Lupus Nephritis Flashcards
Lupus Nephritis
Epidemiology
Epidemiology
It is estimated that 60% of patients with SLE will develop clinically significant LN in the course of the disease.
Lupus Nephritis
Epidemiology
Age:
The majority of patients who develop LN are younger than 55 years old.
Severe nephritis is more common in children than elderly patients.
Lupus Nephritis
Epidemiology
Gender difference (female-to-male ratio) is noted for female predominance and varies with age:
2: 1 in prepubertal children
4: 1 in adolescents
8 to 12:1 in adults
2:1 in adults age greater than 60
Lupus Nephritis
Epidemiology
Renal outcome portends worse prognosis in males than females.
Lupus Nephritis
Epidemiology
Race-related demographics:
SLE is more common in African Americans and Hispanics than whites.
Severe LN is more common in African Americans and Asians than in other ethnic groups.
Lupus Nephritis
Pathogenesis
Production of autoantibodies by mature B cells (plasma cells) against nuclear antigens (e.g., double stranded DNA (dsDNA), ribonucleoproteins, complement factors (e.g., C1q). This process may be driven by:
Antigenic mimicry: antibodies against bacterial or viral peptides cross-react to self-antigens.
Impaired clearance of apoptotic bodies
Lupus Nephritis
Pathogenesis
Production of autoantibodies by mature B cells (plasma cells) against nuclear antigens (e.g., double stranded DNA (dsDNA), ribonucleoproteins, complement factors (e.g., C1q). This process may be driven by:
Polyclonal hyperactivity of the B-cell system or defects of T-cell autoregulation leading to high antibody production
Anti-double stranded DNA (anti-dsDNA) antibody response driven by histone-specific T-helper cells
Lupus Nephritis
Pathogenesis:
IC deposition: deposition of circulating IC in GBM or direct binding of nucleosomal antigens to GBM followed by in situ autoantibody-binding activates both complement-dependent and independent inflammatory cascades.
Lupus Nephritis
IC clearance:
ICs are normally cleared by the C1 complement complex. Binding of C1 complex to IC leads to downstream complement activation and opsonization of the IC for phagocytosis.
Lupus Nephritis
IC clearance:
C1q is a component of the C1 complex. Upon binding of C1 complex to IC, C1 complex undergoes conformational change, exposing antigenic sites of C1q, which then leads to autoantibody formation against C1q. High autoantibody titers against C1q have been suggested to correlate with active lupus.
Lupus Nephritis
Inflammatory effects following impaired apoptotic bodies clearance and/or IC formations and roles of other inflammatory cells:
Neutrophils:
Neutrophils:
NETosis: a process whereby upon exposure to microorganisms, neutrophils release nuclear components, granule proteins, and chromatin to form an extracellular matrix (ECM), referred to as “neutrophil extracellular traps” (NETs) to “trap,” destroy, and clear the invading microorganisms.
Lupus Nephritis
Inflammatory effects following impaired apoptotic bodies clearance and/or IC formations and roles of other inflammatory cells:
Neutrophils:
Neutrophils:
NETs comprise of DNA and histones along with various peptides and proteinases such as high-mobility group protein box-1, cathelicidin, myeloperoxidase, neutrophil elastase, matrix metalloproteinase 9, and proteoglycan recognition protein short.
Lupus Nephritis
Inflammatory effects following impaired apoptotic bodies clearance and/or IC formations and roles of other inflammatory cells:
Neutrophils:
Neutrophils:
NETs may serve as a source of autoantigens in SLE. There are data to suggest that NETs are complement activators and can play a role in increasing C1q deposition.
Lupus Nephritis
Inflammatory effects following impaired apoptotic bodies clearance and/or IC formations and roles of other inflammatory cells:
Basophils:
Basophils:
Cross-linking of IgE to its receptors (FcκRI) on basophil surface leads to the secretion of histamine and proinflammatory cytokines by basophils.
