Version July 2025
INTRODUCTION —
Treatment of lupus nephritis (LN) varies according to the specific International Society of Nephrology (ISN)/Renal Pathology Society (RPS) histopathologic class as well as other clinical and pathologic features and the prior treatment course of the patient. No single regimen is regarded as optimal for all patients with LN, and treatment must be individualized. Combined immunosuppressive therapy is typically indicated in patients with diffuse and focal LN and in many patients with lupus membranous nephropathy.
Some patients with focal or diffuse LN are truly resistant to initial immunosuppressive treatments despite full adherence with the prescribed regimen. By contrast, a greater number of patients are perceived to have resistant LN due to other factors, such as suboptimal adherence to treatment or undertreatment.
This topic reviews the diagnosis and treatment of focal or diffuse LN that is resistant to initial therapy. The initial and subsequent therapy of focal or diffuse LN, treatment of relapsing focal or diffuse LN, treatment of lupus membranous nephropathy, and treatment of recurrent LN in the transplanted kidney are presented separately:
●(See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)
●(See "Lupus nephritis: Therapy of lupus membranous nephropathy".)
●(See "Lupus nephritis: Treatment of relapsing focal or diffuse lupus nephritis".)
●(See "Kidney transplantation in adults: Issues related to lupus nephritis".)
The general approach to management of systemic lupus erythematosus (SLE) in children and adults, as well as management of LN in children, is described elsewhere. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis".)
DEFINITION OF RESISTANT DISEASE —
Among patients with focal or diffuse lupus nephritis (LN), resistant disease (also called refractory disease) typically refers to the failure of initial immunosuppressive therapy to achieve either a complete or partial clinical response. However, some experts would not classify a patient as having resistant disease unless they did not respond to two different treatment regimens. The definition of resistant disease may also vary based on the definition of complete or partial response for focal or diffuse LN. Definitions of complete and partial response that are most commonly used incorporate a reduction in proteinuria, improvement or stabilization of the serum creatinine (or estimated glomerular filtration rate [eGFR]), and improvement of the urinary sediment (eg, resolution of glomerular hematuria/red blood cell casts). Although not included in most formal definitions of clinical response, systemic immunologic activity (measured most commonly by serum complement and anti-double-stranded DNA [anti-dsDNA] levels) is also expected to resolve in most patients. The development of a complete response usually requires a minimum of six months and, in some patients, as long as 12 months or more after the initiation of initial therapy [1-4]. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Definitions of response'.)
The parameters that we use to diagnose resistant disease are outlined below. (See 'Establishing resistant disease' below.)
DIAGNOSIS OF RESISTANT DISEASE
When to suspect resistant disease — Resistant disease should be suspected in any patient with focal or diffuse lupus nephritis (LN) who is not showing signs of clinical improvement (eg, reduction in proteinuria, stabilization or improvement in serum creatinine, improvement in the urinary sediment) after receiving initial immunosuppressive therapy.
Assessment of the patient’s clinical response to therapy should begin as early as two to four weeks after initial therapy is started. After initiating therapy, one would expect improvement or stabilization of clinical parameters by one month with continued improvement over time. A lack of meaningful improvement by three to six months should prompt the clinician to suspect that the patient may be resistant to the regimen used for initial therapy. The 2023 European Alliance of Associations for Rheumatology/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) guidelines suggest a goal of ≥25 percent reduction in proteinuria by three months and ≥50 percent by six months [5]. However, the optimal time to assess a clinical response is uncertain, and giving the patient adequate time to respond to therapy must be balanced against the possibility of ongoing kidney injury. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Monitoring response to therapy'.)
Evaluation for resistant disease — For all patients who are suspected of resistant disease, we confirm that their current therapy is appropriately dosed and assess their adherence to therapy. A repeat kidney biopsy may be useful to differentiate ongoing histologic activity from chronic damage and to exclude alternative diagnoses.
Confirm appropriate dosing — The first step in evaluating suspected treatment resistance is excluding undertreatment by confirming appropriate dosing of the current immunosuppressive regimen. As an example, the dose of mycophenolate mofetil (MMF) may not have been titrated up to the goal dose over time as intended.
Assess patient adherence to therapy — The next step in the evaluation of the patient suspected of treatment resistance is to assess the adequacy of the therapeutic regimen and the patient’s ability to adhere to this initial therapy. In our clinical experience, many cases of suspected treatment resistance are related to nonadherence rather than actual resistance to immunosuppressive therapy. Multiple factors may contribute to treatment nonadherence among patients with systemic lupus erythematosus (SLE), including adverse effects and cost of medications and social determinants of health (eg, low socioeconomic status or health literacy, limited ability to afford and/or access healthcare) [6-10].
