Lupus Nephritis

GENERAL PRINCIPLES

Lupus nephritis (LN) can manifest as proteinuria of varying degrees with dysmorphic RBCs and RBC casts and renal insufficiency. Positive lupus serology (e.g., ANA, anti-double-stranded DNA antibodies, anti-histone antibodies, anti-Smith antibodies) and hypocomplementemia (especially low C3) are often present during acute flares.

DIAGNOSIS

• Renal biopsy can provide diagnostic and prognostic information. The International Society of Nephrology/Renal Pathology Society classification has six major categories based on histologic appearance.³²

î Class I (minimal mesangial LN) does not show mesangial hypercellularity, though mesangial deposits may be seen in immunofluorescence and electron microscopy.

î Class II (mesangial proliferative LN) is characterized by mesangial hypercellularity (four or more nuclei in nonhilar region) or matrix expansion, primarily with mesangial deposits on immunofluorescence and electron microscopy.

î Class III (focal LN) shows glomerular lesions (including endocapillary or extracapillary hypercellularity, necrosis, crescents) with mesangial and subendothelial deposits, involving 50% of glomeruli showing subepithelial deposits with or without mesangial hypercellularity. This may occur in conjunction with class III or class IV disease.

î Class VI (advanced sclerosis LN) with ≥90% globally sclerosed glomeruli.

• Immunofluorescence is usually positive for IgG, IgA, IgM, C1q, and C3, for the “full-house” fluorescence pattern. It is also important to note that these classes could switch, and biopsy is necessary to classify LN patients prior to treatment.

TREATMENT

Aggressiveness of therapy takes into consideration the renal and extrarenal manifestations of the disease.

• Class I LN rarely requires specific treatment, and therapy is directed at the extrarenal manifestations. There are usually no long-term adverse effects on kidney function.

• For class II LN, therapy depends on the amount of proteinuria and the degree of extrarenal manifestations. When proteinuria is 3 g/d, treatment with corticosteroids or calcineurin inhibitors may be required.

• For class III, IV, or V LN, treatment can be divided into initial induction therapy and maintenance therapy.

• Initial induction therapy for aggressive disease is with corticosteroids (IV methylprednisolone 5-10 mg/kg for 3 days followed by oral prednisone 0.5-1.0 mg/kg/d tapered over 6-12 months according to patient's clinical response) PLUS either cyclophosphamide or mycophenolate mofetil.

• Cyclophosphamide can be given IV or PO, though more recent studies utilize the IV route due to a lower cumulative dose. A standard regimen is 0.5-1.0 g/m² monthly for 6 months, although a more recent study in European patients found comparable efficacy with a lower cumulative dose, given as 500 mg IV every 2 weeks for 3 months³³

• Mycophenolate mofetil (2-3 g daily in divided doses) was compared to cyclophosphamide for induction therapy, with no significant difference in the response rate at 6 months³⁴

• For maintenance therapy, mycophenolate mofetil (1-2 g/d in divided doses) with low-dose corticosteroids (less than 10 mg/day of prednisone) was shown to be superior to azathioprine (1.5-2.5 mg/kg/d) combined with corticosteroids.³⁵

• Rituximab therapy has also been shown to have treatment efficacy in lupus nephritis refractory to standard therapy. When combined with corticosteroids and mycophenolate mofetil, however, it did not show improved clinical outcomes after 1 year.³⁶

• Treatment course should be closely followed to ensure remission by monitoring renal function, proteinuria, hematuria, complement levels, and auto-antibody levels.