Lupus Nephritis
Inflammatory effects following impaired apoptotic bodies clearance and/or IC formations and roles of other inflammatory cells:
Basophils:
There are data to suggest that increased titers of both dsDNA-IgE and dsDNA-IgG predict SLE disease activity better than dsDNA-IgG titers alone.
Lupus Nephritis
Inflammatory effects following impaired apoptotic bodies clearance and/or IC formations and roles of other inflammatory cells:
Basophils:
Activated basophils secrete cytokines (IL-4 and IL-6) and express the MHC-II and B cell-activating factor BAFF (also known as B-Lys), which can enhance plasma cell survival and autoantibody production amplification loop.
Lupus Nephritis
Inflammatory effects following impaired apoptotic bodies clearance and/or IC formations and roles of other inflammatory cells:
Basophils:
Other functions of activated basophils: promotion and regulation of TH2 adaptive immune responses, antigen presentation to T cells, plasma cell differentiation and support, monocyte polarization and recruitment, and inflammatory site organization.
Lupus Nephritis
Inflammatory effects following impaired apoptotic bodies clearance and/or IC formations and roles of other inflammatory cells:
Macrophages/monocytes:
Macrophages/monocytes:
NETs containing LL37 stimulate NLRP3 inflammasome in monocytes and result in IL-1β and IL-18 release, NETosis, and amplification of the proinflammatory state.
Lupus Nephritis
Inflammatory effects following impaired apoptotic bodies clearance and/or IC formations and roles of other inflammatory cells:
Macrophages/monocytes:
Macrophages/monocytes:
Polymorphism in the IL-18 gene promoter with associated increased IL-18 production may promote SLE susceptibility.
Lupus Nephritis
Inflammatory effects following impaired apoptotic bodies clearance and/or IC formations and roles of other inflammatory cells:
Autoreactive B-cells and T-cells due to defective regulatory mechanisms.
Lupus Nephritis:
Advances in SLE targeted therapy:
Advances in SLE targeted therapy:
Belimumab: human monoclonal antibody that selectively neutralizes B-cell activating factor (BAFF)
Lupus Nephritis:
Advances in SLE targeted therapy:
FDA approved for treatment of ANA/anti-dsDNA positive adults with high disease activity despite standard therapy
Lupus Nephritis:
Advances in SLE targeted therapy:
Short-term clinical trials suggest reduced SLE activity, flare rates, and corticosteroid need
Lupus Nephritis:
Advances in SLE targeted therapy:
Sifalimumab: human monoclonal antibody that inhibits several IFN-α subtypes1
Lupus Nephritis:
Advances in SLE targeted therapy:
Rontalizumab: humanized mouse monoclonal anti-IFN-α-antibody.
Lupus Nephritis:
Advances in SLE targeted therapy:
Omalizumab: recombinant humanized monoclonal antibody that blocks the binding of IgE to the FcεRI receptor.
Lupus Nephritis:
Diagnosis:
Routine laboratory findings:
Microscopic hematuria ± red blood cell casts, proteinuria ± nephrotic syndrome
Lupus Nephritis:
Diagnosis:
Routine laboratory findings cont’d:
Serologies: positive antinuclear antibody (sensitive, not specific), anti-Smith (specific), anti-dsDNA, hypocomplementemia (particularly low C3). Anti-Smith is specific for the diagnosis of SLE. Anti-dsDNA and hypocomplementemia correlate with kidney disease activity.
Lupus Nephritis:
Histopathology: International Society of Nephrology/Renal Pathology Society classification of LN:
Class I:
Minimal mesangial LN: normal glomeruli by LM; mesangial immune deposits by IF alone or by both IF and EM.
Lupus Nephritis:
Histopathology: International Society of Nephrology/Renal Pathology Society classification of LN:
Class II:
Mesangial proliferative LN: mesangial hypercellularity and matrix expansion on LM; mesangial immune deposits by both IF and EM.
