Immunosuppressive treatment for proliferative lupus nephritis.

BACKGROUND: Cyclophosphamide, in combination with corticosteroids, has been first-line treatment for inducing disease remission for proliferative lupus nephritis, reducing death at five years from over 50% in the 1950s and 1960s to less than 10% in recent years. Several treatment strategies designed to improve remission rates and minimise toxicity have become available. Treatments, including mycophenolate mofetil (MMF) and calcineurin inhibitors, alone and in combination, may have equivalent or improved rates of remission, lower toxicity (less alopecia and ovarian failure) and uncertain effects on death, end-stage kidney disease (ESKD) and infection. This is an update of a Cochrane review first published in 2004 and updated in 2012. OBJECTIVES: Our objective was to assess the evidence and evaluate the benefits and harms of different immunosuppressive treatments in people with biopsy-proven lupus nephritis. The following questions relating to management of proliferative lupus nephritis were addressed: 1) Are new immunosuppressive agents superior to or as effective as cyclophosphamide plus corticosteroids? 2) Which agents, dosages, routes of administration and duration of therapy should be used? 3) Which toxicities occur with the different treatment regimens? SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 2 March 2018 with support from the Cochrane Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing any immunosuppressive treatment for biopsy-proven class III, IV, V+III and V+VI lupus nephritis in adult or paediatric patients were included. DATA COLLECTION AND ANALYSIS: Data were abstracted and the risks of bias were assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) and measures on continuous scales calculated as mean differences (MD) with 95% confidence intervals (CI). The primary outcomes were death (all causes) and complete disease remission for induction therapy and disease relapse for maintenance therapy. Evidence certainty was determined using GRADE. MAIN RESULTS: In this review update, 26 new studies were identified, to include 74 studies involving 5175 participants overall. Twenty-nine studies included children under the age of 18 years with lupus nephritis, however only two studies exclusively examined the treatment of lupus nephritis in patients less than 18 years of age.Induction therapy Sixty-seven studies (4791 participants; median 12 months duration (range 2.5 to 48 months)) reported induction therapy. The effects of all treatment strategies on death (all causes) and ESKD were uncertain (very low certainty evidence) as this outcome occurred very infrequently. Compared with intravenous (IV) cyclophosphamide, MMF may have increased complete disease remission (RR 1.17, 95% CI 0.97 to 1.42; low certainty evidence), although the range of effects includes the possibility of little or no difference.Compared to IV cyclophosphamide, MMF is probably associated with decreased alopecia (RR 0.29, 95% CI 0.19 to 0.46; 170 less (129 less to 194 less) per 1000 people) (moderate certainty evidence), increased diarrhoea (RR 2.42, 95% CI 1.64 to 3.58; 142 more (64 more to 257 more) per 1000 people) (moderate certainty evidence) and may have made little or no difference to major infection (RR 1.02, 95% CI 0.67 to 1.54; 2 less (38 less to 62 more) per 1000 people) (low certainty evidence). It is uncertain if MMF decreased ovarian failure compared to IV cyclophosphamide because the certainty of the evidence was very low (RR 0.36, 95% CI 0.06 to 2.18; 26 less (39 less to 49 more) per 1000 people). Studies were not generally designed to measure ESKD.MMF combined with tacrolimus may have increased complete disease remission (RR 2.38, 95% CI 1.07 to 5.30; 336 more (17 to 1048 more) per 1000 people (low certainty evidence) compared with IV cyclophosphamide, however the effects on alopecia, diarrhoea, ovarian failure, and major infection remain uncertain. Compared to standard of care, the effects of biologics on most outcomes were uncertain because of low to very low certainty of evidence.Maintenance therapyNine studies (767 participants; median 30 months duration (range 6 to 63 months)) reported maintenance therapy. In maintenance therapy, disease relapse is probably increased with azathioprine compared with MMF (RR 1.75, 95% CI 1.20 to 2.55; 114 more (30 to 236 more) per 1000 people (moderate certainty evidence). Multiple other interventions were compared as maintenance therapy, but patient-outcome data were sparse leading to imprecise estimates. AUTHORS' CONCLUSIONS: In this review update, studies assessing treatment for proliferative lupus nephritis were not designed to assess death (all causes) or ESKD. MMF may lead to increased complete disease remission compared with IV cyclophosphamide, with an acceptable adverse event profile, although evidence certainty was low and included the possibility of no difference. Calcineurin combined with lower dose MMF may improve induction of disease remission compared with IV cyclophosphamide, but the comparative safety profile of these therapies is uncertain. Azathioprine may increase disease relapse as maintenance therapy compared with MMF.

