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Lupus Nephritis

by Navin Jaipaul, MD, MHS

Lupus nephritis is glomerulonephritis caused by SLE. Clinical findings include hematuria, nephrotic-range proteinuria, and, in advanced stages, azotemia. Diagnosis is based on renal biopsy. Treatment is of the underlying disorder and usually involves corticosteroids and cytotoxic or other immunosuppressant drugs.

Lupus nephritis is diagnosed in about 50% of patients with SLE (see Systemic Lupus Erythematosus (SLE)) and typically develops within 1 yr of diagnosis. However, the total incidence is probably > 90%, because renal biopsy in patients with suspected SLE without clinical evidence of renal disease shows changes of glomerulonephritis (GN).

Pathophysiology

Pathophysiology involves immune complex deposition with development of GN. The immune complexes consist of nuclear antigens (especially DNA), high-affinity complement-fixing IgG antinuclear antibodies, and antibodies to DNA. Subendothelial, intramembranous, subepithelial, or mesangial deposits are characteristic. Wherever immune complexes are deposited, immunofluorescence staining is positive for complement and for IgG, IgA, and IgM in varying proportions. Epithelial cells may proliferate, forming crescents. Classification of lupus nephritis is based on histologic findings (see Classification of Lupus Nephritis).

Antiphospholipid syndrome nephropathy (APLS)

This syndrome may occur with or without lupus nephritis in up to one third of patients with SLE. The syndrome occurs in the absence of any other autoimmune process in 30 to 50% of affected patients. In the antiphospholipid antibody syndrome (see Antiphospholipid Antibody Syndrome), circulating lupus anticoagulant causes microthrombi, endothelial damage, and cortical ischemic atrophy. Antiphospholipid syndrome nephropathy increases a patient’s risk of hypertension and renal insufficiency or failure compared with lupus nephritis alone.

Symptoms and Signs

The most prominent symptoms and signs are those of SLE; patients who present with renal disease may have edema, foaming urine, hypertension, or a combination.

Classification of Lupus Nephritis

Class

Description

Histologic Findings*

Clinical Findings

Renal Prognosis

I

Minimal mesangial

Normal (although immune complexes are sometimes visible using immunofluorescence or electron microscopy)

None

Excellent

II

Mesangial proliferative

Immune complexes in the mesangium only and mesangial hypercellularity

Possibly microscopic hematuria, proteinuria, or both

Excellent

III

Focal proliferative

Endocapillary and extracapillary cellular proliferation and inflammation in < 50% of glomeruli, usually in a segmental distribution

Usually hematuria and proteinuria

Possibly hypertension, nephrotic syndrome, and elevated serum creatinine

Variable

IV

Diffuse proliferative

Endocapillary and extracapillary cellular proliferation and inflammation in > 50% of glomeruli

Usually hematuria and proteinuria

Frequently hypertension, nephrotic syndrome, and elevated serum creatinine

Variable

V

Membranous

Thickening of the glomerular basement membrane with subepithelial and intramembranous immune complex deposition

Usually nephrotic syndrome

Sometimes microscopic hematuria or hypertension

Serum creatinine usually normal or slightly elevated

Poorly defined

VI

Sclerosing

Sclerosis of > 90% of glomerular capillaries

Bland urinary sediment and end-stage renal disease or slowly increasing serum creatinine

Poor

*Using light microscopy.

Most common form.

Diagnosis

  • Urinalysis and serum creatinine (all patients with SLE)

  • Renal biopsy

Diagnosis is suspected in all patients with SLE, particularly in patients who have proteinuria, microscopic hematuria, RBC casts, or hypertension. Diagnosis is also suspected in patients with unexplained hypertension, elevated serum creatinine levels, or abnormalities on urinalysis who have clinical features suggesting SLE.

Urinalysis is done and serum creatinine is measured. If either is abnormal, renal biopsy is usually done to confirm the diagnosis and classify the disorder histologically. Histologic classification helps determine prognosis and direct treatment.

Some of the histologic subtypes are similar to other glomerulopathies; eg, membranous and diffuse proliferative lupus nephritis are histologically similar to idiopathic membranous GN and type I membranoproliferative GN, respectively. Overlap between these categories is substantial, and patients may progress from one class to another.

Renal function and SLE activity should be monitored regularly. A rising serum creatinine level reflects deteriorating renal function, while a falling serum complement level or a rising anti-DNA antibody titer suggests increased disease activity.

Prognosis

Class of nephritis influences renal prognosis (see Classification of Lupus Nephritis), as do other renal histologic features. Renal biopsies are scored with a semiquantitative activity score and with a chronicity index.

