Version July 2025
INTRODUCTION —
The optimal treatment of lupus nephritis (LN) varies with the classification of the morphological findings present on kidney biopsy. Immunosuppressive therapy is used to treat active focal (class III) or diffuse (class IV) LN or lupus membranous nephropathy (class V LN), or a combination of either focal or diffuse (class III/IV) and membranous (class V) LN. It is not usually used to treat minimal mesangial (class I), mesangial proliferative (class II), or advanced sclerosing (class VI) LN.
The treatment of focal or diffuse LN has two main components: initial therapy with antiinflammatory and immunosuppressive agents to slow or halt kidney injury, followed by long-term subsequent immunosuppressive therapy to control the chronic autoimmune processes of systemic lupus erythematosus and to foster repair of damaged nephrons.
The initial and subsequent therapy of focal or diffuse LN in adults will be reviewed here. Other aspects related to LN are discussed elsewhere:
●(See "Lupus nephritis: Diagnosis and classification".)
●(See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy".)
●(See "Kidney transplantation in adults: Issues related to lupus nephritis".)
●(See "Lupus nephritis: Therapy of lupus membranous nephropathy".)
The general approach to treatment of SLE in adults and the approach to treatment of childhood-onset SLE (cSLE), including patients with lupus nephritis, are discussed separately. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis" and "Systemic lupus erythematosus (SLE) in children: Treatment, complications, and prognosis".)
OVERVIEW OF THERAPY —
The goal of therapy in patients with focal (class III) or diffuse (class IV) lupus nephritis (LN) is resolution of inflammatory and immunologic activity. This is usually, but not always, reflected by a remission of clinical signs and symptoms and normalization of laboratory tests reflecting immunologic activity. (See 'Definitions of response' below.)
The overall approach to therapy is as follows:
●Importance of prompt therapy – Early therapy is crucial to prevent subsequent decreases in kidney function. A single episode of LN can lead to irreversible nephron loss, and every subsequent LN flare contributes to organ damage. Prompt diagnosis after the onset of nephritis and subsequent initiation of appropriate therapy are associated with improved outcomes, regardless of the histologic subclass [1,2]. By contrast, delaying therapy because of presumed mild disease can be associated with increased glomerular injury, progressive tubulointerstitial fibrosis, glomerulosclerosis, and therefore a lesser response to immunosuppressive drugs and a poorer long-term kidney outcome [1-3].
●General measures for all patients – All patients with focal or diffuse LN should receive hydroxychloroquine, unless contraindicated. General supportive measures are also given to slow nonimmunologic progression of the kidney disease. (See 'General measures for all patients' below.)
●Immunosuppressive therapy for active lupus nephritis – Patients whose kidney biopsy shows active lesions of focal or diffuse LN should receive immunosuppressive therapy. Those with solely chronic lesions without activity generally should not be treated with immunosuppressive therapy directed at the kidney and should rather receive supportive treatment for chronic kidney disease (CKD). However, these patients might require immunosuppressive therapy to treat extra-renal manifestations of their systemic lupus erythematosus (SLE). (See "Lupus nephritis: Diagnosis and classification", section on 'Activity and chronicity'.)
Patients who have evidence of concomitant lupus membranous nephropathy (LMN; class III + V or IV + V) should receive treatment directed against the active class III or IV component of the disease.
Immunosuppressive therapy for focal or diffuse LN consists of initial and subsequent phases (algorithm 1):
•Initial therapy – Initial therapy involves the administration of potent antiinflammatory and immunosuppressive drugs to achieve a clinical and immunologic renal response that will prevent progressive nephron loss and end-stage kidney disease (ESKD). The duration of initial therapy varies; it can be as short as three months or as long as one year but averages approximately six months. (See 'Initial immunosuppressive therapy' below.)
•Subsequent therapy – Once the desired renal response is achieved, less aggressive subsequent immunosuppressive therapy is given for a prolonged period to prevent relapse and continue to treat the systemic autoimmunity. (See 'Subsequent immunosuppressive therapy' below.)
●Prophylactic measures – Patients receiving immunosuppressive therapy are at risk for infectious and noninfectious toxicities and should receive additional prophylactic measures as appropriate. (See 'Treatment-related toxicity and prophylaxis' below and "Overview of infections associated with immunomodulatory (biologic) agents".)
●Monitoring treatment response – Patients receiving therapy for focal or diffuse LN should be routinely monitored to assess their response to treatment and evaluate for treatment-related toxicity. (See 'Monitoring response to therapy' below.)
Our approach is largely consistent with the Kidney Disease: Improving Global Outcomes (KDIGO) 2024 clinical practice guidelines for the management of LN, American College of Rheumatology (ACR) guidelines for LN, and the joint European Alliance of Associations for Rheumatology/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) guidelines [4-8].
GENERAL MEASURES FOR ALL PATIENTS
Control of SLE
Hydroxychloroquine — All patients with systemic lupus erythematosus (SLE), regardless of the degree and type of disease activity, should receive treatment with hydroxychloroquine unless contraindicated. The dosing, adverse effects, contraindications, and monitoring of hydroxychloroquine are provided elsewhere. (See "Antimalarial drugs in the treatment of rheumatic disease".)
Hydroxychloroquine has been associated with several benefits in patients with SLE, including improved survival, lower flare rates, and a reduction in organ damage accrual. This is discussed in detail separately. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Hydroxychloroquine for all patients'.)
Coordination with treatment of other SLE manifestations — Patients who have active focal or diffuse lupus nephritis (LN) often simultaneously have other manifestations of SLE. Some forms of immunosuppression may be more effective for certain disease manifestations, highlighting the importance of tailoring the treatment plan to each patient's specific manifestations. More information about the approach to drug therapy in SLE is provided elsewhere. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Approach to drug therapy'.)
Rarely, patients who have active LN may develop other severe, life-threatening complications of SLE that are typically treated with immunosuppressive agents that have not been proven to be effective for LN. As an example, patients with refractory catastrophic antiphospholipid antibody syndrome (CAPS) may receive rituximab or eculizumab, while those with refractory macrophage activation syndrome (MAS) may be treated with emapalumab or ruxolitinib. In such cases, providers must carefully weigh the cumulative risks of multiple immunosuppressive agents.
Supportive measures for kidney disease — General supportive measures in all patients with focal or diffuse LN include dietary sodium and protein restriction, blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, and treatment of dyslipidemia (if present). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may also be of benefit, although studies in patients with focal or diffuse LN are lacking. This approach is consistent with the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines for the management of LN [7]. These issues are discussed in greater detail elsewhere:
●Dietary sodium and protein restriction. (See "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Salt intake' and "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Protein intake'.)
●Antihypertensive therapy. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
●Renin-angiotensin system inhibition. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Renin-angiotensin system inhibitors'.)
●SGLT2 inhibitors. (See "Overview of the management of chronic kidney disease in adults", section on 'Patients with albuminuria'.)
●Lipid lowering. (See "Overview of the management of chronic kidney disease in adults", section on 'Dyslipidemia'.)
INITIAL IMMUNOSUPPRESSIVE THERAPY
Choice of initial therapy — Patients with focal or diffuse lupus nephritis (LN) who have active lesions on kidney biopsy should receive immunosuppressive therapy. Those with solely chronic lesions without activity generally should not be treated with immunosuppressive therapy and should rather receive supportive treatment for chronic kidney disease (CKD). However, these patients might require immunosuppressive therapy to treat extra-renal manifestations of their SLE.
For patients with active focal or diffuse LN, first-line options for initial therapy include the following:
●Dual immunosuppressive therapy – Dual immunosuppressive therapy consists of glucocorticoids plus one of the following agents:
•Mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS).
•Intravenous (IV) or, much less commonly, oral cyclophosphamide.
●Triple immunosuppressive therapy – Triple immunosuppressive therapy consists of glucocorticoids plus one of the following combinations of agents:
•Belimumab plus either MMF (or EC-MPS) or cyclophosphamide.
