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Lupus Nephritis

- Monitor disease activity q3mo (3)[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. http://www.kdigo.org/clinicalpracticeguidelines/pdf/CKD/KDIGO2012CKD_GL.pdf

para>LN is more common and more severe in children: 60 " пїЅ80% have LN at or soon after SLE onset. пїЅ пїЅ

Prevalence

SLE: 7.4 to 159.4/100,000 (2) пїЅ пїЅ

ETIOLOGY AND PATHOPHYSIOLOGY

  • Immune complex " пїЅmediated inflammation injures glomeruli, tubules, interstitium, and vasculature.
  • Glomeruli: varying degrees of mesangial proliferation, crescent formation (see "Test Interpretation " пїЅ), and fibrinoid necrosis causing reduced glomerular filtration rate (GFR)
  • Persistence of 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 пїЅ пїЅ

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 пїЅ пїЅ

COMMONLY ASSOCIATED CONDITIONS

Skin, hematologic, cerebral, pulmonary, GI, and cardiopulmonary systems are often involved in SLE. пїЅ пїЅ

DIAGNOSIS

HISTORY

Assess for risk factors and other signs/symptoms of SLE: rash, photosensitivity, arthritis, neurologic complaints, fever, weight loss, alopecia. пїЅ пїЅ

PHYSICAL EXAM

  • Hypertension, fever
  • Pleural/pericardial rub
  • Skin rash
  • Edema
  • Arthritis

DIFFERENTIAL DIAGNOSIS

  • Primary glomerular disease
  • Secondary renal involvement in other systemic disorders such as antineutrophil cytoplasmic autoantibody (ANCA) associated vasculitis, Henoch-Sch пїЅ пїЅnlein 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 processes.
  • 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 (3)[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) (3)[C]
  • CBC may show anemia, thrombocytopenia, and leukopenia.
  • Renal ultrasound (3)[C]

Follow-Up Tests & Special Considerations

  • Monitor disease activity q3mo (3)[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. 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.

пїЅ пїЅ

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 " пїЅ) 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 lupus nephritis. пїЅ пїЅ

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 mycophenolate mofetil (MMF) and maintenance of remission by low-dose steroids and azathioprine (AZA) or MMF (1).
  • Principles of treatment:Avoid delay in treatment.Inducing remission quickly (3 to 6 months)Maintaining response and avoiding 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) (4,5)[A] ANDCyclophosphamide (CYC): IV CYC (high dose = 0.5 to 1 g/m2 monthly for 6 doses " пїЅNIH regimen; low dose = 0.5 g q2wk for 6 doses " пїЅEuro-Lupus regimen) ORMycophenolate mofetil (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 (6)[A].
  • MAINTENANCE:Glucocorticoids: oral prednisone tapered to low doses (generally <10 mg/day by 6 months) ANDMMF 1 to 2 g/day divided BID PO OR AZA (azathioprine): 1 to 2.5 mg/kg/day PO (4,5)[A]In the ALMS (Aspreva Lupus Management Study) MMF shown to be superior than AZA for maintenance therapy in a varied population (7)[A].In the MAINTAIN nephritis trial, MMF shown to be equal to AZA for maintenance therapy in mostly Caucasian population (8)[A].Cyclophosphamide IV quarterly for 1 to 2 year after renal remission; not used now due to availability of less toxic regimen
  • Class V LN: good prognosis in general, treatment not standardizedFor 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 (5)[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 (9)[C]. пїЅ пїЅ

ISSUES FOR REFERRAL

Nephrology consults for initial management and relapses пїЅ пїЅ

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 (2)[C].
  • Risk of recurrent LN in renal transplant recipients ranges between 0% and 30%; graft loss due to recurrence is rare.

