BASICSNeena R. Gupta, MD
BASICS
DESCRIPTION
• The renal manifestation of systemic lupus erythematosus (SLE)
• American College of Rheumatology (ACR) criteria: persistent proteinuria >500 mg/day or ≥3 on dipstick and/or presence of cellular casts. Alternatively, spot urine protein-to-creatinine ratio >0.5 and “active urinary sediment” (>5 RBC/hpf, >5 WBC/hpf in absence of infection, or cellular casts—RBC or WBC casts) (1)
• Clinical manifestations primarily due to immune complex–mediated glomerular disease. Tubulointerstitial and vascular involvement often coexist. Diagnosis is based on clinical findings, urine abnormalities, autoantibodies, and renal biopsy.
• Treatment and prognosis depend on International Society of Nephrology/Renal Pathology Society (ISN/RPS) histologic class—risk of end-stage renal disease (ESRD) highest in class IV.
• Delay in diagnosis/treatment increases risk of ESRD.
EPIDEMIOLOGY
• Peak incidence of SLE is 15 to 45 years of age.
• Predominant sex: female > male (10:1)
• Once SLE develops, lupus nephritis (LN) affects both genders equally; it is more severe in children and men and less severe in older adults.
Incidence
• SLE: 1.4 to 21.9/100,000
• Up to 60% of SLE patients develop LN over time, and 25–50% of SLE patients have nephritis as the initial presentation.
Pediatric Considerations
LN is more common and more severe in children: 60–80% have LN at or soon after SLE onset.
Prevalence
SLE: 7.4 to 159.4/100,000
ETIOLOGY AND PATHOPHYSIOLOGY
• Immune complex–mediated inflammation injures glomeruli, tubules, interstitium, and vasculature.
• Glomeruli: Varying degrees of mesangial proliferation, crescent formation (see “Test Interpretation”), and fibrinoid necrosis cause reduced glomerular filtration rate (GFR).
• Persistent inflammation (chronicity) leads to sclerosis and glomerular loss.
• Tubulointerstitial injury (edema, inflammatory cell infiltrate acutely; tubular atrophy in chronic phase) with or without tubular basement membrane immune complex deposition leads to reduced renal function.
• Vascular lesions: immune complex deposition and noninflammatory necrosis in arterioles
• SLE is a multifactorial disease, with a multigenic inheritance; exact etiology remains unclear.
• Defective T-cell autoregulation and polyclonal B-cell hyperactivity contribute to dysregulated apoptosis. Impaired clearance of apoptotic cells inhibits self-tolerance to nuclear antigen
• Anti-DNA, anti-C1q, anti-α-actin, and other nuclear component autoantibodies develop.
• Deposition of circulating immune complexes or autoantibodies attaching to local nuclear antigens leads to complement activation, inflammation, and tissue injury.
• Interaction of genetic, hormonal, and environmental factors leads to great variability in LN severity.
Genetics
Multigenic inheritance; clustering in families, ~25% concordance in identical twins
RISK FACTORS
Younger age, African American or Hispanic race, more ACR criteria for SLE, longer disease duration, hypertension, lower socioeconomic status, family history of SLE, anti-dsDNA antibodies
COMMONLY ASSOCIATED CONDITIONS
Skin, hematologic, cerebral, pulmonary, GI, and cardiopulmonary systems are often involved in SLE.
DIAGNOSIS
HISTORY
Assess for risk factors and other signs/symptoms of SLE: rash, photosensitivity, arthritis, neurologic complaints, fever, weight loss, alopecia.
PHYSICAL EXAM
• Hypertension, fever
• Pleural/pericardial rub
• Skin rash
• Edema
• Arthritis
• Alopecia
• Oral ulcers
DIFFERENTIAL DIAGNOSIS
• Primary glomerular disease
• Secondary renal involvement in other systemic disorders such as antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, Henoch-Schönlein purpura (HSP), antiglomerular basement membrane disease, and viral infections
• Mixed connective tissue disorder may have glomerulonephritis indistinguishable from LN.
DIAGNOSTIC TESTS & INTERPRETATION
• Renal biopsy is the gold standard for diagnosing and classifying LN.
• Combine clinical data with serologic and renal biopsy patterns to differentiate LN from other conditions.
• Active urine sediment suggests nephritis.
• Autoantibodies, low C3, C4, and CH50 complement levels support LN diagnosis.
Initial Tests (lab, imaging)
• Urinalysis may show hematuria, proteinuria, and active urine sediment (2)[C].
• Serum electrolytes, BUN, creatinine, albumin, routine serologic markers of SLE such as antinuclear antibody (ANA), anti-dsDNA, anti-Ro, anti-La, anti-RNP, anti-Sm, antiphospholipid antibody, C3, C4, CH50, CBC with differential, and C-reactive protein (CRP) (2)[C]
• CBC may show anemia, thrombocytopenia, and leukopenia.