•A calcineurin inhibitor (CNI; voclosporin, tacrolimus, or cyclosporine) plus MMF (or EC-MPS).
For most patients, we suggest dual therapy with glucocorticoids plus MMF or triple therapy with glucocorticoids plus MMF and either belimumab or a CNI for initial therapy rather than other dual or triple therapies. Some UpToDate contributors prefer triple therapy with glucocorticoids plus MMF and a CNI in patients with higher baseline proteinuria (≥3 g/day) based on data suggesting a benefit with the addition of a CNI to MMF in such patients [9]. For patients who cannot or do not wish to receive MMF, dual or triple therapy with cyclophosphamide (ie, cyclophosphamide plus glucocorticoids or cyclophosphamide plus belimumab plus glucocorticoids, respectively) is a reasonable alternative.
Certain patient characteristics and preferences as well as potential toxicities of treatment may also impact the choice of initial therapy:
●Rapidly deteriorating kidney function and/or severe LN on biopsy – In patients who present with rapidly deteriorating kidney function and/or severe activity on kidney biopsy (eg, extensive crescents, capillary necrosis), some clinicians prefer a regimen that includes high-dose IV cyclophosphamide. However, data to support this approach in this patient population are very limited as such patients were generally excluded from clinical trials.
●Degree of proteinuria – Patients with higher baseline proteinuria (≥3 g/day) have been shown to benefit from triple therapy with glucocorticoids plus MMF and a CNI [9]. By contrast, belimumab may not be as effective in such patients [10].
●History of prior LN flares – Triple therapy with belimumab, glucocorticoids, and either MMF or cyclophosphamide may be useful for patients with a history of prior flares of LN, based on data from a post hoc analysis suggesting that belimumab reduces the risk of LN flare [10].
●Baseline kidney function – CNIs should be used with caution or avoided in patients who have significantly reduced kidney function (arbitrarily defined as an estimated glomerular filtration rate [eGFR] <45 mL/min/1.73 m2) because of the potential nephrotoxicity of these drugs. (See "Cyclosporine and tacrolimus nephrotoxicity".)
●Extrarenal manifestations of SLE – The presence of extrarenal manifestations of SLE may influence the selection of therapy for LN. As an example, belimumab has been found to be helpful for patients with severe or refractory arthritis; thus, triple therapy with belimumab, glucocorticoids, and either MMF or cyclophosphamide might be preferred over alternative regimens in that situation. In addition, regimens for LN that include intravenous cyclophosphamide may be preferable in patients who have certain severe, potentially life-threatening manifestations of SLE such as inflammatory or demyelinating central nervous system disease, severe diffuse alveolar hemorrhage, and/or severe myocarditis. Treatment of specific SLE manifestations is discussed in the respective disease manifestation topics. (See 'Coordination with treatment of other SLE manifestations' above and 'Concomitant thrombotic microangiopathy' below.)
●Exposure to glucocorticoids – Triple therapy with a CNI (particularly voclosporin), MMF, and glucocorticoids may facilitate more rapid tapering of glucocorticoids [11], which reduces exposure to glucocorticoids and their associated adverse effects. (See 'Treatment-related toxicity and prophylaxis' below.)
●Fertility – An MMF-based regimen is preferred for patients with concerns about fertility since cyclophosphamide may adversely affect fertility. However, MMF is teratogenic, and pregnancy in patients with LN should be deferred until achieving remission on medications that are compatible with pregnancy. (See "Pregnancy in women with systemic lupus erythematosus" and "Cyclophosphamide in rheumatic diseases: General principles of use and toxicity", section on 'Fertility preservation for adults'.)
●Adherence – For patients who may have difficulty adhering to oral therapy, an IV cyclophosphamide-based regimen may be preferred to an MMF-based regimen. (See 'Cyclophosphamide-based regimen' below.)
●Cost and availability – The addition of a third agent (eg, a CNI or belimumab) increases the cost of treatment [12], which may limit access for patients. This additional cost must be weighed against the high treatment costs associated with kidney failure. Furthermore, access to newer agents may be limited in certain countries.
Supportive evidence for these therapies comes from randomized trials and meta-analyses that have shown that the combination of glucocorticoids and either mycophenolate or IV cyclophosphamide (dual therapy) [13-22], and the addition of belimumab or a CNI to dual therapy (triple therapy) [11,23-27], improves kidney outcomes in patients with focal or diffuse LN. Trials comparing MMF and cyclophosphamide for initial therapy have not established that one is superior to the other [13,17]. Trials comparing triple therapy with dual therapy have shown a kidney benefit to triple immunosuppressive regimens, but the benefits are modest [11,23]. There are no trials comparing voclosporin with belimumab. These studies are presented in more detail in the sections below.
Despite the use of these regimens, rates of clinical response remain low [28]. Although definitions of clinical response have varied across studies, data from contemporary randomized trials have shown complete response rates of approximately 20 to 40 percent [28].
Dual immunosuppressive regimens — Dual immunosuppressive therapy consists of glucocorticoids plus either mycophenolate or cyclophosphamide.
Mycophenolate-based regimen
●Dosing – If a mycophenolate-based regimen is selected, we use a regimen similar to the one used in the Aspreva Lupus Management Study (ALMS) trial [13]. Specifically, we give 0.5 g of MMF twice daily for the first week, then 1 g twice daily for the second week. Some authors thereafter attempt to increase the total daily dose to 2.5 to 3 g, while other authors only increase the dose if the patient is not responding adequately to 2 g daily. For some patients who are unable to tolerate adequate doses of MMF due to gastrointestinal side effects (eg, nausea, abdominal pain, or diarrhea), enteric-coated mycophenolate sodium (EC-MPS) can be substituted for MMF (1 g of MMF is equivalent to 720 mg of EC-MPS). We usually continue mycophenolate at these doses for six months.
Mycophenolate should be given in combination with glucocorticoids. (See 'Glucocorticoid dosing and taper' below.)
We do not routinely obtain blood mycophenolic acid (MPA) levels to monitor therapy in patients with LN since there are no established thresholds for therapeutic efficacy. However, some clinicians may check a blood MPA level to confirm patient adherence to therapy. Additional information regarding dosing, monitoring, and adverse effects of mycophenolate can be found elsewhere. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)
●Efficacy – Several trials support the role of MMF as an effective alternative to cyclophosphamide for initial therapy of patients with focal or diffuse LN:
•The largest trial (ALMS) that compared initial therapy with MMF or cyclophosphamide included 370 patients with classes III through V LN (68 percent with class IV). Patients were randomly assigned to MMF (target dose 3 g/day) or IV cyclophosphamide (0.5 to 1 g/m2 in monthly pulses); all patients received daily glucocorticoids [13]. The mean urine protein-to-creatinine ratio (UPCR) was 4.1, and the mean serum creatinine was 1.1 mg/dL (100 micromol/L). At 24 weeks, the renal response (defined as a prespecified reduction in the UPCR to less than 3 or by at least 50 percent and stabilization or improvement in the serum creatinine) was similar between the two groups (56 percent in the MMF group versus 53 percent in the cyclophosphamide group). Other outcomes, including complete renal response, systemic disease activity, and safety were also similar.
•In a 2018 meta-analysis that included eight randomized trials comparing IV cyclophosphamide with MMF for initial therapy in over 800 patients with focal or diffuse LN, the mortality rate, incidence of ESKD, and relapse during initial therapy were similar between the two groups [17]. MMF may have produced a higher rate of complete responses (risk ratio [RR] 1.17, 95% CI 0.97-1.42), but this was not statistically significant. Major infections were also similar with both drugs, but MMF therapy resulted in less alopecia.
While these data support the efficacy of MMF as an alternative to cyclophosphamide for initial therapy, longer-term outcome data are available for cyclophosphamide. However, the long-term efficacy of MMF is supported by data from trials evaluating its use for subsequent therapy. (See 'Choice of subsequent therapy' below.)
