Lupus Nephritis

Definition, Etiology, PathogenesisTop

Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE), with approximately 50% to 60% of patients with SLE developing renal involvement during the course of the disease, although some studies suggest that the rate of renal involvement without clinical manifestations may be much higher. Approximately one-third of patients have renal involvement at the time of SLE diagnosis. Patients with LN have an overall worse prognosis than patients without renal involvement. The risk to patients is greater than just that caused by renal disease, suggesting that LN is an indicator of overall disease severity. LN is most common and more severe in African Americans and least common and severe in Whites. Male SLE patients are more likely to acquire LN, although most patients are female, given the large gender difference in the overall SLE prevalence.

LN is primarily an immune complex disease of the glomerulus. Anti–double-stranded DNA (anti-dsDNA) immune complexes are found deposited in various parts of the glomerulus, resulting in an inflammatory response and disease. Immune complexes can deposit in the mesangial, endothelial, and epithelial spaces, with varying presentations depending on location. Other renal diseases can occur in SLE, including thrombotic microangiopathy and tubulointerstitial nephritis.

Classification: LN is divided into 6 different classes based on the International Society of Nephrology and the Renal Pathology Society classification system (Table 1), which correspond to differing levels of severity and treatment requirements:

1) Class I (minimal mesangial LN): Normal light microscopy and mesangial immune deposits on immunofluorescence or electron microscopy. This is not usually seen on biopsy since these patients often have few clinical abnormalities necessitating biopsy.

2) Class II (mesangial proliferative LN): The earliest stage to show light microscopy changes, which consist of mesangial hypercellularity or expansion. These patients often have proteinuria and hematuria but usually normal renal function.

3) Class III (focal LN): Endocapillary or extracapillary glomerulonephritis in <50% of the glomeruli. This is typically associated with subendothelial immune deposits. Patients usually have proteinuria, hematuria, and decreased glomerular filtration rate (GFR). Class III can be subdivided into active or chronic lesions.

4) Class IV (diffuse LN): The most common and most severe form of LN. It is manifested by endocapillary or extracapillary glomerulonephritis in >50% of the glomeruli. Patients will usually have proteinuria, hematuria, and decreased GFR. Class IV can also be subdivided into active or chronic lesions.

5) Class V (membranous LN): Thickening of the glomerular basement membrane (GBM) and subepithelial immune deposits. Patients typically present with nephrotic syndrome. Class V can overlap with classes III and IV.

6) Class VI (advanced sclerosing LN): Glomerulosclerosis in >90% of the glomeruli without evidence of active inflammation. It represents permanent damage from previous class III, IV, or V disease and is unlikely to respond to therapy.

Patients can switch between classes of disease, so changes in clinical situations may necessitate a repeat biopsy to determine if a class switch has occurred and subsequent alteration of management is required.

Clinical FeaturesTop

Renal disease in LN is often asymptomatic, although the patient may exhibit other signs and symptoms of SLE (such as rash, arthritis, fatigue, fever, or weight loss). Proteinuria is almost universal in LN. Microscopic hematuria and red cell casts are very common, while gross hematuria is relatively rare and can represent both renal and nonrenal disease (eg, lupus cystitis). Patients are often hypertensive, with hypertension worsening with the severity of the disease. Nephrotic syndrome can occur with associated significant edema; it is suggestive of membranous LN. Patients often have decreased renal function, hypocomplementemia (both C3 and C4), increased erythrocyte sedimentation rate (ESR), and elevated titers of anti-dsDNA antibodies.

DiagnosisTop

A diagnosis of LN is strongly suggested based on the presence of microscopic hematuria/red cell casts and proteinuria in a patient with SLE and is confirmed on biopsy.

TreatmentTop

General Considerations

In all patients with nephropathy blood pressure should probably be managed according to the current general guidelines (see Renal Parenchymal Hypertension).

In patients with proteinuria, administer an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB). Patients with nephrotic syndrome: see Nephrotic Syndrome.

