Version May 2024
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. However, 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.
●(See "Lupus nephritis: Diagnosis and classification".)
●(See "Lupus nephritis: Therapy of 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.
The treatment of focal or diffuse LN that is resistant to initial therapy will be reviewed here. 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".)
ESTABLISHING RESISTANT DISEASE — Among patients with focal or diffuse lupus nephritis (LN), resistant disease refers to the failure of initial immunosuppressive therapy to achieve either a complete or partial clinical response. There is no consensus, however, on the definition of complete or partial response in patients with focal or diffuse LN; thus, estimates of resistant disease are variable. Definitions of partial and complete response that are most commonly used incorporate a reduction in urine protein excretion, improvement or stabilization of the serum creatinine, and improvement of the urinary sediment (eg, resolution of hematuria/red cell casts). The development of 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'.)
Assessment of the patient's response should begin as early as three to four months after initial therapy to determine whether the patient is demonstrating a clinical response to therapy (ie, a reduction in proteinuria, improvement or stabilization of the serum creatinine, improvement of the urinary sediment) (see "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Monitoring the response to therapy'). In patients who show signs of improvement, we continue their initial therapy and assess their ongoing response. Lack of any improvement at three to four months should prompt the clinician to suspect that the patient may be resistant to the regimen used for initial therapy. The management of patients suspected of treatment resistance is discussed elsewhere in this topic. (See 'Management' below.)
Truly resistant disease may be less common than previously thought. Perceived resistance, which is more common, is often due to incomplete adherence or nonadherence to the prescribed immunosuppressive regimen or to inadequacy of the prescribed regimen. Nonadherence to medical regimens in patients with systemic lupus erythematosus (SLE) varies widely (3 to 83 percent) depending upon the population studied and the definitions used [5,6]. However, nonadherence is higher in studies using objective measurements of nonadherence [7]. (See 'Assessment of patient adherence to therapy' below.)
MANAGEMENT — The first step in the management of the patient suspected of being treatment resistant is to assess the adequacy of the patient's therapeutic regimen and adherence to this initial therapy since nonadherence is frequently the cause of perceived resistance to therapy. (See 'Assessment of patient adherence to therapy' below.)
Diagnosing nonadherence to a medical regimen in patients with lupus nephritis (LN) can be challenging and may require both subjective and objective measurements and a personalized approach to management [7].
Once nonadherence to therapy has been excluded, our general approach to patients with treatment-resistant focal or diffuse LN depends upon which immunosuppressive regimen was used for initial therapy and is presented below. (See 'Approach based on prior initial therapy' below.)
Assessment of patient adherence to therapy — All patients with focal or diffuse LN suspected of being resistant to initial therapy should be evaluated for their adherence to 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 of medications, social determinants of health (eg, socioeconomic status), inability to afford medications, health literacy, and access [7-11].
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 your 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 begin by trying to understand the reasons for nonadherence and tailor our approach to the individual patient. As an example, if nonadherence is due to side 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 smart phone, or switching to an injectable medication.
Nonadherence among patients with SLE appears to be common [8-10,12,13], 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 hydrochloroquine and 83 percent of new users of immunosuppressive medications were nonadherent to therapy (defined as a medication possession ratio [MPR] <80 percent) [5]. Compared with adherence, nonadherence was associated with higher risks of all-cause and SLE-related emergency department visits and hospitalization.
When to repeat a kidney biopsy — In patients with focal or diffuse LN not responsive to initial therapy, 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 hematuria, 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'.)
Approach based on prior initial therapy — Once nonadherence to initial therapy has been excluded or resolved (see 'Assessment of patient adherence to therapy' above), the approach to patients who are considered resistant to initial therapy (ie, who have ongoing clinical or histologic evidence of active nephritis) varies with the agent used for initial therapy (eg, mycophenolate mofetil [MMF] or cyclophosphamide) and the severity of disease (algorithm 1).
Our approach is generally consistent with recommendations made by the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis, the Joint European Alliance of Associations for Rheumatology (formerly known as European League Against Rheumatism)/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA), and the American College of Rheumatology [14-16].
Patients resistant to MMF — For patients with focal or diffuse LN who are resistant to mycophenolate mofetil (MMF) plus glucocorticoids as initial therapy, we suggest switching to intravenous cyclophosphamide plus glucocorticoids. Reasonable alternatives include combination therapy with cyclophosphamide plus belimumab or continuation of MMF with the addition of either a CNI (voclosporin, tacrolimus, or cyclosporine) or rituximab; however, there are minimal data to support the use of these regimens in patients with resistant disease. The choice among these regimens depends upon several factors, including clinician and patient preference, drug availability and cost, toxicity, and tolerability. There is no evidence directly comparing these regimens in the treatment of patients with resistant focal or diffuse LN, and this approach is largely based upon our clinical experience and expert opinion [14-16]. The regimens are the same as those used for initial therapy. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Cyclophosphamide-based regimen' and "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Combination regimens'.)
