Genomics in nephrology: identifying informatics opportunities to improve diagnosis of genetic kidney disorders using a human-centered design approach.

BACKGROUND: Genomic kidney conditions often have a long lag between onset of symptoms and diagnosis. To design a real time genetic diagnosis process that meets the needs of nephrologists, we need to understand the current state, barriers, and facilitators nephrologists and other clinicians who treat kidney conditions experience, and identify areas of opportunity for improvement and innovation. METHODS: Qualitative in-depth interviews were conducted with nephrologists and internists from 7 health systems. Rapid analysis identified themes in the interviews. These were used to develop service blueprints and process maps depicting the current state of genetic diagnosis of kidney disease. RESULTS: Themes from the interviews included the importance of trustworthy resources, guidance on how to order tests, and clarity on what to do with results. Barriers included lack of knowledge, lack of access, and complexity surrounding the case and disease. Facilitators included good user experience, straightforward diagnoses, and support from colleagues. DISCUSSION: The current state of diagnosis of kidney diseases with genetic etiology is suboptimal, with information gaps, complexity of genetic testing processes, and heterogeneity of disease impeding efficiency and leading to poor outcomes. This study highlights opportunities for improvement and innovation to address these barriers and empower nephrologists and other clinicians who treat kidney conditions to access and use real time genetic information.

Glucagon-like peptide-1 receptor agonists and the risk of atrial fibrillation in adults with diabetes: a real-world study.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) have cardiovascular benefits in type 2 diabetes, but none of the cardiovascular trials studied atrial fibrillation/atrial flutter (AF) as a primary endpoint. Data from post-marketing surveillance studies remains sparse. OBJECTIVE: To examine the real-world risk of AF comparing GLP-1RA with other non-insulin glucose-lowering agents. DESIGN: Cohort study using de-identified electronic health record data from the Optum Labs Data Warehouse. PARTICIPANTS: Adult patients with diabetes who were newly prescribed add-on non-insulin glucose-lowering agents and were on metformin between 2005-2020. EXPOSURES: New users of GLP-1RA were separately compared with new users of dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), using 1:1 propensity score matching to adjust for differences in patient characteristics. MAIN MEASURES: The primary outcome was incident AF, defined and captured by diagnosis code for AF. Incidence rate difference (IRD) and hazard ratio (HR) were estimated in the matched cohorts. KEY RESULTS: In the matched cohort of 14,566 pairs of GLP-1RA and DPP4i followed for a median of 3.8 years, GLP-1RA use was associated with a lower risk of AF (IRD, -1.0; 95% CI, -1.8 to -0.2 per 1000 person-years; HR, 0.82; 95% CI, 0.70 to 0.96). In the matched cohort of 9,424 pairs of patients on GLP-1RA and SGLT2i with a median follow-up of 2.9 years, there was no difference in the risk for AF (IRD, 0.4; 95% CI -0.7 to 1.5 per 1000 person-years; HR, 1.12; 95% CI, 0.89 to 1.42). CONCLUSIONS: In this real-word study, GLP-1RA was associated with a lower risk of AF compared with DPP4i, but no difference compared with SGLT2i, suggesting that cardiovascular benefits of GLP-1RA use may extend to prevention for AF in patients with diabetes. Our findings call for future randomized controlled trials to focus on the effects of GLP-1RA on AF prevention.

Development and Validation of the American Heart Association's PREVENT Equations.

BACKGROUND: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD. METHODS: The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-to-creatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3 330 085 participants from 21 additional data sets. RESULTS: Among 6 612 004 adults included, mean±SD age was 53±12 years, and 56% were women. Over a mean±SD follow-up of 4.8±3.1 years, there were 211 515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81-1.16) and 0.94 (0.81-1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD- and heart failure-specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004-0.005] and 0.005 [0.004-0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84-1.20] versus 1.39 [1.14-1.65]; P=0.01). CONCLUSIONS: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables.

The Phenotypic Spectrum of COL4A3 Heterozygotes.

