Evaluating Sex Differences in the Characteristics and Outcomes of Lupus Nephritis: A Systematic Review and Meta-Analysis.

Introduction: More frequent and severe lupus nephritis (LN) has been reported in men compared to women, but data are limited and inconsistent. We conducted a meta-analysis of the literature to compare the histopathologic findings and outcomes between men and women with biopsy-proven LN. Methods: A systematic search of MEDLINE, Embase, Cochrane, and Web of Science databases was conducted through February 2021. Clinical information was extracted and synthesized from 25 studies that met inclusion criteria (1,210 men and 6,635 women). Pooled odds ratios (OR) with corresponding 95% confidence intervals (CIs) were generated via meta-analysis, and meta-regression was performed to assess the impact of several covariates, both using random-effects models. Results: Twenty studies reported kidney histopathology, eleven reported kidney outcomes, and eight reported mortality rates. Men had greater odds of class IV ± V LN (OR 1.26, 95% CI: 1.01-1.56), and the composite of end-stage kidney disease, persistent eGFR <15 mL/min or doubling of serum creatinine (OR 2.20, 95% CI: 1.59-3.06), and lower odds of complete remission (OR 0.52, 95% CI: 0.39-0.68). Mortality was not statistically significantly different between sexes (OR 1.50, 95% CI: 0.92-2.46). Meta-regression did not reveal statistically significant study-level relationships between sex differences in any of the covariates that could account for the greater odds of worse kidney outcome in males. Conclusion: Our analysis confirms the association between male sex and increased severity of LN as well as worse kidney outcomes. Larger prospective studies are needed to validate this association and inform treatment strategies adapted to this population.

Kidney Biopsy Findings and Clinical Outcomes of US Veterans with Inflammatory Bowel Disease.

Introduction: Patients with inflammatory bowel disease (IBD; ulcerative colitis [UC] and Crohn's disease [CD]) may have unique patterns of kidney injury related to their underlying or coexisting disease or to medications. We present the kidney biopsy findings and clinical outcomes of veterans with UC or CD from the US Department of Veteran's Affairs (VA) health system. Methods: Histopathologic and clinical data were extracted by retrospective review of the VA electronic health record of patients with IBD and a kidney biopsy between 2000 and 2018. Incident end-stage kidney disease (ESKD) was defined as requirement of kidney replacement therapy. Statistical analyses were performed using SAS. Results: A total of 140 patients (UC: 91 and CD: 49) underwent kidney biopsy. The three most common diagnoses were IgA nephropathy (17.1%), diabetic nephropathy (14.3%), and acute interstitial nephritis (9.3%). Significant interstitial fibrosis, tubular atrophy, and arteriosclerosis were present in 45% of biopsies. Twenty-six percent of patients with UC and 20% of those with CD progressed to ESKD, with a mean time from kidney biopsy of 3.1 and 1.9 years, respectively. Forty-five percent of patients with UC and 34% of those with CD died, with a mean time from kidney biopsy of 4.3 and 4.6 years, respectively. Conclusion: Among US veterans with IBD who underwent a kidney biopsy, IgA nephropathy, diabetic nephropathy, and interstitial nephritis were among the most common findings. Additionally, features of advanced kidney disease with rapid clinical progression to ESKD or death were observed. These findings suggest a delay and possibly a low rate of diagnosis.

Living Donor Kidney Transplant in Recipients With Glomerulonephritis: Donor Recipient Biologic Relationship and Allograft Outcomes.

Using the Scientific Registry of Transplant Recipients, we examined the association between donor-recipient biologic relationship and long-term recipient and allograft survival among glomerulonephritis (GN) patients. Four GN types were studied: membranous nephropathy, IgA, lupus-associated nephritis, and focal segmental glomerulosclerosis (FSGS). We identified all adult primary living-donor recipients between 2000 and 2018 (n = 19,668): related (n = 10,437); unrelated (n = 9,231). Kaplan-Meier curves were generated for the recipient, death-censored graft survival and death with functioning graft through ten years post-transplant. Multivariable Cox proportional hazard models were used to examine the association between the donor-recipient relationship and outcomes of interest. There was an increased risk for acute rejection by 12 months post-transplant among the unrelated compared to the related group in IgA (10.1% vs. 6.5%, p<0.001), FSGS (12.1% vs. 10%, p-0.016), and lupus nephritis (11.8% vs. 9.2%; p-0.049). The biological donor-recipient relationship was not associated with a worse recipient or graft survival or death with functioning graft in the multivariable models. These findings are consistent with the known benefits of living-related-donor kidney transplants and counter the reports of the potential adverse impact of the donor-recipient biologic relationship on allograft outcomes.

Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis.

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.

Lymphomatous infiltration of the kidney in a patient with Waldenstrom's macroglobulinemia.

Kidney disease can be an initial presentation or a chronic manifestation of plasma cell dyscrasias. Here, we describe a rare presentation of kidney disease driven by lymphomatous infiltration of the kidney in a patient with Waldenstrom's macroglobulinemia (WM). A 70-year-old female with an 8-year history of WM (IgM, κ) was referred for declining renal function. Prior to presentation, she had stable WM disease without evidence of worsening disease burden. She had been previously hospitalized with SARS-CoV-2 infection and acute kidney injury (AKI). Her serum creatinine (sCr) peaked at 3.7 mg/dL (baseline 0.9 mg/dL) but recovered to 1.1 mg/dL by the time of discharge. Two months after discharge, her sCr increased to 1.9 mg/dL, and she had new proteinuria of 1.5 g/day. Kidney biopsy showed lymphomatous infiltration of the interstitium without glomerular involvement. Treatment with rituximab and bendamustine resulted in an improvement in renal function (sCr 1.4 mg/dL). WM is an uncommon hematologic malignancy, and extramedullary involvement, including renal involvement, is rare. This case emphasizes the importance of surveillance for kidney dysfunction in patients with plasma cell dyscrasias, even if patients appear to have stable lymphoproliferative disease.

Clinicopathologic Significance of Predominant Lambda Light Chain Deposition in IgA Nephropathy.

Introduction: IgA nephropathy (IgAN) differs from other glomerular diseases by the frequently predominant lambda over kappa light chain deposition. Using the Cure Glomerulonephropathy (CureGN) IgAN cohort, we aimed to determine whether predominant lambda chain deposition is associated with worse clinical outcomes or histopathologic markers of more active disease. Methods: Patients were categorized based on the intensity of light chain staining. The lambda dominant (LD) group was defined by a difference in intensity score of lambda minus kappa ≥ 1+ and the kappa-lambda codominant (KL) group by a difference < 1+. We compared the clinical course of patients in each category from the time of kidney biopsy and time of enrollment into CureGN to the time of remission (proteinuria < 0.3 g/g), 50% reduction in estimated glomerular filtration rate (eGFR), or progression to end-stage kidney disease (ESKD). We also analyzed differences in histopathologic characteristics between the 2 groups. Results: Among 440 patients, we found no significant differences between groups in baseline clinical characteristics nor in rates of remission, 50% reduction in eGFR, or progression to ESKD. Patients in the LD group had a modestly greater frequency of IgG staining ≥ 1+. The biopsy results of 234 patients reviewed by CureGN pathologists revealed a greater frequency of endocapillary hypercellularity (51.1% vs. 36.3%, P = 0.04) in the LD group, but no other significant difference in histopathologic features. Conclusion: In IgAN, we found an association between lambda predominance and increased endocapillary hypercellularity, but no association with clinical outcomes.

Longitudinal Changes in Health-Related Quality of Life in Primary Glomerular Disease: Results From the CureGN Study.