Some experts would add a CNI to MMF in patients with stable kidney function who continue to have persistent proteinuria above the target while on MMF and also receiving a renin-angiotensin inhibitor. Repeat kidney biopsy may also be appropriate in such patients to confirm that the residual proteinuria correlates with ongoing immunologic activity and not chronic changes. Patients with evidence of necrotizing glomerulonephritis on biopsy may be preferably treated with cyclophosphamide, either alone or in combination with belimumab.
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 therapy with mycophenolate or cyclophosphamide'.)
There is limited evidence to suggest that combination therapy with MMF is effective among MMF-resistant patients [17,18]. 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 [17]. 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 Korean patients were treated with MMF plus tacrolimus after either not achieving a complete response to initial treatment with MMF or cyclophosphamide after 12 months or after achieving a complete response at 12 months but then having a relapse [19]. Fifteen and 26 percent of patients treated with combination therapy achieved a complete response after 6 and 12 months, respectively.
Patients resistant to cyclophosphamide — For patients with focal or diffuse LN who are resistant to cyclophosphamide plus glucocorticoids as initial therapy, we suggest treatment with MMF plus glucocorticoids. Reasonable alternatives include combination therapy with MMF plus either a CNI (voclosporin, tacrolimus, or cyclosporine), belimumab, or rituximab; however, there are minimal data to support the use of these regimens in patients with resistant disease. The choice among these regimens depends upon several factors, including clinician and patient preference, drug availability and cost, toxicity, and tolerability. There is no evidence directly comparing these regimens in the treatment of patients with resistant focal or diffuse LN, and this approach is largely based upon our clinical experience and expert opinion [14-16]. The regimens are the same as those used for initial therapy. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Mycophenolate-based regimen'.)
Limited data from small case series suggest that MMF may be effective in treating patients who are resistant to cyclophosphamide [20-23]. 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 [21]. 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 [23].
Patients resistant to both cyclophosphamide- and MMF-based regimens — For patients with focal or diffuse LN who have failed treatment with or are unable to tolerate both cyclophosphamide- and mycophenolate mofetil (MMF)-based regimens (ie, with or without a CNI [voclosporin, tacrolimus, or cyclosporine] or belimumab), we treat with a rituximab-based regimen. 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 utilized 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. For rituximab dosing, we typically use the dose regimen used for rheumatoid arthritis or membranous nephropathy, administering 1 g of rituximab initially followed 14 days later by another 1 g dose. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis" and "Membranous nephropathy: Treatment and prognosis", section on 'Rituximab'.)
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) [25]. 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 [26]. 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.
PROGNOSIS — Patients with treatment-resistant focal or diffuse lupus nephritis (LN) have a worse kidney prognosis than patients who respond. This is discussed in more detail elsewhere. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Long-term 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".)
SUMMARY AND RECOMMENDATIONS
●Definition of resistant disease – Among patients with focal or diffuse lupus nephritis (LN), resistant disease refers to the failure of initial immunosuppressive therapy to achieve either a complete or partial clinical response. There is no consensus on the definition of complete or partial response; however, definitions that are most commonly used incorporate a reduction in urine protein excretion, improvement or stabilization of the serum creatinine, and improvement of the urinary sediment. (See 'Establishing resistant disease' above.)
●Management
•Assessment of patient adherence – The first step in the management of the patient suspected of being treatment resistant is to assess the adequacy of the patient's therapeutic regimen and adherence to this initial therapy since nonadherence is frequently the cause of perceived resistance to therapy. (See 'Assessment of patient adherence to therapy' above.)
•Approach based on prior initial therapy – Once nonadherence to therapy has been excluded or resolved, our general approach to patients with treatment-resistant focal or diffuse LN depends upon which immunosuppressive regimen was used for initial therapy (algorithm 1):
-Resistant to mycophenolate mofetil (MMF) – For patients with focal or diffuse LN who are resistant to MMF plus glucocorticoids as initial therapy, we suggest switching to intravenous cyclophosphamide plus glucocorticoids (Grade 2C). Reasonable alternatives include combination therapy with cyclophosphamide plus belimumab or continuation of MMF with the addition of either a calcineurin inhibitor (CNI; voclosporin, tacrolimus, or cyclosporine) or rituximab. (See 'Patients resistant to MMF' above.)
-Resistant to cyclophosphamide – For patients with focal or diffuse LN who are resistant to cyclophosphamide plus glucocorticoids as initial therapy, we suggest treatment with MMF plus glucocorticoids (Grade 2C). Reasonable alternatives include combination therapy with MMF plus either a CNI (voclosporin, tacrolimus, or cyclosporine), belimumab, or rituximab. (See 'Patients resistant to cyclophosphamide' above.)
-Resistant to both cyclophosphamide and MMF – For patients with focal or diffuse LN who have failed treatment with or are unable to tolerate both cyclophosphamide- and MMF-based regimens (ie, with or without a CNI [voclosporin, tacrolimus, or cyclosporine] or belimumab), we treat with a rituximab-based regimen. A rituximab-based regimen refers to the use of rituximab in combination with a CNI, MMF, or cyclophosphamide. (See 'Patients resistant to both cyclophosphamide- and MMF-based regimens' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter H Schur, MD, who contributed to an earlier version of this topic review.
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