Introduction: The penetrance and phenotypic spectrum of autosomal dominant Alport Syndrome (ADAS), affecting 1 in 106, remains understudied. Methods: Using data from 174,418 participants in the Geisinger MyCode/DiscovEHR study, an unselected health system-based cohort with whole exome sequencing, we identified 403 participants who were heterozygous for likely pathogenic COL4A3 variants. Phenotypic data was evaluated using International Classification of Diseases (ICD) codes, laboratory data, and chart review. To evaluate the phenotypic spectrum of genetically-determined ADAS, we matched COL4A3 heterozygotes 1:5 to nonheterozygotes using propensity scores by demographics, hypertension, diabetes, and nephrolithiasis. Results: COL4A3 heterozygotes were at significantly increased risks of hematuria, decreased estimated glomerular filtration rate (eGFR), albuminuria, and kidney failure (P < 0.05 for all comparisons) but not bilateral sensorineural hearing loss (P = 0.9). Phenotypic severity was more severe for collagenous domain glycine missense variants than protein truncating variants (PTVs). For example, patients with Gly695Arg (n = 161) had markedly increased risk of dipstick hematuria (odds ratio [OR] 9.50; 95% confidence interval [CI]: 6.32, 14.28) and kidney failure (OR 7.02; 95% CI: 3.48, 14.16) whereas those with PTVs (n = 119) had moderately increased risks of dipstick hematuria (OR 1.64; 95% CI: 1.03, 2.59) and kidney failure (OR 3.44; 95% CI: 1.28, 9.22). Less than a third of patients had albuminuria screening completed, and fewer than 1 of 3 were taking inhibitors of the renin-angiotensin-aldosterone system. Conclusion: This study demonstrates a wide spectrum of phenotypic severity in ADAS due to COL4A3 with phenotypic variability by genotype. Future studies are needed to evaluate the impact of earlier diagnosis, appropriate evaluation, and treatment of ADAS.

GWAS for the composite traits of hematuria and albuminuria.

Our GWAS of hematuria in the UK Biobank identified 6 loci, some of which overlap with loci for albuminuria suggesting pleiotropy. Since clinical syndromes are often defined by combinations of traits, generating a combined phenotype can improve power to detect loci influencing multiple characteristics. Thus the composite trait of hematuria and albuminuria was chosen to enrich for glomerular pathologies. Cases had both hematuria defined by ICD codes and albuminuria defined as uACR > 3 mg/mmol. Controls had neither an ICD code for hematuria nor an uACR > 3 mg/mmol. 2429 cases and 343,509 controls from the UK Biobank were included. eGFR was lower in cases compared to controls, with the exception of the comparison in females using CKD-EPI after age adjustment. Variants at 4 loci met genome-wide significance with the following nearest genes: COL4A4, TRIM27, ETV1 and CUBN. TRIM27 is part of the extended MHC locus. All loci with the exception of ETV1 were replicated in the Geisinger MyCode cohort. The previous GWAS of hematuria reported COL4A3-COL4A4 variants and HLA-B*0801 within MHC, which is in linkage disequilibrium with the TRIM27 variant (D' = 0.59). TRIM27 is highly expressed in the tubules. Additional loci included a coding sequence variant in CUBN (p.Ala2914Val, MAF = 0.014 (A), p = 3.29E-8, OR = 2.09, 95% CI = 1.61-2.72). Overall, GWAS for the composite trait of hematuria and albuminuria identified 4 loci, 2 of which were not previously identified in a GWAS of hematuria.

Associations of Apixaban Dose With Safety and Effectiveness Outcomes in Patients With Atrial Fibrillation and Severe Chronic Kidney Disease.

