IgA nephropathy in adults-treatment standard.

Immunoglobulin A nephropathy (IgAN) is the most common primary form of glomerular disease worldwide and carries a high lifetime risk of kidney failure. The underlying pathogenesis of IgAN has been characterized to a sub-molecular level; immune complexes containing specific O-glycoforms of IgA1 are central. Kidney biopsy remains the gold-standard diagnostic test for IgAN and histological features (i.e. MEST-C score) have also been shown to independently predict outcome. Proteinuria and blood pressure are the main modifiable risk factors for disease progression. No IgAN-specific biomarker has yet been validated for diagnosis, prognosis or tracking response to therapy. There has been a recent resurgence of investigation into IgAN treatments. Optimized supportive care with lifestyle interventions and non-immunomodulatory drugs remains the backbone of IgAN management. The menu of available reno-protective medications is rapidly expanding beyond blockade of the renin-angiotensin-aldosterone system to include sodium-glucose cotransporter 2 and endothelin type A receptor antagonism. Systemic immunosuppression can further improve kidney outcomes, although recent randomized controlled trials have raised concerns regarding infectious and metabolic toxicity from systemic corticosteroids. Studies evaluating more refined approaches to immunomodulation in IgAN are ongoing: drugs targeting the mucosal immune compartment, B-cell promoting cytokines and the complement cascade are particularly promising. We review the current standards of treatment and discuss novel developments in pathophysiology, diagnosis, outcome prediction and management of IgAN.

Pregnancy History and Kidney Disease Progression Among Women Enrolled in Cure Glomerulonephropathy.

Introduction: Preeclampsia increases the risk for future chronic kidney disease (CKD). Among those diagnosed with CKD, it is unclear whether a prior history of preeclampsia, or other complications in pregnancy, negatively impact kidney disease progression. In this longitudinal analysis, we assessed kidney disease progression among women with glomerular disease with and without a history of a complicated pregnancy. Methods: Adult women enrolled in the Cure Glomerulonephropathy study (CureGN) were classified based on a history of a complicated pregnancy (defined by presence of worsening kidney function, proteinuria, or blood pressure; or a diagnosis of preeclampsia, eclampsia, or hemolysis, elevated liver enzymes, and low platelets [HELLP] syndrome), pregnancy without these complications, or no pregnancy history at CureGN enrollment. Linear mixed models were used to assess estimated glomerular filtration rate (eGFR) trajectories and urine protein-to-creatinine ratios (UPCRs) from enrollment. Results: Over a median follow-up period of 36 months, the adjusted decline in eGFR was greater in women with a history of a complicated pregnancy compared to those with uncomplicated or no pregnancies (-1.96 [-2.67, -1.26] vs. -0.80 [-1.19, -0.42] and -0.64 [-1.17, -0.11] ml/min per 1.73 m2 per year, P = 0.007). Proteinuria did not differ significantly over time. Among those with a complicated pregnancy history, eGFR slope did not differ by timing of first complicated pregnancy relative to glomerular disease diagnosis. Conclusions: A history of complicated pregnancy was associated with greater eGFR decline in the years following glomerulonephropathy (GN) diagnosis. A detailed obstetric history may inform counseling regarding disease progression in women with glomerular disease. Continued research is necessary to better understand pathophysiologic mechanisms by which complicated pregnancies contribute to glomerular disease progression.

Tobacco exposure in adults and children with proteinuric glomerulopathies: a NEPTUNE cohort study.

BACKGROUND: Tobacco exposure has been recognized as a risk factor for cardiovascular disease (CVD) and progression of kidney disease. Patients with proteinuric glomerulopathies are at increased risk for cardiovascular morbidity and mortality. Multiple studies have linked tobacco exposure to CVD and chronic kidney disease, but the relationships between smoking and proteinuric glomerulopathies in adults and children have not been previously explored. METHODS: Data from the Nephrotic Syndrome Study Network (NEPTUNE), a multi-center prospective observational study of participants with proteinuric glomerulopathies, was analyzed. 371 adults and 192 children enrolled in NEPTUNE were included in the analysis. Self-reported tobacco exposure was classified as non-smoker, active smoker, former smoker, or exclusive passive smoker. Baseline serum cotinine levels were measured in a sub-cohort of 178 participants. RESULTS: The prevalence of active smokers, former smokers and exclusive passive smoking among adults at baseline was 14.6%, 29.1% and 4.9%, respectively. Passive smoke exposure was 16.7% among children. Active smoking (reference non-smoking) was significantly associated with greater total cholesterol among adults (ß 17.91 95% CI 0.06, 35.76, p = 0.049) while passive smoking (reference non-smoking) was significantly associated with greater proteinuria over time among children (ß 1.23 95% CI 0.13, 2.33, p = 0.03). Higher cotinine levels were associated with higher baseline eGFR (r = 0.17, p = 0.03). CONCLUSION: Tobacco exposure is associated with greater risk for CVD and worse kidney disease outcomes in adults and children with proteinuric glomerulopathies. Preventive strategies to reduce tobacco exposure may help protect against future cardiovascular and kidney morbidity and mortality in patients with proteinuric glomerulopathies.