We take the following approach to assessing adherence to therapy:
●We ask open questions, such as "I realize that it is difficult to remember to take medications every day. On average, how many days per week are you able to take your medications?" We find that this is a nonjudgmental and effective way to elicit this information.
●Some contributors measure drug levels (eg, blood hydroxychloroquine, mycophenolate, or calcineurin inhibitor [CNI] levels). However, drug levels may not reliably reflect long-term adherence, as some patients may only take their medications just prior to the drug level test.
If it is determined that nonadherence to therapy is likely contributing to the patient's lack of clinical response to immunosuppressive therapy, we try to understand the reasons for nonadherence and tailor our approach to the individual patient. As an example, if nonadherence is due to adverse effects (such as nausea or diarrhea), we would switch to an alternative therapy. If the patient has difficulty remembering to take their medications, we may suggest using a pill box/organizer, setting alarms on their smartphone, or switching to an injectable medication.
Nonadherence among patients with SLE appears to be common [7-9,11,12], although there are no data on the prevalence of nonadherence specifically among those with LN. In an analysis of 13,429 Medicaid beneficiaries with SLE who were new users of hydroxychloroquine or immunosuppressive medications, 79 percent of new users of hydroxychloroquine and 83 percent of new users of immunosuppressive medications were nonadherent to therapy (defined as a medication possession ratio [MPR] <80 percent) [13]. Compared with adherence, nonadherence was associated with higher risks of all-cause and SLE-related emergency department visits and hospitalization.
Exclude alternative diagnoses — Once nonadherence to initial therapy has been excluded or resolved, alternative diagnoses that may be mistaken for resistant disease should also be excluded, including the following:
●Early relapsing disease – For patients who have only been on therapy for a short period of time (ie, <6 months), it can be difficult to distinguish resistant and relapsing disease. This is discussed in more detail separately. (See "Lupus nephritis: Treatment of relapsing focal or diffuse lupus nephritis", section on 'Distinguishing early relapse from resistant disease'.)
●Alternative types of kidney disease – Patients with SLE may develop other conditions that impact the recovery of their kidney function. These may be related to SLE (eg, vascular lesions) or unrelated (eg, nonsteroidal anti-inflammatory drug [NSAID]-associated acute kidney injury). When there is high suspicion of an alternative diagnosis, a kidney biopsy may be indicated. (See "Lupus nephritis: Diagnosis and classification", section on 'Other forms of lupus kidney disease' and 'When to repeat a kidney biopsy' below.)
When to repeat a kidney biopsy — In patients with focal or diffuse LN not responsive to initial therapy after an adequate time course (usually >3 months), a repeat kidney biopsy may be useful when a clinician is contemplating a change in immunosuppressive therapy. As an example, the biopsy can help to distinguish active inflammation from chronic changes, particularly in a patient with persistent proteinuria above the target without glomerular hematuria or evidence of active systemic immunologic disease (assessed with serum anti-double-stranded DNA (anti-dsDNA) autoantibody and complement levels) or to exclude an alternative diagnosis. If a decision has already been made to change therapy, a repeat biopsy may be deferred to see how the patient responds to the new therapy.
General indications for repeat kidney biopsy in patients with LN are discussed in more detail elsewhere. (See "Lupus nephritis: Diagnosis and classification", section on 'When to repeat the biopsy'.)
Establishing resistant disease — Establishing that the patient is resistant to initial therapy is largely a clinical diagnosis and based upon the following parameters:
●A lack of clinical improvement (eg, reduction in proteinuria, stabilization or improvement in serum creatinine, improvement in the urinary sediment) with initial immunosuppressive therapy, particularly in a patient with evidence of active systemic immunologic disease (ie, abnormal serum complement and anti-dsDNA autoantibody levels). (See 'Definition of resistant disease' above.)
●Exclusion of patient nonadherence to therapy. (See 'Assess patient adherence to therapy' above.)
●Exclusion of other alternative diagnoses that may resemble resistant disease. This may require a kidney biopsy, especially if the clinician is considering a change in immunosuppressive therapy. (See 'Exclude alternative diagnoses' above and 'When to repeat a kidney biopsy' above.)