Cyclophosphamide-based regimen
●Dosing – If a cyclophosphamide-based regimen is selected, most experts prefer to use the shorter (lower-dose) regimen implemented in the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study (ACCESS) and Euro-Lupus Nephritis Trial (ELNT) studies, rather than the longer (higher-dose) regimen implemented in the NIH trial.
•IV dosing – We prefer IV dosing over oral dosing based on published guidelines and our experience [7,8]. A more detailed discussion of CYC dosing, dose adjustments, adverse effects, and the use of mesna is presented elsewhere. (See "Cyclophosphamide in rheumatic diseases: General principles of use and toxicity", section on 'Intermittent (pulse) cyclophosphamide (most common)'.)
-Shorter, lower dose regimens – If the shorter, lower-dose regimen is used (as was done in the Euro-Lupus trial), IV cyclophosphamide is administered as 500 mg every two weeks for a total of six doses [14,29].
-Longer, higher dose regimens – If the longer, higher-dose regimen is used, pulse IV cyclophosphamide (0.5 to 1 g/m2) is administered monthly for six months [16]. If the leukocyte nadir after the first pulse of cyclophosphamide (usually 10 to 14 days postinfusion) is <3500 cells/microL and/or the absolute neutrophil count (ANC) is <1500 cells/microL, the dose at the next infusion should be reduced by 0.25 g/m2 body surface area or even transiently withheld if the counts are very low. If, on the other hand, the total white blood cell (WBC) nadir is ≥3500 cells/microL, the ANC is ≥1500 cells/microL, and the patient has not improved, the cyclophosphamide dose at the next infusion may be increased by 0.25 g/m2 body surface area. The maximum dose is 1 g/m2 body surface area although some UpToDate contributors to this topic would not exceed 1000 mg per dose.
•Oral dosing – Although most contributors to this topic prefer to use IV cyclophosphamide for initial therapy of LN, some experts use oral rather than IV cyclophosphamide [30]. If oral cyclophosphamide is used, the dose is typically 1 to 1.5 mg/kg per day, titrating up by 0.5 mg/kg per day every week up to 2 mg/kg per day (maximum dose 150 mg) if needed based on response, and continued for two to four months. The dose is reduced as needed to maintain a WBC count ≥3500 cells/microL and an ANC ≥1500 cells/microL. Additional information regarding oral cyclophosphamide dosing can be found elsewhere. (See "Cyclophosphamide in rheumatic diseases: General principles of use and toxicity", section on 'Daily cyclophosphamide (uncommonly used)'.)
Cyclophosphamide should be given in combination with glucocorticoids. (See 'Glucocorticoid dosing and taper' below.)
After initial treatment with cyclophosphamide, subsequent therapy commences with azathioprine or MMF rather than the longer course of cyclophosphamide used in the early National Institutes of Health (NIH) trials. (See 'Subsequent immunosuppressive therapy' below.)
●Efficacy – Several clinical trials have demonstrated a benefit of IV cyclophosphamide plus glucocorticoids compared with glucocorticoids alone or glucocorticoids with azathioprine on kidney survival among patients with focal or diffuse LN:
•Landmark trials performed at the NIH compared monthly IV cyclophosphamide plus prednisone with azathioprine plus prednisone or prednisone alone [15,18-22]. At 10 to 12 years, the probability of avoiding kidney failure among survivors was 90 percent with IV cyclophosphamide, 60 percent with azathioprine, and 20 percent with prednisone alone [15]. In the NIH and other trials, the outcomes with azathioprine were better than those with prednisone alone during the first 10 years of follow-up, but not during longer follow-up, and were inferior to cyclophosphamide [15].
The differences in outcome between IV cyclophosphamide plus glucocorticoids and glucocorticoids alone became apparent after several years. In one of the NIH trials, for example, treatment failure (defined as doubling of the serum creatinine, requiring supplemental immunosuppression, or death) was less likely with dual therapy than with methylprednisolone alone (RR 0.095, 95% CI 0.01-0.84) [19]. However, the treatment failure curves did not diverge until two to three years [19], and the ESKD curve did not diverge until five or more years [15].
•In a 2018 meta-analysis, cyclophosphamide plus glucocorticoids compared with glucocorticoids alone (most patients were from NIH trials) reduced the risk of doubling of the serum creatinine in four trials of 228 patients (24 versus 40 percent; RR 0.59, 95% CI 0.4-0.88), had no statistically significant effect on mortality in five trials of 226 patients (21 versus 17 percent; RR 0.98, 95% CI 0.53-1.82), and increased the risk of ovarian failure in three trials of 147 patients (47 versus 19 percent; RR 2.18, 95% CI 1.1-4.34) [17].
Given the concerns about cyclophosphamide toxicity, several trials have evaluated the efficacy of less intensive cyclophosphamide regimens and shown comparable outcomes [14,17,29,31-33]. The ELNT, for example, which enrolled primarily White patients with mild to moderate kidney function impairment (mean serum creatinine 1.15 mg/dL [102 micromol/L]), showed equivalent outcomes at a median of 41 months with the shorter (lower-dose [ie, 500 mg IV every two weeks for a total of six doses]) and longer (higher-dose) IV cyclophosphamide regimens, each followed by subsequent therapy with azathioprine [14]. The similarity in outcomes persisted at 10 years, regardless of baseline kidney function [34]. On multivariate analysis, a good early response to therapy was predictive of better long-term outcomes [35]. This lower-dose cyclophosphamide regimen was also effective in the ACCESS trial, which included a large proportion of Black patients and Hispanic patients [29].
Although pulse IV cyclophosphamide has been best studied for initial therapy in diffuse LN and is most widely used, daily oral cyclophosphamide has also been used [30,32,36,37], including in a short-course regimen followed by azathioprine or cyclosporine subsequent therapy [37].
Triple immunosuppressive regimens — Triple immunosuppressive therapy consists of glucocorticoids plus one of the following combinations:
●Belimumab plus either mycophenolate or cyclophosphamide
●A CNI (voclosporin, tacrolimus, or cyclosporine) plus mycophenolate
Belimumab plus mycophenolate or cyclophosphamide — Belimumab is a human monoclonal antibody that inhibits the soluble form of a B cell survival factor (known as BLyS or BAFF). Belimumab is US Food and Drug Administration (FDA) approved for the treatment of LN in combination with standard initial and subsequent therapy in adults and children over 5 years old.
●Dosing – Although studies of belimumab in patients with LN used the IV formulation, a subcutaneous form has also been approved for LN. IV belimumab is administered as 10 mg/kg every two weeks for three doses followed by maintenance dosing every four weeks. Subcutaneous belimumab is initiated as 400 mg once weekly for four doses and then 200 mg once weekly thereafter.
Belimumab is given in combination with glucocorticoids and either mycophenolate or cyclophosphamide. (See 'Mycophenolate-based regimen' above and 'Cyclophosphamide-based regimen' above and 'Glucocorticoid dosing and taper' below.)
●Efficacy – The addition of belimumab to initial and subsequent therapy has been shown to improve rates of renal response in patients with active LN. The efficacy and safety of belimumab was evaluated in a phase III multicenter trial that randomly assigned 448 patients with biopsy-proven, active class III, IV, or V LN to receive IV belimumab (10 mg/kg) or placebo, in addition to standard therapy (either IV cyclophosphamide [shorter, low-dose regimen] initial therapy followed by azathioprine subsequent therapy, or MMF for both initial and subsequent therapy) [23]. At week 104, the rate of complete renal response (defined as UPCR <0.5, an estimated glomerular filtration rate [eGFR] no worse than 10 percent below the preflare value or ≥90 mL/min/1.73 m2, and no use of rescue therapy) was higher in the belimumab group compared with the placebo group (30 versus 20 percent; OR 1.7, 95% CI 1.1-2.7), and the risk of a kidney-related event or death was lower in the belimumab group (hazard ratio [HR] 0.51, 95% CI 0.34-0.77). Rates of adverse effects were similar between the groups. A post-hoc analysis of this trial found that the higher rate of complete response with belimumab plus standard therapy was limited to individuals whose baseline UPCR was <3 g/g [10].