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.

Racial and Ethnic Disparities in Acute Care Utilization Among Patients With Glomerular Disease.

RATIONALE & OBJECTIVE: The effects of race, ethnicity, socioeconomic status (SES), and disease severity on acute care utilization in patients with glomerular disease are unknown. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,456 adults and 768 children with biopsy-proven glomerular disease enrolled in the Cure Glomerulonephropathy (CureGN) cohort. EXPOSURE: Race and ethnicity as a participant-reported social factor. OUTCOME: Acute care utilization defined as hospitalizations or emergency department visits. ANALYTICAL APPROACH: Multivariable recurrent event proportional rate models were used to estimate associations between race and ethnicity and acute care utilization. RESULTS: Black or Hispanic participants had lower SES and more severe glomerular disease than White or Asian participants. Acute care utilization rates were 45.6, 29.5, 25.8, and 19.2 per 100 person-years in Black, Hispanic, White, and Asian adults, respectively, and 55.8, 42.5, 40.8, and 13.0, respectively, for children. Compared with the White race (reference group), Black race was significantly associated with acute care utilization in adults (rate ratio [RR], 1.76 [95% CI, 1.37-2.27]), although this finding was attenuated after multivariable adjustment (RR, 1.31 [95% CI, 1.03-1.68]). Black race was not significantly associated with acute care utilization in children; Asian race was significantly associated with lower acute care utilization in children (RR, 0.32 [95% CI 0.14-0.70]); no significant associations between Hispanic ethnicity and acute care utilization were identified. LIMITATIONS: We used proxies for SES and lacked direct information on income, household unemployment, or disability. CONCLUSIONS: Significant differences in acute care utilization rates were observed across racial and ethnic groups in persons with prevalent glomerular disease, although many of these difference were explained by differences in SES and disease severity. Measures to combat socioeconomic disadvantage in Black patients and to more effectively prevent and treat glomerular disease are needed to reduce disparities in acute care utilization, improve patient wellbeing, and reduce health care costs.

Association between cause of kidney failure and fracture incidence in a national US dialysis population cohort study.

Background: Whether fracture rates, overall and by fracture site, vary by cause of kidney failure in patients receiving dialysis is unknown. Methods: Using the US Renal Data System, we compared fracture rates across seven causes of kidney failure in patients who started dialysis between 1997 and 2014. We computed unadjusted and multivariable adjusted proportional sub-distribution hazard models, with fracture events (overall, and by site) as the outcome and immunoglobulin A nephropathy as the reference group. Kidney transplantation and death were competing events. Results: Among 491 496 individuals, with a median follow-up of 2.0 (25%, 75% range 0.9-3.9) years, 62 954 (12.8%) experienced at least one fracture. Patients with diabetic nephropathy, vasculitis or autosomal polycystic kidney disease (ADPKD) had the highest (50, 46 and 40 per 1000 person-years, respectively), and patient with lupus nephritis had the lowest (20 per 1000 person-years) fracture rates. After multivariable adjustment, diabetic nephropathy [hazard ratio (HR) 1.43, 95% confidence interval 1.33-1.53], ADPKD (HR 1.37, 1.26-1.48), vasculitis (HR 1.22, 1.09-1.34), membranous nephropathy (HR 1.16, 1.02-1.30) and focal segmental glomerulosclerosis (FSGS) (HR 1.13, 1.02-1.24) were associated with a significantly higher, and lupus nephritis with a significantly lower (HR 0.85, 0.71-0.98) fracture hazard. The hazards for upper extremity and lower leg fractures were significantly higher in diabetic nephropathy, ADPKD, FSGS and membranous nephropathy, while the hazard for vertebral fracture was significantly higher in vasculitis. Our findings were limited by the lack of data on medication use and whether fractures were traumatic or non-traumatic, among other factors. Conclusions: Fracture risk, overall and by fracture site, varies by cause of end-stage kidney disease. Future work to determine underlying pathogenic mechanisms contributing to differential risks might inform more tailored treatment strategies. Our study was limited by lack of data regarding numerous potential confounders or mediators including medications and measures or bone biomarkers.

