipo II e Tipo III são crioglobulinemias mistas consistindo em complexos imunes circulantes compostos por IgG’s policlonais, como auto-antígenos, e IgM’s monoclonais (tipo II) ou policlonais (tipo III), como auto-anticorpos correspondentes.
Tanto a crioglobulinemia tipo II como a tipo III podem ser essenciais (primárias) ou secundárias (quando associadas a outras patologias como LES ou VHC). O quadro clínico da crioglobulinemia caracteriza-se por sintomas gerais como febre, fraqueza (100%), mialgias, artralgias (98%), púrpura palpável (98%), neuropatia periférica (80%) e acometimento de outros órgãos como pulmão e rim (20 a 30%).
Os parâmetros laboratoriais revelam obrigatoriamente a presença de crioglobulinas circulantes. A composição mais comum é de um fator reumatóide IgM monoclonal formando um complexo com uma IgG policlonal. Entretanto o resultado negativo do laboratório, em pacientes com suspeita de crioglobulinemia não elimina a possibilidade de doença mediada por essas imunoglobulinas, visto que o resultado é freqüentemente falso negativo devido ao erro de manuseio na coleta ou na preparação da amostra de soro. O padrão de consumo de complemento é típico com níveis muito baixos ou indetectáveis de C4 e C3 moderadamente consumido.
A associação com VHC tem sido intensamente relacionada ao diagnóstico de crioglobulinemia, variando de 80 a 95%. Dessa forma, a presença do VHC deve ser sempre investigada. Já o acometimento renal é bastante variável, apresentando-se desde hematúria e proteinúria assintomáticas até síndrome nefrítica, nefrótica ou glomerulonefrite rapidamente progressiva. Na Microscopia Óptica, em 60 a 80% dos casos, observa-se a glomerulonefrite membranoproliferativa e comumente observam-se trombos intraluminais compostos de crioglobulinas. Na Imunofluorescência há depósito de fatores do complemento e imunoglobulinas, principalmente IgM.
No caso apresentado, a paciente apresenta síndrome nefrítica-nefrótica, com consumo importante de C4 e altos títulos de fator reumatóide e, após nova coleta de exames a presença de crioglobulina foi confirmada. Mesmo após investigação, não foi encontrado indícios do VHC. O diagnóstico anátomo-patológico de glomerulonefrite membranoprliferativa só veio corroborar com a hipótese mais provável: crioglobulinemia mista essencial.
A paciente foi tratada com pulso de metil-prednisolona (500mg/dia por 3 dias) e em seguida recebeu ciclofosfamida EV + prednisona VO. Evoluiu com melhora da função renal (creatinina sérica =1,0) após o segundo pulso de ciclofosfamida, mantendo proteinúria nefrótica e normalização da PA através da associação de três classes de anti-hipertensivos.
PROLIFERACOES MESANGIAIS
proliferacao mesagial com nódulos
- diabetes
- deposito de cadeia leve
- gnmp (CRIOGLOBULINEMIA, FIBRILAR
- amiloidose
- esclerose nodular idiopatica
proliferacao mesangial sem nodulos=
- LES
- IgA
- chronic infection related glomerulonephritis
- mesangial without deposits:
minimal change disease focal segmental glomerulosclerosis early diabetic nephropathy
- mesangial and endocapillary membranoprolifrative glomerulonephritis prolifrative lupus nephritis cryoglobulinemia glomerulonephritis postinfectious glomerulonephritis fibrillary glomerulonephritis immunotactoid glomerulopathy dense deposit disease
MESANGIOPROLIFERATIVE GLOMERULONEPHRITIS
IgA Nephropathy
Recovery phase of a postinfectious glomerulonephritis
SLE WHO Class II, mesangial form, and
other IC-mediated diseases Idiopathic Mesangioproliferative GN Some of the deposition diseases
glomerulonefrite apenas com C3 BAIXO
VIA ALTERNATIVA
Disorders in which C3 is decreased but C4 is not include
MPGN and post-infectious glomerulonephritis
, indicating a tendency for the alternative pathway to be active moreso than the classical pathway.
PSGN and MPGN type 2 (DDD)
Glomerulonefrite com C3 E C4 BAIXOS
via classica
Shunt nephritis
Lupus
Cyrgoglobulinemia
MPGN Type 1
Bacterial endocarditis
diagnostico diferencial com glomeruloesclerose nodular diabetica
1)AMILOIDOSE RENAL:
IF- cora para kappa ou lambda cadeia leve no mesangio, mbg, intersticio tubular e parede vasos.
ME= organizacao randomly,
glomeruloesclerose nodular idiopatica=
diagn diferencial glomerulopatia nodular
Nefropatia diabética avançada DM (+). Espessamento MBG e MBT, expansão mesangial, nódulos não isométricos de Kimmelstiel-Wilson, hialinose de arteríolas aferentes e eferentes. Acentuação linear negativa para MBG e MBT para IgG e albumina. Aumento da celularidade e da matriz mesangial, espessamento difuso da MBG e MBT, apagamento difuso dos processos podocitários.