Calcineurin inhibitor plus mycophenolate — CNIs used for LN include tacrolimus and voclosporin. Although there is more experience with tacrolimus, voclosporin has the additional benefit of not requiring blood drug concentration monitoring. Some clinicians have used cyclosporine as an alternative CNI, but evidence to support this approach is more limited, and hirsutism is an undesirable side effect in young patients with SLE [38]. Tacrolimus and voclosporin have not been directly compared as combination therapy for LN. CNIs should be used with caution in patients with preexisting chronic kidney disease and eGFR ≤45 mL/min/1.73 m2 as well as in patients taking medications that are potent cytochrome P450 3A (CYP3A) inhibitors (table 1).
●Tacrolimus
•Dosing – When tacrolimus is used in combination with mycophenolate, we typically start at 1 to 2 mg orally twice daily and titrate up the dose, depending upon the clinical response (eg, reduction in proteinuria). We reduce the dose of tacrolimus if the patient experiences a >30 percent increase in serum creatinine. Some clinicians target a blood trough tacrolimus concentration of 5 to 7 ng/mL; other clinicians do not target specific blood levels and monitor tacrolimus concentrations to check for adherence or toxicity. However, levels that correlate with efficacy are not clear.
•Efficacy – The potential efficacy of CNIs is largely based on several trials including Chinese patients with LN, which compared a "multitarget" regimen of tacrolimus in combination with MMF or IV cyclophosphamide [24-27]. Only one trial has compared tacrolimus without MMF with IV cyclophosphamide for initial therapy [39]. However, important limitations to these trials include the short-term follow-up and the fact that proteinuria was used as a clinical endpoint. Tacrolimus may reduce proteinuria through nonimmune mechanisms (ie, hemodynamic and podocyte stabilizing mechanisms), and renal response in these studies was largely based on improvements in proteinuria. Thus, these limited data are insufficient to support the use of tacrolimus as first-line initial therapy for severe LN, except possibly for patients who cannot tolerate either cyclophosphamide or MMF, or in patients who are pregnant.
As an example, the largest of these trials compared a "multitarget" regimen, consisting of a combination of tacrolimus (4 mg/day), low-dose MMF (1 g/day), and prednisone, with a high-dose IV cyclophosphamide regimen and prednisone in 368 patients with LN (47 percent with focal or diffuse LN, 19 percent with lupus membranous nephropathy, and 34 percent with both) [26]. At 24 weeks, the rate of complete response (defined as 24-hour urine protein of 0.4 g or less, serum albumin of 3.5 g/dL or more, normal serum creatinine, and absence of an active urine sediment) was greater in the multitarget group compared with the IV cyclophosphamide group (46 versus 26 percent). The overall response rate (complete or partial response) was also higher with multitarget therapy (84 versus 63 percent). Serious adverse events, particularly infections, were more common with multitarget therapy (7 versus 3 percent), as was dropout due to adverse events (6 versus 2 percent).
In an extension of this trial, patients who achieved a complete or partial response at 24 weeks were assigned to receive subsequent therapy for 18 months [25]. Patients who had been treated with the multitarget regimen continued to receive tacrolimus, MMF, and prednisone (at lower doses), and those who had been treated with cyclophosphamide received azathioprine (2 mg/kg/day) plus prednisone. At 6, 12, and 18 months, rates of relapse were similar between the two groups; serum creatinine and eGFR also remained stable in both groups.
In the only trial comparing tacrolimus without MMF with high-dose IV cyclophosphamide for initial therapy, which included 314 Chinese patients with LN, the rate of complete response at 24 weeks was higher in the tacrolimus group (50 versus 36 percent, respectively) [39]. However, patients receiving tacrolimus experienced an increase in serum creatinine that was sustained for the duration of the trial (mean change from baseline 10.2 micromol/L [0.12 mg/dL] versus -5.6 micromol/L [-.06 mg/dL] with cyclophosphamide). Rates of serious treatment-emergent adverse events were lower in the tacrolimus group (19 versus 25 percent). Limitations to this study include the use of high-dose IV cyclophosphamide (rather than a shorter, lower-dose regimen), short-term follow-up, and reduction in proteinuria as an outcome measure.
●Voclosporin – Voclosporin is a next-generation calcineurin inhibitor that is structurally similar to cyclosporine but is more potent and does not require monitoring of drug levels. Voclosporin is FDA approved for the treatment of LN in combination with mycophenolate and glucocorticoids.
•Dosing – When voclosporin is used in combination with mycophenolate, it is administered at 23.7 mg orally twice daily. Dose adjustments are required in patients with kidney function impairment or mild to moderate hepatic impairment (Child-Pugh class A or B). Patients must have serum creatinine and eGFR assessed monthly during the first year of therapy with appropriate dose adjustments. Voclosporin should generally be avoided in patients with a baseline eGFR ≤45 mL/min/1.73 m2, unless benefit exceeds risk, and those with severe hepatic impairment (Child-Pugh class C). Monitoring of blood concentrations is not necessary with voclosporin. (See 'Follow-up evaluation' below.)
•Efficacy – The efficacy and safety of voclosporin in active LN were evaluated in a phase III, multicenter, randomized, double-blind controlled trial of 357 patients (61 percent with focal or diffuse LN, 14 percent with lupus membranous nephropathy, and 25 percent with both) [11]. Patients were randomly assigned to treatment with voclosporin (23.7 mg twice daily) or placebo for 52 weeks, in combination with MMF (1 g twice daily) and rapidly tapered low-dose prednisone. At 52 weeks, the rate of complete renal response (defined as a composite of UPCR of ≤0.5 mg/mg, eGFR ≥60 mL/min/1.73 m2 or no decrease of >20 percent from baseline eGFR, no use of rescue therapy, and no more than 10 mg prednisone equivalent per day for ≥3 consecutive days or for ≥7 days during weeks 44 through 52) was higher among patients treated with voclosporin compared with those receiving placebo (41 versus 23 percent). A subgroup analysis found that this benefit was also seen in patients with high levels of proteinuria (baseline UPCR ≥3 g/g) [9]. Serious adverse events, including infections, were comparable between the groups, and there were more deaths among those in the placebo group (5 versus 1 patient). A reduction in eGFR was seen in 26 percent of the voclosporin group and 9 percent of the placebo group (although reductions in eGFR of >30 percent were found in an equal number of both arms of the study); most reductions were readily reversible. Hypertension occurred in 19 and 9 percent of the voclosporin and placebo groups, respectively.
Longer-term safety and efficacy were reported in a double-blind extension of the above trial, in which 216 patients continued therapy with voclosporin or placebo in combination with MMF and low-dose prednisone for an additional two years [40]. Reductions in proteinuria achieved at the end of the initial trial were sustained in both groups at 36 months. Mean eGFR remained normal and stable in both groups. At 36 months, the rate of complete renal response was higher with voclosporin than with placebo (51 versus 39 percent), but this difference was not statistically significant. Rates of serious adverse events were similar in both treatment groups; hypertension and a decrease in eGFR occurred more frequently in the voclosporin group compared with the placebo group (8.6 versus 7.0 percent and 10.3 versus 5.0 percent, respectively). Of note, over three years, approximately half of patients required a dose reduction, and 20 percent had to stop therapy.
●Cyclosporine
•Dosing – When cyclosporine is used in combination with mycophenolate, we typically start at 100 to 200 mg orally twice daily and titrate up the dose, depending on the clinical response (eg, reduction in proteinuria). We reduce the dose of cyclosporine if the patient experiences a >30 percent increase in serum creatinine. Some clinicians target a blood cyclosporine concentration of 100 to 150 ng/mL; other clinicians do not target specific blood levels and monitor cyclosporine concentrations to check for compliance or toxicity.
