Growth in children with nephrotic syndrome: a post hoc analysis of the NEPTUNE study.

BACKGROUND: Steroids, the mainstay of treatment for nephrotic syndrome in children, have multiple adverse effects including growth suppression. METHODS: Anthropometric measurements in children < 18 years enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were collected. The longitudinal association of medication exposure and nephrotic syndrome characteristics with height z-score and growth velocity was determined using adjusted Generalized Estimating Equation regression and linear regression. RESULTS: A total of 318 children (57.2% males) with a baseline age of 7.64 ± 5.04 years were analyzed. The cumulative steroid dose was 216.4 (IQR 61.5, 652.7) mg/kg (N = 233). Overall, height z-scores were not significantly different at the last follow-up compared to baseline (- 0.13 ± 1.21 vs. - 0.23 ± 1.71, p = 0.21). In models adjusted for age, sex, and eGFR, greater cumulative steroid exposure (ß - 7.5 × 10-6, CI - 1.2 × 10-5, - 3 × 10-6, p = 0.001) and incident cases of NS (vs. prevalent) (ß - 1.1, CI - 2.22, - 0.11, p = 0.03) were significantly associated with lower height z-scores over time. Rituximab exposure was associated with higher height z-scores (ß 0.16, CI 0.04, 0.29, p = 0.01) over time. CONCLUSION: Steroid dose was associated with lower height z-score, while rituximab use was associated with higher height z-score.

Longitudinal analysis of blood pressure and lipids in childhood nephrotic syndrome.

BACKGROUND: In the current study, longitudinal BP and lipid measurements were examined in a NEPTUNE cohort of children with newly diagnosed nephrotic syndrome (cNEPTUNE). We hypothesized that hypertensive BP and dyslipidemia would persist in children with nephrotic syndrome, regardless of steroid treatment response. METHODS: A multi-center longitudinal observational analysis of data obtained from children < 19 years of age with new onset nephrotic syndrome enrolled in the Nephrotic Syndrome Study Network (cNEPTUNE) was conducted. BP and lipid data were examined over time stratified by disease activity and steroid exposure. Generalized estimating equation regressions were used to find determinants of hypertensive BP and dyslipidemia. RESULTS: Among 122 children, the prevalence of hypertensive BP at any visit ranged from 17.4% to 57.4%, while dyslipidemia prevalence ranged from 40.0% to 96.2% over a median of 30 months of follow-up. Hypertensive BP was found in 46.2% (116/251) of study visits during active disease compared with 31.0% (84/271) of visits while in remission. Dyslipidemia was present in 88.2% (120/136) of study visits during active disease and in 66.0% (101/153) while in remission. Neither dyslipidemia nor hypertensive BP were significantly different with/without medication exposure (steroids and/or CNI). In regression analysis, male sex and urine protein:creatinine ratio (UPC) were significant determinants of hypertensive BP over time, while eGFR was found to be a determinant of dyslipidemia over time. CONCLUSIONS: Results demonstrate persistent hypertensive BPs and unfavorable lipid profiles in the cNEPTUNE cohort regardless of remission status or concurrent steroid or calcineurin inhibitor treatment.

Population Pharmacokinetics of Caffeine in Neonates with Congenital Heart Disease and Associations with Acute Kidney Injury.

Cardiac surgery-associated acute kidney injury (CS-AKI) occurs in approximately 65% of neonates undergoing cardiac surgery on cardiopulmonary bypass and contributes to morbidity and mortality. Caffeine may reduce CS-AKI by counteracting adenosine receptor upregulation after bypass, but pharmacokinetics (PK) in this population are unknown. The goal of our analysis is to address knowledge gaps in age-, disease-, and bypass-related effects on caffeine disposition and explore preliminary associations between caffeine exposure and CS-AKI using population PK modeling techniques and an opportunistic, electronic health record-integrated trial design. We prospectively enrolled neonates receiving preoperative caffeine per standard of care and collected PK samples. We retrospectively identified neonates without caffeine exposure undergoing surgery on bypass as a control cohort. We followed US Food and Drug Administration guidance for population PK model development using NONMEM. Effects of clinical covariates on PK parameters were evaluated. We simulated perioperative exposures and used multivariable logistic regression to evaluate the association between caffeine exposure and CS-AKI. Twenty-seven neonates were included in model development. A 1-compartment model with bypass time as a covariate on clearance and volume of distribution best fit the data. Twenty-three neonates with caffeine exposure and 109 controls were included in the exposure-response analysis. Over half of neonates developed CS-AKI. On multivariable analysis, there were no significant differences between CS-AKI with and without caffeine exposure. Neonates with single-ventricle heart disease without CS-AKI had consistently higher simulated caffeine exposures. Our results highlight areas for further study to better understand disease- and bypass-specific effects on drug disposition and identify populations where caffeine may be beneficial.