Immunosuppression Exposure and Risk of Infection-Related Acute Care Events in Patients With Glomerular Disease: An Observational Cohort Study.

Rationale & Objective: Infections cause morbidity and mortality in patients with glomerular disease. The relative contributions from immunosuppression exposure and glomerular disease activity to infection risk are not well characterized. To address this unmet need, we characterized the relationship between time-varying combinations of immunosuppressant exposure and infection-related acute care events while controlling for disease activity, among individuals with glomerular disease. Study Design: Prospective, multicenter, observational cohort study. Setting & Participants: Adults and children with biopsy-proven minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or immunoglobulin A nephropathy/vasculitis were enrolled at 71 clinical sites in North America and Europe. A total of 2,388 Cure Glomerulonephropathy Network participants (36% aged <18 years) had at least 1 follow-up visit and were included in the analysis. Exposures: Immunosuppression exposure modeled on a weekly basis. Outcome: Infections leading to an emergency department visit or hospitalization. Analytical Approach: Marginal structural models were used to estimate the effect of time-varying immunosuppression exposure on hazard of first infection-related acute care event while accounting for baseline sociodemographic and clinical factors, and time-varying disease activity. Results: A total of 2,388 participants were followed for a median of 3.2 years (interquartile range, 1.6-4.6), and 15% experienced at least 1 infection-related emergency department visit or hospitalization. Compared to no immunosuppression exposure, steroid exposure, steroid with any other immunosuppressant, and nonsteroid immunosuppressant exposure were associated with a 2.65-fold (95% CI, 1.83-3.86), 2.68-fold (95% CI, 1.95-3.68), and 1.7-fold (95% CI, 1.29-2.24) higher risk of first infection, respectively. Limitations: Absence of medication dosing data, lack of a control group, and potential bias in ascertainment of outcome events secondary to the coronavirus 2 pandemic. Conclusions: Corticosteroids with or without concomitant additional immunosuppression significantly increased risk of infection leading to acute care utilization in adults and children with glomerular disease.

Rituximab Dosing in Glomerular Diseases: A Scoping Review.

Purpose of Review: Rituximab is increasingly prescribed for glomerular diseases. However, the recently published Kidney Disease Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases lacks details on recommended dosing regimens for most individual glomerular diseases. We performed this scoping review summarizing the evidence for rituximab dosing in glomerular disease. Sources of Information: PubMed database. Methods: The PubMed search methodology was developed with a medical librarian and performed by the first, with review by a second, author. Randomized controlled trials (RCTs) and prospective cohort studies (PCSs) examining rituximab efficacy and/or safety in antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), membranous nephropathy (MN), lupus nephritis (LN), or podocytopathies (minimal change disease or focal segmental glomerulosclerosis [FSGS]) were included. Fifty-three studies (14 RCTs and 39 PCSs) were included. Key Findings: We identified 16 different rituximab dosing regimens studied as induction therapy for one or more of the 5 glomerular diseases of interest. The most frequently studied rituximab induction regimens were 1000 mg as 2 doses 2 weeks apart (17 studies, 32%) and 4 doses of 375 mg/m2/week (18 studies, 33.9%). Twenty-six studies (49%) examined rituximab as monotherapy or in conjunction with corticosteroids alone, while the remaining studies examined rituximab as part of combination immunosuppression. Adapting treatment to achieve B-cell depletion, with frequent evaluation of disease-specific biomarkers, might prove the optimal approach to achieving and maintaining remission. Rituximab might also enable steroid minimization or avoidance. Limitations: Restriction of the search to a single database and to studies published in the English language, and with an accompanying abstract, could have led to selection bias. While the search was limited to prospective observational studies and RCTs, no formal assessment of study quality was performed.