INPATIENT 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

IV Fluids

Patients who have nephrotic syndrome or acute kidney injury should be fluid restricted. пїЅ пїЅ

Discharge Criteria

Once the patient is stabilized and renal biopsy is performed, manage safely as an outpatient. пїЅ пїЅ

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 (3)[C].
  • Once stable on maintenance therapy with no active disease, follow-up every 6 to 12 months (3)[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. пїЅ пїЅ

PATIENT EDUCATION

Medication adherence and self-monitoring for relapse пїЅ пїЅ

PROGNOSIS

  • 10-year survival of 88% and 94% in SLE patients with and without renal involvement (1)
  • Relapse rate is ~35%. 10 " пїЅ20% of patients progress to ESRD within 10 years (10).
  • 5-year renal survival of class IV LN <30% before 1970 has improved to >80% in last 2 decades (2).
  • Early and complete remission with treatment is the best prognostic factor. Predictors of remission include low baseline proteinuria, normal creatinine, Caucasian race, and treatment initiation within 3 months of clinical 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 from immunosuppression: 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 " пїЅ20% of patients develop ESRD from progressive disease refractory to treatment requiring dialysis/kidney transplantation.

REFERENCES

11 Hahn пїЅ пїЅBH, McMahon пїЅ пїЅMA, Wilkinson пїЅ пїЅA, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken). 2012;64(6):797 " пїЅ808.22 Ortega пїЅ пїЅLM, Schultz пїЅ пїЅDR, Lenz пїЅ пїЅO, et al. Review: lupus nephritis: pathologic features, epidemiology and a guide to therapeutic decisions. Lupus. 2010;19(5):557 " пїЅ574.33 Mosca пїЅ пїЅM, Tani пїЅ пїЅC, Aringer пїЅ пїЅM, 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 " пїЅ1274.44 Ponticelli пїЅ пїЅC, Glassock пїЅ пїЅRJ, Moroni пїЅ пїЅG. Induction and maintenance therapy in proliferative lupus nephritis. J Nephrol. 2010;23(1):9 " пїЅ16.55 Bomback пїЅ пїЅAS, Appel пїЅ пїЅGB. Updates on the treatment of lupus nephritis. J Am Soc Nephrol. 2010;21(12):2028 " пїЅ2035.66 Henderson пїЅ пїЅLK, Masson пїЅ пїЅPM, Craig пїЅ пїЅJC, et al. Induction and maintenance treatment of proliferative lupus nephritis: a meta-analysis of randomized controlled trials. Am J Kidney Dis. 2013;61(1):74 " пїЅ87.77 Dooley пїЅ пїЅMA, Jayne пїЅ пїЅD, Ginzler пїЅ пїЅEM, et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med. 2011;365(20):1886 " пїЅ1895.88 Morris пїЅ пїЅHK, Canetta пїЅ пїЅPA, Appel пїЅ пїЅGB. Impact of ALMS and MAINTAIN trials on the management of lupus nephritis. Nephrol Dial Transplant. 2013;28(6):1371 " пїЅ1376.99 Lo пїЅ пїЅMS, Tsokos пїЅ пїЅGC. Treatment of systemic lupus erythematosus: new advances in targeted therapy. Ann N Y Acad Sci. 2012;1247:138 " пїЅ152.

ADDITIONAL READING

  • Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Inter. 2012;2(Suppl):139 " пїЅ274.
  • Ward пїЅ пїЅMM. Recent clinical trials in lupus nephritis. Rheum Dis Clin North Am. 2014;40(3):519 " пїЅ535.
  • Weening пїЅ пїЅJJ, D 'Agati пїЅ пїЅVD, Schwartz пїЅ пїЅMM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15(2):241 " пїЅ250.

CODES

ICD10

M32.14 Glomerular disease in systemic lupus erythematosus пїЅ пїЅ

ICD9

  • 710.0 Systemic lupus erythematosus
  • 583.81 Nephritis and nephropathy, not specified as acute or chronic, in diseases classified elsewhere

SNOMED

  • 68815009 Systemic lupus erythematosus glomerulonephritis syndrome (disorder)
  • 73286009 SLE glomerulonephritis syndrome, WHO class I
  • 4676006 SLE glomerulonephritis syndrome, WHO class II
  • 76521009 SLE glomerulonephritis syndrome, WHO class III
  • 52042003 SLE glomerulonephritis syndrome, WHO class V
  • 36402006 SLE glomerulonephritis syndrome, WHO class IV
  • 11013005 SLE glomerulonephritis syndrome, WHO class VI

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