A reappraisal of risk factors for hypertension after pediatric acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalized children and increases the risk of chronic kidney disease (CKD) and hypertension, but little is known about the patient level risk factors for pediatric hypertension after AKI. The aims of this study are to evaluate the prevalence and risk factors for new onset hypertension in hospitalized children with AKI and to better understand the role of acute kidney disease (AKD) in the development of hypertension. METHODS: This study was an observational cohort of all children ≤ 18 years old admitted to a single tertiary care children's hospital from 2015 to 2019 with a diagnosis of AKI. Hypertension was defined as blood pressure > 95th percentile for sex, age, height, diagnosis of hypertension on the problem list, or prescription of antihypertensive medication for > 90 days after AKI. RESULTS: A total of 410 children were included in the cohort. Of these, 78 (19%) developed hypertension > 90 days after AKI. A multivariable logistic regression model identified AKD, need for kidney replacement therapy, congenital heart disease, and non-kidney solid organ transplantation as risk factors for hypertension after AKI. CONCLUSIONS: Incident hypertension after 3 months is common among hospitalized children with AKI, and AKD, need for dialysis, congenital heart disease, and non-kidney solid organ transplant are significant risk factors for hypertension after AKI. Monitoring for hypertension development in these high-risk children is critical to mitigate long-term adverse kidney and cardiovascular outcomes.

Cure Glomerulonephropathy Pathology Classification and Core Scoring Criteria, Reproducibility, and Clinicopathologic Correlations.

Introduction: Cure Glomerulonephropathy (CureGN) is an observational cohort study of patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), or IgA nephropathy. We developed a conventional, consensus-based scoring system to document pathologic features for application across multiple pathologists and herein describe the protocol, reproducibility, and correlation with clinical parameters at biopsy. Methods: Definitions were established for glomerular, tubular, interstitial, and vascular lesions evaluated semiquantitatively using digitized light microscopy slides and electron micrographs, and reported immunofluorescence. Cases with curated pathology materials as of April 2019 were scored by a randomly assigned pathologist, with at least 10% of cases scored by a second pathologist. Scoring reproducibility was assessed using Gwet's agreement coefficient (AC)1 statistic and correlations with clinical variables were performed. Results: Of 800 scored biopsies (134 MCD, 194 FSGS, 206 MN, 266 IgA), 94 were scored twice (11.8%). Of 60 pathology features, 46 (76.7%) demonstrated excellent (AC1>0.8), and 12 (20.0%) had good (AC1 0.6-0.8) reproducibility. Mesangial hypercellularity scored as absent, focal, or diffuse had moderate reproducibility (AC1 = 0.58), but good reproducibility (AC1 = 0.71) when scored as absent or focal versus diffuse. The percent glomeruli scored as no lesions had fair reproducibility (AC1 = 0.34). Strongest correlations between pathologic features and clinical characteristics at biopsy included interstitial inflammation, interstitial fibrosis, and tubular atrophy with estimated glomerular filtration rate, foot process effacement with urine protein/creatinine ratio, and active crescents with hematuria. Conclusions: Most scored pathology features showed excellent reproducibility, demonstrating consistency for these features across multiple pathologists. Correlations between certain pathologic features and expected clinical characteristics show the value of this approach for future studies on clinicopathologic correlations and biomarker discovery.

Genetic risk variants for childhood nephrotic syndrome and corticosteroid response.