•Efficacy – Limited data from one small randomized trial comparing cyclosporine with intravenous cyclophosphamide for initial and subsequent therapy reported similar rates of remission and relapse-free survival [38]. In the United States, tacrolimus has largely replaced cyclosporine as the calcineurin inhibitor use in LN due to more hirsutism with cyclosporine. However, cyclosporine may still be used in places where it is much less expensive than tacrolimus.
Glucocorticoid dosing and taper — There is no consensus about the best oral glucocorticoid regimen, and there are no data suggesting that one regimen is superior to another. However, given the adverse effects of long-term glucocorticoid therapy [41], lower-dose glucocorticoid regimens are generally preferred [7,8]. We typically administer IV pulse methylprednisolone (250 to 1000 mg daily for one to three days) prior to initiation of oral glucocorticoids to induce a rapid antiinflammatory effect and to facilitate more rapid glucocorticoid tapering. We then start oral prednisone (or its equivalent) at 0.3 to 0.5 mg/kg per day (maximum of 40 mg/day) and taper the dose to ≤7.5 mg/day (and preferably ≤5 mg daily) by three to six months [8].
This approach is based upon limited evidence showing that following initial IV pulse methylprednisolone, a lower starting dose of oral glucocorticoids may be as effective as higher doses [42-44]. As an example, in the voclosporin trial that led to FDA approval, patients were started on 20 to 25 mg of oral prednisone, and 80 percent were able to reduce their dose to 2.5 mg or less by month four of treatment [11]. In addition, a systematic review and meta-analysis of 50 individual control arms of clinical trials in patients with LN found a dose response relationship between the initial dose of oral glucocorticoids and the rates of complete response, serious infections, and mortality at six months [44]. There was a disproportionate increase in serious infections and mortality when patients received a starting dose of >40 mg/day of glucocorticoids in addition to pulse doses. These data highlight the importance of individualizing the glucocorticoid regimen for each patient to balance the potential risks and benefits of therapy.
Monotherapy with glucocorticoids is not appropriate. Prior to the introduction of cyclophosphamide as a therapy for focal or diffuse LN, the majority of patients were treated with glucocorticoid monotherapy, but mortality rates with this approach were high [15].
MONITORING RESPONSE TO THERAPY
Follow-up evaluation — During initial immunosuppressive therapy, we typically schedule follow-up visits every two to four weeks for the first three months. In stable patients, the duration between follow-up visits can then be extended to every two to three months. The goal of these visits is to evaluate the patient's response to therapy (ie, whether a clinical response and normalization of laboratory tests reflecting immunologic activity are achieved) and the toxicity of the regimen (ie, adverse effects, infections due to immunosuppression). Once patients are transitioned from their initial to their subsequent immunosuppressive regimen, we generally perform follow-up visits every three months to determine whether the patient is experiencing a flare or toxicity from therapy [4].
The following data are obtained during these follow-up visits:
●History and physical examination.
●Quantification of urine protein excretion (usually with a random spot urine protein-to-creatinine ratio [UPCR], but some experts occasionally perform a 24-hour urine).
●Serum creatinine (as well as a comprehensive metabolic profile). Patients receiving voclosporin should have serum creatinine measured monthly for the first year.
●Urinalysis (with microscopy).
●Serum complement levels (C3 and C4) and anti-double-stranded DNA (anti-dsDNA) antibody levels.
●Complete blood count (which is monitored every other week in patients receiving higher-dose cyclophosphamide) and liver function tests.
●Some experts also monitor erythrocyte sedimentation rate (ESR) as a nonspecific marker of disease activity in those whose anti-dsDNA antibody levels and/or serum complement levels do not return to normal. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Laboratory evaluation'.)
●Blood tacrolimus or cyclosporine trough levels (in patients receiving one of these agents). Trough levels are not required if voclosporin is used.
Based on these parameters, we closely monitor the patient’s clinical response to ensure that they are continuing to improve in terms of proteinuria reduction, kidney function, and clinical symptoms, as well as immunologic serologies (serum complement and anti-dsDNA levels) :
●If patients are improving, we aim to achieve target goals for proteinuria and kidney function as established by the 2019 European Alliance of Associations for Rheumatology (formerly known as European League Against Rheumatism)/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) guidelines [4,8,45-47]. While guidelines advise formally assessing these targets at three, six, and 12 months after the start of therapy, we follow patients more frequently than this while initiating therapy, as discussed above, and expect to see progressive, incremental improvements. These target measures are discussed below. (See 'Definitions of response' below.).
●If patients are not improving, we assess for the possibility of treatment resistance or nonadherence. (See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy".)
Definitions of response — There is no consensus definition of clinical response in patients with focal or diffuse lupus nephritis (LN) who are treated with immunosuppressive therapy. Commonly used definitions that we use in our assessment of patient response include the following (see 'Follow-up evaluation' above):
●Complete renal response – Most definitions have incorporated the following elements:
•A substantial reduction in proteinuria – We target a decrease in proteinuria of ≥25 percent by three months, ≥50 percent by six months, and proteinuria below 0.5 to 0.7 g/day by 12 months of initial therapy. Patients with nephrotic-range proteinuria at baseline may require an additional 6 to 12 months to reach complete clinical response. These targets are consistent with the 2019 EULAR/ERA-EDTA guidelines [4,8,45-47].
Clinical studies have used various definitions of a proteinuria response [13,14,29,48-52]. However, more contemporary studies have found that a proteinuria level of <0.7 to 0.8 g/day at month 12 after initiation of initial therapy was the best predictor of a favorable long-term kidney outcome [49,51,52].
•Improvement or stabilization of kidney function – We target improvement or stabilization in estimated glomerular filtration rate (eGFR), with no more than a 20 percent decline below the pre-flare value. Kidney function in patients with a complete clinical response has been defined differently in different studies, including a normal serum creatinine [13], a serum creatinine <1.2 mg/dL (106 micromol/L) [29], a serum creatinine ≤1.4 mg/dL (124 micromol/L) [48], or a serum creatinine within 15 to 25 percent of the baseline value [29,50].
•Improvement of the urinary sediment – We believe that attaining an inactive urinary sediment (ie, no or rare dysmorphic red blood cells [RBCs] and no RBC casts) is an essential component of a complete response. In clinical studies, an improvement in the urinary sediment is also part of some, but not all, definitions of complete response. Several studies specified a reduction in the number of RBCs to ≤10 high-power field or ≤5 RBC/high-power field [48,50], whereas others also required the absence of RBC casts [13]. It is important to recognize that urinary RBCs are not always indicative of glomerular injury, because they can originate from multiple sources in the genitourinary tract.
●Partial renal response – The definition of partial response is less stringent than that for complete response; most definitions require a reduction in proteinuria of ≥50 percent from baseline and to less than 3.5 g/day. As with a complete renal response, there should also be improvement or stabilization in eGFR, with no more than a 20 percent decline below the pre-flare value.
●No response – No response is defined as no complete or partial renal response after 6 to 12 months of starting therapy.
In addition to a clinical response, some experts also aim for normalization of serum complement levels and anti-dsDNA antibody titers. LN is part of a systemic autoimmune disease and, as such, treatment goals should include resolution of systemic and organ-specific immune system activation. At present, the main clinical markers available to assess this include complement and anti-dsDNA levels. These markers are imperfect with only modest sensitivity and specificity for immune system activation. Nonetheless, resolution of hypocomplementemia (if present) and decline of anti-dsDNA autoantibody titers (if elevated) provide increased confidence that therapy is working systemically. (See "Acquired disorders of the complement system", section on 'Systemic lupus erythematosus' and "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP", section on 'Titer, pathogenicity, and disease activity'.)
A clinical “response” is not synonymous with histologic “remission”. Complete remission can only be established by a repeat kidney biopsy demonstrating the absence of active inflammatory lesions. In some studies, repeat biopsies have demonstrated a discordance between clinical and histologic disease activity [53,54]. Potential reasons for this discordance include the following scenarios:
●Laboratory measures of lupus nephritis such as eGFR and proteinuria may improve despite persistent LN, leading to a complete renal response but ongoing immunologic activity on biopsy.
