Increased risk of kidney failure in patients with genetic kidney disorders.

BACKGROUNDIt is unknown whether the risk of kidney disease progression and failure differs between patients with and without genetic kidney disorders.METHODSThree cohorts were evaluated: the prospective Cure Glomerulonephropathy Network (CureGN) and 2 retrospective cohorts from Columbia University, including 5,727 adults and children with kidney disease from any etiology who underwent whole-genome or exome sequencing. The effects of monogenic kidney disorders and APOL1 kidney-risk genotypes on the risk of kidney failure, estimated glomerular filtration rate (eGFR) decline, and disease remission rates were evaluated along with diagnostic yields and the impact of American College of Medical Genetics secondary findings (ACMG SFs).RESULTSMonogenic kidney disorders were identified in 371 patients (6.5%), high-risk APOL1 genotypes in 318 (5.5%), and ACMG SFs in 100 (5.2%). Family history of kidney disease was the strongest predictor of monogenic disorders. After adjustment for traditional risk factors, monogenic kidney disorders were associated with an increased risk of kidney failure (hazard ratio [HR] = 1.72), higher rate of eGFR decline (-3.06 vs. 0.25 mL/min/1.73 m2/year), and lower risk of complete remission (odds ratioNot achieving CR = 5.25). High-risk APOL1 genotypes were associated with an increased risk of kidney failure (HR = 1.67) and faster eGFR decline (-2.28 vs. 0.25 mL/min/1.73 m2), replicating prior findings. ACMG SFs were not associated with personal or family history of associated diseases, but were predicted to impact care in 70% of cases.CONCLUSIONSMonogenic kidney disorders were associated with an increased risk of kidney failure, faster eGFR decline, and lower rates of complete remission, suggesting opportunities for early identification and intervention based on molecular diagnosis.TRIAL REGISTRATIONNA.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases grants U24DK100845 (formerly UM1DK100845), U01DK100846 (formerly UM1DK100846), U01DK100876 (formerly UM1DK100876), U01DK100866 (formerly UM1DK100866), U01DK100867 (formerly UM1DK100867), U24DK100845, DK081943, RC2DK116690, 2U01DK100876, 1R01DK136765, 5R01DK082753, and RC2-DK122397; NephCure Kidney International; Department of Defense Research Awards PR201425, W81XWH-16-1-0451, and W81XWH-22-1-0966; National Center for Advancing Translational Sciences grant UL1TR001873; National Library of Medicine grant R01LM013061; National Human Genome Research Institute grant 2U01HG008680.

Age of Onset and Disease Course in Biopsy-Proven Minimal Change Disease: An Analysis From the Cure Glomerulonephropathy Network.