INTRODUCTION: Prior cross-sectional studies suggest that health-related quality of life (HRQOL) worsens with more severe glomerular disease. This longitudinal analysis was conducted to assess changes in HRQOL with changing disease status. METHODS: Cure Glomerulonephropathy (CureGN) is a cohort of patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA vasculitis, or IgA nephropathy. HRQOL was assessed at enrollment and follow-up visits 1 to 3 times annually for up to 5 years with the Patient-Reported Outcomes Measurement Information System (PROMIS). Global health, anxiety, and fatigue domains were measured in all; mobility was measured in children; and sleep-related impairment was measured in adults. Linear mixed effects models were used to evaluate HRQOL responsiveness to changes in disease status. RESULTS: A total of 469 children and 1146 adults with PROMIS scores were included in the analysis. HRQOL improved over time in nearly all domains, though group-level changes were modest. Edema was most consistently associated with worse HRQOL across domains among children and adults. A greater number of symptoms also predicted worse HRQOL in all domains. Sex, age, obesity, and serum albumin were associated with some HRQOL domains. The estimated glomerular filtration rate (eGFR) was only associated with fatigue and adult physical health; proteinuria was not associated with any HRQOL domain in adjusted models. CONCLUSION: HRQOL measures were responsive to changes in disease activity, as indicated by edema. HRQOL over time was not predicted by laboratory-based markers of disease. Patient-reported edema and number of symptoms were the strongest predictors of HRQOL, highlighting the importance of the patient experience in glomerular disease. HRQOL outcomes inform understanding of the patient experience for children and adults with glomerular diseases.

The longitudinal relationship between patient-reported outcomes and clinical characteristics among patients with focal segmental glomerulosclerosis in the Nephrotic Syndrome Study Network.

BACKGROUND: Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS). METHODS: FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied. RESULTS: There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (-7.6 points, P = 0.02) and mobility (-4.2, P = 0.02), the number of reported symptoms was associated with worse depression (-2.7 per symptom, P = 0.009) and anxiety (-2.3, P = 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (-2.8 per visit, P < 0.001) and fatigue (-2.4, P = 0.03). Multivariable analyses among adults found the number of reported symptoms was associated with worse function in all eight PROMIS measures and the number of ER visits was associated with worse fatigue, pain interference, sleep impairment, depression, anxiety and social satisfaction. Laboratory markers of disease severity (i.e. proteinuria, estimated glomerular filtration rate and serum albumin) did not predict PRO in multivariable analyses, with the single exception of complete remission and better pain interference scores among children (+9.3, P = 0.03). CONCLUSIONS: PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes.

Assessing the Impact of Losmapimod on Proteinuria in Idiopathic Focal Segmental Glomerulosclerosis.

INTRODUCTION: Idiopathic focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease. In preclinical models and biopsies of human FSGS kidneys, p38 mitogen-activated protein kinase (MAPK) has demonstrated enhanced activity; and p38 MAPK inhibition has improved disease markers. This proof-of-concept trial aimed to assess efficacy, safety, tolerability, and pharmacokinetics of losmapimod, an oral p38 MAPK inhibitor, in humans with FSGS. METHODS: A single-arm, multicenter, open-label, Phase II trial (NCT02000440) was conducted in adults with FSGS; proteinuria ≥2.0 g/d; estimated glomerular filtration rate (eGFR) ≥45 ml/min per 1.73 m2; blood pressure <140/90 mm Hg. Collapsing and genetic forms of FSGS were excluded. The primary endpoint was number of patients with ≥50% proteinuria reduction and eGFR ≥70% of baseline after receiving losmapimod twice-daily for 16 to 24 weeks. RESULTS: Seventeen patients received ≥1 losmapimod dose. No patients achieved the primary endpoint; therefore, the study was terminated following a prespecified interim analysis. At week 24, proteinuria reductions between 20% and <50% were observed in 4 patients and proteinuria increases >20% in 3 patients. One patient achieved a proteinuria response (≥50% reduction) at week 2 but subsequently relapsed. Losmapimod pharmacokinetics were consistent with prior studies. No serious adverse events (AEs) were reported. CONCLUSION: p38 MAPK inhibition with losmapimod did not result in ≥50% reduction of proteinuria in patients with FSGS. However, study population heterogeneity may have contributed to our negative findings and therefore this does not eliminate the potential to demonstrate benefit in a population more sensitive to p38 MAPK inhibition if identifiable in the future by precision-medicine methods.

Persistent Disease Activity in Patients With Long-Standing Glomerular Disease.