Lupus Nephritis:
Histopathology: International Society of Nephrology/Renal Pathology Society classification of LN:
Class III: focal LN (<50% of glomeruli are involved)
Class III(A): Active lesions (leukocytes, karyhorrexis, cellular or fibrocellular crescents, large subendothelial deposits forming “wire loops” or “hyaline thrombi”)
Class III(A/C): Active and chronic lesions
Class III(C): Chronic lesions (segmental or global glomerulosclerosis, fibrotic crescents)
Lupus Nephritis:
Histopathology: International Society of Nephrology/Renal Pathology Society classification of LN:
Class IV: Diffuse LN (≥50% glomeruli)
Diffuse segmental (IV-S) or global (IV-G)
Class IV(A): Active lesions
Class IV(A/C): Active and chronic lesions
Class IV(C): Chronic lesions
Lupus Nephritis:
Histopathology: International Society of Nephrology/Renal Pathology Society classification of LN:
Class V:
Membranous LN (>50% subepithelial deposits with or without mesangial hypercellularity)
Lupus Nephritis:
Histopathology: International Society of Nephrology/Renal Pathology Society classification of LN:
Class VI:
Advanced sclerosing LN (≥90% globally sclerosed glomeruli without residual activity)
Lupus Nephritis:
Management:
Class I LN:
Benign, no long-term adverse effect on kidney function
Disease-specific therapy not necessary. Routine chronic kidney disease (CKD) progression risk reduction management.
Lupus Nephritis:
Management:
Class II LN:
<1 g/d proteinuria: routine CKD progression risk reduction management and management of extrarenal manifestations of SLE as needed.
> 3 g/d proteinuria: Treatment with corticosteroids or calcineurin inhibitors (CNIs) as described for MCD/FSGS is suggested.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
Class III and class IV LN initial induction therapy:
Initial therapy with corticosteroids plus either CYC or MMF.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
Corticosteroids: oral prednisone 1 mg/kg, taper over 6 to 12 months per clinical response. Initial IV methylprednisolone (e.g., 5 to 10 mg/kg × 3 days may be considered at induction for aggressive disease—NOTE: dosing and duration have not been tested in any randomized controlled trials [RCTs]).
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
CYC
CYC
Intravenous cyclophosphamide (IV CYC):
“NIH regimen”: (0.5 to 1.0 g/m2) given monthly for 6 months
Euro-Lupus regimen: (500 mg) given every 2 weeks for 3 months (equivalent efficacy as NIH regimen in Caucasians).
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
CYC
Euro-Lupus study was limited to less severe patients (severe disease was defined as >50% segmental glomerular necrosis or crescents and rapidly progressive kidney failure).
Whether efficacy of Euro-Lupus is similar to that of NIH regimen in class III/IV or in non-Caucasians is not known.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
CYC
Oral cyclophosphamide (PO CYC): 1.0 to 1.5 mg/kg/d (maximum dose 150 mg/d) for 2 to 4 months.
Similar efficacy to IV CYC in prospective observational studies.
Some but not all investigators suggested more adverse effects with PO CYC compared with IV CYC.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
CYC
Safety notes for use of CYC:
Maximum lifetime dose of 36 g of CYC is suggested to minimize risk of hematologic malignancies.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
CYC
Dose reduction with renal insufficiency (20% and 30% reduction for CrCl 25 to 50 and 10 to 25 mL/min, respectively
Adjust CYC dose to keep nadir leukocyte count ≥ 3,000/μL (typically occurs in 10 to 14 days for IV CYC and 1 week for PO CYC)
Use sodium-2-mercaptoethane (mesna) to minimize bladder toxicity
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
CYC
Fertility protection while on CYC treatment:
Women: leuprolide, ovarian tissue cryopreservation
Men: testosterone (efficacy poorly established), sperm banking
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
MMF
MMF: 750 to 1,500 mg twice daily for 6 months
MMF was shown to have similar efficacy as PO CYC in Chinese population; severe LN were excluded.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
MMF
Aspreva Lupus Management Study (ALMS), RCT involving patients with class III, IV, and V LN: MMF had an equivalent response rate for induction compared with IV CYC at 6 months, with similar incidence of adverse events including serious infections and deaths.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
MMF
Post hoc analysis of ALMS indicated inferior outcomes with CYC compared to MMF in black, Hispanic, and mixed-race patients (patients considered to have more resistant LN).