Motif de la revue: Le rituximab est de plus en plus prescrit pour traiter les maladies glomérulaires. Les lignes directrices de pratique clinique 2021 pour la prise en charge des maladies glomérulaires, publiées récemment par KDIGO, ne contiennent cependant aucun détail sur les schémas posologiques recommandés pour la plupart des maladies glomérulaires. Cette étude de portée résume les données concernant l'administration de rituximab pour le traitement des maladies glomérulaires. Sources: Base de données PubMed. Méthodologie: La méthodologie de recherche PubMed a été élaborée avec un bibliothécaire médical, réalisée par le premier auteur et révisée par le deuxième auteur. Ont été inclus des essais contrôlés randomisés (ECR) et des études de cohortes prospectives (ÉCP) portant sur l'efficacité et/ou l'innocuité du rituximab dans le traitement des vascularites associés aux ANCA (VAA), de la néphropathie membraneuse (NM), de la néphrite lupique (NL) ou des podocytopathies (maladie à changement minimal ou hyalinose segmentaire et focale (HSF). Cinquante-trois études (14 ECR et 39 ÉCP) ont été incluses. Principaux résultats: Nous avons répertorié 16 différents schémas posologiques de rituximab étudiés comme traitement d'induction pour une ou plusieurs des cinq maladies glomérulaires d'intérêt. Les traitements d'induction avec rituximab les plus fréquemment étudiés étaient l'administration de 1 000 mg à raison de deux doses à deux semaines d'intervalle (17 études; 32 %) et de quatre doses de 375 mg/m2/semaine (18 études; 33,9 %). Vingt-six études (49 %) avaient examiné le rituximab en monothérapie ou en association avec des corticostéroïdes seuls; les autres études avaient examiné le rituximab dans le cadre d'un traitement immunosuppresseur combiné. Adapter le traitement pour atteindre l'épuisement des cellules B, avec évaluation fréquente des biomarqueurs spécifiques de la maladie, pourrait s'avérer l'approche optimale pour atteindre et maintenir la rémission. Le rituximab pourrait également permettre de minimiser ou d'éviter les stéroïdes. Limites: La restriction de la recherche à une seule base de données et à des études publiées en anglais accompagnées d'un résumé pourrait avoir entraîné un biais de sélection. Bien que la recherche se limitait aux études observationnelles prospectives et aux ECR, aucune évaluation formelle de la qualité des études n'a été effectuée.

The Utilization of Packed Red Blood Cell Transfusion and Angiography in Pediatric Inpatients after Kidney Biopsy in the United States.

This article contains the largest analysis of pRBC transfusion and renal angiogram in inpatient pediatric patients.We provide accurate estimates of rates of pRBC transfusion and renal angiography after kidney biopsy in inpatient pediatric patients.

Chronic kidney disease and adverse pregnancy outcomes: a systematic review and meta-analysis.

OBJECTIVE: Limited evidence exists on the role that the cause of chronic kidney disease plays in determining pregnancy outcomes. The aim of this systematic review and meta-analysis was to examine the association between chronic kidney disease and adverse pregnancy outcomes by the cause and severity of chronic kidney disease where reported. The protocol was registered under the International Prospective Register of Systematic Reviews (CRD42020211925). DATA SOURCES: PubMed, Embase, and Web of Science were searched until May 24, 2021, supplemented with reference list checking. STUDY ELIGIBILITY CRITERIA: Studies that compared the pregnancy outcomes in women with or without chronic kidney disease were included. Two reviewers independently screened titles, abstracts, and full-text articles according to a priori defined inclusion criteria. METHODS: Data extraction and quality appraisal were performed independently by 3 reviewers. The grading of recommendations, assessment, development, and evaluation approach was used to assess the overall certainty of the evidence. Random-effects meta-analyses were used to calculate the pooled estimates using the generic inverse variance method. The primary outcomes included preeclampsia, cesarean delivery, preterm birth (<37 weeks' gestation), and small for gestational age babies. RESULTS: Of 4076 citations, 31 studies were included. Prepregnancy chronic kidney disease was significantly associated with a higher odds of preeclampsia (pooled crude odds ratio, 8.13; [95% confidence interval, 4.41-15], and adjusted odds ratio, 2.58; [1.33-5.01]), cesarean delivery (adjusted odds ratio, 1.65; [1.21-2.25]), preterm birth (adjusted odds ratio, 1.73; [1.31-2.27]), and small for gestational age babies (adjusted odds ratio, 1.93; [1.06-3.52]). The association with stillbirth was not statistically significant (adjusted odds ratio, 1.67; [0.96-2.92]). Subgroup analyses indicated that different causes of chronic kidney disease might confer different risks and that the severity of chronic kidney disease is associated with a risk of adverse pregnancy outcomes, as pregnancies with later stages of chronic kidney disease had higher odds of preeclampsia, preterm birth, and small for gestational age babies than those at earlier stages. The grading of recommendations, assessment, development, and evaluation certainty of the evidence overall was "very low". CONCLUSION: This meta-analysis quantified the associations between prepregnancy chronic kidney disease and adverse pregnancy outcomes, both overall and according to the cause and severity of the disease. These findings might support the clinicians aiming to counsel women having chronic kidney disease by allowing them to tailor their advice according to cause and severity of the chronic kidney disease. We identified the gaps in the literature, and further studies examining the effect of specific kidney diseases and other clinical characteristics (eg, proteinuria, hypertension) on adverse pregnancy outcomes are warranted.

