American College of Rheumatology Guidelines for Screening, Treatment, andManagement of Lupus Nephritis Dr. Amit Agrawal
Disease Burden• 35% of adults with SLE have clinical evidence of nephritis at the time of diagnosis.• 50–60% developing nephritis during the first 10 years of disease.• Higher in men than in women.• Survival with SLE - 95% at 5 years• 92% at 10 years• Lupus nephritis reduces survival 88% at 10 years
Case definition• Persistent proteinuria 0.5 gm per day• Or greater than 3+ by dipstickAnd/or• Cellular casts including red blood cells, hemoglobin, granular, tubular, or mixed
• Spot urine protein/creatinine ratio of >0.5Active Urinary Sediment:• >5 RBCs/hpf• >5WBCs/hpf in the absence of infection• cellular casts limited to RBC or WBC casts
Renal Biopsy• All patients with clinical evidence of active LN, previously untreated, undergo renal biopsy (unless strongly contraindicated) so that glomerular disease can be classified by current ISN/RPS classification• Evaluated for activity and chronicity and for tubular and vascular changes
Principles of treatment• Class I and Class II- do not require immunosuppressive treatment.• Class III And Class IV aggressive therapy with glucocorticoids and immunosuppressive agents• Class V when combined with class III or IV should be treated in the same manner as class III or IV• Class VI requires preparation for renal replacement therapy rather than immunosuppression
• All SLE patients with nephritis be treated with a background HCQ unless there is a contraindicationRationale:• Lower rates of Flare• Reduced renal damage• Less clotting events
• LN patients with proteinuria >0.5 gm per 24 hours should have blockade of the renin– angiotensin system, which drives intraglomerular pressureRationale:• Reduces proteinuria by 30%, and• Significantly delays doubling of serum creatinine• Delays progression to end-stage renal disease
• Control of hypertension, with a target of <130/80 mm Hg• Statin therapy be introduced in patients with low-density lipoprotein cholesterol >100 mg/dl
Class I LN (minimal-mesangial LN)• Treatment as dictated by the extrarenal clinical manifestations of lupusRATIONALE:• Class I LN has no clinical kidney manifestations.• Class I LN is not associated with long-term impairment of kidney function
Class II LN (mesangial-proliferative LN)• Treat patients with class II LN and proteinuria <1 g/d as dictated by the extrarenal clinical manifestations of lupus.• Class II LN with proteinuria >3 g/d be treated with corticosteroids or CNIs as described for MCD.RATIONALE: There are no evidence-based data on the treatment of class II LN.
Class III LN (focal LN) and class IV LN (diffuse LN)• Initial therapy with corticosteroids , combined with either cyclophosphamide or MMF• if patients have worsening LN (rising SCr, worsening proteinuria) during the first 3 months of treatment, a change be made to an alternative recommended initial therapy, or a repeat kidney biopsy be performed to guide further treatment
Regimens for initial therapy in class III/ class IV LN
Other Initial Regimens• Azathioprine• Cyclosporine• Combination of tacrolimus and MMF (sometimes called ‘‘multitarget’’ therapy).
Important considerations• Lifetime maximum of 36 g cyclophosphamide in patients with systemic lupus.• The dose of cyclophosphamide should be decreased by 20%(CrCl 25–50 ml/min) or 30% (10–25 ml/min)
Choice of Initial Therapy• In severe class III/IV LN, a cyclophosphamide- containing protocol for initial therapy may be preferred.• In patients with less severe proliferative LN, an initial regimen not containing cyclophosphamide should be considered.
Class III LN and class IV LN maintenance therapy• Patients with class III and IV LN receive maintenance therapy with• Azathioprine (1.5–2.5 mg/kg/d) or• MMF (1–2 g/d in divided doses), and• low-dose oral corticosteroids
• CNIs with low-dose cortico-steroids be used for maintenance therapy in patients who are intolerant of MMF and azathioprine.• After complete remission is achieved, maintenance therapy be continued for at least 1 year before consideration is given to tapering the immunosuppression.
• If complete remission has not been achieved after 12 months of maintenance therapy, consider performing a repeat kidney biopsy before determining if a change in therapy is indicated.• While maintenance therapy is being tapered, if kidney function deteriorates and/or proteinuria worsens, treatment be increased to the previous level of immunosuppression that controlled the LN.
Duration of Therapy• There is no evidence to help determine the duration of maintenance therapy.• The average duration of immunosuppression was 3.5 years in seven RCTs.• Immunosuppressive therapy should usually be slowly tapered after patients have been in complete remission for a year.
• Immunosuppression should be continued for patients who achieve only a partial remission.• The strategy of trying to convert a partial remission to a complete remission by increasing corticosteroids or using alternative immunosuppressive agents is not supported by evidence.
Predictors of Response to Treatment of Class III/IV LNPredictors for not achieving remission:• SCr at the start of treatment• Magnitude of increase in SCr during relapse• Delay in starting therapy for more than 3 months after a clinical diagnosis of LN.• Severity of proteinuria• Failure to achieve complete remission a major risk factor for kidney relapse.
Monitoring Therapy of Class III/IV LN• Proteinuria• SCr• Urine sediment• C3 and C4,• Anti–double-stranded DNA antibodies
Class V LN (membranous LN)• Patients with class V LN,normal kidney function, and non–nephrotic-range proteinuria be treated with antiproteinuric and antihypertensive medications, and only receive corticosteroids and immunosup- pressives as dictated by the extrarenal man- ifestations of systemic lupus.
• Pure class V LN and persistent nephrotic proteinuria be treated with corticosteroids plus an additional immunosuppressive agent:• cyclophosphamide• CNI• MMF• Azathioprine
General treatment of LN• All patients with LN of any class are treated with hydroxychloroquine(maximum daily dose of 6–6.5 mg/kg ideal body weight), unless they have a specific contraindication to this drug.
Class VI LN (advanced sclerosis LN)• Treated with corticosteroids and immuno- suppressives only as dictated by the extrarenal manifestations of systemic lupus.
Relapse of LN• Relapse of LN after complete or partial remission be treated with the initial therapy followed by the maintenance therapy that was effective in inducing the original remission• If resuming the original therapy would put the patient at risk for excessive lifetime cyclophosphamide exposure, then we suggest a non cyclophosphamide based initial regimen be used.
• Consider a repeat kidney biopsy during relapse if there is suspicion that the histologic class of LN has changed, or there is uncertainty whether a rising SCr and/or worsening proteinuria represents disease activity or chronicity.
Treatment of resistant disease• In patients with worsening SCr and/or protei- nuria after completing one of the initial treatment regimens, consider performing a repeat kidney biopsy to distinguish active LN from scarring.• Treat patients with worsening SCr and/or proteinuria who continue to have active LN on biopsy with one of the alternative initial treat- ment regimens.
• Nonresponders who have failed more than one of the recommended initial regimens may be considered for treatment with rituximab, i.v.immunoglobulin, or CNIs.
Systemic lupus and thrombotic microangiopathy• The antiphospholipid anti-body syndrome (APS) involving the kidney in systemic lupus patients, with or without LN,be treated by anticoagulation target INR 2–3.• Patients with systemic lupus and thrombotic thrombocytopenic purpura (TTP) receive plasma exchange as for patients with TTP without systemic lupus.