Lupus Nephritis Treatment & Management

Updated: Feb 25, 2021
  • Author: Lawrence H Brent, MD; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Approach Considerations

The principal goal of therapy in lupus nephritis is to normalize kidney function or, at least, to prevent the progressive loss of kidney function. Therapy differs depending on the pathologic lesion. [25, 42] It is important to treat extrarenal manifestations and other variables that may affect the kidneys. Patients should be on hydroxychloroquine if possible, as data suggest that this improves outcomes in patients who have lupus nephritis, in addition to reducing lupus-related flares and disease damage accrual. [43]

Corticosteroid therapy should be instituted if the patient has clinically significant renal disease. Use immunosuppressive agents, particularly cyclophosphamide, azathioprine, or mycophenolate mofetil, if the patient has aggressive proliferative renal lesions, as they improve the renal outcome. Immunosuppressives can also be used if the patient has an inadequate response or excessive sensitivity to corticosteroids. [42, 44, 45, 40]

Calcineurin inhibitors, especially tacrolimus, have demonstrated benefit in lupus nephritis. However, most studies have been limited to Asian patients, and further research is required on long-term benefits and disadvantages. [46, 47, 48, 40]  The calcineurin inhibitor voclosporin is the first oral therapy approved by the US Food and Drug Administration (FDA) for lupus nephritis in conjunction with immunosuppressive treatment. [49]

Leflunomide, a pyrimidine synthesis inhibitor that is approved by the FDA for use in rheumatoid arthritis, has shown efficacy in proliferative lupus nephritis in Chinese patients. [50, 51]  More recent evidence indicates that leflunomide may also have some efficacy in lupus nephritis in patients of other ethnic groups.

Treat hypertension aggressively. On the basis of beneficial effects in other nephropathies, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have been routinely used to treat proteinuria in lupus nephritis.

Alter the diet according to the presence of hypertension, hyperlipidemia, and renal insufficiency. Restrict fat intake or use lipid-lowering therapy such as statins for hyperlipidemia secondary to nephrotic syndrome. Restrict protein intake if renal function is significantly impaired.

Administer calcium supplementation to prevent osteoporosis if the patient is on long-term corticosteroid therapy, and consider adding a bisphosphonate (depending on renal function).

Avoid drugs that affect renal function, including nonsteroidal anti-inflammatory drugs (NSAIDs), especially in patients with elevated creatinine levels. Nonacetylated salicylates can be used to safely treat inflammatory symptoms in patients with renal disease.

Patients with active lupus nephritis should avoid pregnancy, because it may worsen their renal disease and because certain medications used in the treatment may be teratogenic. [52] In women who desire pregnancy, the following approach is advised [53] :

  • A preconception evaluation to establish and inform the patient about pregnancy risks
  • Plan for pregnancy during inactive lupus nephritis
  • Keep the lupus nephritis inactive with the lowest possible dosage of allowed drugs
  • Treat known risk factors (hypertension, antiphospholipid and antibodies)
  • Monitor closely during and after pregnancy to rapidly identify and treat SLE flares and obstetric complications

Patients with end-stage renal disease (ESRD), sclerosis, and a high chronicity index based on renal biopsy findings are unlikely to respond to aggressive therapy. In these cases, focus therapy on extrarenal manifestations of systemic lupus erythematosus (SLE) and on possible kidney transplantation.


Pharmacotherapy for Lupus Nephritis Based on Stage

Classes I and II

Minimal mesangial (class I) lupus nephritis requires no specific therapy. [25]

Mesangial proliferative (class II) lupus nephritis may require treatment if proteinuria is greater than 1000 mg/day. Consider prednisone in low-to-moderate doses (ie, 20-40 mg/day) for 1-3 months, with subsequent taper.

Classes III and IV

Patients with either focal (class III) or diffuse (class IV) lupus nephritis are at high risk of progressing to ESRD and thus require aggressive therapy.

Administer prednisone 1 mg/kg/day for at least 4 weeks, depending on clinical response. Then, taper it gradually to a daily maintenance dose of 5-10 mg/day for approximately 2 years. In acutely ill patients, intravenous (IV) methylprednisolone at a dosage of up to 1000 mg/day for 3 days may be used to initiate corticosteroid therapy.

In patients who do not respond to corticosteroids alone, who have unacceptable toxicity to corticosteroids, who have worsening renal function, who have severe proliferative lesions, or who have evidence of sclerosis on renal biopsy specimens, use immunosuppressive drugs in addition to corticosteroids.