INTRODUCTION: Glomerular diseases are characterized by variable disease activity over many years. We aimed to analyze the relationship between clinical disease activity and duration of glomerular disease. METHODS: Disease activity in adults with chronic minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy (IgAN; first diagnostic biopsy >5 years before enrollment; Of Longstanding Disease [OLD] cohort, n = 256) followed at Columbia University Medical Center (CUMC), was compared with disease activity of an internal and external cohort of patients with first diagnostic biopsy <5 years before enrollment drawn from the Cure Glomerulonephropathy Network (CureGN cohort, n = 1182; CUMC-CureGN cohort, n = 362). Disease activity was defined by (i) Kidney Disease: Improving Global Outcomes-recommended threshold criteria for initiation of immunosuppression in primary glomerulonephropathy (GN) and (ii) CureGN's Disease Activity Working Group definitions for activity. RESULTS: No significant differences were detected among the 3 cohorts in terms of age, sex, serum creatinine, and urinary protein-to-creatinine ratio. For each GN subtype, disease activity in the OLD cohort was comparable with disease activity in the entire CureGN and the CUMC-CureGN cohort. When limiting our comparisons to disease activity in incident CUMC-CureGN patients (first diagnostic biopsy within 6 months of enrollment), OLD patients demonstrated similar activity rates as incident patients. CONCLUSION: Disease activity did not differ among patients with shorter versus longer duration of disease. Such survivor patients, with long-term but persistent disease, are potentially highly informative for understanding the clinical course and pathogenesis of GN and may help identify factors mediating more chronic subtypes of disease.

Serum Albumin at Partial Remission Predicts Outcomes in Membranous Nephropathy.

BACKGROUND: In primary membranous nephropathy (MN), partial remission (PR) (≥50% reduction of proteinuria to <3.5 g/d) is associated with a greater risk of relapse and end-stage kidney disease (ESKD) compared with complete remission (CR). We aimed to determine factors associated with relapse or renal failure in patients who attain the standard definition of PR. METHODS: We captured PR, CR, relapse, and the composite of doubling of serum creatinine or ESKD in a cohort of 267 patients with MN, nephrotic syndrome, and >12 months of follow-up. Characteristics at the time of PR associated with the composite outcome or relapse were evaluated using a time-to-event analysis. RESULTS: A total of 192 patients attained PR and 86 attained CR. Serum albumin at PR (hazard ratio [HR]: 1.58 per 0.5 g/dl decrease from 4.0 g/dl; 95% confidence interval [CI]: 1.03-2.43) and duration of nephrotic proteinuria (HR: 1.01 per month increase; 95% CI: 1.00-1.03) were independent risk factors for the composite endpoint. Serum albumin at PR was associated with an increased risk of relapse (HR: 1.58 per 0.5 g/dl decrease below 4.0 g/dl; 95% CI: 1.24-2.01). A cutoff for serum albumin ≤3.5 g/dl at PR performed best in predicting relapse and composite outcome. CONCLUSIONS: Patients with serum albumin >3.5 g/dl at PR have decreased risk of composite outcome or relapse compared with PR with low albumin. A definition of PR that includes normalization of serum albumin may be a more robust surrogate endpoint in MN than the traditional definition of PR.

Measuring Circulating Complement Activation Products in Myeloperoxidase- and Proteinase 3-Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: There is accumulating evidence that complement activation is important in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) pathogenesis. This study was undertaken to investigate complement activation in AAV with myeloperoxidase (MPO) positivity and AAV with proteinase 3 (PR3) positivity after determining optimal methods for measuring activated complement factors in circulation. METHODS: Participants included 98 patients with AAV (45 MPO-ANCA positive, 53 PR3-ANCA positive) and 35 healthy controls. Plasma was obtained from blood collected using EDTA tubes, with or without 100 µg/ml Futhan. Levels of Bb, C3a, C5a, soluble C5b-9 (sC5b-9), properdin, and C4d were measured by enzyme-linked immunosorbent assay. Group comparisons were made using Wilcoxon's 2-sample test. Paired data were analyzed using a matched pairs signed rank test. RESULTS: Compared to healthy controls, certain complement analyte levels were high in patients with active AAV with MPO positivity, including C3a (P < 0.0001), C5a (P = 0.0004), and sC5b-9 (P = 0.0007). During remission, levels of Bb (P = 0.001), C3a (P < 0.0001), and sC5b-9 (P = 0.003) were higher. Compared to healthy controls, C3a (P < 0.0001), C5a (P = 0.002), sC5b-9 (P = 0.0001), and C4d (P = 0.005) levels were higher in patients with active AAV with PR3 positivity; levels of C3a (P < 0.0001) and C4d (P = 0.007) were also higher duriing remission. There were no significant differences in any complement analyte for either ANCA serotype between patients with active disease and those with disease in remission. Among patients with paired samples, sC5-9 levels were significantly lower during disease remission compared to active disease. C5a was significantly lower among patients with disease in long-term remission who were not receiving therapy. For Bb, C5a, and sC5b-9, median levels and individual values were considerably higher in control and patient samples processed without Futhan compared to those processed with Futhan. CONCLUSION: Complement activation occurs in both MPO-positive AAV and PR3-positive AAV. The complement activation profile differs according to disease activity and possibly ANCA serotype. Futhan reduces in vitro complement activation and provides a more accurate measurement.