BACKGROUND: Recommendations for apixaban dosing on the basis of kidney function are inconsistent between the US Food and Drug Administration and European Medicines Agency for patients with atrial fibrillation. Optimal apixaban dosing in chronic kidney disease remains unknown. METHODS: With the use of deidentified electronic health record data from the Optum Labs Data Warehouse, patients with atrial fibrillation and chronic kidney disease stage 4/5 initiating apixaban between 2013 and 2021 were identified. Risks of bleeding and stroke/systemic embolism were compared by apixaban dose (5 versus 2.5 mg), adjusted for baseline characteristics by the inverse probability of treatment weighting. The Fine-Gray subdistribution hazard model was used to account for the competing risk of death. Cox regression was used to examine risk of death by apixaban dose. RESULTS: Among 4313 apixaban new users, 1705 (40%) received 5 mg and 2608 (60%) received 2.5 mg. Patients treated with 5 mg apixaban were younger (mean age, 72 versus 80 years), with greater weight (95 versus 80 kg) and higher serum creatinine (2.7 versus 2.5 mg/dL). Mean estimated glomerular filtration rate was not different between the groups (24 versus 24 mL·min-1·1.73 m-2). In inverse probability of treatment weighting analysis, apixaban 5 mg was associated with a higher risk of bleeding (incidence rate 4.9 versus 2.9 events per 100 person-years; incidence rate difference, 2.0 [95% CI, 0.6-3.4] events per 100 person-years; subdistribution hazard ratio, 1.63 [95% CI, 1.04-2.54]). There was no difference between apixaban 5 mg and 2.5 mg groups in the risk of stroke/systemic embolism (3.3 versus 3.0 events per 100 person-years; incidence rate difference, 0.2 [95% CI, -1.0 to 1.4] events per 100 person-years; subdistribution hazard ratio, 1.01 [95% CI, 0.59-1.73]), or death (9.9 versus 9.4 events per 100 person-years; incidence rate difference, 0.5 [95% CI, -1.6 to 2.6] events per 100 person-years; hazard ratio, 1.03 [95% CI, 0.77-1.38]). CONCLUSIONS: Compared with 2.5 mg, use of 5 mg apixaban was associated with a higher risk of bleeding in patients with atrial fibrillation and severe chronic kidney disease, with no difference in the risk of stroke/systemic embolism or death, supporting the apixaban dosing recommendations on the basis of kidney function by the European Medicines Agency, which differ from those issued by the US Food and Drug Administration.

Blockbuster Medications for Obesity: A Primer for Nephrologists.

The prevalence of obesity in the United States and across the world continues to climb, imparting increased risk of chronic disease. This impact is doubly felt in nephrology because obesity not only increases the risk of chronic kidney disease (CKD) but also exacerbates existing cardiovascular morbidity and mortality. The role of medical weight loss therapy in CKD has been debated, but increasing evidence suggests that intentional weight loss is protective against adverse kidney and cardiovascular outcomes. This may be particularly true with the advent of novel pharmacotherapies taking advantage of the incretin system, resulting in weight loss approaching that seen with surgical interventions. Moreover, these novel therapies have repeatedly demonstrated protective effects on the cardiovascular system. Here, we review the impact of obesity and weight loss on CKD, and the biological basis and clinical evidence for incretin therapy. This perspective provides recommended prescribing practices as a practical tool to engage nephrologists and patients with CKD in the treatment of obesity-related morbidity.

Racial Differences and Contributory Cardiovascular and Non-Cardiovascular Risk Factors Towards Chronic Kidney Disease Progression.

Background: The prevalence of advanced chronic kidney disease (CKD) is higher in Black than in White Americans. We evaluated CKD progression in Black and White participants and the contribution of biological risk factors. We included the study of lung function (measured by forced vital capacity [FVC]), which is part of the emerging notion of interorgan cross-talk with the kidneys to racial differences in CKD progression. Methods: This longitudinal study included 2175 Black and 2207 White adult Coronary Artery Risk Development in Young Adults (CARDIA) participants. Estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) were measured at study year 10 (age 27-41y) and every five years for 20 years. The outcome was CKD progression through no CKD, low, moderate, high, or very high-risk categories based on eGFR and UACR in combination. The association between race and CKD progression as well as the contribution of risk factors to racial differences were assessed in multivariable-adjusted Cox models. Results: Black participants had higher CKD transition probabilities than White participants and more prevalent risk factors during the 20-year period studied. Hazard ratios for CKD transition for Black (vs White participants) were 1.38 from No CKD into ≥ low risk, 2.25 from ≤ low risk into ≥ moderate risk, and 4.49 from ≤ moderate risk into ≥ high risk. Racial differences in CKD progression from No CKD into ≥ low risk were primarily explained by FVC (54.8%), hypertension (30.9%), and obesity (20.8%). In contrast, racial differences were less explained in more severe transitions. Conclusion: Black participants had a higher risk of CKD progression, and this discrepancy may be partly explained by FVC and conventional risk factors.

The Phenotypic Spectrum of COL4A3 Heterozygotes.