RATIONALE & OBJECTIVE: Adolescent- and adult-onset minimal change disease (MCD) may have a clinical course distinct from childhood-onset disease. We characterized the course of children and adults with MCD in the Cure Glomerulonephropathy Network (CureGN) and assessed predictors of rituximab response. STUDY DESIGN: Prospective, multicenter, observational study. STUDY PARTICIPANTS: CureGN participants with proven MCD on biopsy. EXPOSURE: Age at disease onset, initiation of renin-angiotensin-aldosterone system (RAAS) blockade, and immunosuppression including rituximab during the study period. OUTCOME: Relapse and remission, change in estimated glomerular filtration rate (eGFR), and kidney failure. ANALYTICAL APPROACH: Remission and relapse probabilities were estimated using Kaplan-Meier curves and gap time recurrent event models. Linear regression models were used for the outcome of change in eGFR. Cox proportional hazards models were used to estimate the association between rituximab administration and remission. RESULTS: The study included 304 childhood- (≤12 years old), 49 adolescent- (13-17 years old), and 201 adult- (≥18 years) onset participants with 2.7-3.2 years of follow-up after enrollment. Children had a longer time to biopsy (238 vs 23 and 36 days in adolescent- and adult-onset participants, respectively; P<0.001) and were more likely to have received therapy before biopsy. Children were more likely to be treated with immunosuppression but not RAAS blockade. The rate of relapse was higher in childhood- versus adult-onset participants (HR, 1.69 [95% CI, 1.29-2.21]). The probability of remission was also higher in childhood-onset disease (HR, 1.33 [95%CI, 1.02-1.72]). In all groups eGFR loss was minimal. Children were more likely to remit after rituximab than those with adolescent- or adult-onset disease (adjusted HR, 2.1; P=0.003). Across all groups, glucocorticoid sensitivity was associated with a greater likelihood of achieving complete remission after rituximab (adjusted HR, 2.62; P=0.002). LIMITATIONS: CureGN was limited to biopsy-proven disease. Comparisons of childhood to nonchildhood cases of MCD may be subject to selection bias, given that childhood cases who undergo a biopsy may be limited to patients who are least responsive to initial therapy. CONCLUSIONS: Among patients with MCD who underwent kidney biopsy, there were differences in the course (relapse and remission) of childhood-onset compared with adolescent- and adult-onset disease, as well as rituximab response. PLAIN-LANGUAGE SUMMARY: Minimal change disease is a biopsy diagnosis for nephrotic syndrome. It is diagnosed in childhood, adolescence, or adulthood. Patients and clinicians often have questions about what to expect in the disease course and how to plan therapies. We analyzed a group of patients followed longitudinally as part of the Cure Glomerulonephropathy Network (CureGN) and describe the differences in disease (relapse and remission) based on the age of onset. We also analyzed rituximab response. We found that those with childhood-onset disease had a higher rate of relapse but also have a higher probability of reaching remission when compared with adolescent- or adult-onset disease. Children and all steroid-responsive patients are more likely to achieve remission after rituximab.

Total fluid intake, caffeine, and other bladder irritant avoidance among adults having urinary urgency with and without urgency incontinence: The Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN).

INTRODUCTION: Caffeine has long been vilified as a cause for urinary urgency incontinence (UUI) along with other potential bladder irritants such as carbonation, alcohol, and acidic juices. The objective of this study was to assess the fluid intake behavior of people with urgency, UUI, and those with lower urinary tract symptoms (LUTS) without UUI or urgency to assess if they avoided certain potential bladder irritants or had different fluid intake. We hypothesized that patients with UUI would avoid caffeine as a self-management method more so than these other two groups. METHODS: Treatment-seeking men and women with LUTS in the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) Observational Cohort study completed a baseline 3-day voiding and intake diary. "Complete" diaries had 3 days of data and no missing intake or voided volumes. Beverages with any caffeine, alcohol, carbonation, or acidic juice were identified and the total volume was recorded as well as the type of beverage containing caffeine to calculate the daily caffeine dose. RESULTS: Four hundred and ninety-one participants (277 men and 214 women) with a median age of 63 had complete diaries. Urinary urgency was more prevalent in women than men (79% vs. 55%, p < 0.0001) as was UUI (84% vs. 47%, p < 0.0001). Total fluid intake over 3 days was lower among the urgency group versus the nonurgency group (median [interquartile range] 5.2 [4.0-6.8] L vs. 5.7 [4.3-7.0] L, p = 0.028) and the UUI group compared to the urgency without incontinence group were less likely to consume alcohol (26% vs. 37%, p = 0.04). After adjusting for sex, BMI, age, and total intake volume, UUI participants had 54% lower odds of consuming any caffeine (odds ratio = 0.46, 95% confidence interval = 0.22-0.96, p = 0.04) than those without incontinence, but among those that did consume caffeine, no difference in the volume of caffeinated beverages or milligrams of caffeine consumed was detected between those with UUI and those with urgency without incontinence. No difference in carbonation or acidic juice intake was detected between groups. CONCLUSIONS: Individuals with urgency consume a lower volume of fluid than those without urgency. UUI participants more often abstain from caffeine, but among those that consume caffeine, the dose is similar to those without UUI. One explanation for these results is that only a subset of individuals with urgency or UUI are caffeine sensitive.

Kynurenine pathway metabolites predict subclinical atherosclerotic disease and new cardiovascular events in chronic kidney disease.