Glomerulonefrite membranoproliferativa Etiologiadependente. Proliferação endocapilar, acentuação lobular, espessamento difuso da MBG com contorno duplo. MBG difusa e granular e coloração mesangial da IgG (policlonal ou monoclonal); dominante ou somente C3. Depósitos granulares mesangiais e subendoteliais.
GNIdiopatica Tabagismo e hipertensão, história (-) para diabetes. Expansão da matriz mesangial com aparência nodular, espessamento da MBG, hialinose arteriolar e glomerulomegalia. Acentuação linear negative da MBG e MBT para IgG e albumina. Aumento na matriz mesangial, espessamento da MBG, apagamento variável dos processos podocitários, ausência de depósitos eletrodensos.
Amiloidose Etiologiadependente. Material acelular, amorfo, rosa-pálido no mesângio, MBG, interstício e artérias. Birrefringência positive para vermelho Congo e verde maçã. Coloração monoclonal restrita da cadeia leve. Fibrilas retas, com orientação aleatória, sem ramificações (8–12 nm em diâmetro) e apagamento dos processos podocitários.
Glomerulonefrite fibrilar Etiologia desconhecida. Aparência nodular e membranoproliferativa. Negative para vermelho Congo. Coloração policlonal IgG (IgG4) e C3. Fibrilas retas, com orientação aleatória, sem ramificações (8–12 nm em diâmetro) no mesângio e MBG.
Glomerulonefrite Imunotactóide Doença de Paraproteinemia ou linfoproliferativa. Aparência nodular e membranoproliferativa. Negative para vermelho Congo. IgG monoclonal com coloração de cadeia leve kappa ou lambda. Depósitos microtubulares e mesangiais na MBG em arranjos paralelos (>30 nm em diâmetro).
Doença de deposição de imunoglobulina monoclonal Paraproteína no sangue e/ou na urina. Expansão mesangial com aparência nodular. Coloração monoclonal de cadeias leves e/ou pesadas no mesângio, MBT e MBG. Depósitos de aparência finamente granulares ou salpicada na porção exterior da MBT e parte interna da MBG.
Glomerulopatia do Colágeno Tipo III Peptídeo III do pró-colágeno no terminal-N presente no sangue e na urina. Pode ser hipercelular. Negativo. Fibras curvas com periodicidade de 60 nm.
Glomerulopatia de fibronectina História familiar. Depósitos mesangiais PAS-positivos. Negativo, exceto pela coloração da fibronectina. Maciços depósitos eletrodensos na matriz mesangial.
Condições isquêmicas ou cianóticas crônicas Etiologiadependente. Espessamento mesangial centrolobular, depósitos de padrão hialínico em mosaico, lesões mesangiolíticas, depósitos hialinos nas arteríolas e microaneurismas nos glomérulos
crioglobulinemica
Glomerulonefrite crioglobulêmica
FORTE ASSOCIACAO COM VIRUS C
criterios sorologicos: mixed crioglobuinemia, c4 baixo, hbv+, hcv +,fator reumatoide +
depositos mesangiais e subendoteliais , depositos intracapilares, apagamento extenso dos podocitos, hipercelularidade endocapilar.
é uma doença de indivíduos na 5º ou 6º década de vida frequentemente acompanhadas de manifestações sistêmicas como púrpuras, artralgias, úlceras de membros inferiores, vasculites e neuropatias periféricas que podem preceder em anos o acometimento renal.
vasculite leucocitoclastica
achados + comuns: proteinúria não nefrótica (menos freqüente na faixa nefrótica) e hematúria microscópica.
Síndrome nefrítica aguda ocorre em 25% dos casos como manifestação inicial.
caracteriza-se por aspectos da GNMP tipo 1, diferenciando-se pela presença de depósitos amorfos, eosinofílicos, PAS + preenchendo o lúmen capilar (pseudotrombos situados na região subendotelial). Estes depósitos são constituidos por crioglobulinas, fator reumatóide e antígenos relacionados ao HCV. Há consumo de fatores do complemento principalmente os iniciais com diminuição marcante de C4. Crioglobulinemia mista foi detectada em pacientes com doenças linfoproliferativas e doenças do tecido conectivo, maioria dos casos está relacionado à infecção pelo vírus da hepatite C.
via do complemento
Pauci-immune disorder: almost 80 to 90% of cases are positive for ANCA.
