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
gn proliferativa
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.
glomerulopatias biopsia
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
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
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
Qual l achado a seguir?
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
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 tto
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
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
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)
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=
via do complemento
PADRAO IMUNOFLUORESCENCIA