Immunomodulatory treatment: In all patients with lupus nephritis, including those in remission, antimalarial therapy is recommended. Otherwise, specific treatment is based on the underlying class of LN seen on biopsy.

Specific Treatment

Treatment is based on the underlying class of LN seen on biopsy. Class I is not associated with long-term renal impairment and is not specifically treated (patients in this class are also typically not biopsied). Class II also does not usually require immunosuppression, although it can be considered in individuals with nephrotic range proteinuria. SLE in classes I and II should be treated according to the patient’s extrarenal manifestations.

Classes III and IV are associated with very poor outcomes if left untreated. These patients are provided with initial immunosuppression followed by maintenance immunosuppression. Initial immunosuppression consists of glucocorticoids and either cyclophosphamide or mycophenolate mofetil (MMF), based on a number of different studies.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Illei GG, Austin HA, Crane M, et al. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med. 2001 Aug 21;135(4):248-57. PubMed PMID: 11511139. Houssiau FA, Vasconcelos C, D'Cruz D, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002 Aug;46(8):2121-31. PubMed PMID: 12209517. Appel GB, Contreras G, Dooley MA, et al; Aspreva Lupus Management Study Group. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009 May;20(5):1103-12. doi: 10.1681/ASN.2008101028. Epub 2009 Apr 15. PubMed PMID: 19369404; PubMed Central PMCID: PMC2678035. Glucocorticoids should consist of prednisone 1 mg/kg/d tapered over 6 to 12 months with pulse solumedrol often being used initially in the setting of severe disease. Additional immunosuppression includes one of the following regimens:

1) IV cyclophosphamide 0.5 to 1 g/m2 monthly for 6 months.

2) IV cyclophosphamide 500 mg every 2 weeks for 3 months.

3) Oral cyclophosphamide 1 to 1.5 mg/kg/d for 2 to 4 months.

4) Oral MMF up to 3 g/d for 6 months.

MMF may be more useful than cyclophosphamide in African Americans and Latin Americans, and cyclophosphamide may be more useful in severe disease. The patient’s preferences may also play a role in treatment decisions, as many SLE patients are young and cyclophosphamide has potential for gonadal toxicity.

Maintenance therapy should consist of either MMF 1 to 2 g/d or azathioprine 1.5 to 2.5 mg/kg/d combined with low-dose prednisone. Some evidence suggests that MMF may be better than azathioprine at preventing the progression of chronic kidney disease or flares of disease. Maintenance therapy is suggested for at least 1 year after remission is achieved, although its appropriate duration is unknown.

There is significantly less evidence for treatment of class V compared with class III or IV. Patients with non–nephrotic range proteinuria can be treated with antiproteinuric (eg, angiotensin-converting enzyme inhibitor [ACEI]/angiotensin receptor blocker [ARB]) and antihypertensive medications. In those with nephrotic range proteinuria, glucocorticoids in addition to another immunosuppressive medication (cyclophosphamide, calcineurin inhibitor, or MMF) can be used. In contrast to idiopathic membranous nephropathy, membranous LN rarely resolves spontaneously.

Patients with a combination of class V and class III or IV have significantly worse outcomes than those assigned to class V alone and should be treated similarly to those in class III or IV. Class VI represents advanced chronic damage that does not benefit from immunosuppression; such patients should be treated according to extrarenal manifestations and with therapies aimed at reducing the progression of chronic kidney disease/delaying end-stage renal disease.

PrognosisTop

Survival has improved substantially with the introduction of immunosuppressive therapy for LN. Whereas previously <50% of patients with class IV LN survived >5 years, the 10-year survival rate for patients with LN is now approximately 88% (compared with 92% for SLE patients without LN). Estimates on the rate of end-stage renal disease vary between 3% and 36% for patients with LN.

Achieving a complete renal response to therapy is an important marker of prognosis. Definitions of complete response vary between studies but it usually consists of stabilization of creatinine to previous disease activity levels and substantial reduction of proteinuria. The Lupus Nephritis Collaborative Study Group demonstrated renal survival of 94% at 10 years in those with a complete renal response to therapy compared with only 31% in those that did not.

TablesTop