• Renal ultrasound (2)[C]
Follow-Up Tests & Special Considerations
• Monitor disease activity q3mo (2)[C]: urinalysis for hematuria and proteinuria; blood for C3, C4, anti-dsDNA, serum albumin, and creatinine.
• Patients with estimated glomerular filtration rate (eGFR) of <60 mL should be managed according to the National Kidney Foundation guidelines for chronic kidney disease (CKD). http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf
Pregnancy Considerations
• Pregnancy leads to worsening of renal function in LN. Risk factors include renal impairment at baseline, active disease, hypertension, and proteinuria.
• Risk factors for fetal loss include elevated serum creatinine, heavy proteinuria, hypertension, and anticardiolipin antibodies.
• Mycophenolate mofetil (MMF) is contraindicated in pregnancy; azathioprine can be safely used.
Test Interpretation
• Adequate renal biopsy (at least 10 glomeruli for light microscopy or total 20 to 25 glomeruli) is essential. Light, immunofluorescence, and electron microscopy are needed for accurate classification.
• On immunofluorescence microscopy: Immune complex deposits consisting of IGG, IGA, IGM, C1q, and C3 (“full house”) are highly suggestive of LN.
• Revised ISN/RPS histologic classification guides therapeutic decisions. http://jasn.asnjournals.org/content/15/2/241.full.pdf
• LN is classified as purely mesangial (classes I and II), focal proliferative: <50% glomeruli (class III), diffuse proliferative: ≥50% (class IV), membranous (class V), and advanced sclerosis (class VI). Subdivisions for activity (A) and chronicity (C) in class III/IV and for segmental (S) or global (G) glomerular involvement in class IV (Class III A, C, A/C and class IV S[A], G[A], S[A/C], S[C], G[C]).
• LN may change to another class over time or with therapy.
• Focal and diffuse proliferative LN (classes III and IV) are common and most likely to progress to ESRD.
TREATMENT
GENERAL MEASURES
• Monitor bone density; optimize vitamin D and calcium intake in patients on glucocorticoid therapy.
• Low-salt diet for hypertension and edema. For eGFR <60 mL: Follow National Kidney Foundation guidelines for chronic kidney disease.
• Avoid sun or ultraviolet light exposure.
MEDICATION
Note: Other than methylprednisolone and prednisone, no other medications listed below are FDA approved for LN.
First Line
• Class I + II LN: No specific therapy is needed, as long-term renal prognosis is good. Renin-angiotensin system blockade (ACE inhibitors or angiotensin receptor blockers) to manage BP and proteinuria. There are many drugs in this class (e.g., lisinopril 5 to 40 mg/day PO, losartan 25 to 100 mg/day PO).
• Proliferative LN (Class III, IV, V + III/IV): Induce remission by steroids + IV cyclophosphamide or MMF and maintenance of remission by low-dose steroids and azathioprine (AZA) or MMF (1).
– Avoid delay in treatment.
– Induce remission quickly (3 to 6 months).
– Maintain response and avoid iatrogenic morbidity (5 to 10 years).
• INDUCTION: steroids + immunosuppressive agent (for mild class III, high-dose steroids may be sufficient):
– Glucocorticoids: methylprednisolone pulse 0.5 to 1 g/day for 3 days followed by oral prednisone 0.5 to 1 mg/kg/day PO (max 60 mg/day, taper after 4 to 8 weeks) (3)[A] AND
– Cyclophosphamide (CYC): IV CYC (high dose = 0.5 to 1 g/m2 monthly for 6 doses—NIH regimen; low dose = 0.5 g q2wk for 6 doses—Euro-Lupus regimen) OR
– MMF: 1 to 3 g/day PO divided BID (target 3 g/day as tolerated) for 6 months. MMF is as effective as CYC in achieving remission with fewer side effects (3)[A].
• MAINTENANCE:
– Glucocorticoids: oral prednisone tapered to low doses (generally <10 mg/day by 6 months) AND
– MMF 1 to 2 g/day divided BID PO OR AZA (azathioprine): 1 to 2.5 mg/kg/day PO (3)[A]
– In the ALMS (Aspreva Lupus Management Study) MMF shown to be superior than AZA for maintenance therapy in a varied population (4)[A].
– In the MAINTAIN nephritis trial, MMF shown to be equal to AZA for maintenance therapy in mostly Caucasian population (5)[A].
– Cyclophosphamide IV quarterly for 1 to 2 year after renal remission; not used now due to availability of less toxic regimen
– Optimum duration of maintenance therapy is unclear, but periods ranging from 3 to 10 years have been studied in clinical trials (4,5).
