Version May 2024
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), whereas 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 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".)
GENERAL PRINCIPLES
Goals of therapy — The goal of immunosuppressive therapy is resolution of inflammatory and immunologic activity, with achievement of a complete response.
Definitions of response — There is no consensus definition of complete response in patients with focal or diffuse lupus nephritis (LN) who are treated with immunosuppressive therapy. Most definitions of complete response have incorporated the following elements:
●A substantial reduction in protein excretion – Clinical studies have used various definitions of a proteinuria response. The Lupus Nephritis Collaborative Study Group, for example, defined a complete proteinuria response as protein excretion ≤0.33 g/day [1]. Large randomized trials such as the Aspreva Lupus Management Study (ALMS), Lupus Nephritis Assessment with Rituximab (LUNAR), and Abatacept and Cyclophosphamide Combination Efficacy and Safety Study (ACCESS) trials defined a complete proteinuria response as ≤0.5 g/day [2-4], whereas the Euro-Lupus Nephritis Trial (ELNT) used a definition of <1.0 g/day [5].
Subsequent studies 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 [6-8]. In light of these data, the Belimumab International Study in Lupus Nephritis (BLISS-LN), which evaluated the addition of belimumab to standard therapy for initial therapy of LN, utilized a proteinuria level of ≤0.7 g/day as a component of the renal response primary efficacy endpoint [9].
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 recommend as goals of therapy 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 [10,11].
●Improvement or stabilization of the serum creatinine – Kidney function in patients with a complete clinical response has also been defined differently in different studies, including a normal serum creatinine [2], a serum creatinine <1.2 mg/dL (106 micromol/L) [3], a serum creatinine ≤1.4 mg/dL (124 micromol/L) [1], or a serum creatinine within 15 to 25 percent of the baseline value [3,4].
●Improvement of the urinary sediment – Some but not all definitions of complete response in clinical studies have required an improvement in the urinary sediment. Several studies specified a reduction in the number of red blood cells (RBCs) to ≤10 high-power field or ≤5 RBC/high-power field [1,4], whereas others also required the absence of RBC casts [2]. We believe that attaining an inactive urinary sediment (ie, no or rare dysmorphic RBCs and no RBC casts) is an essential component of a complete response. 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.
A clinical "response" is not synonymous with histologic "remission." Only a repeat kidney biopsy demonstrating the absence of active inflammatory lesions can establish a complete remission. In some studies, repeat biopsies have demonstrated a discordance between clinical and histologic disease activity [12,13]. 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 'Monitoring the response to therapy' below.)
Not all successfully treated patients who have a histologic remission have a complete clinical response. The reasons for this discordance are as follows:
●Proteinuric chronic kidney disease can result from irreversible scarring despite resolution of inflammation.
●Hematuria may persist for various reasons (for example, cyclophosphamide-induced bladder injury).
As with complete renal response, there is no uniformly accepted definition of 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.
Importance of prompt therapy — The likelihood of a successful initial outcome is greater if therapy for LN is initiated relatively early in the course of the disease. A single episode of LN can lead to irreversible nephron loss, and every subsequent LN flare contributes to organ damage. Early therapy is crucial to prevent subsequent decreases in kidney function [11,14,15]. 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 [16-18].
Patients with persistent, relapsing, or remitting mild hematuria and/or subnephrotic-range proteinuria often have a "smoldering" but active disease that causes progressive kidney injury [19]. At first, there may be little or no elevation in the serum creatinine since adaptive glomerular hyperfiltration in the less involved nephrons can initially maintain the glomerular filtration rate (GFR) despite marked nephron loss [20].
By contrast, prompt diagnosis after the onset of nephritis and subsequent initiation of appropriate therapy are associated with improved outcomes, regardless of the histologic subclass [16,18]. This issue was addressed in a study of 91 patients with LN who were followed for a median of six years [18]. There was a much higher rate of end-stage kidney disease (ESKD) among patients who had clinically recognized kidney disease for greater than or equal to six months prior to biopsy (47 versus 14 per 1000 patient-years in patients who had an earlier biopsy; hazard ratio [HR] 9.3, 95% CI 1.8-47).