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
CYC versus MMF for induction therapy:
If disease worsens as evidenced by increasing SCr or proteinuria during the first 3 months of therapy with either CYC or MMF, switch therapy (e.g., from CYC to MMF or vice versa) or use alternative therapy (see options below). Consider rebiopsy.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
CYC versus MMF for induction therapy:
Definitions of response:
Complete response: return of SCr to baseline, plus a decline in urine protein to creatinine ratio (uPCR) < 500 mg/g
Partial response: stabilization (±25%) or improvement of SCr plus ≥ 50% decrease in uPCR where final uPCR is <3,000 mg/g
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
CYC versus MMF for induction therapy:
Response rates appear equivalent, but current data suggest a trend for more relapses, prolonged proteinuria > 1 g/d, and persistent SCr > 2 mg/dL in MMF compared to CYC induction therapy.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
CYC versus MMF for induction therapy:
CYC RCTs included patients with more severe LN compared to MMF trial. CYC may thus be preferred over MMF in patients with severe LN.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
Other alternative therapies:
AZA: AZA + corticosteroids had similar induction response rate compared with that for IV CYC + corticosteroids at 2 years. AZA had fewer adverse effects, but had higher late relapse rate, risk of doubling of SCr, and more chronic changes on late follow-up biopsies.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
Other alternative therapies:
Cyclosporine (CSA): 4 to 5 mg/kg/d
Comparable remissions to IV CYC
Nephrotoxicity limits use in patients with elevated SCr.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
Other alternative therapies:
Tacrolimus (TAC): comparable remission rates between combination TAC (4 mg/d) + MMF (1 g/d) + glucocorticoids and IV CYC (0.75 g/m2) for 6 months (Chinese RCT).
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
Other alternative therapies:
Adding rituximab to standard MMF + corticosteroids for induction therapy provided no added benefit and is not recommended.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
Class III and IV LN maintenance therapy:
Either AZA (1.5 to 2.5 mg/kg/d) or MMF (1 to 2 g/d in divided doses) and low-dose oral corticosteroids (≤10 mg/d prednisone equivalent) is recommended.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
Class III and IV LN maintenance therapy:
With the exception of the ALMS trial where MMF is a better maintenance agent compared to AZA in composite treatment failure endpoint (death, ESRD, kidney failure, sustained doubling of SCr, or requirement for rescue therapy), AZA and MMF generally have comparable maintenance efficacy.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
Class III and IV LN maintenance therapy:
Maintenance therapy with AZA or MMF has been suggested to be superior to CYC based on risk of death and development of CKD.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
Class III and IV LN maintenance therapy:
Use of CNIs is suggested for patients who cannot tolerate MMF or AZA.
Duration of maintenance is not known, but suggested to be at least 1 year. Average duration of immunosuppressive therapy from 7 RCTs was 3.5 years.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
Class III and IV LN maintenance therapy:
If disease relapses during tapering period, go back to previous level of immunosuppression that controlled disease.
Lupus Nephritis:
Management:
Class III and class IV LN initial induction therapy:
Monitoring of LN:
Serial proteinuria and SCr
Hematuria may persist for months even with improved proteinuria and SCr.
Complement levels (up to 80% sensitivity) and anti-double-stranded DNA antibodies (up to 70% to 80%)
Lupus Nephritis:
Lupus and Pregnancy
Measurable SLE disease activity is present in 40% to 50% of pregnancies, with LN occurring in up to 75% of these cases.