MANAGEMENT OF RESISTANT DISEASE —
Once it has been established that the patient is resistant to initial therapy (ie, has ongoing going clinical or histologic evidence of active nephritis), we modify immunosuppressive therapy. In addition, we continue to optimize care for systemic lupus erythematosus (SLE) and provide supportive measures for chronic kidney disease.
Modify immunosuppressive therapy — Once nonadherence to initial therapy has been excluded or resolved (see 'Assess patient adherence to therapy' above), the approach to treating resistant disease (ie, ongoing clinical or histologic evidence of active nephritis) varies depending upon the disease severity and the initial therapeutic regimen.
Choice of immunosuppressive therapy — There are no high-quality data to guide the optimal treatment of resistant focal or diffuse lupus nephritis (LN). The choice of therapy should be individualized based on prior initial therapy, therapeutic goals, patient preferences, adverse effects of therapy, and other factors (table 1). While the choice of specific agents should depend on these factors, possible management strategies include the following:
●Patients on an MMF-based regimen – Patients on mycophenolate mofetil (MMF) may be on a dual immunosuppressive regimen (ie, MMF plus glucocorticoids) or a triple immunosuppressive regimen (ie, MMF, glucocorticoids, and either belimumab or a calcineurin inhibitor [CNI; eg, voclosporin, tacrolimus, or cyclosporine]).
In some cases, patients taking MMF may develop a compelling reason to replace MMF with alternative immunosuppression (eg, significant adverse effects, difficulty with taking daily medications). These patients may switch to a cyclophosphamide (CYC)-based dual or triple immunosuppressive regimen or a rituximab-based regimen that does not include MMF.
Otherwise, patients who are tolerating an MMF-based regimen may benefit from continuing MMF and glucocorticoids and adding or modifying a third type of immunosuppression. Specifically, for those on dual therapy with MMF and glucocorticoids alone, they may add a CNI, belimumab, or rituximab. For those on triple therapy with belimumab as the third immunosuppressive agent, options include switching from belimumab to a CNI or rituximab, or adding rituximab. For those on triple therapy with a CNI as the third agent, one could either switch from the CNI to belimumab or rituximab, or add rituximab as a fourth agent. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Dual immunosuppressive regimens' and "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Triple immunosuppressive regimens' and 'Rituximab as alternative therapy' below.)
●Patients on a CYC-based regimen – Patients on intravenous (IV) CYC may be on a dual immunosuppressive regimen (ie, CYC plus glucocorticoids) or a triple immunosuppressive regimen (ie, CYC, glucocorticoids, and belimumab).
If these patients develop a strong reason to switch from CYC to alternative immunosuppression (eg, significant adverse effects), they may switch to an MMF-based dual or triple immunosuppressive regimen or a rituximab-based regimen that does not include CYC.
Otherwise, those who are tolerating a CYC-based regimen can continue CYC and glucocorticoids and either add or modify a third type of immunosuppression. Specifically, those taking CYC and glucocorticoids alone can add belimumab or rituximab, while those who are also taking belimumab as a third agent can either add rituximab or switch from belimumab to rituximab. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Dual immunosuppressive regimens' and "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Triple immunosuppressive regimens' and 'Rituximab as alternative therapy' below.)
There is no evidence directly comparing these regimens in the treatment of patients with resistant focal or diffuse LN, and the approaches discussed above are largely based upon our clinical experience and expert opinion [5,14-16]. Evidence for specific immunosuppressive agents includes the following:
●Cyclophosphamide – There are no studies that have examined the efficacy of cyclophosphamide among patients who are resistant to therapy with MMF. However, indirect evidence for the use of cyclophosphamide comes from large, multinational, randomized trials showing efficacy in patients with severe (but not necessarily resistant) LN. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Initial immunosuppressive therapy'.)
●MMF – Limited data from small case series suggest that MMF may be effective in treating patients who are resistant to cyclophosphamide [17-20]. As an example, in one series of 12 patients who were resistant to or relapsed following cyclophosphamide and treated with MMF for a mean of 13 months, proteinuria decreased and serum creatinine was stable or decreased in 10 patients [18]. Also, the urine sediment returned to normal in six patients. In another study of 14 patients with diffuse LN who did not respond to initial therapy with cyclophosphamide, treatment with MMF resulted in complete remission in 10 patients and partial remission in four patients [20].