APPROACH TO TREATMENT — Immunosuppressive therapy for focal (class III) or diffuse (class IV) lupus nephritis (LN) consists of initial and subsequent phases (algorithm 1):
●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 therapy with mycophenolate or cyclophosphamide' below.)
●Once a 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 therapy' below.)
Some patients may also have evidence of lupus membranous nephropathy (class III + V or IV + V), but treatment is directed against the active class III or IV component of the disease. General supportive measures are also given to slow nonimmunologic progression of the kidney disease. (See 'General supportive measures in all patients' below.)
Our approach is in general agreement with the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines for glomerulonephritis, 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 [10,21-23].
Initial therapy with mycophenolate or cyclophosphamide — For patients with diffuse or focal LN, we suggest initial therapy consisting of glucocorticoids in combination with either mycophenolate mofetil (MMF) or intravenous (IV) or oral cyclophosphamide. Reasonable alternatives for initial therapy include MMF in combination with either a calcineurin inhibitor (voclosporin or tacrolimus) or belimumab, or cyclophosphamide in combination with belimumab. We do not use rituximab as initial therapy. (See 'Combination regimens' below.)
The efficacy of MMF and cyclophosphamide as initial therapy for focal or diffuse LN is supported by randomized trials that are discussed further below. Comparative trials have not established that one is superior to the other. MMF is preferred for patients with concerns about fertility since cyclophosphamide may adversely affect fertility (see "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Infertility risk'). Conversely, IV cyclophosphamide may be preferred for patients with preexisting gastrointestinal conditions or who may have difficulty adhering to oral 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 [24]. IV cyclophosphamide in combination with glucocorticoids became standard-of-care therapy for inducing renal response based upon seminal trials performed at the National Institutes of Health (NIH) that found that combination therapy was superior to glucocorticoids alone in preventing ESKD [25]. These seminal trials are presented in the discussion on cyclophosphamide-based regimens below. (See 'Cyclophosphamide-based regimen' below.)
Subsequently, several trials supported the role of MMF as an effective alternative to cyclophosphamide for initial therapy of patients with focal or diffuse LN:
●The largest trial (Aspreva Lupus Management Study [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 [2]. The mean urine protein-to-creatinine ratio 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 urine protein-to-creatinine ratio 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 which 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 [26]. 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 'Cyclophosphamide-based regimen' below.)
Mycophenolate-based regimen — If a mycophenolate-based regimen is selected, we prefer the regimen used in the ALMS trial [2]. Specifically, we give 0.5 g of MMF twice daily for the first week, then 1 g twice daily for the second week, and thereafter attempt to increase the dose to 1.5 g twice daily. However, this target dose may not be tolerated, and many patients may only tolerate a total daily dose of 2 to 2.5 g. 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.
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".)
Cyclophosphamide-based regimen — 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, regardless of the patient's race and ethnicity, rather than the longer (higher-dose) regimen implemented in the NIH trial.
●IV dosing (shorter, lower dose) – If the shorter, lower-dose regimen is used, IV cyclophosphamide is administered as 500 mg every two weeks for a total of six doses [3,5].
●IV dosing (longer, higher dose) – If the longer, higher-dose regimen is used, pulse IV cyclophosphamide (0.5 to 1 g/m2) is administered monthly for six to seven months [25]. If the leukocyte nadir after the first pulse of cyclophosphamide (usually 10 to 14 days postinfusion) is less than 3500 cells/microL and/or the absolute neutrophil count (ANC) is less than 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 greater than 3500 cells/microL, the ANC is greater than 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. A more detailed discussion of dosing, dose adjustments, adverse effects, and the use of mesna is presented elsewhere. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Intermittent (pulse) cyclophosphamide' and "General toxicity of cyclophosphamide in rheumatic diseases".)