Most data on Alport Syndrome (AS) due to COL4A3 are limited to families with autosomal recessive AS or severe manifestations such as focal segmental glomerulosclerosis (FSGS). Using data from 174,418 participants in the Geisinger MyCode/DiscovEHR study, an unselected health system-based cohort with whole exome sequencing, we identified 403 participants (0.2%) who were heterozygous for likely pathogenic COL4A3 variants. Phenotypic data was evaluated using International Classification of Diseases (ICD) codes, laboratory data, and chart review. To evaluate the phenotypic spectrum of genetically-determined autosomal dominant AS, we matched COL4A3 heterozygotes 1:5 to non-heterozygotes using propensity scores by demographics, hypertension, diabetes, and nephrolithiasis. COL4A3 heterozygotes were at significantly increased risks of hematuria, decreased estimated glomerular filtration rate (eGFR), albuminuria, and end-stage kidney disease (ESKD) (p<0.05 for all comparisons) but not bilateral sensorineural hearing loss (p=0.9). Phenotypic severity tended to be more severe among patients with glycine missense variants located within the collagenous domain. For example, patients with Gly695Arg (n=161) had markedly increased risk of dipstick hematuria (OR 9.47, 95% CI: 6.30, 14.22) and ESKD diagnosis (OR 7.01, 95% CI: 3.48, 14.12) whereas those with PTVs (n=119) had moderately increased risks of dipstick hematuria (OR 1.63, 95% CI: 1.03, 2.58) and ESKD diagnosis (OR 3.43, 95% CI: 1.28, 9.19). Less than a third of patients had albuminuria screening completed, and fewer than 1/3 were taking inhibitors of the renin-angiotensin-aldosterone system (RAASi). Future studies are needed to evaluate the impact of earlier diagnosis, appropriate evaluation, and treatment of ADAS.

Association between the diagnostic classification of newly diagnosed coronary artery disease and future heart failure development.

OBJECTIVE: The first clinical manifestation of coronary artery disease (CAD) varies widely from unheralded myocardial infarction (MI) to mild, incidentally detected disease. The primary objective of this study was to quantify the association between different initial CAD diagnostic classifications and future heart failure. METHODS: This retrospective study incorporated the electronic health record of a single integrated health care system. Newly diagnosed CAD was classified into a mutually exclusive hierarchy as MI, CAD with coronary artery bypass graft (CABG), CAD with percutaneous coronary intervention, CAD only, unstable angina, and stable angina. An acute CAD presentation was defined when the diagnosis was associated with a hospital admission. New heart failure was identified after the CAD diagnosis. RESULTS: Among 28 693 newly diagnosed CAD patients, initial presentation was acute in 47% and manifested as MI in 26%. Within 30 days of CAD diagnosis, MI [hazard ratio (HR) = 5.1; 95% confidence interval: 4.1-6.5] and unstable angina (3.2; 2.4-4.4) classifications were associated with the highest heart failure risk (compared to stable angina), as was acute presentation (2.9; 2.7-3.2). Among stable, heart failure-free CAD patients followed on average 7.4 years, initial MI (adjusted HR = 1.6; 1.4-1.7) and CAD with CABG (1.5; 1.2-1.8) were associated with higher long-term heart failure risk, but an initial acute presentation was not (1.0; 0.9-1.0). CONCLUSION: Nearly 50% of initial CAD diagnoses are associated with hospitalization, and these patients are at high risk of early heart failure. Among stable CAD patients, MI remained the diagnostic classification associated with the highest long-term heart failure risk, however, having an initial acute CAD presentation was not associated with long-term heart failure.

Nontraditional Risk Factors for Progression Through Chronic Kidney Disease Risk Categories: The Coronary Artery Risk Development in Young Adults Study.

BACKGROUND: There may be nontraditional pathways of chronic kidney disease (CKD) progression that are complementary to classical pathways. Therefore, we aimed to examine nontraditional risk factors for incident CKD and its progression. METHODS: We used the generally healthy population (n = 4382) starting at age 27-41 years in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, which is an observational longitudinal study. Nontraditional risk factors included forced vital capacity, inflammation, serum urate, and serum carotenoids. CKD risk category was classified using the estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) measured in 1995-1996 and repeated every 5 years for 20 years: No CKD, low risk, moderate risk, high risk, and very high risk. RESULTS: At baseline, 84.8% had no CKD (eGFR ≥60 mL/min/1.73 m2 and UACR <10 mg/g), 10.3% were in the low risk (eGFR ≥60 and UACR 10-29), and 4.9% had CKD (eGFR <60 and/or UACR ≥ 30). Nontraditional risk factors were significantly associated with the progression of CKD to higher categories. Hazard ratios per standard deviation of the predictor for incident CKD and its progression from the No CKD and low and moderate risk into CKD were inverse for forced vital capacity and serum carotenoids and positive for serum urate, GlycA, and C-reactive protein, the first 3 even after adjustment for conventional risk factors. CONCLUSION: Several nontraditional markers were significantly associated with an increased risk of progression to higher CKD categories in generally healthy young to middle-aged adults.

Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease.

ALG8 protein-truncating variants (PTVs) have previously been described in patients with polycystic liver disease and in some cases cystic kidney disease. Given a lack of well-controlled studies, we determined whether individuals heterozygous for ALG8 PTVs are at increased risk of cystic kidney disease in a large, unselected health system-based observational cohort linked to electronic health records in Pennsylvania (Geisinger-Regeneron DiscovEHR MyCode study). Out of 174,172 patients, 236 were identified with ALG8 PTVs. Using ICD-based outcomes, patients with these variants were significantly at increased risk of having any kidney/liver cyst diagnosis (Odds Ratio 2.42, 95% confidence interval: 1.53-3.85), cystic kidney disease (3.03, 1.26-7.31), and nephrolithiasis (1.89, 1.96-2.97). To confirm this finding, blinded radiology review of computed tomography and magnetic resonance imaging studies was completed in a matched cohort of 52 thirty-plus year old ALG8 PTV heterozygotes and related non-heterozygotes. ALG8 PTV heterozygotes were significantly more likely to have cystic kidney disease, defined as four or more kidney cysts (57.7% vs. 7.7%), or bilateral kidney cysts (69.2% vs. 15.4%), but not one or more liver cyst (11.5% vs. 7.7%). In publicly available UK Biobank data, ALG8 PTV heterozygotes were at significantly increased risk of ICD code N28 (other disorders of kidney/ureter) (3.85% vs. 1.33%). ALG8 PTVs were not associated with chronic kidney disease or kidney failure in the MyCode study or the UK Biobank data. Thus, PTVs in ALG8 result in increased risk of a mild cystic kidney disease phenotype.

A National Registry for People With All Stages of Kidney Disease: The National Kidney Foundation (NKF) Patient Network.

RATIONALE & OBJECTIVE: The National Kidney Foundation (NKF) launched the first national US kidney disease patient registry, the NKF Patient Network, that is open to patients throughout the continuum of chronic kidney disease (CKD). The Network provides individualized education and will facilitate patient-centered research, clinical care, and health policy decisions. Here, we present the overall design and the results of a feasibility study that was conducted July through December 2020. STUDY DESIGN: Longitudinal observational cohort study of patient-entered data with or without electronic health care record (EHR) linkage in collaboration with health systems. SETTING & PARTICIPANTS: People with CKD, age≥18 years, are invited through their provider, NKF communications, or national outreach campaign. People self-enroll and share their data through a secure portal that offers individualized education and support. The first health system partner is Geisinger. EXPOSURE: Any cause and stage of CKD, including dialysis and kidney transplant recipients. OUTCOME: Feasibility of the EHR data transfer, participants' characteristics, and their perspectives on usability and content. ANALYTICAL APPROACH: Data were collected and analyzed through the registry portal powered by the Pulse Infoframe healthie 2.0 platform. RESULTS: During the feasibility study, 80 participants completed their profile, and 42 completed a satisfaction survey. Mean age was 57.5 years, 51% were women, 83% were White, and 89% were non-Hispanic or Latino. Of the participants, 60% were not aware of their level of estimated glomerular filtration rate and 91% of their urinary albumin-creatinine ratio. LIMITATIONS: Challenges for the Network are lack of awareness of kidney disease for many with CKD, difficulty in recruiting vulnerable populations or those with low digital readiness, and loss to follow-up, all leading to selection bias. CONCLUSIONS: The Network is positioned to become a national and international platform for real-world data that can inform the development of patient-centered research, care, and treatments.

Exome Sequencing of a Clinical Population for Autosomal Dominant Polycystic Kidney Disease.