- Granulomatosis with polyangiitis [GPA], previously called Wegener granulomatosis
- Microscopic polyangiitis -MPA
- Eosinophilic granulomatosis with polyangiitis – EGPA, Churg-Strauss syndrome
- There are various drugs associated with the GN (renal limited or systemic)
Hydralazine
Levamisole contaminated cocaine
Propylthiouracil and methimazole
Allopurinol
Sulfasalazine
Minocycline
Penicillamine
Rifampicin
Aminoguanidine
Sofosbuvir
Anti-TNF alfa therapy for rheumatoid arthritis and ankylosing spondyliti
PADRAO IMUNOFLUORESCENCIA
Small-sized vessels: Smaller vessels within the kidneys (interlobar artery, arcuate artery, interlobar artery, arterioles)
Immune complex deposits in vessel walls:
Cryoglobulins: cryoglobulin deposits often affecting both skin and glomeruli
IgA-dominant deposits (HSP): vasculitis involving skin, gut, and glomeruli, with associated arthritis/arthralgias
Systemic lupus erythematosus (SLE) or rheumatoid arthritis
Others: postinfectious, hypocomplementemic urticarial (anti-C1q) vasculitis
Circulating ANCA with paucity of vascular or glomerular immunoglobulin staining:
Granulomas and no asthma: granulomatous polyangiitis (Wegener’s)
Eosinophilia, asthma, and granuloma: eosinophilic granulomatosus with polyangiitis (Churg–Strauss)
No asthma or granulomas: microscopic polyangiitis
ANCA
. Em nosso paciente, esta pesquisa se revelou positiva, com padrão perinuclear (ANCA-p).
Segundo a classificação de vasculites de acordo com a Conferência de Chapel Hill, a presença de inflamação granulomatosa com envolvimento da árvore respiratória superior apontaria para o diagnóstico de Granulomatose de Wegener (freqüentemente associada a ANCA-c), ao passo que asma, infiltrado inflamatório granulomatoso rico em eosinófilos e eosinofilia periférica definiria síndrome de Churg-Strauss, e vasculite necrotizante sem granulomas, poliangiíte microscópica (geramente associada ao ANCA-p). O caso deste paciente, sem achados compatíveis em outros órgãos, classifica-se como vasculite ANCA-relacionada restrita ao rim. A síndrome anti-membrana basal glomerular, que é a forma mais agressiva de glomerulonefrite, pode associar-se em cerca de 30% dos casos com a vasculite ANCA relacionada (principalmente MPO-ANCA), apresentando um prognóstico intermediário entre as duas síndromes quando isoladas.
O quadro clínico, devido à falta de achados em outros órgãos, pode ser pobre, e os pacientes podem se apresentar com graus avançados de insuficiência renal, freqüentemente em níveis dialíticos. Estudos retrospectivos têm descrito como fatores de pior prognóstico de sobrevida renal, em pacientes idosos (>60 anos) com glomerulonefrite ANCA-relacionada: hipertensão (PA>140/90, descrito como o melhor preditor de sobrevida renal), idade, proteinúria >500mg e creatinina no momento da biópsia >400umol/l. O Estudo Europeu de Vasculites descreveu, ainda, lesões de cronificação como potentes preditores de função renal em 18 meses, principalmente crescentes celulares e necrose fibrinóide. Em relação ao diagnóstico, descreve-se na literatura que a sobrevida renal em 1 e 3 anos é pior para pacientes com GN restrita ao rim (75 e 37%) em relação a granulomatose de Wegener (80 e 80%) e Poliangiíte microscópica (85 e 85 %), talvez pelo diagnóstico mais tardio da apresentação restrita ao tecido renal.
Quanto ao ANCA, especula-se que este grupo de anticorpos - dirigidos contra uma variedade de antígenos citoplasmáticos neutrofílicos, tais como a mieloperoxidase e a proteinase 3, - tenham verdadeiramente um papel patogênico na vasculite. Na granulomatose de Wegener, sabe-se que um aumento no título ao ELISA tem um valor preditivo positivo de 71% para recidiva da doença. Foi relatado em um estudo de casuística clínica que, nenhum paciente evoluiu com recidiva sem apresentar aumento no título do ANCA.
O tratamento da vasculite ANCA-relacionada é objeto de constantes estudos, e os regimes imunossupressores combinando corticosteróides em altas doses e ciclofosfamida induzem remissão em mais de 75% dos pacientes. Em relação ao uso da ciclofosfamida por via oral ou endovenosa, observou-se maior freqüência de efeitos colaterais com a via oral (principalmente infecções), talvez associada à maior dose acumulada, e maior taxa de remissão e recidiva com a ciclofosfamida EV. Em torno de 20 a 46% dos pacientes apresentam recidivas no curso de vários anos; assim, uma imunossupressão suficiente versus os efeitos colaterais desta, permanecem um desafio na escolha do melhor tratamento. Estudos recentes mostraram que a suspensão precoce da ciclofosfamida (3 a 6 meses), e a introdução de azatioprina, em comparação ao uso de ciclofosfamida por 1 ano, resultou na mesma taxa de recidiva, com tendência a menos efeitos colaterais no grupo que recebeu azatioprina. Deve-se prevenir, entretanto, a toxicidade urotelial da ciclofosfamida com hidratação adequada e uso de Mesna, e diminuir sua dose em pacientes idosos ou com clearance de creatinina alterado. Plasmaférese, por sua vez, é