National and international kidney failure registries: characteristics, commonalities, and contrasts.

Registries are essential for health infrastructure planning, benchmarking, continuous quality improvement, hypothesis generation, and real-world trials. To date, data from these registries have predominantly been analyzed in isolated "silos," hampering efforts to analyze "big data" at the international level, an approach that provides wide-ranging benefits, including enhanced statistical power, an ability to conduct international comparisons, and greater capacity to study rare diseases. This review serves as a valuable resource to clinicians, researchers, and policymakers, by comprehensively describing kidney failure registries active in 2021, before proposing approaches for inter-registry research under current conditions, as well as solutions to enhance global capacity for data collaboration. We identified 79 kidney-failure registries spanning 77 countries worldwide. International Society of Nephrology exemplar initiatives, including the Global Kidney Health Atlas and Sharing Expertise to support the set-up of Renal Registries (SharE-RR), continue to raise awareness regarding international healthcare disparities and support the development of universal kidney-disease registries. Current barriers to inter-registry collaboration include underrepresentation of lower-income countries, poor syntactic and semantic interoperability, absence of clear consensus guidelines for healthcare data sharing, and limited researcher incentives. This review represents a call to action for international stakeholders to enact systemic change that will harmonize the current fragmented approaches to kidney-failure registry data collection and research.

Racial-ethnic differences in health-related quality of life among adults and children with glomerular disease.

INTRODUCTION: Disparities in health-related quality of life (HRQOL) have been inadequately studied in patients with glomerular disease. The aim of this study was to identify relationships between race/ethnicity, socioeconomic status, disease severity, and HRQOL in an ethnically and racially diverse cohort of patients with glomerular disease. METHODS: Cure Glomerulonephropathy (CureGN) is a multinational cohort study of patients with biopsy-proven glomerular disease. Associations between race/ethnicity and HRQOL were determined by the following: 1. Missed school or work due to kidney disease; 2. Responses to Patient Reported Outcomes Measurement Information System (PROMIS) questionnaires. We adjusted for demographics, socioeconomic status, and disease characteristics using multivariable logistic and linear regression. RESULTS: Black and Hispanic participants had worse socioeconomic status and more severe glomerular disease than White or Asian participants. Black adults missed work or school most frequently due to kidney disease (30% versus 16-23% in the other three groups, p=0.04), and had the worst self-reported global physical health (median score 44.1 versus 48.0-48.2, p<0.001) and fatigue (53.8 versus 48.5-51.1, p=0.002), compared to other racial/ethnic groups. However, these findings were not statistically significant with adjustment for socioeconomic status and disease severity, both of which were strongly associated with HRQOL in adults. Among children, disease severity but not race/ethnicity or socioeconomic status were associated with HRQOL. CONCLUSIONS: Among patients with glomerular disease enrolled in CureGN, the worse HRQOL reported by Black adults was attributable to lower socioeconomic status and more severe glomerular disease. No racial/ethnic differences in HRQOL were observed in children.

Association of Obesity with Cardiovascular Risk Factors and Kidney Disease Outcomes in Primary Proteinuric Glomerulopathies.