Both cyclophosphamide and azathioprine are effective in proliferative lupus nephritis, although cyclophosphamide is apparently more effective in preventing progression to ESRD. Mycophenolate mofetil has been shown to be at least as effective as intravenous (IV) cyclophosphamide, with less toxicity, in patients with focal or diffuse lupus nephritis who have stable renal function. [54, 55] It may be used alone [54, 55] or sequentially after a 6-month course of IV cyclophosphamide. [56]

Administer IV cyclophosphamide monthly for 6 months and every 2-3 months thereafter, depending on clinical response. The usual duration of therapy is 2-2.5 years. Reduce the dose if the creatinine clearance is less than 30 mL/min. Adjust the dose depending on the hematologic response. [57, 58]  The gonadotropin-releasing hormone analog leuprolide acetate has been shown to protect against ovarian failure. [59]

Shorter courses and lower doses of IV cyclophosphamide are used currently, which reduces the overall toxicity of cyclophosphamide. Sequential therapy with monthly IV cyclophosphamide for 6 months followed by mycophenolate mofetil [56] or Euro-Lupus dosing, which is 500 mg of IV cyclophosphamide every 2 weeks for 3 months followed by azathioprine. [60]  Both of those regimens have been shown to be effective in proliferative lupus nephritis.

Appel et al studied 370 patients with lupus nephritis in a randomized open-label study and found no significant difference in clinical improvement was observed with mycophenolate mofetil compared with IV cyclophosphamide. [61] The study included induction and maintenance therapy, and both study groups received prednisone.

Azathioprine can also be used as a second-line agent, with dose adjustments depending on hematologic response.

Mycophenolate mofetil was found to be superior to azathioprine in maintaining control and preventing relapses of lupus nephritis in patients who have responded to induction therapy. [62]

In a 10-year follow-up of the MAINTAIN Nephritis Trial, which compared azathioprine and mycophenolate mofetil as maintenance therapy of proliferative lupus nephritis, Tamirou and colleagues found that the two treatments resulted in similar outcomes. Two deaths and one case of end-stage renal disease developed in the azathioprine group, versus three deaths and three cases of end-stage renal disease in the mycophenolate mofetil group. [63]

Class V

Patients with membranous lupus nephritis are generally treated with prednisone for 1-3 months, followed by tapering for 1-2 years if a response occurs. If no response occurs, the drug is discontinued. Immunosuppressive drugs are generally not used unless renal function worsens or a proliferative component is present on kidney biopsy specimens. Some clinical evidence indicates that azathioprine, cyclophosphamide, cyclosporine, and chlorambucil are effective in reducing proteinuria. Mycophenolate mofetil may also be effective. European guidelines recommend mycophenolate mofetil as first choice for class V disease, with calcineurin inhibitors (especially tacrolimus) as alternative options. [64]

In a study of membranous lupus nephritis, 38 patients were treated with corticosteroids and azathioprine; after 12 months of treatment, 67% of patients had a complete remission and 22% had a partial remission, with only 11% resistant to treatment. [65] Long-term follow-up of 12 years showed 19 episodes of renal flares. Retreatment with corticosteroids and azathioprine showed similar responses.


New Therapies

Belimumab (Benlysta) is an anti–B-lymphocyte stimulator [BLyS] monoclonal antibody). [66]  It is approved by the US Food and Drug Administration (FDA) to treat adults with active lupus nephritis who are receiving standard therapy.

Efficacy was based on a phase III, BLISS-LN trial that randomized patients (n=448) with lupus nephritis—including patients with focal (class III), diffuse (class IV), and membranous (class V) lupus nephritis—to receive either belimumab or placebo with standard therapy. The Primary Efficacy Renal Response (PERR) was significantly higher in the belimumab arm than the placebo arm at Week 52 (47% versus 35%, respectively) and Week 104 (43% versus 32%, respectively). Patients in the belimumab group also had improved outcomes, including complete renal response (CRR) over a 2-year period. [67]

Voclosporin (Lupkynis), a calcineurin inhibitor, is the first FDA-approved oral therapy used in combination with immunosuppressive therapy for lupus nephritis. Approval was based on data from 2 clinical trials, the phase III AURORA trial and the phase II AURA-LV trial. Both studies enrolled patients with lupus nephritis of Class III or IV (alone or in combination with Class V) or pure Class V.

