The Treatment of Primary IgA Nephropathy: Change, Change, Change.

IgA nephropathy (IgAN) is the most common glomerular disease in the world. However, the approach to treatment remains controversial. There has been an explosion of clinical trials over the past decade both to further examine corticosteroid use and usher in additional treatment considerations, including 2 newly approved therapies for IgAN. Sodium glucose cotransporter 2 inhibitors are proving to be effective therapy across proteinuric chronic kidney diseases, and IgAN is not likely to be an exception. Further supportive agents are looking highly promising and so are novel agents that specifically focus on the pathophysiology of this disease, including endothelin blockade, complement inhibition, and B-cell targeted strategies. We suggest a present-day approach to treatment of individuals with IgAN, expose the limitations in our knowledge, and discuss new treatments that may arise, hoping they come with evidence about optimal utilization. Change appears to be inevitable for our approach to the treatment of IgA nephropathy. This is truly an exciting and optimistic time.

One antigen closer to understanding membranous nephropathy.

Membranous nephropathy is an immune-mediated kidney disease characterized by subepithelial immune deposits. Through the utilization of advanced proteomic techniques, multiple target antigens have been identified, including those associated with primary and secondary etiologies. Nonsteroidal anti-inflammatory drugs represent an important secondary cause of membranous nephropathy. In this study by Sethi et al., advanced proteomic techniques identify proprotein convertase subtilisin/kexin type 6 as a target antigen in nonsteroidal anti-inflammatory drug-associated membranous nephropathy.

Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.

BACKGROUND: Voclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis, improved complete renal response rates in patients with lupus nephritis in a phase 2 trial. This study aimed to evaluate the efficacy and safety of voclosporin for the treatment of lupus nephritis. METHODS: This multicentre, double-blind, randomised phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus with lupus nephritis according to the American College of Rheumatology criteria, and a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible. Patients were randomly assigned (1:1) to oral voclosporin (23·7 mg twice daily) or placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low-dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks defined as a composite of urine protein creatinine ratio of 0·5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate [eGFR] ≥60 mL/min/1·73 m2 or no confirmed decrease from baseline in eGFR of >20%), no administration of rescue medication, and no more than 10 mg prednisone equivalent per day for 3 or more consecutive days or for 7 or more days during weeks 44 through 52, just before the primary endpoint assessment. Safety was also assessed. Efficacy analysis was by intention-to-treat and safety analysis by randomised patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03021499. FINDINGS: Between April 13, 2017, and Oct 10, 2019, 179 patients were assigned to the voclosporin group and 178 to the placebo group. The primary endpoint of complete renal response at week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients; odds ratio 2·65; 95% CI 1·64-4·27; p<0·0001). The adverse event profile was balanced between the two groups; serious adverse events occurred in 37 (21%) of 178 in the voclosporin group and 38 (21%) of 178 patients in the placebo group. The most frequent serious adverse event involving infection was pneumonia, occurring in 7 (4%) patients in the voclosporin group and in 8 (4%) patients in the placebo group. A total of six patients died during the study or study follow-up period (one [<1%] patient in the voclosporin group and five [3%] patients in the placebo group). None of the events leading to death were considered by the investigators to be related to the study treatments. INTERPRETATION: Voclosporin in combination with MMF and low-dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low-dose steroids alone, with a comparable safety profile. This finding is an important advancement in the treatment of patients with active lupus nephritis. FUNDING: Aurinia Pharmaceuticals.

Development of an international Delphi survey to establish core outcome domains for trials in adults with glomerular disease.