BACKGROUND/AIMS: Obesity is a known risk factor for cardiovascular disease and contributes to the development and progression of kidney disease. However, the specific influence of obesity on outcomes in primary glomerular disease has not been well characterized. METHODS: In this prospective cohort study, data were from 541 participants enrolled in the Nephrotic Syndrome Study Network (NEPTUNE), between 2010 and 2019, at 23 sites across North America. Blood pressure, lipids, and kidney disease outcomes including complete proteinuria remission, kidney failure, and chronic kidney disease progression were evaluated. Data were analyzed using linear and logistic regression with generalized estimating equations and time-varying Cox regression with Kaplan-Meier plots. RESULTS: The prevalence of obesity at baseline was 43.3% (N = 156) in adults and 37.6% (N = 68) in children. In adults, obesity was longitudinally associated with higher systolic BP (ß = 6.49, 95% CI: 2.41, 10.56, p = 0.002), dyslipidemia (OR = 1.74, 95% CI: 1.30, 2.32, p < 0.001), triglycerides (ß = 41.92, 95% CI: 17.12, 66.71, p = 0.001), and lower HDL (ß = -6.92, 95% CI: -9.32, -4.51, p < 0.001). In children, obesity over time was associated with higher systolic BP index (ß = 0.04, 95% CI: 0.02, 0.06, p < 0.001) and hypertension (OR = 1.43, 95% CI: 1.04, 1.98, p = 0.03). In both adults and children, obesity was associated with a significantly lower hazard of achieving complete remission of proteinuria (adult HR = 0.80, 95% CI: 0.69, 0.88, p < 0.001; pediatric HR = 0.72, 95% CI: 0.61, 0.84, p < 0.001). CONCLUSION: Obesity was associated with higher cardiovascular risk and less proteinuria remission from nephrotic syndrome in adults and children with proteinuric glomerulopathies. Weight-loss strategies may forestall cardiovascular disease and progressive kidney function decline in this high-risk patient group.

Complement in IgA Nephropathy: The Role of Complement in the Pathogenesis, Diagnosis, and Future Management of IgA Nephropathy.

Immunoglobulin A (IgA) nephropathy (IgAN) is an important cause of chronic and end-stage kidney disease. IgAN pathogenesis is incompletely understood. In particular, we cannot adequately explain the heterogeneity in clinical and histologic features and severities that characterizes IgAN. This limits patient stratification to appropriate and effective treatments and the development of disease-targeted therapies. Studies of the role of the alternative, lectin, and terminal complement pathways in IgAN have enhanced our understanding of disease pathogenesis and inform the development of novel diagnostic and therapeutic strategies. For example, recent genetic, serologic, and immunohistologic evidence suggests that imbalances between the main alternative complement pathway regulator protein (factor H) and competitor proteins that deregulate complement activity (factor H-related proteins 1 and 5, FHR1, and FHR5) associate with IgAN severity: a relative abundance of FHR1 and FHR5 amplifies complement-dependent inflammation and exacerbates kidney injury. Ongoing characterization of the mechanisms by which complement activity contributes to IgAN pathogenesis will facilitate the development of complement-based diagnostic techniques, biomarkers of disease activity and severity, and novel targeted therapies.

Histologic Case Definition of an Atypical Glomerular Immune-Complex Deposition Following Kidney Transplantation.

INTRODUCTION: Immune-complex deposition in the transplanted kidney can present as well-phenotyped recurrent or de novo glomerular disease. However, a subset, herein termed immune-complex glomerulopathy not otherwise specified (ICG-NOS), defies classification. We quantified, categorized, and characterized cases of transplant ICG-NOS occurring at a single US academic medical center. METHODS: We retrospectively reviewed our single-institution pathology database (July 2007-July 2018) to identify and categorize all cases of immune-complex deposition in kidney allografts (based on immunofluorescence microscopy). We extracted clinicopathologic and outcome data for ICG-NOS (i.e., immune complex deposition not conforming to any well-characterized glomerular disease entity). RESULTS: Of 104 patients with significant immune deposits, 28 (27%) were classified as ICG-NOS. We created 5 mutually exclusive ICG-NOS categories: Full-house, Quasi-full-house, IgA-rich, C1q-rich, and C1q-poor. Overall, 16 (57%) patients met criteria for definite or possible allograft rejection, including 9 (32%) with antibody-mediated rejection (ABMR), 3 (11%) suspicious for ABMR, 1 (4%) with T-cell-mediated rejection (TCMR), and 9 (32%) with borderline TCMR. After a median follow-up of 2.3 (range, 0.1-14.0) years after biopsy, 7 (25%) allografts had failed and an additional 8 (29%) had persistent renal dysfunction (hematuria, 14%; proteinuria, 21%; and estimated glomerular filtration rate <60 ml/min per 1.73 m2, 11%). CONCLUSION: In contrast to prior studies, our findings suggest that ICG-NOS is not necessarily a benign glomerular process and that there may be an association between ICG-NOS and alloimmunity. Our immunofluorescence-based classification provides a framework for future studies aiming to further elucidate ICG-NOS pathogenesis and prognosis.