●Oral dosing – Although most contributors to this topic prefer to use IV cyclophosphamide for initial therapy of LN, some authorities use oral rather than IV cyclophosphamide [27]. 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 greater than 3500 cells/microL and an ANC greater than 1500 cells/microL. Additional information regarding oral cyclophosphamide dosing can be found elsewhere. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Daily oral cyclophosphamide'.)
After initial treatment with cyclophosphamide, subsequent therapy commences with azathioprine or MMF rather than the longer course of cyclophosphamide used in the early NIH trials. (See 'Subsequent therapy' below.)
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 [24,28-32]. 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 [24]. 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 [24].
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 combination therapy than with methylprednisolone alone (RR 0.095, 95% CI 0.01-0.84) [29]. However, the treatment failure curves did not diverge until two to three years [29], and the ESKD curve did not diverge until five or more years [24].
●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) [26].
Given the concerns about cyclophosphamide toxicity, several trials have evaluated the efficacy of less intensive cyclophosphamide regimens and shown comparable outcomes [3,5,26,33-35]. 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 [5]. The similarity in outcomes persisted at 10 years, regardless of baseline kidney function [36]. On multivariate analysis, a good early response to therapy was predictive of better long-term outcomes [37]. This lower-dose cyclophosphamide regimen was also effective in the ACCESS trial, which included a large proportion of Black patients and Hispanic patients [3].
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 [27,34,38,39], including in a short-course regimen followed by azathioprine or cyclosporine subsequent therapy [39].
Glucocorticoid dosing and taper — Oral glucocorticoid therapy is typically started at 0.5 to 1 mg/kg per day (maximum of 60 mg/day of oral prednisone or its equivalent) for most patients. In patients with severe active disease (eg, acute kidney injury [AKI], crescentic glomerulonephritis, severe extrarenal disease), we administer IV pulse methylprednisolone (250 to 1000 mg given over 30 minutes daily for one to three days) prior to initiation of oral glucocorticoids to induce a rapid antiinflammatory effect.
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 [40], lower-dose glucocorticoid regimens are generally preferred. As an example, the 2019 EULAR/ERA-EDTA recommendations advocate for a starting oral prednisone dose of 0.3 to 0.5 mg/kg per day after giving pulse methylprednisolone (total dose of 500 to 2500 mg) and tapering the dose to ≤7.5 mg/day by three to six months [10]. 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 [41,42]. Some contributors to this topic aim to taper prednisone to a dose of 10 mg/day by week 12 at the latest.
Combination regimens — The role of combination regimens as initial therapy is not well established, and some experts (including several of the authors of this topic) reserve this approach for patients who do not demonstrate a clinical response within three to four months of either mycophenolate or cyclophosphamide as described above (see 'Initial therapy with mycophenolate or cyclophosphamide' above). Others may choose to use these combination regimens as initial therapy. More data and experience are needed to determine which patients are most likely to benefit from initial therapy with a combination regimen.
Belimumab in combination with standard initial therapy, and calcineurin inhibitors (such as tacrolimus or voclosporin) in combination with MMF, have been used as alternative initial therapies in patients with LN. The management of patients with relapsing or resistant LN is presented separately. (See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy".)
Rituximab is not used as initial therapy based upon data from a randomized trial that found no statistically significant difference in rates of complete or partial remission with rituximab plus MMF versus MMF alone [4]. However, rituximab may be used in the management of patients with resistant or relapsing LN, which is discussed separately. (See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy" and "Lupus nephritis: Treatment of relapsing focal or diffuse lupus nephritis", section on 'Moderate to severe relapse'.)
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. However, experience with this regimen for LN is limited, and its role in initial therapy has not been clearly established.
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.
The addition of belimumab to standard initial and subsequent therapy appears 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) [9]. At week 104, the rate of complete renal response (defined as a urinary protein-to-creatinine ratio [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). Note, however, that in this composite outcome there was only one death in the belimumab group compared with two in the placebo group. 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 [43].