Introduction: The etiology of most cases of nephrotic syndrome (NS) remains unknown, therefore patients are phenotypically categorized based on response to corticosteroid therapy as steroid sensitive NS (SSNS), or steroid resistant NS (SRNS). Genetic risk factors have been identified for SSNS from unbiased genome-wide association studies (GWAS), however it is unclear if these loci are disease risk loci in other forms of NS such as SRNS. Additionally, it remains unknown if these risk loci are associated with response to therapy. Thus, we investigated the association between SSNS risk loci and therapy response in a large, multi-race cohort of children along the entire spectrum of childhood-onset NS. Methods: We enrolled 1,000 patients with childhood-onset NS comprised of SSNS and SRNS. Genotyping was done using TaqMan and Direct Sanger Sequencing for 9 previously reported childhood SSNS risk loci. We compared the allele frequencies (AF) and variant burden between NS vs. controls and SRNS vs. SSNS. Results: All 9 risk loci were associated with NS compared with healthy controls (p = 3.5 × 10-3-<2.2 × 10-16). Variant burden greater than 7 was associated with risk of SRNS (OR 7.4, 95% CI 4.6-12.0, p = 8.2 × 10-16). Conclusion: Our study showed that genetic risk loci for childhood SSNS are associated with pattern of therapy response, may help predict disease outcome, and set the stage for individualized treatment of NS.

Assessment of the Needs of Nephrology Divisions to Implement Return of Clinically Significant Research Genetic Results: A Survey of Nephrotic Syndrome Study Network (NEPTUNE) Investigators.

Introduction: There is an increasing need to return genetic testing results to patients with kidney disease who were first genotyped on a research basis. Operationalizing this process in nephrology clinics is challenged by a limited number of genetic providers with whom to partner and a general lack of support services for all clinicians. Methods: We administered a survey in March 2022 to assess the current ability and ongoing needs of nephrology divisions to return clinically significant research genetic results to patients and to implement clinical genetic testing. This survey was distributed to institutions within the Nephrotic Syndrome Study Network (NEPTUNE) as part of the planning process for return of research genetic results to participants with pathogenic variants in Mendelian nephrotic syndrome genes. Results: Twenty-seven of 28 sites (96%) completed the survey. 59% (n = 16) of sites said they could handle return of research genetic results independently, with the rest expressing hesitation about the volume and complexity of patients and the limited resources and access to genetics services. 81% (n = 22) of these institutions did have a genetics clinic and 26% (n = 7) have a nephrology genetics clinic. However, 70% (n = 10) of these clinics have a waiting time over 1 month. 89% of divisions (n = 24) were conducting genetic testing and 96% of those (n = 23) used a kidney multi-gene panel. In 46% of divisions (n = 11), nephrologists were handling logistics of obtaining genetic testing samples themselves. Conclusion: We identified specific areas of support needed for return of clinically significant genetic results from research studies. While the surveyed nephrologists were conducting genetic testing, there were limitations in the support services available. This survey will help guide other research studies that wish to return genetic results to participants and also highlight the need for increasing support to effectively operationalize genetic testing in nephrology clinics.

A randomized controlled trial of preemptive rituximab to prevent recurrent focal segmental glomerulosclerosis post-kidney transplant (PRI-VENT FSGS): protocol and study design.

Background: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease requiring kidney transplantation and can recur in the allograft in 30-80% of recipients resulting in reduced graft survival. Plasmapheresis has shown efficacy in treating some cases of recurrent FSGS but isolated plasmapheresis has not demonstrated efficacy in preventing recurrent FSGS. Rituximab has had anecdotal success in preventing recurrence in a single center study but has not been studied in combination with plasmapheresis for preventing FSGS recurrence. Methods: We are conducting a randomized, controlled, multicenter clinical trial of adult and pediatric kidney transplant recipients with primary FSGS to assess whether plasmapheresis in combination with rituximab prevents recurrent disease post-transplantation. Discussion: Rituximab combined with plasmapheresis is a promising, novel therapy to prevent recurrent FSGS, a disease with limited therapeutic options and no consensus guidelines for prevention or treatment. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03763643, identifier NCT03763643.

Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome.

