Kidney Disease in Systemic Lupus Erythematosus

Background

• Kidney disease due to systemic lupus erythematosus (SLE) has been reported to occur in 20%-60% of patients with SLE.
• It is more common in Black, Asian, and Hispanic patients compared to White patients.

Evaluation

• No single clinical or laboratory finding rules out lupus nephritis.
• Diagnostic criteria for nephritis in patients with systemic lupus erythematosus include any of:
  • persistent proteinuria (such as > 0.5 g/day protein, > 3+ protein on urine dipstick, or spot urine protein to creatinine ratio > 0.5)
  • active urine sediment: red blood cells, white blood cells, or cellular casts (red blood cell, hemoglobin, granular, renal tubular, and/or mixed)
• Perform a renal biopsy in all patients with clinical evidence of kidney involvement, particularly if there is either an unexplained reduction in estimated glomerular filtration rate (GFR) or persistent proteinuria ≥ 0.5 g/24 hours (Strong recommendation).
• Classification by the International Society of Nephrology/Renal Pathology Society (ISN/RPS) is based on findings by light microscopy, electron microscopy, and immunofluorescence.

Management

Management Based on Class and/or Treatment Response

• Management of class I or II lupus nephritis is based on level of proteinuria and extrarenal manifestations. In patients with nephrotic syndrome or extrarenal manifestations, consider maintenance combination therapy including low-dose corticosteroid plus another immunosuppressive agent.
• Management of class III or IV lupus nephritis with or without membranous involvement (class V) consists of corticosteroids plus immunosuppressive therapy (Strong recommendation).
  • Total duration of initial immunosuppression plus maintenance immunosuppression for proliferative disease should be at least 36 months.
  • For initial therapy, offer corticosteroids (typically methylprednisolone 500-2,000 mg IV pulse followed by prednisone 0.3-0.5 mg/kg/day orally for up to 4 weeks, then tapered to ≤ 7.5 mg/day by 3-6 months) plus either mycophenolic acid analog (MPAA) (mycophenolate mofetil typically initiated at 500 mg twice daily and increased to maximum of 1.5 g twice daily if tolerated or equivalent dose mycophenolic acid) or low-dose cyclophosphamide (500 mg IV every 2 weeks for 6 doses or 0.5-1 g/m² IV monthly for 6 months or 1-1.5 mg/kg/day orally for up to 6 months) (Strong recommendation). Alternative options include:
    • MPAA (mycophenolate mofetil typically initiated at 500 mg twice daily and increased to maximum of 1.5 g twice daily if tolerated or equivalent dose mycophenolic acid) plus calcineurin inhibitor (tacrolimus) (if nephrotic-range proteinuria or high risk of kidney failure) (Weak recommendation)
      • if using tacrolimus, dose is typically 0.05 mg/kg/day to achieve target trough level of 4-6 ng/mL
      • if using voclosporin, dose is 23.7 mg orally twice daily
      • if using cyclosporine, dose is typically 3-5 mg/kg/day to achieve trough level of 60-100 ng/mL (50-83 nmol/L)
    • reduced-dose MPAA (mycophenolate mofetil 1 g/day or equivalent dose mycophenolic acid) plus calcineurin inhibitor (same dosing as above) plus corticosteroids (if unable to tolerate standard-dose MPAA or cyclophosphamide)
    • high-dose cyclophosphamide (0.5-0.75 g/m² IV monthly for 6 months) (Weak recommendation)
    • addition of belimumab (10 mg/kg IV every 2 weeks for 3 doses, then every 4 weeks) (if extrarenal manifestations, flares, or trying to limit corticosteroid dose) (Weak recommendation) or rituximab (1 g IV on days 1 and 15) (if refractory disease, repeat flares or try to limit corticosteroid dose)
    • azathioprine (1.5-2 mg/kg/day) or leflunomide (10-20 mg/day) plus corticosteroids (if issues related to intolerance, availability, or cost; however, reported to have decreased efficacy compared to other options)
  • For maintenance therapy, offer MPAA (mycophenolate mofetil 1-2 g/day or equivalent dose mycophenolic acid) as first choice, especially in patients initially treated with MPAA (Strong recommendation). Azathioprine (2 mg/kg/day) is an option especially in patients planning to become pregnant (Strong recommendation). A calcineurin inhibitor may also be considered as an option.
  • If relapse occurs after complete or partial response IS achieved, treat using either the same initial therapy that was originally used or another first-line option.
• Management of pure class V lupus nephritis includes monitoring of proteinuria and preventing or treating complications (such as thrombosis, dyslipidemia, and edema).
  • If low level proteinuria, treatment may include immunosuppression based on extrarenal manifestations of SLE in addition to adjunctive therapy, including hydroxychloroquine, renin-angiotensin system blockade, and blood pressure control. If proteinuria worsens or complications develop, consider immunosuppressive regimen similar to nephrotic syndrome.
  • If nephrotic syndrome, treatment may include immunosuppression with corticosteroid plus 1 other drug (such as MPAA, cyclophosphamide, calcineurin inhibitor, rituximab, or azathioprine) in addition to adjunctive therapy, including hydroxychloroquine, renin-angiotensin system blockade, and blood pressure control.
    • For initial immunosuppression, offer MPAA 2-3 g/day of mycophenolate mofetil or equivalent dose of mycophenolic acid plus corticosteroids (Weak recommendation). Alternative options include calcineurin inhibitor with or without MPAA (Weak recommendation) or cyclophosphamide IV (Weak recommendation).
    • For maintenance therapy, consider continuation of, switching to, or addition of calcineurin inhibitor (such as tacrolimus or voclosporin) at lowest effective dose after considering potential risk of nephrotoxicity (Weak recommendation).
• Management of patients who fail to achieve partial or complete remission includes:
  • evaluation of possible cause of failure, including assessment of medication adherence and therapeutic drug levels
  • repeat biopsy (consider if concern regarding chronicity or other diagnosis, such as thrombotic microangiopathy)
  • switching to an alternative first-line regimen, such as MPAA plus calcineurin inhibitor, addition of rituximab (1,000 mg/day on days 0 and 14) or other biologic therapies, or extended course of pulse cyclophosphamide IV (consider if refractory to first-line treatment regimens) (Weak recommendation)

Adjunctive Therapy

• Provide hydroxychloroquine for all patients with lupus nephritis (if tolerated) (Strong recommendation).
• Provide angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARBs) for patients with proteinuria or arterial hypertension (Strong recommendation).
• Consider statin therapy based on lipid levels and estimated risk for cardiovascular disease (Weak recommendation).
• Consider aspirin for patients with antiphospholipid antibodies with consideration of benefits and potential bleeding risk (Weak recommendation).
• Consider vitamin D, calcium supplementation, and/or antiresorptive agent for bone health (Weak recommendation).
• Consider immunizations with nonlive vaccines as appropriate (Weak recommendation).
• Consider anticoagulation for patients with nephrotic syndrome with serum albumin < 20 g/L (Weak recommendation).