There is limited evidence to suggest that triple therapy with MMF is effective among MMF-resistant patients [21,22]. In one observational study, tacrolimus (0.075 mg/kg/day) was added to MMF in 17 patients with MMF-resistant class IV (n = 15) or class V (n = 2) LN [21]. After a mean follow-up of 24 months, six patients (35 percent) had a complete response (defined as urinary protein excretion of <0.3 g/day, normal sediment, and normal or stable kidney function), and six patients had a partial response (defined as protein excretion of <2.9 g/day with stable or improved kidney function). Tacrolimus was well tolerated. In another retrospective study, 29 patients were transitioned from their initial therapy with MMF or cyclophosphamide to MMF plus tacrolimus after either not achieving a complete response at 12 months or after achieving a complete response at 12 months but then having a relapse [23]. Fifteen and 26 percent of patients treated with combination therapy achieved a complete response after 6 and 12 months, respectively.
Additional support for the addition of a CNI in patients who have ongoing kidney disease despite treatment with MMF comes from the AURORA 1 trial, which evaluated the efficacy of voclosporin when added to background therapy with MMF plus glucocorticoids [4]. In this study, approximately 55 percent of participants were already taking MMF at the time of screening, and this subgroup had a higher odds of complete renal response (odds ratio 5.8, 95% CI 2.8-11.9) compared with the placebo group. Details of this trial are presented separately. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Calcineurin inhibitor plus mycophenolate'.)
Glucocorticoid management — When switching from one regimen to another, most UpToDate contributors to this topic would not restart a new course of glucocorticoids if the patient had already completed the initial course of glucocorticoids. Some contributors would administer a short course of glucocorticoids (eg, prednisone 20 to 30 mg once daily for two to four weeks), followed by a taper. If the patient had a repeat kidney biopsy showing very active inflammation (eg, crescents) and was more than three months from the start of initial therapy, some contributors would administer pulse glucocorticoids (eg, intravenous methylprednisolone 250 to 1000 mg daily for one to three days).
Duration of therapy — The optimal duration of therapy for resistant disease is unclear. In general, treatment duration should be determined based on the patient’s response to therapy as well as treatment-related toxicity. If a patient who was previously resistant to initial therapy begins to respond to a modification to their treatment regimen, we would continue this new regimen until the patient has achieved the best possible clinical response, as determined by stabilization of the responding parameters. We then transition the patient to long-term subsequent immunosuppressive therapy, which is typically administered for at least three years, as is done for the treatment of focal or diffuse LN that is not resistant to initial therapy [5,15]. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Dosing and duration of subsequent therapy'.)
Rituximab as alternative therapy — For patients with focal or diffuse LN who have not responded to or are unable to tolerate treatment with mycophenolate-and cyclophosphamide-based dual or triple regimens, a rituximab-based regimen is a reasonable alternative approach. If rituximab is given, we typically add rituximab to the patient’s most recent initial therapy regimen. Patients should be carefully monitored for hypogammaglobulinemia and signs of infection, particularly if they are already receiving therapy with belimumab (which also has anti-B cell activity). For rituximab dosing, we typically administer 1 g of rituximab initially followed 14 days later by another 1 g dose. (See "Rituximab: Principles of use and adverse effects in rheumatologic disease" and "Secondary immunodeficiency induced by biologic therapies".)
Although the addition of rituximab to MMF as initial therapy has not been shown to improve clinical outcomes in one randomized trial [1], observational studies suggest a possible benefit in patients with resistant disease. Various rituximab-based regimens have been used in open-label studies and case series, including rituximab plus MMF, rituximab plus cyclosporine, or rituximab plus cyclophosphamide. Importantly, none of these regimens have demonstrated efficacy in randomized controlled trials.
While there are no data from randomized trials, favorable results with rituximab have been noted in a systematic review of observational studies and case reports of LN that is resistant to either cyclophosphamide or MMF [24-30]. Data supporting rituximab are more limited in patients who are resistant to both cyclophosphamide and MMF and in those who cannot tolerate either drug:
●The largest reported experience included 22 patients with focal or diffuse LN who had persistent disease activity despite a variety of immunosuppressive drugs; most had been treated with cyclophosphamide (11 patients) or MMF (12 patients) as well as other drugs (eg, cyclosporine, azathioprine) [24]. Rituximab (0.5 to 1 g on days 1 and 15) was added to the existing immunosuppressive regimen. Three months after the administration of rituximab, five patients had a complete response (normal serum creatinine, inactive urine sediment, and protein excretion of <500 mg/day), and seven patients had a partial response (>40 percent improvement in kidney parameters). The effect of rituximab in those patients who were initially treated with cyclophosphamide was not specifically noted.