Identifying Patients with Rare Disease Using Electronic Health Record Data: The Kaiser Permanente Southern California Membranous Nephropathy Cohort.

INTRODUCTION: Developing a reliable means to identify and study real-world populations of patients with membranous nephropathy (MN) using electronic health records (EHRs) would help advance glomerular disease research. Identifying MN cases using EHRs is limited by the need for manual reviews of biopsy reports. OBJECTIVE: To evaluate the accuracy of identifying patients with biopsy-proven MN using the EHR in a large, diverse population of an integrated health system. METHODS: A retrospective cohort study was performed between June 28, 1999, and June 25, 2015, among patients with kidney biopsy results (N = 4723), which were manually reviewed and designated as MN or non-MN. The sensitivity, specificity, and positive predictive value (PPV) of International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes were determined using 2 approaches: 1) clinical (MN-specific codes 581.1, 582.1, or 583.1) and 2) agnostic/data-derived (codes selected from supervised learning at the highest predictive performance). RESULTS: One year after biopsy, the sensitivity and specificity of an MN diagnosis were 86% and 76%, respectively, but the PPV was 26%. The data-driven approach detected that using only 2 codes (581.1 or 583.1) improved specificity to 94% and PPV to 58%, with a small decrease in sensitivity to 83%. When any code was reported at least 3 times, specificity was 98%; PPV, 78%; and sensitivity, 64%. DISCUSSION: Our findings suggest that ICD-9 diagnosis codes might be a convenient tool to identify patients with MN using EHR and/or administrative claims information. Codes selected from supervised learning achieved better overall performance, suggesting the potential of developing data-driven methods.

Recurrence of FSGS after Kidney Transplantation in Adults.

BACKGROUND AND OBJECTIVES: FSGS recurrence after kidney transplantation is a major risk factor for graft loss. However, the natural history, clinical predictors, and response to treatment remain unclear because of small sample sizes and poor generalizability of single-center studies, and disease misclassification in registry-based studies. We therefore aimed to determine the incidence, predictors, and treatment response of recurrent FSGS in a large cohort of kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Post-Transplant Glomerular Disease (TANGO) project is an observational, multicenter, international cohort study that aims to investigate glomerular disease recurrence post-transplantation. Transplant recipients were screened for the diagnosis of idiopathic FSGS between 2005 and 2015 and details were recorded about the transplant, clinical outcomes, treatments, and other risk factors. RESULTS: Among 11,742 kidney transplant recipients screened for FSGS, 176 had a diagnosis of idiopathic FSGS and were included. FSGS recurred in 57 patients (32%; 95% confidence interval [95% CI], 25% to 39%) and 39% of them lost their graft over a median of 5 (interquartile range, 3.0-8.1) years. Multivariable Cox regression revealed a higher risk for recurrence with older age at native kidney disease onset (hazard ratio [HR], 1.37 per decade; 95% CI, 1.09 to 1.56). Other predictors were white race (HR, 2.14; 95% CI, 1.08 to 4.22), body mass index at transplant (HR, 0.89 per kg/m2; 95% CI, 0.83 to 0.95), and native kidney nephrectomies (HR, 2.76; 95% CI, 1.16 to 6.57). Plasmapheresis and rituximab were the most frequent treatments (81%). Partial or complete remission occurred in 57% of patients and was associated with better graft survival. CONCLUSIONS: Idiopathic FSGS recurs post-transplant in one third of cases and is associated with a five-fold higher risk of graft loss. Response to treatment is associated with significantly better outcomes but is achieved in only half of the cases.