Outcomes relevant to treatment decision-making are inconsistently reported in trials involving glomerular disease. Here, we sought to establish a consensus-derived set of critically important outcomes designed to be reported in all future trials by using an online, international two-round Delphi survey in English. To develop this, patients with glomerular disease, caregivers and health professionals aged 18 years and older rated the importance of outcomes using a Likert scale and a Best-Worst scale. The absolute and relative importance was assessed and comments were analyzed thematically. Of 1198 participants who completed Round 1, 734 were patients/caregivers while 464 were health care professionals from 59 countries. Of 700 participants that completed Round 2, 412 were patients/caregivers and 288 were health care professionals. Need for dialysis or transplant, kidney function, death, cardiovascular disease, remission-relapse and life participation were the most important outcomes to patients/caregivers and health professionals. Patients/caregivers rated patient-reported outcomes higher while health care professionals rated hospitalization, death and remission/relapse higher. Four themes explained the reasons for their priorities: confronting death and compounded suffering, focusing on specific targets in glomerular disease, preserving meaning in life, and fostering self-management. Thus, consistent reporting of these critically important outcomes in all trials involving glomerular disease is hoped to improve patient-centered decision-making.

Proteomic Analysis Identifies Distinct Glomerular Extracellular Matrix in Collapsing Focal Segmental Glomerulosclerosis.

BACKGROUND: The mechanisms leading to extracellular matrix (ECM) replacement of areas of glomerular capillaries in histologic variants of FSGS are unknown. This study used proteomics to test the hypothesis that glomerular ECM composition in collapsing FSGS (cFSGS) differs from that of other variants. METHODS: ECM proteins in glomeruli from biopsy specimens of patients with FSGS not otherwise specified (FSGS-NOS) or cFSGS and from normal controls were distinguished and quantified using mass spectrometry, verified and localized using immunohistochemistry (IHC) and confocal microscopy, and assessed for gene expression. The analysis also quantified urinary excretion of ECM proteins and peptides. RESULTS: Of 58 ECM proteins that differed in abundance between cFSGS and FSGS-NOS, 41 were more abundant in cFSGS and 17 in FSGS-NOS. IHC showed that glomerular tuft staining for cathepsin B, cathepsin C, and annexin A3 in cFSGS was significantly greater than in other FSGS variants, in minimal change disease, or in membranous nephropathy. Annexin A3 colocalized with cathepsin B and C, claudin-1, phosphorylated ERK1/2, and CD44, but not with synaptopodin, in parietal epithelial cells (PECs) infiltrating cFSGS glomeruli. Transcripts for cathepsins B and C were increased in FSGS glomeruli compared with normal controls, and urinary excretion of both cathepsins was significantly greater in cFSGS compared with FSGS-NOS. Urinary excretion of ECM-derived peptides was enhanced in cFSGS, although in silico analysis did not identify enhanced excretion of peptides derived from cathepsin B or C. CONCLUSIONS: ECM differences suggest that glomerular sclerosis in cFSGS differs from that in other FSGS variants. Infiltration of activated PECs may disrupt ECM remodeling in cFSGS. These cells and their cathepsins may be therapeutic targets.

Management and treatment of glomerular diseases (part 2): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

In November 2017, the Kidney Disease: Improving Global Outcomes (KDIGO) initiative brought a diverse panel of experts in glomerular diseases together to discuss the 2012 KDIGO glomerulonephritis guideline in the context of new developments and insights that had occurred over the years since its publication. During this KDIGO Controversies Conference on Glomerular Diseases, the group examined data on disease pathogenesis, biomarkers, and treatments to identify areas of consensus and areas of controversy. This report summarizes the discussions on primary podocytopathies, lupus nephritis, anti-neutrophil cytoplasmic antibody-associated nephritis, complement-mediated kidney diseases, and monoclonal gammopathies of renal significance.

Neutrophil exocytosis induces podocyte cytoskeletal reorganization and proteinuria in experimental glomerulonephritis.

Acute glomerulonephritis is characterized by rapid glomerular neutrophil recruitment, proteinuria, and glomerular hypercellularity. The current study tested the hypothesis that the release of neutrophil granule contents plays a role in both the loss of filtration barrier leading to proteinuria and the increase in glomerular cells. Inhibition of neutrophil exocytosis with a peptide inhibitor prevented proteinuria and attenuated podocyte and endothelial cell injury but had no effect on glomerular hypercellularity in an experimental acute glomerulonephritis model in mice. Cultivation of podocytes with neutrophil granule contents disrupted cytoskeletal organization, an in vitro model for podocyte effacement and loss of filtration barrier. Activated, cultured podocytes released cytokines that stimulated neutrophil chemotaxis, primed respiratory burst activity, and stimulated neutrophil exocytosis. We conclude that crosstalk between podocytes and neutrophils contributes to disruption of the glomerular filtration barrier in acute glomerulonephritis. Neutrophil granule products induce podocyte injury but do not participate in the proliferative response of intrinsic glomerular cells.