The AURA-LV study randomized patients to placebo or an induction regimen that combined voclosporin with mycophenolate mofetil and low-dose oral corticosteroids. CRR at week 24 was achieved by 32.6% in the low-dose voclosporin group, 27.3% in the high-dose voclosporin group, and 19.3% in the placebo group. The CRR rate in the low-dose and high-dose voclosporin groups was higher compared with placebo at 48 weeks. [68]  

The phase III AURORA trial compared the efficacy and safety of voclosporin (23.7 mg twice daily) with placebo in combination with mycophenolate and low-dose oral corticosteroids. At 1 year, the renal response rate was higher in the voclosporin group than in the placebo group (40.8% vs 22.5%; odds ratio, 2.65; P < 0.001). In addition, the median time to the achievement of a urine protein-to-creatinine ratio below 0.5 mg/mg was significantly and clinically better with voclosporin than with placebo (169 vs 372 days; log rank < 0.001). [69]


Investigational Therapies for Lupus Nephritis and SLE


B-lymphocytes play a pivotal role in the pathogenesis of SLE, which makes rituximab, a B-lymphocyte–depleting therapy, an attractive therapeutic option in SLE and lupus nephritis. [70]  In meta-analyses, rituximab has proved effective, especially in lupus nephritis that is refractory to standard therapy. [71]  Most of the studies have been retrospective, but one prospective observational single-center cohort study demonstrated the efficacy of a steroid-sparing regimen of rituximab and mycophenolate mofetil for lupus nephritis. For the study, Condon et al treated 50 consecutive patients 2 doses of rituximab (1 g) and methylprednisolone (500 mg) on days 1 and 15, and mycophenolate mofetil for maintenance therapy. By 52 weeks, 52% of patients had achieved complete biochemical remission and 34% had achieved partial remission. [72]

However, despite wide clinical use, rituximab remains a controversial choice for lupus nephritis, due to the lack of robust supporting evidence and some negative results. For example, a randomized, double-blind, phase II/III trial of rituximab in moderately-to-severely active SLE (EXPLORER) failed to show differences compared with placebo, although a beneficial effect of rituximab was noted in the African-American and Hispanic subgroups. [73]   A randomized, double-blind, phase III trial of rituximab in active proliferative lupus nephritis (LUNAR) showed that rituximab therapy resulted in more responders and greater reductions in anti-DNA antibodies in increases in C3 and C4 levels, but it did not improve clinical outcomes after 1 year of treatment. [74]

Other anti-CD20 monoclonal antibodies

Other anti-CD20 monoclonal antibodies have been used experimentally for lupus nephritis; for example, in patients who respond to rituximab but develop intolerable adverse effects. Case series have described benefit with ofatumumab. [75, 76]  In a phase III trial of ocrelizumab for class III/IV lupus nephritis, overall renal response rates with ocrelizumab were numerically but not statistically significantly superior to those with placebo, and the trial was terminated early because of higher rates of serious infections in patients receiving ocrelizumab and background mycophenolate mofetil. [77]


Atacicept is a TACI-Ig fusion protein that inhibits BLyS and a proliferation-inducing ligand [APRIL]). [66] In early phase studies, atacicept was demonstrated to have biologic effects in patients with SLE, resulting in a dose-dependent reduction in B cells and immunoglobulin levels. [78]


Abetimus is a B-lymphocyte tolerogen that was found to be ineffective in preventing flares of lupus nephritis in a large controlled trial, although it did reduce levels of anti-DNA antibodies. [79]

Anticytokine therapies

Various anticytokine therapies have been proposed, including monoclonal antibodies directed against the following [66] :

  • Interferon-α
  • Interleukin (IL)-1
  • IL-6
  • IL-10
  • Tumor necrosis factor alpha (TNF-α)

Management of End-Stage Renal Disease

Patients with ESRD require dialysis and are good candidates for kidney transplantation (see Renal Transplantation). Patients with ESRD secondary to SLE represent 1.5% of all patients on dialysis in the United States. The survival rate among patients on dialysis is fair (5-year survival rate, 60-70%) and is comparable with that among patients on dialysis who do not have SLE.

Hemodialysis is preferred to peritoneal dialysis; several studies have documented higher levels of antibodies to double-stranded DNS (dsDNA), more thrombocytopenia, and higher steroid requirements in patients with SLE and ESRD who are on peritoneal dialysis. Hemodialysis also has anti-inflammatory effects with decreased T-helper lymphocyte levels. SLE is generally quiescent in patients on hemodialysis, although flares, including rash, arthritis, serositis, fever, and leukopenia may occur, necessitating specific treatment.


Kidney Transplantation

Patients with SLE account for 3% of all kidney transplantations in the United States. It is important ensure that the patient does not have active SLE disease at the time of transplantation. A 3-month period of dialysis is usually prudent in the event of spontaneous renal recovery.

Substantial evidence shows that patients with SLE fare worse than patients without SLE in terms of graft survival. Living-related allografts show better outcomes than cadaveric allografts. In patients with SLE, reasons for a more severe outcome after transplantation include recurrent lupus nephritis and concomitant antiphospholipid antibody syndrome resulting in allograft loss. [80]



It is frequently advisable to consult a nephrologist for renal biopsy or, if desired, for help in the management of renal disease.

The experience of pathologists in reading lupus nephritis biopsy specimens varies considerably. The most consistent readers of these specimens are usually found in larger academic centers that have substantial populations of patients with SLE.