Calcineurin inhibitors plus mycophenolate — Calcineurin inhibitors 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 calcineurin inhibitor, but evidence to support this approach is more limited [44]. Tacrolimus and voclosporin have not been directly compared as combination therapy for LN. Calcineurin inhibitors should be used with caution in patients with preexisting chronic kidney disease and eGFR ≤45 mL/min/1.73 m2.
●Tacrolimus – 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.
The potential efficacy of calcineurin inhibitors 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 [45-48]. Only one trial has compared tacrolimus without MMF with IV cyclophosphamide for initial therapy [49]. 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) [48]. 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 [45]. Patients who had been treated with the multitarget regimen continued to receive tacrolimus, MMF, and prednisone, 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) [49]. 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.
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). 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.
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) [50]. 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) [51]. 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 [52]. 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).
●Cyclosporine – 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.
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 [44]. 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.
Subsequent therapy — After a complete or partial response has been achieved with initial therapy, patients are switched to a subsequent regimen to decrease the risk of developing ESKD.
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 LN relapse following reduction in or cessation of immunosuppressive therapy [53-58]. 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 [58]. Relapse is more common when partial rather than complete response is obtained with initial therapy.
Choice of subsequent therapy — In most patients who achieve a renal response after initial immunosuppressive therapy, we suggest 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 since it is associated with an increased risk of congenital malformations and spontaneous abortion. Azathioprine is also a reasonable option for patients who are intolerant to MMF or cannot 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 azathioprine can be treated with cyclosporine or tacrolimus. In one trial, cyclosporine was as effective as azathioprine but was associated with more adverse effects [39].
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 [35]. 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 [26,59]. 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 [35,60,61]:
●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 [60]. Diffuse LN was present in 61, focal LN was present in 33, and lupus membranous nephropathy was present in 11. 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 [62]. 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 [63].
●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 [61]. 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 lupus membranous nephropathy) received initial therapy IV pulse cyclophosphamide and glucocorticoids [35]. 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 — The timing of initiation of subsequent therapy depends upon the initial therapy regimen used:
●Cyclophosphamide as initial therapy – In patients who receive IV cyclophosphamide as initial therapy, subsequent therapy is started two to four weeks after the last dose of cyclophosphamide when the following criteria are met: the WBC count is >3500 cells/microL, and the ANC is >1500 cells/microL. The risk of infection is increased when the ANC is <1000 cells/microL (table 1). The ANC is equal to the product of the total WBC count and the fraction of polymorphonuclear cells and band forms noted on the differential analysis (calculator 1). In patients who receive oral cyclophosphamide as initial therapy, subsequent therapy is initiated immediately after discontinuation of cyclophosphamide, provided the WBC count is >3500 cells/microL and the ANC is >1500 cells/microL.
●MMF as initial therapy – In patients who receive MMF as 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 two years or longer, and some expert panels suggest that subsequent therapy be continued for at least three to five years [22]. 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 [35]. 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) 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 0.05 to 0.2 mg/kg per day [5,35,39,53].
Patients who remain asymptomatic can be slowly tapered off prednisone, and approaches vary. Once the prednisone dose reaches 5 mg/day, tapering should proceed at a rate of 1 mg/day reduction in dose every four weeks. Some experts prefer to alternate 5 and 2.5 mg daily after the first month, then reduce the dose to 2.5 mg daily, and ultimately, 2.5 mg every other day at the third month. However, some clinicians prefer prolonged low-dose prednisone therapy (eg, 5 mg/day or less).
Monitoring the 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 response is achieved) and the toxicity of the regimen (ie, adverse effects, infections due to immunosuppression) (see 'Definitions of response' above). 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 [10].
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, but some experts occasionally perform a 24-hour urine).
●Serum creatinine (as well as a basic metabolic profile).
●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 "Overview of the management and prognosis of systemic lupus erythematosus in adults", 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.