●Proteinuric chronic kidney disease can result from irreversible scarring despite resolution of inflammation, leading to histologic remission without a complete renal response.
●Hematuria may persist for various reasons (for example, cyclophosphamide-induced bladder injury or an underlying diagnosis of thin basement membrane nephropathy), leading to histologic remission without a complete renal response.
Thus, some experts routinely perform repeat kidney biopsies in their patients treated for focal or diffuse LN (regardless of the clinical response to therapy). However, in common practice, most patients treated for focal or diffuse LN do not undergo repeat kidney biopsies to determine the histologic effects of therapy. Rather, patients are typically followed with clinical measures such as serum creatinine, urine protein excretion, and urine microscopy. These parameters are used to judge the clinical response to therapy. (See 'Follow-up evaluation' above.)
The importance of achieving a clinical response is discussed elsewhere in this topic. (See 'Prognosis and outcomes' below.)
SUBSEQUENT IMMUNOSUPPRESSIVE THERAPY —
After a complete or partial response has been achieved with initial therapy (see 'Definitions of response' above), patients are switched to a subsequent regimen to decrease the risk of flares and developing end-stage kidney disease (ESKD). Patients with no response should be evaluated to determine if they have resistant disease. (See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy", section on 'Evaluation for resistant disease'.)
The importance of continuing immunosuppressive therapy after initial therapy is highlighted by the fact that up to 50 percent of patients with focal or diffuse lupus nephritis (LN) relapse following reduction in or cessation of immunosuppressive therapy [55-60]. The relapse rates range from 5 to 15 per 100 patient-years, with an average of approximately 8 per 100 patient-years for the first five years of follow-up [60]. Relapse is more common when partial rather than complete response is obtained with initial therapy. (See "Lupus nephritis: Treatment of relapsing focal or diffuse lupus nephritis".)
Choice of subsequent therapy — For most patients who achieve a renal response after initial immunosuppressive therapy, we suggest mycophenolate mofetil (MMF) rather than azathioprine for subsequent therapy. Although randomized trials have shown that the mortality and rates of ESKD are similar for MMF and azathioprine, the risk of relapse appears to be higher for azathioprine. However, azathioprine is preferred for patients who want to become pregnant; MMF should be avoided in pregnancy since it is associated with an increased risk of congenital malformations and spontaneous abortion. Azathioprine is also a reasonable option for patients who cannot tolerate and/or afford the cost of MMF. MMF would be the preferred medication for patients with gout who require treatment with allopurinol. (See "Safety of rheumatic disease medication use during pregnancy and lactation" and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Xanthine oxidase inhibitors'.)
Patients who are intolerant to both MMF (and enteric-coated mycophenolate sodium [EC-MPS]) and azathioprine can be treated with cyclosporine or tacrolimus. In one trial, cyclosporine was as effective as azathioprine but was associated with more adverse effects [37].
Patients who received a triple immunosuppressive regimen containing either belimumab or a calcineurin inhibitor (CNI) for initial therapy should continue to receive belimumab or the CNI as part of subsequent therapy. (See 'Triple immunosuppressive regimens' above and 'Dosing and duration of subsequent therapy' below.)
The use of MMF and azathioprine for subsequent therapy is based on studies that demonstrated that treatment with either agent was more effective and less toxic than treatment with IV cyclophosphamide for preventing kidney failure or death [33]. MMF and azathioprine have also been directly compared in several trials.
The best data come from a meta-analysis of six trials involving 514 patients, three of which compared MMF with azathioprine for subsequent therapy [17,61]. Although the risk of mortality or ESKD was similar between the MMF and azathioprine groups, the risk of relapse was higher in patients who received azathioprine (RR 1.83, 95% CI 1.24-2.7). The rate of adverse effects was similar with both drugs. Details of the three trials included in this meta-analysis that directly compared MMF with azathioprine are as follows [33,62,63]:
●The MAINTAIN Nephritis Trial was a randomized, open-label trial that included 105 European patients (83 White individuals) with biopsy-proven LN and urinary protein excretion exceeding 500 mg/day [62]. Diffuse LN was present in 61, focal LN was present in 33, and concomitant lupus membranous nephropathy (LMN) was present in 11; there were no patients with pure LMN. At three years, the rate of renal relapse was similar between the two groups. In addition, protocol biopsies at two years revealed no significant histologic differences between the groups [64]. Adverse events were similar in the two groups except for leukopenia and anemia, which occurred more frequently in the azathioprine group (14 versus 2 patients).
Ten-year follow-up data from the MAINTAIN trial confirm similar efficacy between MMF and azathioprine as subsequent therapy agents. The time to renal flare, ESKD, or death were similar for MMF and azathioprine groups [45].
●The ALMS Maintenance Trial was a multinational study in which 227 patients who had achieved a renal response with either MMF or monthly pulse cyclophosphamide were randomly assigned to MMF or azathioprine as subsequent therapy for 36 months [63]. Among patients who responded to initial therapy with either MMF or cyclophosphamide, treatment failure at 36 months (defined by renal relapse, the need to intensify therapy, doubling of the serum creatinine, or death) was lower with MMF compared with azathioprine groups (16 versus 32 percent). The superiority of MMF was independent of the type of initial therapy, race, or region.
●In the third randomized trial, 59 patients with severe LN (46 with diffuse, 12 with focal, and 1 with LMN) received initial therapy IV pulse cyclophosphamide and glucocorticoids [33]. Renal response was achieved in 83 percent, and patients who responded early had fewer cycles of cyclophosphamide. The patients were then randomly assigned to subsequent therapy with either MMF (500 to 3000 mg/day), azathioprine (1 to 3 mg/kg per day), or IV cyclophosphamide (0.5 to 1 g/m2 every three months) in combination with prednisone.
At six-year follow-up, the event-free survival rate for the composite endpoint for patient and kidney survival was higher with MMF and azathioprine compared with cyclophosphamide (90 and 80 versus 45 percent), which was also associated with more infections and a higher incidence of amenorrhea. Seventeen patients (29 percent) had a renal relapse (three, six, and eight patients in the MMF, azathioprine, and cyclophosphamide groups, respectively). The relapse rate was significantly higher with cyclophosphamide compared with MMF.
When to start subsequent therapy — For patients who have achieved a complete or partial renal response after initial immunosuppression therapy, the timing of initiation of subsequent therapy depends upon the initial therapy regimen used:
●Cyclophosphamide for initial therapy – In patients who receive IV cyclophosphamide as part of initial therapy, subsequent therapy is started two to four weeks after the last dose of cyclophosphamide.
In patients who receive oral cyclophosphamide as initial therapy, subsequent therapy is initiated immediately after discontinuation of cyclophosphamide.
●MMF for initial therapy – In patients who receive MMF as part of initial therapy, the dose of MMF is gradually lowered over time, usually starting after six months of therapy at the initial dose. The long-term dose of mycophenolate is usually lower than the initial dose. As an example, the long-term dose is often 1000 to 2000 mg/day, whereas the initial dose is often 2000 to 3000 mg/day.
Dosing and duration of subsequent therapy — The optimal duration of subsequent therapy is unknown. Subsequent therapy is typically administered for at least three years [7,8]. Our approach to the dosing and duration of subsequent therapy is based upon the protocols used in the trials presented above (see 'Choice of subsequent therapy' above):
●Mycophenolate mofetil – The usual subsequent therapy dose of MMF is 1000 mg twice daily. The dose may be tapered over time in stable patients. In one trial, the MMF dose was 1500 mg/day in the first year, 1000 to 1250 mg/day in the second year, and 500 to 1000 mg/day in the third year [33]. For some patients who are unable to tolerate adequate doses of MMF due to gastrointestinal side effects (eg, nausea, abdominal pain, or diarrhea), EC-MPS can be substituted for MMF (1 g of MMF is equivalent to 720 mg of EC-MPS). Additional information regarding dosing, monitoring, and adverse effects of mycophenolate can be found elsewhere. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)
●Azathioprine – The azathioprine dose is 2 mg/kg per day to a maximum of 150 to 200 mg/day. Some clinicians perform testing for thiopurine methyltransferase (TPMT) and NUDT15 prior to initiation of azathioprine. Additional information regarding dosing, monitoring, and adverse effects of azathioprine can be found elsewhere. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)
●Low-dose glucocorticoids – Low-dose oral prednisone (or its equivalent) is continued in most patients receiving subsequent therapy. The goal is to attain the minimum prednisone dose required for control of extrarenal manifestations, which varies among patients. In different trials, the extended prednisone dose ranged from 2.5 mg daily to 0.2 mg/kg per day [11,14,33,37,40,55].