Introduction: Inflammation and oxidative stress contribute to the disproportionate burden of cardiovascular disease (CVD) in chronic kidney disease (CKD). Disordered catabolism of tryptophan via the kynurenine and indole pathways is linked to CVD in both CKD and dialysis patients. However, the association between specific kynurenine and indole metabolites with subclinical CVD and time to new cardiovascular (CV) events in CKD has not been studied. Methods: We measured kynurenine and indole pathway metabolites using targeted mass spectrometry in a cohort of 325 patients with moderate to severe CKD and a median follow-up of 2 years. Multiple linear regression and Cox regression analyses were used to assess the relationship between these tryptophan metabolites and subclinical CVD, including calcium scores, carotid intima-media thickness and time to new cardiovascular (CV) events. Results: Elevated quinolinic and anthranilic acids were independently associated with reduced time to new CVD [hazard ratio (HR) 1.28, P = .01 and HR 1.02, P = .02, respectively). Low tryptophan levels were associated with reduced time to new CV events when adjusting for demographics and CVD history (HR 0.30, P = .03). Low tryptophan levels were also associated with aortic calcification in a fully adjusted linear regression model (ß = -1983, P = .006). Similarly, high levels of several kynurenine pathway metabolites predicted increased coronary, aortic and composite calcification scores. Conclusions: We demonstrate the association of kynurenine pathway metabolites, and not indole derivatives, with subclinical and new CV events in an advanced CKD cohort. Our findings support a possible role for altered tryptophan immune metabolism in the pathogenesis of CKD-associated atherosclerosis.

Subtyping of common complex diseases and disorders by integrating heterogeneous data. Identifying clusters among women with lower urinary tract symptoms in the LURN study.

We present a methodology for subtyping of persons with a common clinical symptom complex by integrating heterogeneous continuous and categorical data. We illustrate it by clustering women with lower urinary tract symptoms (LUTS), who represent a heterogeneous cohort with overlapping symptoms and multifactorial etiology. Data collected in the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN), a multi-center observational study, included self-reported urinary and non-urinary symptoms, bladder diaries, and physical examination data for 545 women. Heterogeneity in these multidimensional data required thorough and non-trivial preprocessing, including scaling by controls and weighting to mitigate data redundancy, while the various data types (continuous and categorical) required novel methodology using a weighted Tanimoto indices approach. Data domains only available on a subset of the cohort were integrated using a semi-supervised clustering approach. Novel contrast criterion for determination of the optimal number of clusters in consensus clustering was introduced and compared with existing criteria. Distinctiveness of the clusters was confirmed by using multiple criteria for cluster quality, and by testing for significantly different variables in pairwise comparisons of the clusters. Cluster dynamics were explored by analyzing longitudinal data at 3- and 12-month follow-up. Five clusters of women with LUTS were identified using the developed methodology. None of the clusters could be characterized by a single symptom, but rather by a distinct combination of symptoms with various levels of severity. Targeted proteomics of serum samples demonstrated that differentially abundant proteins and affected pathways are different across the clusters. The clinical relevance of the identified clusters is discussed and compared with the current conventional approaches to the evaluation of LUTS patients. The rationale and thought process are described for the selection of procedures for data preprocessing, clustering, and cluster evaluation. Suggestions are provided for minimum reporting requirements in publications utilizing clustering methodology with multiple heterogeneous data domains.

Kidney Biopsy Features Most Predictive of Clinical Outcomes in the Spectrum of Minimal Change Disease and Focal Segmental Glomerulosclerosis.