Induction and maintenance treatment of proliferative lupus nephritis: a meta-analysis of randomized controlled trials.

BACKGROUND: Lupus nephritis accounts for ~1% of patients starting dialysis therapy. Treatment regimens combining cyclophosphamide with steroids preserve kidney function but have significant side effects. Newer immunosuppressive agents may have improved toxicity profiles. STUDY DESIGN: Systematic review and random-effects meta-analysis, searching MEDLINE (1966 to April 2012), EMBASE (1988-2011), and the Cochrane Renal Group Specialised Register. SETTING & POPULATION: Patients with biopsy-proven proliferative lupus nephritis (classes III, IV, V+III, and V+IV). SELECTION CRITERIA: Randomized controlled trials. INTERVENTION: Immunosuppressive treatment regimens used for induction and maintenance therapy of lupus nephritis. OUTCOMES: Mortality, renal remission and relapse, doubling of creatinine level, proteinuria, incidence of end-stage kidney disease, ovarian failure, alopecia, leukopenia, infections, diarrhea, vomiting, malignancy, and bladder toxicity. RESULTS: 45 trials (2,559 participants) of induction therapy and 6 (514 participants) of maintenance therapy were included. In induction regimens comparing mycophenolate mofetil (MMF) with intravenous cyclophosphamide, there was no significant difference in mortality (7 studies, 710 patients; risk ratio [RR], 1.02; 95% CI, 0.52-1.98), incidence of end-stage kidney disease (3 studies, 231 patients; RR, 0.71; 95% CI, 0.27-1.84), complete renal remission (6 studies, 686 patients; RR, 1.39; 95% CI, 0.99-1.95), and renal relapse (1 study, 140 patients; RR, 0.97; 95% CI, 0.39-2.44). MMF-treated patients had significantly lower risks of ovarian failure (2 studies, 498 patients; RR, 0.15; 95% CI, 0.03-0.80) and alopecia (2 studies, 522 patients; RR, 0.22; 95% CI, 0.06-0.86). In maintenance therapy comparing azathioprine with MMF, the risk of renal relapse was significantly higher (3 studies, 371 patients; RR, 1.83; 95% CI, 1.24-2.71). LIMITATIONS: Heterogeneity in interventions and definitions of remission and lack of long-term outcome reporting. CONCLUSIONS: MMF is as effective as cyclophosphamide in achieving remission in lupus nephritis, but is safer, with a lower risk of ovarian failure. MMF is more effective than azathioprine in maintenance therapy for preventing relapse, with no difference in clinically important side effects.

Treatment for lupus nephritis.