Patients who remain asymptomatic can be slowly tapered off prednisone, and approaches vary. Our goal is to decrease the prednisone dose to ≤7.5 mg daily (and preferably ≤5 mg daily) by three to six months and then slowly taper as tolerated by the patient and their extrarenal needs. However, some clinicians prefer prolonged low-dose prednisone therapy (eg, 5 mg/day or less).
●Continuation of belimumab or a CNI – Patients who received a triple immunosuppressive regimen containing either belimumab or a CNI for initial therapy should continue to receive belimumab or the CNI as part of subsequent therapy. The optimal duration of therapy with these agents is uncertain. In the trial evaluating use of belimumab in combination with standard therapy, belimumab was administered for up to two years [23]. Data on the continuous use of voclosporin extends to three years, and in this study, 20 percent of patients had to stop therapy while half required a dose reduction [11,40]. Dosing of these agents is discussed above. (See 'Triple immunosuppressive regimens' above.)
TREATMENT-RELATED TOXICITY AND PROPHYLAXIS —
Immunosuppressive therapy with cyclophosphamide, mycophenolate mofetil (MMF), calcineurin inhibitors (CNIs), and/or high-dose glucocorticoids has both infectious and noninfectious toxicities that warrant additional prophylactic measures.
●Vaccinations for all patients - Patients receiving immunosuppressive therapy for lupus nephritis (LN) are at increased risk for infection and should receive age-appropriate vaccinations for immunosuppressed individuals. These are discussed separately. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults", section on 'Approach to vaccination' and "Overview of infections associated with immunomodulatory (biologic) agents".)
●Prophylaxis for specific immunosuppressive agents
•Glucocorticoids – Patients receiving systemic glucocorticoids are at risk for several adverse effects on multiple organ systems (table 2). These adverse effects and potential interventions to minimize them (table 3) are discussed in detail separately. (See "Major adverse effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Patients receiving a glucocorticoid dose equivalent to ≥20 mg of prednisone daily for one month or longer along with other immunosuppressive therapies should receive prophylaxis for Pneumocystis jirovecii (PJP) pneumonia. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
•Cyclophosphamide – Cyclophosphamide is associated with a variety of toxicities, including hematologic toxicity, infection, gonadal toxicity, malignancy, alopecia, and bladder toxicity. These toxicities and measures for the prevention of cyclophosphamide-induced bladder and gonadal toxicity are discussed separately. (See "Cyclophosphamide in rheumatic diseases: General principles of use and toxicity", section on 'Adverse effects' and "Cyclophosphamide in rheumatic diseases: General principles of use and toxicity", section on 'Pretreatment considerations'.)
Patients receiving cyclophosphamide, especially when combined with glucocorticoids, should receive prophylaxis for Pneumocystis jirovecii (PJP) pneumonia. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
SPECIAL POPULATIONS
Pregnant patients — Ideally, disease activity in systemic lupus erythematosus (SLE) should be quiescent for six months on medications compatible with pregnancy before a patient with SLE attempts to conceive. However, SLE flares are still possible during pregnancy. (See "Pregnancy in women with systemic lupus erythematosus", section on 'Preconception counseling'.)
When considering treatment options in pregnant patients, both cyclophosphamide and mycophenolate should be avoided because of the possible risk of congenital malformations. There is no optimal regimen for initial therapy of focal or diffuse LN during pregnancy; treatment options include a combination of glucocorticoids, calcineurin inhibitors (tacrolimus or cyclosporine), and azathioprine. In general, dosing and drug monitoring of these agents in pregnant patients are similar to that in nonpregnant patients. Pharmacokinetic factors, such as volume of distribution and metabolism, are altered with pregnancy, and drug levels require more frequent monitoring and adjustment. Voclosporin should not be used in pregnancy due to the alcohol content of its drug formulation, and data on the use of belimumab are very limited.
In patients with lupus nephritis who are not pregnant but are interested in becoming pregnant, medications may need to be adjusted as outlined in the table (table 4).
A more detailed discussion of the issues related to pregnancy in patients with LN and the safety of immunosuppressive drugs to treat active SLE during pregnancy and lactation are discussed in detail separately:
●(See "Pregnancy in women with systemic lupus erythematosus".)
●(See "Safety of rheumatic disease medication use during pregnancy and lactation".)
Both focal or diffuse LN and lupus membranous nephropathy — We treat patients with both focal or diffuse LN and lupus membranous nephropathy (class III + V or class IV + V) with the same approach as used for those with focal or diffuse LN alone. (See 'Overview of therapy' above.)
The treatment of pure lupus membranous nephropathy (without class III or IV LN) is presented separately. (See "Lupus nephritis: Therapy of lupus membranous nephropathy".)
Concomitant thrombotic microangiopathy — Some patients with focal or diffuse LN may present with concomitant thrombotic microangiopathy (TMA), either diagnosed by kidney biopsy or by laboratory findings. In such patients, it is important to investigate the underlying etiology of the TMA. Potential causes of TMA in patients with systemic lupus erythematosus (SLE) include SLE-associated thrombotic thrombocytopenic purpura (TTP), complement-mediated TMA, and antiphospholipid antibody syndrome. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
In general, the treatment of patients with LN and concomitant TMA should include management of the underlying etiology of TMA as well as concurrent treatment of LN (algorithm 1). The presence of concomitant TMA does not influence the choice of immunosuppressive therapy for LN. The management of specific forms of TMA is discussed separately:
●SLE-associated TTP (see "Immune TTP: Initial treatment")
●Complement-mediated TMA (see "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS")
●Antiphospholipid antibody syndrome nephropathy (see "Antiphospholipid syndrome: Management")
PROGNOSIS AND OUTCOMES —
Lupus nephritis (LN) is associated with considerable morbidity and mortality caused by either irreversible kidney damage from inflammatory injury or prolonged treatment with glucocorticoids and other immunosuppressive agents.
●Mortality – Patients with lupus nephritis (LN) have a higher risk of mortality compared with the general population. In one population-based study that included 72 patients with incident LN between 1976 and 2018, survival was 89 percent at 5 years and 70 percent at 10 years after diagnosis [65]. Compared with the general population, patients with LN had a sixfold higher rate of mortality (standardized mortality ratio 6.33, 95% CI 1.81-9.89). The most common cause of death was infection, followed by systemic lupus erythematosus (SLE) disease activity and cardiovascular disease.
Attaining a complete or partial response is associated with better long-term patient survival. In a report from the Lupus Nephritis Collaborative Study Group of 86 patients with severe LN, patients who attained a complete response (ie, an inactive urine sediment, a serum creatinine ≤1.4 mg/dL [124 micromol/L], and protein excretion ≤330 mg/day) or partial response (a 50 percent reduction in proteinuria to less than 1.5 g/day and stable serum creatinine) had higher rates of patient survival compared with those who had no response (95 and 76 versus 46 percent at 10 years, respectively) [48,66].
Among patients who progress to end-stage kidney disease (ESKD), patient survival with either hemodialysis or continuous ambulatory peritoneal dialysis appears to be similar to that in the general population of patients with ESKD [67-69]. In an analysis of 11,023 patients with ESKD and SLE initiating peritoneal dialysis or hemodialysis, there was a similar overall mortality between the two groups of 21 to 22 percent over three years. This was also true for cardiovascular- and infection-related mortality [70]. There is, however, an increased risk of death during the first three months of dialysis due primarily to sepsis and other complications of high-dose immunosuppressive therapy [68]. In addition, peritoneal dialysis is associated with an increased risk of peritonitis and non-catheter-related infection [71,72].