ABIN1 Determines Severity of Glomerulonephritis via Activation of Intrinsic Glomerular Inflammation.

Transcription factor NF-κB regulates expression of numerous genes that control inflammation and is activated in glomerular cells in glomerulonephritis (GN). We previously identified genetic variants for a NF-κB regulatory, ubiquitin-binding protein ABIN1 as risk factors for GN in systemic autoimmunity. The goal was to define glomerular inflammatory events controlled by ABIN1 function in GN. Nephrotoxic serum nephritis was induced in wild-type (WT) and ubiquitin-binding deficient ABIN1[D485N] mice, and renal pathophysiology and glomerular inflammatory phenotypes were assessed. Proteinuria was also measured in ABIN1[D485N] mice transplanted with WT mouse bone marrow. Inflammatory activation of ABIN1[D472N] (D485N homolog) cultured human-derived podocytes, and interaction with primary human neutrophils were also assessed. Disruption of ABIN1 function exacerbated proteinuria, podocyte injury, glomerular NF-κB activity, glomerular expression of inflammatory mediators, and glomerular recruitment and retention of neutrophils in antibody-mediated nephritis. Transplantation of WT bone marrow did not prevent the increased proteinuria in ABIN1[D845N] mice. Tumor necrosis factor-stimulated enhanced expression and secretion of NF-κB-targeted proinflammatory mediators in ABIN1[D472N] cultured podocytes compared with WT cells. Supernatants from ABIN1[D472N] podocytes accelerated chemotaxis of human neutrophils, and ABIN1[D472N] podocytes displayed a greater susceptibility to injurious morphologic findings induced by neutrophil granule contents. These studies define a novel role for ABIN1 dysfunction and NF-κB in mediating GN through proinflammatory activation of podocytes.

Re-Examining Neutrophil Participation in GN.

Significant advances in understanding the pathogenesis of GN have occurred in recent decades. Among those advances is the finding that both innate and adaptive immune cells contribute to the development of GN. Neutrophils were recognized as key contributors in early animal models of GN, at a time when the prevailing view considered neutrophils to function as nonspecific effector cells that die quickly after performing antimicrobial functions. However, advances over the past two decades have shown that neutrophil functions are more complex and sophisticated. Specifically, research has revealed that neutrophil survival is regulated by the inflammatory milieu and that neutrophils demonstrate plasticity, mediate microbial killing through previously unrecognized mechanisms, demonstrate transcriptional activity leading to the release of cytokines and chemokines, interact with and regulate cells of the innate and adaptive immune systems, and contribute to the resolution of inflammation. Therefore, neutrophil participation in glomerular diseases deserves re-evaluation. In this review, we describe advances in understanding classic neutrophil functions, review the expanded roles of neutrophils in innate and adaptive immune responses, and summarize current knowledge of neutrophil contributions to GN.

Characterization of glomerular extracellular matrix by proteomic analysis of laser-captured microdissected glomeruli.

Abnormal extracellular matrix (ECM) remodeling is a prominent feature of many glomerular diseases and is a final common pathway of glomerular injury. However, changes in ECM composition accompanying disease-related remodeling are unknown. The physical properties of ECM create challenges for characterization of composition using standard protein extraction techniques, as the insoluble components of ECM are frequently discarded and many ECM proteins are in low abundance compared to other cell proteins. Prior proteomic studies defining normal ECM composition used a large number of glomeruli isolated from human kidneys retrieved for transplantation or by nephrectomy for cancer. Here we examined the ability to identify ECM proteins by mass spectrometry using glomerular sections compatible with those available from standard renal biopsy specimens. Proteins were classified as ECM by comparison to the Matrisome database and previously identified glomerular ECM proteins. Optimal ECM protein identification resulted from sequential decellularization and protein extraction of 100 human glomerular sections isolated by laser capture microdissection from either frozen or formalin-fixed, paraffin-embedded tissue. In total, 147 ECM proteins were identified, including the majority of structural and GBM proteins previously identified along with a number of matrix and glomerular basement membrane proteins not previously associated with glomeruli. Thus, our study demonstrates the feasibility of proteomic analysis of glomerular ECM from retrieved glomerular sections isolated from renal biopsy tissue and expands the list of known ECM proteins in glomeruli.