Introduction: Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of kidney disease in children worldwide. Genome-wide association studies (GWAS) have demonstrated the association of SSNS with genetic variation at HLA-DQ/DR and have identified several non-HLA loci that aid in further understanding of disease pathophysiology. We sought to identify additional genetic loci associated with SSNS in children of Sri Lankan and European ancestry. Methods: We conducted a GWAS in a cohort of Sri Lankan individuals comprising 420 pediatric patients with SSNS and 2339 genetic ancestry matched controls obtained from the UK Biobank. We then performed a transethnic meta-analysis with a previously reported European cohort of 422 pediatric patients and 5642 controls. Results: Our GWAS confirmed the previously reported association of SSNS with HLA-DR/DQ (rs9271602, P = 1.12 × 10-27, odds ratio [OR] = 2.75). Transethnic meta-analysis replicated these findings and identified a novel association at AHI1 (rs2746432, P = 2.79 × 10-8, OR = 1.37), which was also replicated in an independent South Asian cohort. AHI1 is implicated in ciliary protein transport and immune dysregulation, with rare variation in this gene contributing to Joubert syndrome type 3. Conclusions: Common variation in AHI1 confers risk of the development of SSNS in both Sri Lankan and European populations. The association with common variation in AHI1 further supports the role of immune dysregulation in the pathogenesis of SSNS and demonstrates that variation across the allele frequency spectrum in a gene can contribute to disparate monogenic and polygenic diseases.

Association of Urine Biomarkers With Acute Kidney Injury and Fluid Overload in Infants After Cardiac Surgery: A Single Center Ancillary Cohort of the Steroids to Reduce Systemic Inflammation After Infant Heart Surgery Trial.

To examine the association between three perioperative urine biomarker concentrations (urine cystatin C [uCysC], urine neutrophil gelatinase-associated lipocalin [uNGAL], and urine kidney injury molecule 1 [uKIM-1]), and cardiac surgery-associated acute kidney injury (CS-AKI) and fluid overload (FO) in infants with congenital heart disease undergoing surgery on cardiopulmonary bypass. To explore how urine biomarkers are associated with distinct CS-AKI phenotypes based on FO status. DESIGN: Ancillary prospective cohort study. SETTING: Single U.S. pediatric cardiac ICU. PATIENTS: Infants less than 1 year old enrolled in the Steroids to Reduce Systemic Inflammation after Infant Heart Surgery trial (NCT03229538) who underwent heart surgery from June 2019 to May 2020 and opted into biomarker collection at a single center. Infants with preoperative CS-AKI were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty infants met inclusion criteria. Median (interquartile) age at surgery was 103 days (5.5-161 d). Modified Kidney Disease Improving Global Outcomes-defined CS-AKI was diagnosed in 22 (55%) infants and 21 (53%) developed FO. UCysC and uNGAL peaked in the early postoperative period and uKIM-1 peaked later. In unadjusted analysis, bypass time was longer, and Vasoactive-Inotropic Score at 24 hours was higher in infants with CS-AKI. On multivariable analysis, higher uCysC (odds ratio [OR], 1.023; 95% CI, 1.004-1.042) and uNGAL (OR, 1.019; 95% CI, 1.004-1.035) at 0-8 hours post-bypass were associated with FO. UCysC, uNGAL, and uKIM-1 did not significantly correlate with CS-AKI. In exploratory analyses of CS-AKI phenotypes, uCysC and uNGAL were highest in CS-AKI+/FO+ infants. CONCLUSIONS: In this study, uCysC and uNGAL in the early postoperative period were associated with FO at 48 hours. UCysC, uNGAL, and uKIM-1 were not associated with CS-AKI. Further studies should focus on defining expected concentrations of these biomarkers, exploring CS-AKI phenotypes and outcomes, and establishing clinically meaningful endpoints for infants post-cardiac surgery.

Patient level factors increase risk of acute kidney disease in hospitalized children with acute kidney injury.