Active SLE during pregnancy is associated with:
Increased risk of preeclampsia to 30% compared to 5% in the general population
Increased risk of fetal death and preterm birth
Lupus Nephritis:
Lupus and Pregnancy
Active LN during pregnancy is associated with:
Increased maternal adverse outcomes including increased risk of gestational HTN, preeclampsia, and maternal death. There is evidence to suggest that LN classes III and IV may be associated with greater risk for hypertension/preeclampsia compared to other LN classes.
Likely increased risks of preterm birth, intrauterine growth restriction, stillbirth, and neonatal death. (Inconsistent findings in the literature.)
Lupus Nephritis:
Lupus and Pregnancy
Risk factors for adverse outcomes in pregnancy:
Active disease at conception
Antiphospholipid antibodies
HTN, proteinuria, reduced GFR in the first trimester
Chronicity of disease
Lupus Nephritis:
Lupus and Pregnancy
Management of antiphospholipid syndrome (APS)/nephrotic syndrome during pregnancy:
Adverse outcomes of APS and positive antiphospholipid antibodies: late fetal loss (after 10 weeks of gestation), increased relative risk of preeclampsia
Women with APS and arterial thrombotic events are also at high risks for stroke and maternal morbidity and mortality.
Routine screening for antiphospholipid antibodies is recommended.
Lupus Nephritis:
Lupus and Pregnancy
Anticoagulation:
For women with known APS receiving chronic anticoagulation: convert warfarin to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) during pregnancy.
Lupus Nephritis:
Lupus and Pregnancy
Anticoagulation cont’d:
For women with no known history of thrombotic events, but with obstetric criteria for APS of having either ≥3 pregnancy losses or late pregnancy loss, prophylactic anticoagulation consisting of a low dose aspirin with either UFH or LMWH should be initiated
Lupus Nephritis:
Lupus and Pregnancy
Anticoagulation cont’d:
For women with antiphospholipid antibodies but not meeting clinical criteria for APS, clinical surveillance with either antepartum aspirin or prophylactic UFH or LMWH is suggested.
For patients with nephrotic syndrome, prophylactic anticoagulation should be considered.
Lupus Nephritis:
Lupus and Pregnancy
Differentiating between lupus flare and preeclampsia in a woman with AKI:
Lupus flare: AKI may occur any time including prior to 20 weeks of gestation and postpartum, presence of hypocomplementemia, red blood cell casts, and leukopenia
Preeclampsia: AKI only occurs after 20 weeks of gestation with absence of findings seen with lupus flare above.
Lupus Nephritis:
Lupus and Pregnancy
Management of SLE/LN in pregnancy per KDIGO 2012:
Management of SLE/LN in pregnancy per KDIGO 2012:
Delay pregnancy until complete remission
Use of CYC, MMF, ACEI, and ARB is not recommended due to potential teratogenicity.
Lupus Nephritis:
Lupus and Pregnancy
Management of SLE/LN in pregnancy per KDIGO 2012:
Methotrexate is teratogenic and is contraindicated in pregnancy. Methotrexate should be discontinued ≥3 months prior to conception.
Lupus Nephritis:
Lupus and Pregnancy
Management of SLE/LN in pregnancy per KDIGO 2012:
Hydroxychloroquine maintenance therapy should be continued during pregnancy. Discontinuation of hydroxychloroquine may lead to lupus flares including LN.
Lupus Nephritis:
Lupus and Pregnancy
Management of SLE/LN in pregnancy per KDIGO 2012:
LN patients who become pregnant while being treated with MMF be switched to AZA.
Lupus Nephritis:
Lupus and Pregnancy
Management of SLE/LN in pregnancy per KDIGO 2012:
Patients with LN relapse during pregnancy should be treated with corticosteroids, and if necessary, AZA.
Lupus Nephritis:
Lupus and Pregnancy
Management of SLE/LN in pregnancy per KDIGO 2012:
Patients receiving corticosteroids or AZA during pregnancy should not be tapered until at least 3 months postpartum.
Administration of low-dose aspirin during pregnancy is suggested to reduce risk of fetal loss.