BACKGROUND: Cyclophosphamide, in combination with corticosteroids has been used to induce remission in proliferative lupus nephritis, the most common kidney manifestation of the multisystem disease, systemic lupus erythematosus. Cyclophosphamide therapy has reduced mortality from over 70% in the 1950s and 1960s to less than 10% in recent years. Cyclophosphamide combined with corticosteroids preserves kidney function but is only partially effective and may cause ovarian failure, infection and bladder toxicity. Several new agents, including mycophenolate mofetil (MMF), suggest reduced toxicity with equivalent rates of remission. This is an update of a Cochrane review first published in 2004. OBJECTIVES: To assess the benefits and harms of different immunosuppressive treatments in biopsy-proven proliferative lupus nephritis. SEARCH METHODS: For this update, we searched the Cochrane Renal Group's Specialised Register (up to 15 April 2012) through contact with the Trials' Search Coordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing any treatments for biopsy-proven lupus nephritis in both adult and paediatric patients with class III, IV, V +III and V +IV lupus nephritis were included. All immunosuppressive treatments were considered. DATA COLLECTION AND ANALYSIS: Data were abstracted and quality assessed independently by two authors, with differences resolved by discussion. Dichotomous outcomes were reported as risk ratio (RR) and measurements on continuous scales reported as mean differences (MD) with 95% confidence intervals (CI). MAIN RESULTS: We identified 50 RCTs involving 2846 participants. Of these, 45 studies (2559 participants) investigated induction therapy, and six studies (514 participants), considered maintenance therapy.Compared with intravenous (IV) cyclophosphamide, MMF was as effective in achieving stable kidney function (5 studies, 523 participants: RR 1.05, 95% CI 0.94 to 1.18) and complete remission of proteinuria (6 studies, 686 participants: RR 1.16, 95% CI 0.85 to 1.58). No differences in mortality (7 studies, 710 participants: RR 1.02, 95% CI 0.52 to 1.98) or major infection (6 studies, 683 participants: RR 1.11, 95% CI 0.74 to 1.68) were observed. A significant reduction in ovarian failure (2 studies, 498 participants: RR 0.15, 95% CI 0.03 to 0.80) and alopecia (2 studies, 522 participants: RR 0.22, 95% CI 0.06 to 0.86) was observed with MMF. In maintenance therapy, the risk of renal relapse (3 studies, 371 participants: RR 1.83, 95% CI 1.24 to 2.71) was significantly higher with azathioprine compared with MMF. Multiple other interventions were compared but outcome data were relatively sparse. Overall study quality was variable. The internal validity of the design, conduct and analysis of the included RCTs was difficult to assess in some studies because of the omission of important methodological details. No study adequately reported all domains of the risk of bias assessment so that elements of internal bias may be present. AUTHORS' CONCLUSIONS: MMF is as effective as cyclophosphamide in inducing remission in lupus nephritis, but is safer with a lower risk of ovarian failure. MMF is more effective than azathioprine in maintenance therapy for preventing relapse with no increase in clinically important side effects. Adequately powered trials with long term follow-up are required to more accurately define the risks and eventual harms of specific treatment regimens.

Mitogen activated protein kinases in renal fibrosis.

The mitogen-activated protein (MAP) kinases are involved in both normal renal physiology and in the pathology of various forms of kidney injury, including renal fibrosis. In vitro studies have shown a role for all three MAP kinase (ERK, p38 and JNK) in the production of the major pro-fibrotic factor, transforming growth factor-beta1 (TGF-beta1) by intrinsic renal cell types. There is also considerable cross-talk between TGF-beta1 and MAP kinase signalling pathways in the synthesis and turnover of extracellular matrix by fibroblast-like cells in the kidney. In addition, MAP kinase signalling contributes to TGF-beta1 induced transition of tubular epithelial cells into myofibroblasts. Administration of specific inhibitors of individual MAP kinases has identified a pathogenic role for both p38 and JNK pathways in animal models of renal fibrosis. There is also evidence to suggest that MAP kinases are activated in human renal fibrosis. Thus, blockade of p38 and JNK pathways may have therapeutic potential for the treatment of chronic renal fibrosis.

Blockade of the c-Jun amino terminal kinase prevents crescent formation and halts established anti-GBM glomerulonephritis in the rat.

Macrophages induce acute renal injury in anti-glomerular basement membrane (GBM) glomerulonephritis. This operates, in part, via activation of the c-Jun amino terminal kinase (JNK) signaling pathway. However, it is unknown whether inhibition of JNK signaling is effective once the proinflammatory response is established in the injured kidney. This study examined whether blockade of JNK signaling could halt disease progression, including crescent formation, in a model of severe crescentic anti-GBM glomerulonephritis. WKY rats were immunized with sheep IgG and then injected with sheep anti-GBM serum (day 0). Animals were treated with the JNK inhibitor, CC-401, vehicle alone, or no treatment from day 7 until being killed on day 24 of disease. Untreated animals at day 7 showed significant proteinuria, focal glomerular lesions, marked glomerular macrophage and T-cell accumulation, and upregulation of proinflammatory mediators (TNF-alpha, iNOS, MMP-12). Untreated and vehicle-treated groups displayed severe glomerulonephritis at day 24 with renal impairment and worsening proteinuria. These animals had severe glomerular lesions, with 60% of glomeruli exhibiting fibrocellular crescents, in association with increased macrophage and T-cell accumulation (including macrophage giant cells) and a further increase in mRNA levels of TNF-alpha, iNOS, MMP-12, and TGF-beta1. In contrast, CC-401 treatment prevented renal impairment, suppressed proteinuria, and prevented severe glomerular and tubulointerstitial lesions, including crescent formation and granulomatous-like lesions. These protective effects were independent of glomerular macrophage and T-cell accumulation, and of the humoral immune response. CC-401 treatment inhibited expression of both pro- and antiinflammatory molecules (interleukin-10 and heme oxygenase-1). In addition, IL-1 induced MMP-12 and IL-10 production by cultured macrophages was found to be JNK dependent. In conclusion, blockade of JNK signaling provides substantial protection against the progression of crescentic anti-GBM glomerulonephritis, which may be, in part, due to inhibition of the macrophage proinflammatory response.