BACKGROUND: Heterogeneity in disease course and treatment response among patients with MCD/FSGS necessitates a granular evaluation of kidney tissue features. This study aimed to identify histologic and ultrastructural descriptors of structural changes most predictive of clinical outcomes in the Nephrotic Syndrome Study Network (NEPTUNE). METHODS: Forty-eight histologic (37 glomerular, 9 tubulointerstitial, 2 vascular) and 20 ultrastructural descriptors were quantified by applying the NEPTUNE Digital Pathology Scoring System to NEPTUNE kidney biopsies. Outcomes included time from biopsy to disease progression, first complete remission of proteinuria, and treatment response. Relative importance of pathology and clinical predictors was obtained from random forest models, and predictive discrimination was assessed. RESULTS: Among 224 participants (34% Black, 24% Hispanic), model performance was excellent, with predictive discrimination of 0.9 for disease progression, 0.85 for complete remission, and 0.81 for treatment response. The most predictive descriptors of outcomes included both conventional-e.g., global sclerosis or segmental sclerosis and interstitial fibrosis/tubular atrophy-and novel features, including adhesion, interstitial foam cells, deflation, periglomerular fibrosis, mononuclear white blood cells, endothelial cell abnormalities, microvillous transformation, and acute tubular injury. CONCLUSIONS: The most predictive descriptors of clinical outcomes among MCD/FSGS patients reflected structural changes in multiple renal compartments. Reporting these descriptors should be standardized to guide prognostication of proteinuric glomerular diseases.

Experimental Pain and Auditory Sensitivity in Overactive Bladder Syndrome: A Symptoms of the Lower Urinary Tract Dysfunction Research Network (LURN) Study.

PURPOSE: The objective of this study was to investigate the presence of nonbladder sensory abnormalities in participants with overactive bladder syndrome (OAB). MATERIALS AND METHODS: Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) study participants with OAB symptoms and controls were recruited from 6 U.S. tertiary referral centers. Quantitative sensory testing (QST) was performed to determine pressure pain sensitivity at the thumbnail bed and auditory sensitivity. Fixed and mixed effect multivariable linear regressions and Weibull models were used to compare QST responses between groups. Pearson correlations were used to assess the relationship between QST measures. Associations between QST and self-reported symptoms were explored with linear regression. RESULTS: A total of 297 participants were analyzed (191 OAB, 106 controls; 76% white, 51% male). OAB cases were older than controls (57.4 vs 52.2 years, p=0.015). No significant differences in experimental thumbnail (nonbladder) pain or auditory sensitivity were detected between OAB cases and controls. Correlations between pressure and auditory derived metrics were weak to moderate overall for both groups, with some significantly stronger correlations for cases. Exploratory analyses indicated increased pressure pain and auditory sensitivity were modestly associated with greater self-reported bladder pain and pain interference with physical function. CONCLUSIONS: As a group, no significant differences between OAB cases and controls were observed in experimental nonbladder pain or auditory sensitivity during QST. Associations between QST outcomes and clinical pain raise the possibility of centrally mediated sensory amplification in some individuals with OAB.

Quantification of Glomerular Structural Lesions: Associations With Clinical Outcomes and Transcriptomic Profiles in Nephrotic Syndrome.

RATIONALE & OBJECTIVE: The current classification system for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) does not fully capture the complex structural changes in kidney biopsies nor the clinical and molecular heterogeneity of these diseases. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 221 MCD and FSGS patients enrolled in the Nephrotic Syndrome Study Network (NEPTUNE). EXPOSURE: The NEPTUNE Digital Pathology Scoring System (NDPSS) was applied to generate scores for 37 glomerular descriptors. OUTCOME: Time from biopsy to complete proteinuria remission, time from biopsy to kidney disease progression (40% estimated glomerular filtration rate [eGFR] decline or kidney failure), and eGFR over time. ANALYTICAL APPROACH: Cluster analysis was used to group patients with similar morphologic characteristics. Glomerular descriptors and patient clusters were assessed for associations with outcomes using adjusted Cox models and linear mixed models. Messenger RNA from glomerular tissue was used to assess differentially expressed genes between clusters and identify genes associated with individual descriptors driving cluster membership. RESULTS: Three clusters were identified: X (n = 56), Y (n = 68), and Z (n = 97). Clusters Y and Z had higher probabilities of proteinuria remission (HRs of 1.95 [95% CI, 0.99-3.85] and 3.29 [95% CI, 1.52-7.13], respectively), lower hazards of disease progression (HRs of 0.22 [95% CI, 0.08-0.57] and 0.11 [95% CI, 0.03-0.45], respectively), and lower loss of eGFR over time compared with X. Cluster X had 1,920 genes that were differentially expressed compared with Y+Z; these reflected activation of pathways of immune response and inflammation. Six descriptors driving the clusters individually correlated with clinical outcomes and gene expression. LIMITATIONS: Low prevalence of some descriptors and biopsy at a single time point. CONCLUSIONS: The NDPSS allows for categorization of FSGS/MCD patients into clinically and biologically relevant subgroups, and uncovers histologic parameters associated with clinical outcomes and molecular signatures not included in current classification systems.