Other treatment considerations
General supportive measures in all patients — 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. This approach is consistent with the KDIGO clinical practice guidelines for glomerulonephritis [23]. 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')
●Lipid lowering (see "Overview of the management of chronic kidney disease in adults", section on 'Dyslipidemia')
Treatment-associated toxicity — Immunosuppressive therapy with cyclophosphamide, MMF, and/or high-dose glucocorticoids has both infectious and noninfectious toxicities that warrant additional prophylactic measures. The recommended regimens are discussed elsewhere:
●For prevention of Pneumocystis jirovecii pneumonia (see "Treatment and prevention of Pneumocystis pneumonia in patients without HIV")
●For prevention of cyclophosphamide-induced bladder and gonadal toxicity (see "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Prevention of drug-induced cystitis' and "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Infertility risk')
●For minimizing glucocorticoid-induced bone loss and other adverse effects (see "Prevention and treatment of glucocorticoid-induced osteoporosis" and "Major adverse effects of systemic glucocorticoids")
●For age-appropriate vaccinations in immunosuppressed patients (see "Immunizations in autoimmune inflammatory rheumatic disease in adults")
SPECIAL POPULATIONS
Pregnant patients — 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/diffuse LN during pregnancy; treatment options include a combination of glucocorticoids, calcineurin inhibitors, 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.
A more detailed discussion of the issues related to pregnancy in patients with LN and the safety of immunosuppressive drugs to treat active lupus during pregnancy are discussed in detail separately:
●(See "Pregnancy in women with systemic lupus erythematosus".)
●(See "Safety of rheumatic disease medication use during pregnancy and lactation".)
Patients with both focal/diffuse LN and lupus membranous nephropathy — We treat patients with both focal/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 'Approach to treatment' above.)
In some studies, patients with combined diffuse LN and lupus membranous nephropathy have had a worse prognosis than those with diffuse disease alone, which has raised the possibility that such patients may benefit from more intensive therapy [64]. These observations led to a clinical trial of 40 patients that showed better outcomes with mycophenolate mofetil (MMF) plus tacrolimus compared with intravenous (IV) cyclophosphamide; all patients were treated with glucocorticoids. However, 26 of the 40 patients had previously been treated with cyclophosphamide or MMF. (See "Lupus nephritis: Therapy of lupus membranous nephropathy".)
Patients with concomitant thrombotic microangiopathy — Some patients with focal or diffuse LN may present with concomitant thrombotic microangiopathy (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 nephropathy. In general, the treatment of patients with LN and concomitant TMA should include management of the underlying etiology of TMA as well as treatment of LN (algorithm 1):
●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 "Management of antiphospholipid syndrome")
PROGNOSIS
Long-term outcomes — A better long-term prognosis is associated with attaining complete response of active lupus nephritis (LN). Either a complete or partial response is associated with an improved outcome compared with no response. Partial response is associated with a much greater likelihood of a subsequent relapse than complete response and therefore also with a poorer long-term outcome than in those who achieve a complete response. The criteria used to determine a clinical response are discussed above. (See 'Goals of therapy' above.)
The importance of attaining a complete response was illustrated in a report from the Lupus Nephritis Collaborative Study Group of 86 patients with severe LN [1,65]. The 43 percent of 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) had much higher kidney survival rates at five years (94 versus 46 percent) and at 10 years (94 versus 31 percent) compared with those who did not attain a complete response. Improvement was also noted in patient survival (95 versus 60 percent at 10 years). Similar findings have been reported by others [66].
The value of partial response was also demonstrated in the 10-year study of the same 86 adults with severe LN that evaluated the correlation among clinical outcomes and partial response (a 50 percent reduction in proteinuria to less than 1.5 g/day and stable serum creatinine), complete response, and no response [65]. Compared with no response, partial response was associated with significantly higher rates of kidney (45 versus 19 percent) and patient (76 versus 46 percent) survival. As in the above study, the best outcomes were observed in those who attained complete response (kidney and patient survival of 94 and 96 percent, respectively).