BACKGROUND: Studies in adults have shown that persistent kidney dysfunction ≥7-90 days following acute kidney injury (AKI), termed acute kidney disease (AKD), increases chronic kidney disease (CKD) and mortality risk. Little is known about the factors associated with the transition of AKI to AKD and the impact of AKD on outcomes in children. The aim of this study is to evaluate risk factors for progression of AKI to AKD in hospitalized children and to determine if AKD is a risk factor for CKD. METHODS: Retrospective cohort study of children age ≤18 years admitted with AKI to all pediatric units at a single tertiary-care children's hospital between 2015 and 2019. Exclusion criteria included insufficient serum creatinine values to evaluate for AKD, chronic dialysis, or previous kidney transplant. RESULTS: A total of 528 children with AKI were included in the study. There were 297 (56.3%) hospitalized AKI survivors who developed AKD. Among children with AKD, 45.5% developed CKD compared to 18.7% in the group without AKD (OR 4.0, 95% CI 2.1-7.4, p-value <0.001 using multivariable logistic regression analysis including other covariates). Multivariable logistic regression model identified age at AKI diagnosis, PCICU and NICU admission, prematurity, malignancy, bone marrow transplant, previous AKI, mechanical ventilation, AKI stage, duration of kidney injury, and need for kidney replacement therapy during day 1-7 as risk factors for AKD after AKI. CONCLUSIONS: AKD is common among hospitalized children with AKI and multiple risk factors are associated with AKD. Children that progress from AKI to AKD are at higher risk of developing CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Cytokine storm-based mechanisms for extrapulmonary manifestations of SARS-CoV-2 infection.

Viral illnesses like SARS-CoV-2 have pathologic effects on nonrespiratory organs in the absence of direct viral infection. We injected mice with cocktails of rodent equivalents of human cytokine storms resulting from SARS-CoV-2/COVID-19 or rhinovirus common cold infection. At low doses, COVID-19 cocktails induced glomerular injury and albuminuria in zinc fingers and homeoboxes 2 (Zhx2) hypomorph and Zhx2+/+ mice to mimic COVID-19-related proteinuria. Common Cold cocktail induced albuminuria selectively in Zhx2 hypomorph mice to model relapse of minimal change disease, which improved after depletion of TNF-α, soluble IL-4Rα, or IL-6. The Zhx2 hypomorph state increased cell membrane to nuclear migration of podocyte ZHX proteins in vivo (both cocktails) and lowered phosphorylated STAT6 activation (COVID-19 cocktail) in vitro. At higher doses, COVID-19 cocktails induced acute heart injury, myocarditis, pericarditis, acute liver injury, acute kidney injury, and high mortality in Zhx2+/+ mice, whereas Zhx2 hypomorph mice were relatively protected, due in part to early, asynchronous activation of STAT5 and STAT6 pathways in these organs. Dual depletion of cytokine combinations of TNF-α with IL-2, IL-13, or IL-4 in Zhx2+/+ mice reduced multiorgan injury and eliminated mortality. Using genome sequencing and CRISPR/Cas9, an insertion upstream of ZHX2 was identified as a cause of the human ZHX2 hypomorph state.

Rationale and Design of the Diet, CKD, and Apolipoprotein L1 Study in Low-Income and Middle-Income Countries.

Introduction: Diet, chronic kidney disease (CKD), and Apolipoprotein L1 (APOL1) (DCA) Study is examining the role of dietary factors in CKD progression and APOL1 nephropathy. We describe enrollment and retention efforts and highlight facilitators and barriers to enrollment and operational challenges, as well as accommodations made in the study protocol. Methods: The DCA study is enrolling participants in 7 centers in West Africa. Participants who consented were invited to complete dietary recalls and 24-hour urine collections in year 1. We conducted focus groups and semistructured interviews among study personnel to identify facilitators and barriers to enrollment as well as retention and operational challenges in the execution of the study protocol. We analyzed emerging themes using content analyses. Results: A total of 712 participants were enrolled in 18 months with 1256 24-hour urine and 1260 dietary recalls. Barriers to enrollment were the following: (i) a lack of understanding of research, (ii) the burden of research visits, and (iii) incorporating cultural and traditional nuances when designing research protocols. Factors facilitating enrollment were the following: (i) designing convenient research visits, (ii) building rapport and increased communication between the research team and participants, and (iii) cultural sensitivity - adapting research protocols for the populations involved. Offering home visits, providing free dietary counseling, reducing the volume of study blood collection, and reducing the frequency of visits were some changes made in the study protocol that increased participant satisfaction. Conclusion: Adopting a participant-centered approach with accommodations in the protocol for cultural adaptability and incorporating participant feedback is vital for carrying out research in low-income and middle-income regions.