A pathogenic role for c-Jun amino-terminal kinase signaling in renal fibrosis and tubular cell apoptosis.

Renal fibrosis and tubular apoptosis are common mechanisms of progressive kidney disease. In vitro studies have implicated the c-Jun amino-terminal kinase (JNK) pathway in these processes. Both of the major JNK isoforms, JNK1 and JNK2, are expressed in the kidney, but their relative contribution to JNK signaling is unknown. This study investigated the role of JNK signaling in renal fibrosis and tubular apoptosis in the unilateral ureteral obstruction model using two different approaches: (1) Mice that were deficient in either JNK1 or JNK2 and (2) a specific inhibitor of all JNK isoforms, CC-401. Western blotting and immunostaining identified a marked increase in JNK signaling in the obstructed kidney, with substantial redundancy between JNK1 and JNK2 isoforms. Administration of CC-401 blocked JNK signaling in the rat obstructed kidney and significantly inhibited renal fibrosis in terms of interstitial myofibroblast accumulation and collagen IV deposition. This effect was attributed to suppression of gene transcription for the profibrotic molecules TGF-beta1 and connective tissue growth factor. CC-401 treatment also significantly reduced tubular apoptosis in the obstructed kidney. Genetic deletion of JNK1 or JNK2 did not protect mice from renal fibrosis in the unilateral ureteral obstruction model, but JNK1 deletion did result in a significant reduction in tubular cell apoptosis. In conclusion, this is the first study to demonstrate that JNK signaling plays a pathogenic role in renal fibrosis and tubular apoptosis. Furthermore, JNK1 plays a nonredundant role in tubular cell apoptosis. These studies identify the JNK pathway as a potential therapeutic target in progressive kidney disease.

Treatment of diffuse proliferative lupus nephritis: a meta-analysis of randomized controlled trials.

BACKGROUND: In this systematic review of randomized controlled trials (RCTs), we assess the benefits and harm of current treatments for diffuse proliferative lupus nephritis (DPLN). METHODS: The Cochrane Controlled Trial Registry, MEDLINE, and EMBASE were searched for RCTs of treatment for DPLN. All available RCTs of patients with biopsy-proven DPLN were included, and data were extracted for overall mortality, end-stage renal disease, doubling of serum creatinine level, relapse, major infection, herpes zoster infection, ovarian failure, malignancy, and bladder toxicity. Treatment effects on these outcomes were summarized as relative risk (RR) with 95% confidence interval (CI) and pooled by using a random-effects model. RESULTS: Twenty-five of 920 articles identified were eligible RCTs and were included. The majority compared cyclophosphamide or azathioprine plus steroids versus steroids alone. Cyclophosphamide plus steroids reduced the risk for doubling of serum creatinine level (4 RCTs, 228 patients; RR, 0.59; 95% CI, 0.40 to 0.88) compared with steroids alone, but had no impact on overall mortality (5 RCTs, 226 patients; RR, 0.98; 95% CI, 0.53 to 1.82). However, risk for ovarian failure was increased significantly (3 RCTs, 147 patients; RR, 2.18; 95% CI, 1.10 to 4.34). In studies from the 1970s, azathioprine plus steroids reduced the risk for all-cause mortality compared with steroids alone (3 RCTs, 78 patients; RR, 0.60; 95% CI, 0.36 to 0.99), but had no effect on renal outcomes. Neither therapy was associated with increased risk for major infection. The addition of plasma exchange to these treatments offered no benefit, and information on other agents, including mycophenolate mofetil, was insufficient for analysis. CONCLUSION: Until future RCTs of newer agents are completed, the current use of cyclophosphamide combined with steroids remains the best option to preserve renal function in patients with DPLN. The smallest effective dose and shortest duration of treatment should be used to minimize gonadal toxicity without compromising efficacy.