Features generally predictive of attaining complete response are stable kidney function after four weeks on therapy, lower chronicity index on kidney biopsy, being a White patient, and lower baseline proteinuria and serum creatinine concentration [67]. On the other hand, male sex and earlier development of nephritis from the time of diagnosis of systemic lupus erythematosus may be associated with a lower likelihood of sustained complete response [68].
Patients with LN have a higher risk of mortality and end-stage kidney disease (ESKD) 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 [69]. 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. The cumulative incidence of ESKD was 10 percent at 5 years and 13 percent at 10 years.
Among patients who progress to 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 [70-72]. 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 [73]. 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 [71]. In addition, peritoneal dialysis is associated with an increased risk of peritonitis and non-catheter-related infection [74,75].
Risk factors for progression — Even with aggressive therapy, some patients with focal or diffuse LN will have a progressive decline in kidney function leading to ESKD. 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 [16,19,76-79].
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 [16,77,80,81]. (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 [82].
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
●General principles – The goal of immunosuppressive therapy in patients with focal or diffuse lupus nephritis (LN) is resolution of inflammatory and immunologic activity, with achievement of a complete response. While there is no consensus definition of a complete response, most definitions include the following elements: a substantial reduction in protein excretion, improvement or stabilization of the serum creatinine, and improvement of the urinary sediment. Of note, a clinical response is not synonymous with histologic "remission." The likelihood of a successful initial outcome is greater if therapy for LN is initiated relatively early in the course of the disease. (See 'Goals of therapy' above and 'Definitions of response' above and 'Importance of prompt therapy' above.)
●Initial treatment approach – Immunosuppressive therapy for focal (class III) or diffuse (class IV) LN consists of initial and subsequent phases. 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) (algorithm 1). Once a 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 'Approach to treatment' above.)
•Initial therapy – For patients with diffuse or focal LN, we suggest an initial regimen consisting of glucocorticoids in combination with either mycophenolate mofetil (MMF) or intravenous (IV) or oral cyclophosphamide (Grade 2C). Reasonable alternatives for initial therapy include MMF in combination with either a calcineurin inhibitor (voclosporin or tacrolimus) or belimumab, or cyclophosphamide in combination with belimumab. We do not use rituximab as initial therapy. Data from randomized trials have shown comparable efficacy with MMF or cyclophosphamide as initial agents. (See 'Initial therapy with mycophenolate or cyclophosphamide' above and 'Combination regimens' above.)
Dosing and duration of MMF, cyclophosphamide, and glucocorticoids as initial therapy are discussed above. (See 'Mycophenolate-based regimen' above and 'Cyclophosphamide-based regimen' above and 'Glucocorticoid dosing and taper' above.)
•Subsequent therapy – For most patients who achieve a renal response after initial immunosuppressive therapy, we suggest subsequent therapy with MMF rather than azathioprine (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 since it has been associated with an increased risk of congenital malformations and spontaneous abortion. Azathioprine is also a reasonable option for patients who are intolerant to MMF or cannot afford the cost of MMF. Low-dose oral prednisone (or its equivalent) is continued in most patients receiving subsequent therapy. The dosing and duration of MMF, azathioprine, and low-dose glucocorticoids for subsequent therapy are discussed above. (See 'Choice of subsequent therapy' above and 'Dosing and duration of subsequent therapy' above.)
●Monitoring – 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 is 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 the response to therapy' above.)
●Other treatment considerations – Other treatment considerations in patients with focal or diffuse LN include general supportive measures such as dietary sodium and protein restriction, blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, and treatment of dyslipidemia. Immunosuppressive therapy with cyclophosphamide, MMF, and/or high-dose glucocorticoids has both infectious and noninfectious toxicities that warrant additional prophylactic measures. (See 'Other treatment considerations' 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 (Consultant/Advisory Boards: BMS [Lupus]; DILIsym [Drug-induced liver injury]; Immunovant [Lupus]).
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