The case for treatment of monogenic SRNS with calcineurin inhibitors.

Currently, no evidence-based guidelines exist for treatment of children with monogenic steroid-resistant nephrotic syndrome. A retrospective study on 141 patients from Malakasioti et al. revealed that 27.6% responded to calcineurin inhibitor (CNI) treatment, and 75% of responders maintained stable kidney function. Virtually all CNI nonresponders developed progressive loss of kidney function. This study emphasized roles for CNIs in patients with monogenic steroid-resistant nephrotic syndrome, and the need for future studies to identify CNI response biomarkers.

Cardiovascular Risk Factor Burden and Association With CKD in Ghana and Nigeria.

Introduction: Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD); however, the burden of cardiovascular risk factors in patients with CKD in Africa is not well characterized. We determined the prevalence of selected cardiovascular risk factors, and association with CKD in the Human Heredity for Health in Africa Kidney Disease Research Network study. Methods: We recruited patients with and without CKD in Ghana and Nigeria. CKD was defined as estimated glomerular filtration rate of <60 ml/min per 1.73 m2 and/or albuminuria as albumin-to-creatinine ratio <3.0 mg/mmol (<30 mg/g) for ≥3 months. We assessed self-reported (physician-diagnosis and/or use of medication) hypertension, diabetes, and elevated cholesterol; and self-reported smoking as cardiovascular risk factors. Association between the risk factors and CKD was determined by multivariate logistic regression. Results: We enrolled 8396 participants (cases with CKD, 3956), with 56% females. The mean age (45.5 ± 15.1 years) did not differ between patients and control group. The prevalence of hypertension (59%), diabetes (20%), and elevated cholesterol (9.9%), was higher in CKD patients than in the control participants (P < 0.001). Prevalence of risk factors was higher in Ghana than in Nigeria. Hypertension (adjusted odds ratio [aOR] = 1.69 [1.43-2.01, P < 0.001]), elevated cholesterol (aOR = 2.0 [1.39-2.86, P < 0.001]), age >50 years, and body mass index (BMI) <18.5 kg/m2 were independently associated with CKD. The association of diabetes and smoking with CKD was modified by other risk factors. Conclusion: Cardiovascular risk factors are prevalent in middle-aged adult patients with CKD in Ghana and Nigeria, with higher proportions in Ghana than in Nigeria. Hypertension, elevated cholesterol, and underweight were independently associated with CKD.

Rapid Progression of Focal Segmental Glomerulosclerosis in Patients with High-Risk APOL1 Genotypes.

BACKGROUND: FSGS is a heterogeneous diagnosis with a guarded prognosis. Polymorphisms in the apolipoprotein L1 ( APOL1 ) gene are associated with developing FSGS and faster progression to kidney failure in affected patients. Better understanding the natural history of patients with FSGS and APOL1 risk alleles is essential to improve patient care and support the design and interpretation of interventional studies. The objective of this study was to evaluate the quantitative association between APOL1 and kidney disease progression and the interaction with other clinical and laboratory factors. METHODS: CureGN cohort study participants with biopsy diagnosis of FSGS, regardless of self-identified race, were included. The exposure of interest was two APOL1 risk alleles (high risk) versus zero to one risk alleles (low risk). The primary outcome was eGFR slope categorized as rapid progressor (eGFR slope ≤-5 ml/min per year), intermediate progressor (slope between 0 and -5), or nonprogressor (slope ≥0). Multivariable ordinal logistic and linear regressions were used for adjusted analyses. Missing data were addressed using multiple imputation. RESULTS: Of 650 participants, 476 (73%) had genetic testing, among whom 87 (18%) were high risk. High-risk participants were more likely to have lower median eGFR (62 [interquartile range, 36-81] versus low-risk participants 76 ml/min per 1.73 m 2 [interquartile range, 44-106]; P <0.01). In adjusted analysis, the odds of more rapid progression of eGFR was 2.75 times higher (95% confidence interval, 1.67 to 4.53; P <0.001) in the high-risk versus low-risk groups. CONCLUSIONS: In patients with FSGS, high-risk APOL1 genotype is the predominant factor associated with more rapid loss of kidney function.