Demographic, Comorbid, and Clinical Variables Associated With Pointwise Visual Field Damage in Glaucoma: Data From the AGIS and CIGTS Clinical Trials.

Purpose: To investigate differences across the visual field (VF) in the rate of glaucomatous progression, the likelihood of defect in four disease severity cross-sections, and comparisons of subgroups in each of between 12 demographic, comorbid, and clinical variables. Methods: Two long-term glaucoma clinical trials used Humphrey Field Analyzer 24-2 VFs to calculate pointwise deviations from age-matched normal controls. Slopes of glaucomatous progression over time were calculated per participant using linear mixed models. Pointwise differences between subgroups in slopes and cross-sectional categories were tested, adjusting for multiple comparisons using false discovery rate (FDR) and Q values. Results: Pointwise data were available for 1118 patients who had 15,073 VFs. On average, defects were seen at all VF points. Of the 12 variables, six had average pointwise slopes where Subgroup 1 had significantly faster progression than Subgroup 2 at all or many of the 52 VF points: participants who were older (≥65 vs. younger), 52/52; were male, 13/52; had diabetes, 29/52; had hypertension, 46/52; had a larger cup-to-disc ratio (≥0.7), 36/52; or had larger differences in absolute mean deviation (MD) between eyes (>3 dB), 52/52. Cross-sectional patterns at MD severity of -12 to -6.1 dB showed strong midline effects for gender and other patterns for hypertension, cup-to-disc ratio, absolute difference in MD between eyes, and disc notching. Conclusions: The approach used provides new longitudinal and cross-sectional insights into variation across the VF associated with demographic, comorbid, and clinical variables. Translational Relevance: This exploration and characterization of variable effects in the setting of pointwise VF testing may enable clinicians to anticipate patterns of VF loss based on demographic, comorbid, and clinical associations.

Midlife Vision Impairment and Cognitive Function in Later Life: The Study of Women's Health Across the Nation, Michigan Cohort.

BACKGROUND: In older adults, vision impairment (VI) is associated with worse cognitive function. However, the relationship between midlife vision and future cognitive function remains unknown. METHODS: The Study of Women's Health Across the Nation, Michigan site, is a longitudinal cohort of midlife women aged 42-52 years at baseline. Presenting Titmus visual acuity (VA) in the better-seeing eye was assessed at baseline and categorized as no or mild VI (VA ≥20/60), or moderate or worse VI (VA <20/60). Cognitive function was measured 8 times over 15 years using the East Boston Memory Test immediate (EBMTi) and delayed (EBMTd) recall and the Digit Span Backwards (DSB) test. Linear mixed models with a random intercept and slope for age were constructed to detect associations between VI at baseline and future repeated measures of cognitive function, adjusting for age, race, education, financial strain, alcohol use, and tobacco use. RESULTS: About 394 women aged 42-52 at baseline with a maximum follow-up of 20 years were included in this analysis. After covariate adjustment, moderate or worse VI was associated with lower EMBTi (ß = -0.56, p = .012), EBMTd (ß = -0.60, p = .009), and DSB (ß = -0.84, p = .04). While we detected significant associations between VI and levels of cognitive function scores, rates of cognitive decline as individuals aged did not vary by VI status. CONCLUSION: Moderate or worse VI, assessed during midlife, was associated with lower scores on measures of cognitive function over a 15-year period during which women transitioned from midlife to older adulthood.

Improving data quality in observational research studies: Report of the Cure Glomerulonephropathy (CureGN) network.