ABIN1 dysfunction as a genetic basis for lupus nephritis.

The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-κB is involved. We reported previously that a knockin mouse expressing an inactive form of ABIN1 (ABIN1[D485N]) develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-κB and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study, we show that ABIN1[D485N] mice develop progressive GN similar to class III and IV lupus nephritis in humans. To investigate the clinical relevance of ABIN1 dysfunction, we genotyped five single-nucleotide polymorphisms in the gene encoding ABIN1, TNIP1, in samples from European-American, African American, Asian, Gullah, and Hispanic participants in the Large Lupus Association Study 2. Comparing cases of systemic lupus erythematosus with nephritis and cases of systemic lupus erythematosus without nephritis revealed strong associations with lupus nephritis at rs7708392 in European Americans and rs4958881 in African Americans. Comparing cases of systemic lupus erythematosus with nephritis and healthy controls revealed a stronger association at rs7708392 in European Americans but not at rs4958881 in African Americans. Our data suggest that variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-κB and mitogen-activated protein kinase activity.

Safety and Efficacy of Long-Term Voclosporin Treatment for Lupus Nephritis in the Phase 3 AURORA 2 Clinical Trial.

OBJECTIVE: AURORA 2 evaluated the long-term safety, tolerability, and efficacy of voclosporin compared to placebo in patients with lupus nephritis (LN) receiving an additional two years of treatment following completion of the one-year AURORA 1 study. METHODS: Enrolled patients continued their double-blinded treatment of voclosporin or placebo randomly assigned in AURORA 1, in combination with mycophenolate mofetil and low-dose glucocorticoids. The primary objective was safety assessed with adverse events (AEs) and biochemical and hematological assessments. Efficacy was measured by renal response. RESULTS: A total of 216 patients enrolled in AURORA 2. Treatment was well tolerated with 86.1% completing the study and no unexpected safety signals. AEs occurred in 86% and 80% of patients in the voclosporin and control groups, respectively, with an AE profile similar to that seen in AURORA 1, albeit with reduced frequency. Investigator reported AEs of both glomerular filtration rate (GFR) decrease and hypertension occurred more frequently in the voclosporin than the control group (10.3% vs 5.0%, and 8.6% vs 7.0%, respectively). Mean corrected estimated GFR (eGFR) was within the normal range and stable in both treatment groups. eGFR slope over the two-year period was -0.2 mL/min/1.73 m2 (95% confidence interval [CI] -3.0 to 2.7) in the voclosporin group and -5.4 mL/min/1.73 m2 (95% CI -8.4 to -2.3) in the control group. Improved proteinuria persisted across three years of treatment, leading to more frequent complete renal responses in patients treated with voclosporin (50.9% vs 39.0%; odds ratio 1.74; 95% CI 1.00-3.03). CONCLUSION: Data demonstrate the safety and efficacy of long-term voclosporin treatment over three years of follow-up in patients with LN.

Management of Lupus Nephritis: New Treatments and Updated Guidelines.

Management of lupus nephritis has evolved considerably over the past years. Here, we provide a comprehensive review of clinical trials that form the basis for the Kidney Disease: Improving Global Outcomes and EULAR/ERA-EDTA updated guidelines and present day trials that will change the landscape of lupus nephritis therapy in years to come. In addition, we highlight the issues related to cost of therapy, resistant disease, and downstream adverse effects of specific therapies.

Clinicopathological Characteristics of Adult IgA Nephropathy in the United States.