●End-stage kidney disease – Even with aggressive therapy, some patients with focal or diffuse LN will have a progressive decline in kidney function leading ESKD. In one population-based study of 72 patients with incident LN, the cumulative incidence of ESKD was 10 percent at 5 years and 13 percent at 10 years [65].
Attaining a complete or partial response is associated with better kidney survival. In the report from the Lupus Nephritis Collaborative Study Group cited above, patients who attained a complete response or partial response had higher rates of kidney survival compared with those who had no response (94 and 45 versus 19 percent at 10 years, respectively) [48,66].
Clinical risk factors for progression, evident at the time of initial presentation, include an elevated serum creatinine, hypertension, nephrotic-range proteinuria, anemia with a hematocrit below 26 percent, nonadherence to therapy, having noncommercial health insurance (in the United States), and being a Black patient or a Hispanic patient [1,73-77].
The severity of acute and chronic tubulointerstitial disease and interstitial inflammation, as well as the presence of cellular crescents, also correlate with long-term prognosis in LN, as they do in many other chronic progressive glomerular diseases [1,75,78,79]. (See "Secondary factors and progression of chronic kidney disease", section on 'Tubulointerstitial fibrosis'.)
Risk factors for progression that become evident after initial presentation and during therapy are the frequency and severity of relapses (renal flares) and the degree to which the abnormal features of kidney involvement are controlled (complete or partial response of proteinuria, hematuria, and the severity of azotemia). A complete renal response based upon these clinical criteria may or may not correspond to a histologic complete remission. Persistent isolated C3 hypocomplementemia (without C4 hypocomplementemia) at six months after kidney biopsy has also been associated with a higher risk of ESKD in patients with focal or diffuse LN [80].
●Cardiovascular disease – Patients with LN have an increased risk of atherosclerotic cardiovascular disease compared with patients with SLE who do not have LN. In one population-based cohort study of 1644 patients with incident SLE (233 with a diagnosis of LN during follow-up), those with LN had a higher risk of myocardial infarction (hazard ratio [HR] 8.5, 95% CI 2.2-33) and cardiovascular mortality (HR 4.9, 95% CI 1.8-13.7) but not stroke [81]. Another case control study found a two-fold higher risk of carotid plaques among patients with LN when compared with age-matched patients with SLE who do not have LN [81,82].
●Impact of social determinants of health on outcomes – Adverse social determinants of health (SDoH) have been associated with worse outcomes among patients with LN. In a meta-analysis of 13 studies that assessed the impact of four SDoH domains (individual [eg, insurance], health care [eg, fragmented care], community [eg, neighborhood socioeconomic status], and health behaviors [eg, smoking]) on outcomes, patients with any adverse SDoH had a 1.5-fold higher odds of poor LN outcomes (death, ESKD, or cardiovascular disease) than those without any adverse SDoH [83]. The presence of ≥2 adverse SDoH had a multiplicative negative effect; as an example, Black patients with public insurance and/or with care fragmentation had 12-fold higher odds of poor LN outcomes.
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults" and "Society guideline links: Systemic lupus erythematosus".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Lupus and kidney disease (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Overview – The goal of therapy in patients with focal (class III) or diffuse (class IV) lupus nephritis (LN) is resolution of inflammatory and immunologic activity. Patients who have active lesions on kidney biopsy should receive immunosuppressive therapy, while those with solely chronic lesions without activity generally should not receive immunosuppressive therapy and should rather receive supportive treatment for chronic kidney disease (CKD). However, these patients might require immunosuppressive therapy to treat extra-renal manifestations of their systemic lupus erythematosus (SLE). Patients who have evidence of concomitant lupus membranous nephropathy (LMN; class III + V or IV + V) should receive treatment directed against the active class III or IV component of the disease. (See 'Overview of therapy' above.)
●General measures for all patients – All patients with SLE, regardless of the degree and type of disease activity, should receive treatment with hydroxychloroquine unless contraindicated. Patients with focal or diffuse LN often simultaneously have other manifestations of SLE, and treatment plans should be tailored to each patient’s specific manifestations. Supportive measures in all patients with LN include dietary sodium and protein restriction, blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, and treatment of dyslipidemia. (See 'General measures for all patients' above.)
●Initial immunosuppressive therapy – For most patients with active focal or diffuse LN, we suggest dual therapy with glucocorticoids plus mycophenolate mofetil (MMF) or triple therapy with glucocorticoids plus MMF plus either belimumab or a calcineurin inhibitor (CNI; voclosporin, tacrolimus, or cyclosporine) as initial treatment rather than other dual or triple therapies (Grade 2C) (algorithm 1). Some UpToDate contributors prefer triple therapy with glucocorticoids plus MMF and a CNI in patients with higher baseline proteinuria (≥3 g/day). For patients who cannot or do not wish to receive MMF, dual or triple therapy with cyclophosphamide (ie, cyclophosphamide plus glucocorticoids or cyclophosphamide plus belimumab plus glucocorticoids, respectively) is a reasonable alternative. Certain patient characteristics and preferences as well as potential toxicities of treatment may also impact the choice of therapy. (See 'Choice of initial therapy' above.)
●Monitoring response to therapy – During initial immunosuppressive therapy, we typically schedule follow-up visits every two to four weeks for the first three months. In stable patients, the duration between follow-up visits can then be extended to every two to three months. The goal of these visits is to evaluate the patient's response to therapy (ie, whether a clinical renal response and normalization of laboratory tests reflecting immunologic activity are achieved) and the toxicity of the regimen (ie, adverse effects, infections due to immunosuppression). Once patients are transitioned from their initial to their subsequent immunosuppressive regimen, we generally perform follow-up visits every three months to determine whether the patient is experiencing a flare or toxicity from therapy. (See 'Monitoring response to therapy' above.)
●Subsequent immunosuppressive therapy – After a complete or partial response has been achieved with initial therapy, patients are switched to a subsequent regimen to prevent relapse and decrease the risk of developing end-stage kidney disease (ESKD). For most patients who achieve a renal response after initial immunosuppressive therapy, we suggest MMF rather than azathioprine for subsequent therapy (Grade 2B). Although randomized trials have shown that the mortality and rates of ESKD are similar for MMF and azathioprine, the risk of relapse appears to be higher for azathioprine. However, azathioprine is preferred for patients who want to become pregnant; MMF should be avoided in pregnancy since it is associated with an increased risk of congenital malformations and spontaneous abortion. Azathioprine is also a reasonable option for patients who cannot tolerate and/or afford the cost of MMF. Patients who received a triple immunosuppressive regimen containing either belimumab or a CNI for initial therapy should continue to receive belimumab or the CNI as part of subsequent therapy, although the optimal duration for these agents is uncertain. (See 'Choice of subsequent therapy' above.)
●Treatment-related toxicity and prophylaxis - Immunosuppressive therapy with cyclophosphamide, MMF, CNIs, and/or high-dose glucocorticoids has both infectious and noninfectious toxicities that warrant additional prophylactic measures. (See 'Treatment-related toxicity and prophylaxis' above.)
ACKNOWLEDGMENTS —
The UpToDate editorial staff acknowledges Peter H Schur, MD, who contributed to earlier versions of this topic review.
The UpToDate editorial staff acknowledges the help of the following panel of reviewers who helped to address questions in the June 16, 2021 update of this topic: Bradley M Denker, MD (Nothing to disclose), Mark A Perazella, MD, FACP (Nothing to disclose), and David S Pisetsky, MD, PhD (Grant/Research/Clinical Trial Support: Immunovant [Lupus]. Consultant/Advisory Boards: BMS [DSMB – Lupus, psoriatic arthritis]; DILIsym [Drug-induced liver injury]; Immunovant [Lupus].).