BACKGROUND: High data quality is of crucial importance to the integrity of research projects. In the conduct of multi-center observational cohort studies with increasing types and quantities of data, maintaining data quality is challenging, with few published guidelines. METHODS: The Cure Glomerulonephropathy (CureGN) Network has established numerous quality control procedures to manage the 70 participating sites in the United States, Canada, and Europe. This effort is supported and guided by the activities of several committees, including Data Quality, Recruitment and Retention, and Central Review, that work in tandem with the Data Coordinating Center to monitor the study. We have implemented coordinator training and feedback channels, data queries of questionable or missing data, and developed performance metrics for recruitment, retention, visit completion, data entry, recording of patient-reported outcomes, collection, shipping and accessing of biological samples and pathology materials, and processing, cataloging and accessing genetic data and materials. RESULTS: We describe the development of data queries and site Report Cards, and their use in monitoring and encouraging excellence in site performance. We demonstrate improvements in data quality and completeness over 4 years after implementing these activities. We describe quality initiatives addressing specific challenges in collecting and cataloging whole slide images and other kidney pathology data, and novel methods of data quality assessment. CONCLUSIONS: This paper reports the CureGN experience in optimizing data quality and underscores the importance of general and study-specific data quality initiatives to maintain excellence in the research measures of a multi-center observational study.

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.

Burden and Cost of Caring for US Veterans With CKD: Initial Findings From the VA Renal Information System (VA-REINS).

Kidney disease is a common, complex, costly, and life-limiting condition. Most kidney disease registries or information systems have been limited to single institutions or regions. A national US Department of Veterans Affairs (VA) Renal Information System (VA-REINS) was recently developed. We describe its creation and present key initial findings related to chronic kidney disease (CKD) without kidney replacement therapy (KRT). Data from the VA's Corporate Data Warehouse were processed and linked with national Medicare data for patients with CKD receiving KRT. Operational definitions for VA user, CKD, acute kidney injury, and kidney failure were developed. Among 7 million VA users in fiscal year 2014, CKD was identified using either a strict or liberal operational definition in 1.1 million (16.4%) and 2.5 million (36.3%) veterans, respectively. Most were identified using an estimated glomerular filtration rate laboratory phenotype, some through proteinuria assessment, and very few through International Classification of Diseases, Ninth Revision coding. The VA spent ∼$18 billion for the care of patients with CKD without KRT, most of which was for CKD stage 3, with higher per-patient costs by CKD stage. VA-REINS can be leveraged for disease surveillance, population health management, and improving the quality and value of care, thereby enhancing VA's capacity as a patient-centered learning health system for US veterans.

The Utility of Routine Fundus Photography Screening for Posterior Segment Disease: A Stepped-wedge, Cluster-randomized Trial in South India.

PURPOSE: To assess whether routine fundus photography (RFP) to screen for posterior segment disease at community eye clinics (vision centers [VCs]) in India increases referral to centralized ophthalmolic care. DESIGN: Stepped-wedge, cluster-randomized trial. PARTICIPANTS: Patients aged 40 to 75 years and those aged 20 to 40 years with a known history of hypertension or diabetes mellitus presenting to 4 technician-run VCs associated with the Aravind Eye Care System in India. METHODS: VCs (clusters) were randomized to standard care or RFP across five 2-week study periods (steps). Patients in each cluster received standard care initially. At the start of each subsequent step, a randomly chosen cluster crossed over to providing RFP to eligible patients. All clusters took part in RFP during the last step. Standard care involved technician eye exams, optional fundus photography, and teleconsultation with an ophthalmologist. RFP involved eye exams, dilation and 40-degree fundus photography, and teleconsultation with an ophthalmologist. MAIN OUTCOME MEASURES: Standard care and RFP clusters were compared by the proportion of patients referred for in-person evaluation by an ophthalmologist because of fundus photography findings and urgency of referral (urgently in ≤ 2 weeks vs. nonurgently in > 2 weeks). Generalized linear mixed models adjusting for cluster and step were used to estimate the odds of referral due to fundus photography findings compared with standard care. RESULTS: A total of 1447 patients were enrolled across the VCs, including 737 in the standard care group and 710 in the RFP group. Compared with standard care, the RFP group had a higher proportion of referrals due to fundus photography findings (11.3% vs. 4.4%), nonurgent referrals due to fundus photography (9.3% vs. 3.3%), and urgent referrals due to fundus photography (1.8% vs. 1.1%). The RFP intervention was associated with a 2-fold increased odds of being referred because of photography findings compared with standard care (odds ratio, 2.07; 95% confidence interval, 0.98-4.40; P = 0.058). CONCLUSIONS: Adding RFP to community eye clinics was associated with an increased odds of referral compared with standard care. This increase in referral was mostly due to nonurgent posterior segment disease.