Introduction: IgA nephropathy (IgAN) is a progressive autoimmune kidney disease and a leading cause of glomerular disease that can result in kidney failure (KF). The median age at diagnosis is 35 to 37 years and approximately 50% of patients will progress to KF within 20 years. We aimed to enhance the understanding of renal histology and chronic kidney disease (CKD) stage at the time of IgAN diagnosis using a large real-world biopsy cohort. Methods: This retrospective cohort study evaluated biopsy data and clinical characteristics from adult patients within the US who were diagnosed with IgAN between January 1, 2016 to May 31, 2020. Descriptive statistics were summarized and relationship(s) between each Oxford Classification (MEST-C) component score with 24-hour proteinuria or CKD stage were examined using regression analysis. Results: A total of 4375 patients (mean age 47.7 years, 62.7% male) met eligibility criteria. Mild to moderate mesangial hypercellularity (47.3%), segmental sclerosis (65.0%), tubular atrophy ≥25% (57.4%), and crescents (18.5%) were identified; and 74.6% of patients were at CKD stage ≥3. Proteinuria ≥1 g/d was associated with higher MEST-C scores, and the odds of mesangial hypercellularity, segmental sclerosis, tubular atrophy, and crescents increased with CKD stage. Conclusion: Most patients with IgAN in our US cohort were diagnosed at CKD stage ≥3 and had high MEST-C scores and proteinuria that are suggestive of significant disease burden at the time of kidney biopsy. Strategies are required to raise awareness and promote earlier detection of asymptomatic urinary abnormalities before extensive irreversible kidney damage has occurred.

Corrigendum to "Clinicopathological Characteristics of Adult IgA Nephropathy in the United States" [Kidney International Reports Volume 8, Issue 9, September 2023, Pages 1792-1800].

[This corrects the article DOI: 10.1016/j.ekir.2023.06.016.].

Update on the Efficacy and Safety Profile of Voclosporin: An Integrated Analysis of Clinical Trials in Lupus Nephritis.

OBJECTIVE: This integrated analysis evaluates the efficacy and safety of voclosporin, a novel calcineurin inhibitor, at 23.7 mg twice daily in combination with mycophenolate mofetil (MMF) and oral glucocorticoids in lupus nephritis (LN) using pooled data from two large phase II and phase III clinical trials. The purpose was to expand the pool of patients for safety analyses and to increase power for efficacy analyses in patient subpopulations. METHODS: Aurinia Urinary Protein Reduction in Active Lupus with Voclosporin (AURA-LV) (phase II) and Aurinia Renal Response in Active Lupus With Voclosporin (AURORA 1) (phase III) were randomized, placebo-controlled, double-blind trials with similar designs and end points comparing voclosporin to control in combination with MMF and oral glucocorticoids for the treatment of LN. The primary efficacy outcome of the integrated analysis was complete renal response (CRR) at approximately one year (Week 48 data from AURA-LV and Week 52 from AURORA 1). Safety was assessed throughout the trials. RESULTS: Overall, 534 patients (268 voclosporin; 266 control) were included in the integrated analysis. Significantly more patients achieved a CRR at one year in the voclosporin group than in the control group (43.7% vs. 23.3%; OR 2.76; 95% CI 1.88, 4.05 P < 0.0001). The incidence of adverse events (AEs) was similar (91.4% voclosporin; 87.2% control). Most AEs were mild to moderate in severity; the most commonly reported AEs were classified as infections and infestations (62.2% voclosporin; 54.9% control) and gastrointestinal disorders (45.3% voclosporin; 35.3% placebo). No new or unexpected safety signals were detected. CONCLUSIONS: This integrated analysis demonstrates the efficacy and safety of voclosporin in the treatment of LN across the diverse racial and ethnic groups studied.

The Potential of Nrf2 Activation as a Therapeutic Target in Systemic Lupus Erythematosus.