●Rituximab was also assessed in a series of 20 patients with diffuse LN (15 patients) or lupus membranous nephropathy (5 patients), all but two of whom had resistant or relapsing disease [25]. Fifteen patients had been previously treated with cyclophosphamide. Rituximab was given at a dose of 375 mg/m2 weekly for four weeks. Ten patients received additional doses of rituximab as maintenance therapy because of an increase in B cell count. At a mean follow-up of 22 months, 5 of the 15 patients with diffuse LN achieved complete response, defined as protein excretion of <500 mg/day, absence of hematuria, and an increase in estimated glomerular filtration rate (eGFR) by at least 50 percent. In addition, five patients had a partial response, defined as a decrease in protein excretion by at least 50 percent and stabilization of the eGFR.
Optimize care for SLE and kidney disease — In addition to providing targeted treatment for LN, we ensure that patients are receiving other key components of management for patients with SLE and kidney disease, such as hydroxychloroquine and supportive measures for kidney disease (eg, treatment of comorbid hypertension and dyslipidemia). (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'General measures for all patients'.)
Investigational approaches — Therapies that are under investigation for patients with resistant LN include chimeric antigen receptor modified T (CAR-T) cell immunotherapy [31,32] and bispecific T cell engagers. Additional studies are required before these therapies can be routinely used in clinical practice. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Agents under investigation'.)
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".)
SUMMARY AND RECOMMENDATIONS
●Definition – Among patients with focal or diffuse lupus nephritis (LN), resistant disease (also called refractory disease) typically refers to the failure of initial immunosuppressive therapy to achieve either a complete or partial clinical response. Some experts would not classify a patient as having resistant disease unless they did not respond to two different treatment regimens. The definition of resistant disease may also vary based on the definition of complete or partial response for focal or diffuse LN. Definitions that are most commonly used incorporate a reduction in proteinuria, improvement or stabilization of the serum creatinine (or estimated glomerular filtration rate [eGFR]), and improvement of the urinary sediment. (See 'Definition of resistant disease' above.)
●Diagnosis
•When to suspect resistant disease – Resistant disease should be suspected in any patient with focal or diffuse LN who does not show signs of clinical improvement (eg, reduction in proteinuria, stabilization or improvement in serum creatinine, improvement in the urinary sediment) after receiving initial immunosuppressive therapy. (See 'When to suspect resistant disease' above.)
•Evaluation – For all patients suspected of resistant disease, we confirm that their current therapy is appropriately dosed and assess their adherence to therapy. A repeat kidney biopsy may be useful to differentiate ongoing histologic activity from chronic damage and to exclude alternative diagnoses, such as early relapsing disease and alternative types of kidney disease. (See 'Evaluation for resistant disease' above and 'Establishing resistant disease' above.)
●Management
•Modify immunosuppressive therapy – Once a diagnosis of resistant disease has been established, we modify immunosuppressive therapy. There are no high-quality data to guide the optimal treatment of resistant focal or diffuse LN. The choice of therapy should be individualized based on prior initial therapy, therapeutic goals, patient preferences, adverse effects of therapy, and other factors (table 1). Possible management strategies are discussed above. (See 'Choice of immunosuppressive therapy' above.)
•Glucocorticoid management – When switching from one regimen to another, most UpToDate contributors to this topic would not restart a new course of glucocorticoids if the patient had already completed the initial course of glucocorticoids. Some contributors would administer a short course of glucocorticoids (eg, prednisone 20 to 30 mg once daily for two to four weeks), followed by a taper. If the patient had a repeat kidney biopsy showing very active inflammation (eg, crescents) and was more than three months from the start of initial therapy, some contributors would administer pulse glucocorticoids (eg, intravenous methylprednisolone 250 to 1000 mg daily for one to three days). (See 'Glucocorticoid management' above.)
•Duration of therapy – The optimal duration of therapy for resistant disease is unclear; however, most patients remain on treatment for three years or more. (See 'Duration of therapy' above.)
●Optimize care for SLE and kidney disease - In addition to providing targeted treatment for LN, we ensure that patientsreceive other key components of management for patients with SLE and kidney disease, such as hydroxychloroquine and supportive measures for kidney disease (eg, treatment of comorbid hypertension and dyslipidemia). (See 'Optimize care for SLE and kidney disease' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Peter H Schur, MD, who contributed to an earlier version of this topic review.