Using PROMIS® to create clinically meaningful profiles of nephrotic syndrome patients.

OBJECTIVE: Nephrotic syndrome (NS) is a kidney disease known to adversely impact health-related quality of life (HRQOL). Patient-reported outcome (PRO) measures are commonly used to characterize HRQOL and the patient disease experience. This study aims to improve the interpretability and clinical utility of the Patient-Reported Outcomes Measurement Information System® (PROMIS®) by identifying distinct meaningful HRQOL profiles in children and adults with NS. METHOD: Patients were from 2 prospective NS cohort studies (PROMIS-II®: 121 children; NEPTUNE: 40 children and 219 adults) with data from 6 PROMIS® domains. Latent Profile Analysis was used to identify subgroups of patients based on PROMIS® score patterns. A 3-step analysis of latent profile predictors was used to determine how clinical parameters predicted HRQOL profile membership. RESULTS: We identified 3 HRQOL profiles (Good, Average, and Poor) with strong indicators of membership classification (entropy >0.86). Complete proteinuria remission, reduction in symptoms, and shorter disease duration, were significant predictors of better HRQOL profile membership. CONCLUSIONS: Patients with NS can be classified by HRQOL into clinically meaningful categories. Integrating this approach into clinic may help in the identification of individuals with poor HRQOL will help clinicians better manage their symptoms and researchers study the causes and possible interventions for these patients. PROMIS® HRQOL profiles were reproducible in replication cohorts. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Understanding Long-term Remission Off Therapy in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

INTRODUCTION: In antineutrophil cytoplasmic antibody-associated (ANCA) vasculitis, relapse risk and long-term immunosuppressive therapy are problematic. Stopping immunotherapy has not been well described. METHODS: The Glomerular Disease Collaborative Network ANCA vasculitis inception cohort was evaluated. Patients who stopped all immunotherapy and those continuously on immunotherapy (≥2 years) were included. Time to first period off therapy was modeled with end-stage kidney disease and death as competing risks to understand influences of stopping therapy. Cause-specific hazard ratios (HRs) with 95% confidence intervals (CI) and P values are reported. Models controlled for age, sex, ANCA specificity, organ involvement, diagnosis era, and treatments (yes/no). Repeated events analysis was used to assess the time-dependent variable of time off treatment on recurrent relapse with HRs, 95% CIs, and P values are reported (same control variables without treatments). RESULTS: In 427 patients, 277 (65%) stopped therapy (median 20 months from initial induction); 14% for ≥2 different periods of time and 23% for periods ≥5 years. In multivariable models of time to discontinuation of treatment, women (HR 1.33; 95% CI 1.04-1.70; P = 0.024) and those treated with pulse methylprednisolone (HR 1.39; 95% CI 1.05-1.84; P = 0.020) were more likely to stop. The time-dependent variable of time off treatment was associated with fewer recurrent relapses (HR 0.51; 95% CI 0.41-0.63; P < 0.001). CONCLUSIONS: Stopping immunotherapy was common. Women and those treated with methylprednisolone stop treatment more often, but underlying mechanisms are unknown. Stopping treatment was associated with fewer relapses, suggesting that even without guidelines there may be benefits without an untoward detriment of relapse.