Inflammation and oxidative stress are well established in systemic lupus erythematosus (SLE) and are critical to the pathogenesis of autoimmune diseases. The transcription factor NF-E2 related factor 2 (Nrf2) is a central regulator of cellular anti-oxidative responses, inflammation, and restoration of redox balance. Accumulating reports support an emerging role for the regulation of Nrf2 in SLE. These include findings on the development of lupus-like autoimmune nephritis and altered immune cell populations in mice lacking Nrf2, as well as decreased Nrf2 abundance in the dendritic cells of patients with SLE. Nrf2-inducing agents have been shown to alleviate oxidative and inflammatory stress and reduce tissue injury in SLE mouse models. Since Nrf2 expression can be increased in activated T cells, the precise role of Nrf2 activation in different immune cell types and their function remains to be defined. However, targeting Nrf2 for the treatment of diseases associated with oxidative stress and inflammation, such as SLE, is promising. As investigation of Nrf2-inducing agents in clinical trials grows, defining the signaling and molecular mechanisms of action and downstream effects in response to different Nrf2-inducing agents in specific cells, tissues, and diseases, will be critical for effective clinical use.

Serum and Urine Interferon Gamma-Induced Protein 10 (IP-10) Levels in Lupus Nephritis.

Background: Lupus nephritis (LN) is a prevalent and severe complication of systemic lupus erythematosus (SLE). Non-invasive diagnostics are limited, and current therapies have inadequate response rates. Expression of the chemokine Interferon-γ-induced protein 10 (IP-10) is regulated by Interferon-γ signaling and NF-κB, and its molecular activity and enhanced urine concentrations are implicated in LN, but its utility as a diagnostic marker and association with demographic, clinical, or pathologic features is not defined. Methods: 38 LN patients and 11 patients with non-LN glomerular diseases (GD) with active disease were included. Eighteen of the LN patients had achieved remission at one follow-up during the study time. Serum and urine were obtained from these samples, and the IP-10 levels were measured. Results: Serum and urine IP-10 levels are significantly enhanced in LN patients with active disease as compared with normal individuals (serum average 179.7 pg/mL vs. 7.2 pg/mL, p < 0.0001; urine average 28.7 pg/mg vs. 1.6 pg/mg, p = 0.0019) and patients with other forms of glomerular disease (serum average 179.7 pg/mL vs. 84.9 pg/mL, p = 0.0176; urine average 28.7 pg/mg vs. 0.18 pg/mg, p = 0.0011). Urine IP-10 levels are significantly higher in patients with proliferative LN (PLN) than those with membranous LN (MLN) (average 32.8 pg/mg vs. 7.6 pg/mg, p = 0.0155). Urine IP-10 levels are also higher in MLN versus primary membranous nephropathy (MN) (average 7.6 pg/mg vs. 0.2 pg/mg, p = 0.0193). Importantly, serum IP-10 levels remain elevated during active LN and LN remission, but urine IP-10 levels are decreased from active LN to remission in 72% of our patients. Lastly, serum, but not urine IP-10 levels are significantly higher in African American than White American LN patients in active LN (average 227.8 pg/mL vs. 103.4 pg/mL, p = 0.0309) and during LN remission (average 254.6 pg/mL vs. 89.2 pg/mL, p = 0.0399). Conclusions: Our findings suggest that serum and urine IP-10 measurements provide promising tests for monitoring LN activity, differentiation between classifications of LN, and differentiation between LN and other forms of glomerular disease. We also conclude that further assessment of elevated IP-10 levels in the serum and urine of high-risk populations (i.e., African American) could be beneficial in determining why many of these patients have worse outcomes and are non-responsive to standard therapeutics.

Efficacy and Safety of ACE Inhibitor and Angiotensin Receptor Blocker Therapies in Primary Focal Segmental Glomerulosclerosis Treatment: A Systematic Review and Meta-Analysis.