Estimated GFR Trajectories in Pediatric and Adult Nephrotic Syndrome: Results From the Nephrotic Syndrome Study Network (NEPTUNE).

RATIONALE & OBJECTIVE: Surrogate outcomes for end-stage kidney disease often assume linear changes, which may not reflect true estimated glomerular filtration rate (eGFR) trajectories. This study's objective was to characterize nonlinear eGFR trajectories in nephrotic syndrome. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Nephrotic Syndrome Study Network (NEPTUNE) is a multicenter study of adult and pediatric patients with proteinuria enrolled at clinically indicated kidney biopsy or initial presentation of disease (pediatric only). PREDICTORS: Patient demographic, clinical, and pathology variables at study enrollment and follow-up time. OUTCOME: eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (patients ≥ 18 years old) or modified Chronic Kidney Disease in Children Study-Schwartz (patients < 18 years) formulas. The probability of nonlinearity (PNL) was calculated for individual eGFR trajectories. ANALYTICAL APPROACH: Associations between predictors and PNL were assessed using multivariable linear regression. RESULTS: 453 patients with ≥3 eGFR measurements and 1 or more year of follow-up were included (median follow-up, 3.6 years). Median PNL was 0.052; 56% and 16% had PNL < 10% and >50%, respectively. In both adults and pediatric patients, higher baseline eGFR was associated with higher PNL, whereas longer follow-up time was associated with lower PNL. Higher urine protein-creatinine ratio and steroid use were also associated with higher PNL in adults. Higher percentages of tubular atrophy and foot-process effacement were associated with lower and higher PNLs, respectively, in adults. LIMITATIONS: Relatively short follow-up time, inability to assess acute kidney injury events, and variable eGFR measurement frequency across patients. CONCLUSIONS: Although increasing follow-up time resulted in more linear trajectories, nonlinear eGFR trajectories were common in this cohort. Future studies in nephrotic syndrome should consider novel outcomes that do not rely on linearity assumptions.

Patient demographic and psychosocial characteristics associated with 30-day recall of self-reported lower urinary tract symptoms.

AIMS: Measurement of self-reported lower urinary tract symptoms (LUTS) typically uses a recall period, for example, "In the past 30 days…." Compared to averaged daily reports, 30-day recall is generally unbiased, but recall bias varies by item. We examined the associations between personal characteristics (eg, age, symptom bother) and 30-day recall of LUTS using items from the Symptoms of Lower Urinary Tract Dysfunction Research Network Comprehensive Assessment of Self-reported Urinary Symptoms questionnaire. METHODS: Participants (127 women and 127 men) were recruited from 6 US tertiary care sites. They completed daily assessments for 30 days and a 30-day recall assessment at the end of the study month. For each of the 18 tested items, representing 10 LUTS, the average of the participant's daily responses was modeled as a function of their 30-day recall, the personal characteristic, and the interaction between the 30-day recall and the characteristic in separate general linear regression models, adjusted for sex. RESULTS: Nine items representing 7 LUTS exhibited under- or overreporting (recall bias) for at least 25% of participants. Bias was associated with personal characteristics for six LUTS. Underreporting of incontinence was associated with older age, lower anxiety, and negative affect; overreporting of other LUTS was associated with, symptom bother, symptom variability, anxiety, and depression. CONCLUSIONS: We identified under- or overreporting that was associated with personal characteristics for six common LUTS. Some cues (eg, less bother and lower anxiety) were related to recall bias in an unexpected direction. Thus, providers should exercise caution when making judgments about the accuracy of a patient's symptom recall based on patient demographic and psychosocial characteristics.