• Class V LN: good prognosis in general, treatment not standardized
– For subnephrotic patients, no specific treatment except renin-angiotensin system blockade.
– Options for nephrotic patients include steroids with either calcineurin inhibitors, IV CYC, AZA, or MMF (3)[B].
– Class V LN with presence of class III or class IV biopsy findings needs aggressive combination regimen as for class III/IV.
Second Line
Other treatments in selected patients: rituximab, plasma exchange, IVIG, calcineurin inhibitors. Belimumab was approved by FDA in 2011, but trials excluded patients with severe active LN (3)[C].
ISSUES FOR REFERRAL
Nephrology consults for initial management and relapses.
ADDITIONAL THERAPIES
• KDIGO 2012 guidelines for LN state that all patients with LN of any class be treated with hydroxychloroquine (maximum daily dose of 6 to 6.5 mg/kg ideal body weight), unless they have a specific contraindication to this drug.
• BP control; treat dyslipidemia and other modifiable cardiovascular risk factors.
• Anticoagulation for symptomatic antiphospholipid antibody syndrome
SURGERY/OTHER PROCEDURES
• Renal transplant for ESRD when indicated
• Patient and graft survival rates are similar to non-SLE patients.
• Risk of recurrent LN in renal transplant recipients ranges between 0% and 30%; graft loss due to recurrence is rare.
ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS
• Admission criteria/initial stabilization
– Uncontrolled hypertension, acute kidney injury
– Severe extrarenal manifestation
– Control hypertension and proteinuria, if present.
– Labs to help confirm SLE/LN, renal ultrasound
– Nephrology for manage input and renal biopsy
• Patients who have nephrotic syndrome or acute kidney injury should be fluid restricted.
• Once the patient is stabilized and renal biopsy is performed, manage safely as an outpatient.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
• Monitor urine protein-to-creatinine ratio, urine microscopy, serum albumin and creatinine, antibody titers (especially anti-dsDNA), C3, C4, BP at least every 3 months for first 2 to 3 years (2)[C].
• Once stable on maintenance therapy with no active disease, follow-up every 6 to 12 months (2)[C].
• Cyclophosphamide: CBC, ensure adequate hydration
• MMF: CBC, LFT, SrCr
• Azathioprine: CBC
DIET
Low-salt diet. For eGFR <60 mL: Follow National Kidney Foundation guidelines for chronic kidney disease.
PATIENT EDUCATION
Medication adherence and self-monitoring for relapse
PROGNOSIS
• 10-year survival of 88% and 94% in SLE patients with and without renal involvement (1)
• Relapse rate is ~35%. 10–20% of patients progress to ESRD within 10 years.
• 5-year renal survival of class IV LN <30% before 1970 has improved to >80% in last 2 decades.
• Early and complete remission of proteinuria with treatment is the best prognostic factor. Other predictors of remission include low baseline proteinuria, normal creatinine, Caucasian race, and treatment initiated within 3 months of diagnosis.
• Indicators of poor prognosis: diffuse proliferative LN (especially crescentic), higher activity/chronicity index, African American race, lower socioeconomic status, poor response to treatment, high creatinine at baseline, uncontrolled hypertension, and relapse
COMPLICATIONS
• Risks of immunosuppressive therapy: infections, malignancy
• Treatment side effects: Cyclophosphamide causes primary amenorrhea.
• MMF may cause GI upset and nausea and is a teratogen (azathioprine recommended for women who desire pregnancy).
• Risk of vascular thromboses (hypercoagulable state from antiphospholipid antibodies)
• About 10–20% of patients develop ESRD from progressive disease refractory to treatment requiring dialysis/kidney transplantation.
REFERENCES
1. Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken). 2012;64(6):797–808.
2. Mosca M, Tani C, Aringer M, et al. European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies. Ann Rheum Dis. 2010;69(7):1269–1274.
3. Parikh SV, Rovin BH. Current and emerging therapies for lupus nephritis. J Am Soc Nephrol. 2016;27:2929–2939.
4. Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med. 2011;365(20):1886–1895.
5. Tamirou F, D’Cruz D, Sangle S, et al. Long term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis. Ann Rheum Dis. 2016;75:526–531.
ADDITIONAL READING
• Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Inter. 2012;2(Suppl):139–274.
• Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15(2):241–250.
CODES
ICD10
M32.14 Glomerular disease in systemic lupus erythematosus
CLINICAL PEARLS
• Early diagnosis, correct classification (requires renal biopsy), and rapid treatment improve renal survival in patients with LN.
• Treat proliferative/progressive LN with a short induction course followed by maintenance therapy using glucocorticoids and immunosuppressants.
• Survival rates for patients with LN have improved dramatically over the past several decades.