Rationale and Objective: Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy (renin-angiotensin-aldosterone system [RAAS] inhibitor) to control proteinuria in primary and genetic focal segmental glomerulosclerosis (FSGS) follows guidelines based on other proteinuria-related kidney diseases. There is no consensus on the efficacy and safety of RAAS inhibitor therapies in primary and genetic FSGS. This systematic review assessed the effects of RAAS inhibitor therapy on kidney outcomes in these patients. Study Design: Systematic review of randomized controlled trials, interventional nonrandomized studies, observational studies, and retrospective studies. Setting & Study Populations: Patients with primary and genetic FSGS. Selection Criteria for Studies: PubMed, Cochrane Library, and Embase. Data Extraction: 2 investigators independently screened studies and extracted data. Analytical Approach: Results were summarized as the ratio of means (ROM) between baseline and follow-up measurements or as the hazard ratio using random-effects models. Results: 30 publications were selected; 5 were controlled trials (4 randomized controlled trials). 8 assessed RAAS inhibitor monotherapy, while the rest studied RAAS inhibitors in combination with other drugs, mainly immunosuppressants. On average, a 32% proteinuria reduction (ROM, 0.68; 95% CI, 0.47-0.98) and no change in creatinine clearance (ROM, 0.95; 95% CI, 0.77-1.16) from baseline to the last reported follow-up was observed in patients treated with RAAS inhibitor monotherapy. When a RAAS inhibitor was combined with other drugs, a 72% proteinuria reduction was observed from baseline to the last reported follow-up (ROM, 0.24; 95% CI, 0.08-0.75). The published data did not allow for the assessment of the effects of RAAS inhibitor monotherapy on estimated glomerular filtration rate and end-stage kidney disease risks. Limitations: Large study heterogeneity in design, patient populations, and treatment regimens. No access to individual patient-level data. Conclusions: This review supports the tendency to observe a proteinuria reduction with RAAS inhibitors in patients with primary FSGS. RAAS inhibitor monotherapy was associated with maintained kidney function, as shown by no change in creatinine clearance. Strong evidence to quantify the effects of RAAS inhibitor monotherapy on end-stage kidney disease and glomerular filtration rate was lacking. Larger, well-designed clinical trials are needed to better understand the effects of RAAS inhibitors on primary FSGS.

Efficacy and Safety of Immunosuppressive Therapy in Primary Focal Segmental Glomerulosclerosis: A Systematic Review and Meta-analysis.

Rationale & Objective: Focal segmental glomerulosclerosis (FSGS) is a rare condition that can lead to kidney function decline and chronic kidney failure. Immunosuppressants are used to treat primary FSGS. However, their efficacy and safety in FSGS are not clearly established. We assessed current knowledge on clinical effectiveness and safety of immunosuppressants for primary FSGS. Study Design: Systematic review of randomized controlled trials, interventional nonrandomized controlled trials, observational studies, retrospective studies, and registries. Setting & Participants: Patients with primary and genetic FSGS. Selection Criteria for Studies: Medline, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for English-language, primary-FSGS studies from inception to 2019. Clinical outcomes were changes from baseline in proteinuria, kidney function, and kidney survival. Data Extraction: 2 investigators independently screened studies and extracted data. Analytical Approach: Study results were summarized using random-effects models either as ratios of means between follow-up and baseline measurements or as HRs. Results: We included 98 articles. Substantial heterogeneity was observed in patient baseline characteristics and study designs. Most studies assessed treatment with corticosteroids alone or combined with other drugs, mainly immunosuppressants. Patients treated with immunosuppressants showed reduced proteinuria (14 studies; ratio of means, 0.36; 95% CI, 0.20-0.47), decreased creatinine clearance (mean difference, -25.03; 95% CI, -59.33 to -9.27) and (significantly) lower estimated glomerular filtration rates (mean difference, -7.61 mL/min/1.73 m2; 95% CI, -14.98 to 0.25 mL/min/1.73 m2). Immunosuppressant therapy had an uncertain effect on reducing the chronic kidney failure risk. Hypertension and infections were the most commonly reported adverse events. Limitations: Heterogeneity in study designs, patient populations, and treatment regimens; no access to individual patient-level data. Conclusions: This systematic review supports proteinuria reduction with immunosuppressant therapy in primary FSGS over varying follow-up periods. The effects of immunosuppressants on kidney survival remain uncertain. This review underscores the need for better-designed and adequately controlled studies to assess immunosuppressant therapy in patients with primary FSGS.