The activity score describes the degree of inflammation. The score is based on cellular proliferation, fibrinoid necrosis, cellular crescents, hyaline thrombi, wire loop lesions, glomerular leukocyte infiltration, and interstitial mononuclear cell infiltration.

The chronicity index describes the degree of scarring. It is based on presence of glomerular sclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis. The chronicity index predicts progression of lupus nephritis to renal failure. A mild to moderate chronicity score suggests at least partially reversible disease, whereas more severe chronicity scores may indicate irreversible disease. The activity score is less well correlated with disease progression, perhaps because it is based on the degree of inflammation, which is more reversible with treatment.

Black patients with lupus nephritis are also at higher risk of progression to end-stage renal disease.

Patients with lupus nephritis are at high risk of cancers, primarily B-cell lymphomas. Risk of atherosclerotic complications (eg, coronary artery disease, ischemic stroke) is also high, because of frequent vasculitis, hypertension, hyperlipidemia, and use of corticosteroids.

Treatment

  • Angiotensin inhibition for hypertension or proteinuria

  • Cyclophosphamide and prednisone for active, potentially reversible nephritis

  • Kidney transplantation for patients with end-stage renal disease

Immunosuppression

Treatment is toxic and thus is reserved for nephritis that has the following characteristics:

  • Is active

  • Has the potential for a poor prognosis

  • Is potentially reversible

Activity is estimated by the activity score as well as clinical criteria (eg, urine sediment, increasing urine protein, increasing serum creatinine). Many experts believe that a mild to moderate chronicity score, because it suggests reversibility, should provoke more aggressive therapy than a more severe chronicity score. Nephritis with the potential for deterioration and for reversibility is usually class III or IV; it is unclear whether class V nephritis warrants aggressive treatment.

Treatment for proliferative lupus nephritis usually combines cytotoxic drugs, corticosteroids, and sometimes other immunosuppressants. One induction regimen consists of cyclophosphamide, which is usually given in IV boluses (monthly for up to 6 mo) beginning with 0.75 g/m 2 in a saline solution over 30 to 60 min and, assuming a WBC count > 3000/μL, increasing to a maximum of 1 g/m 2 . Oral or IV fluid administration to create rapid urine flow minimizes the bladder toxicity of cyclophosphamide, as does mesna (see Protocol for Chemotherapy With Cyclophosphamide and IV Mesna). Another induction regimen uses mycophenolate mofetil with a target dose of 3 g/day. Prednisone is also begun at 60 to 80 mg po once/day and tapered according to response to 20 to 25 mg every other day over 6 to 12 mo. The amount of prednisone is determined by the extrarenal manifestations and number of relapses. Relapses are usually treated with increasing doses of prednisone. Both induction regimens are equally efficacious, although systemic toxicity may be less with mycophenolate mofetil than with cyclophosphamide.

Many experts are replacing the more toxic cyclophosphamide maintenance regimens (after induction with 6 or 7 monthly IV cyclophosphamide doses) with protocols using mycophenolate mofetil 500 mg to 1 g po bid or, as a second choice, azathioprine 2 mg/kg po once/day (maximum 150 to 200 mg/day). Chlorambucil, cyclosporine, and tacrolimus have also been used, but relative efficacies are not clear. Low-dose prednisone 0.05 to 0.2 mg/kg po once/day is continued and titrated based on disease activity. Duration of maintenance therapy is at least 1 yr.

Other treatments

Angiotensin inhibition with an ACE inhibitor or angiotensin II receptor blocker is indicated for patients with even mild hypertension (eg, BP > 130/80 mm Hg) or proteinuria. Also, hyperlipidemia and risk factors for atherosclerosis should be treated aggressively.

Anticoagulation is of theoretical benefit for patients with antiphospholipid syndrome nephropathy, but the value of such treatment has not been established.

Kidney transplantation is an option for patients with end-stage renal disease due to lupus nephritis. Recurrent disease in the graft is uncommon (< 5%), but risk may be increased in blacks, females, and younger patients.

Key Points

  • Nephritis, although clinically evident in only 50%, occurs in probably > 90% of patients with SLE.

  • Do urinalysis and measure serum creatinine in all patients with lupus and do renal biopsy if an unexplained abnormality is found in either.

  • Initiate angiotensin inhibition for even mild hypertension and treat atherosclerotic risk factors aggressively.

  • Treat active, potentially reversible nephritis with corticosteroids plus cyclophosphamide and/or mycophenolate mofetil.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • CYTOXAN (LYOPHILIZED)
  • RAYOS
  • PROGRAF
  • LEUKERAN
  • NEORAL, SANDIMMUNE
  • IMURAN
  • MESNEX

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