Importance: Most studies of autosomal dominant polycystic kidney disease (ADPKD) genetics have used kidney specialty cohorts, focusing on PKD1 and PKD2. These can lead to biased estimates of population prevalence of ADPKD-associated gene variants and their phenotypic expression. Objective: To determine the prevalence of ADPKD and contributions of PKD1, PKD2, and other genes related to cystic kidney disease in a large, unselected cohort. Design, Setting, and Participants: This retrospective observational study used an unselected health system-based cohort in central and northeast Pennsylvania with exome sequencing (enrolled from 2004 to 2020) and electronic health record data (up to October 2021). The genotype-first approach included the entire cohort and the phenotype-first approach focused on patients with ADPKD diagnosis codes, confirmed by chart and imaging review. Exposures: Loss-of-function (LOF) variants in PKD1, PKD2, and other genes associated with cystic kidney disease (ie, ALG8, ALG9, DNAJB11, GANAB, HNF1B, IFT140, SEC61B, PKHD1, PRKCSH, SEC63); likely pathogenic missense variants in PKD1 and PKD2. Main Outcomes and Measures: Genotype-first analysis: ADPKD diagnosis code (Q61.2, Q61.3, 753.13, 753.12); phenotype-first analysis: presence of a rare variant in PKD1, PKD2, or other genes associated with cystic kidney disease. Results: Of 174 172 patients (median age, 60 years; 60.6% female; 93% of European ancestry), 303 patients had ADPKD diagnosis codes, including 235 with sufficient chart review data for confirmation. In addition to PKD1 and PKD2, LOF variants in IFT140, GANAB, and HNF1B were associated with ADPKD diagnosis after correction for multiple comparisons. Among patients with LOF variants in PKD1, 66 of 68 (97%) had ADPKD; 43 of 43 patients (100%) with LOF variants in PKD2 had ADPKD. In contrast, only 24 of 77 patients (31.2%) with a PKD1 missense variant previously classified as "likely pathogenic" had ADPKD, suggesting misclassification or variable penetrance. Among patients with ADPKD diagnosis confirmed by chart review, 180 of 235 (76.6%) had a potential genetic cause, with the majority being rare variants in PKD1 (127 patients) or PKD2 (34 patients); 19 of 235 (8.1%) had variants in other genes associated with cystic kidney disease. Of these 235 patients with confirmed ADPKD, 150 (63.8%) had a family history of ADPKD. The yield for a genetic determinant of ADPKD was higher for those with a family history of ADPKD compared with those without family history (91.3% [137/150] vs 50.6% [43/85]; difference, 40.7% [95% CI, 29.2%-52.3%]; P < .001). Previously unreported PKD1, PKD2, and GANAB variants were identified with pedigree data suggesting pathogenicity, and several PKD1 missense variants previously reported as likely pathogenic appeared to be benign. Conclusions and Relevance: This study demonstrates substantial genetic and phenotypic variability in ADPKD among patients within a regional health system in the US.

Progression of Chronic Kidney Disease Risk Categories and Risk of Cardiovascular Disease and Total Mortality: Coronary Artery Risk Development in Young Adults Cohort.

Background Previous studies of worsening chronic kidney disease (CKD) based on declining estimated glomerular filtration rate (eGFR) or increasing urine albumin-creatinine ratio (UACR) are limited to later middle-age and older adults. We examined associations of CKD progression and incident cardiovascular disease (CVD) and mortality in younger adults. Methods and Results We studied 4382 adults in CARDIA (Coronary Artery Risk Development in Young Adults) initially aged 27 to 41 years and prospectively over 20 years. Five-year transition probabilities across CKD risk categories were based on eGFR and UACR measured at each exam. Proportional hazards models predicted incident CVD and all-cause mortality by time-varying CKD risk category, adjusting for demographics and CVD risk factors. Progression of CKD risk categories over 20 years occurred in 28.7% (1256/4382) of participants, driven by increases in UACR, but including 5.8% (n=255) with eGFR<60 mL/min per 1.73 m2 or UACR ≥300 mg/g. Compared with eGFR ≥60 and UACR <10, demographic and smoking-adjusted hazard ratios for CVD were 1.62 (95% CI, 1.21-2.18) for low CKD risk (eGFR ≥60 with UACR 10-29) and 13.65 (95% CI, 7.52-24.79) for very high CKD risk (eGFR <30 or eGFR 30-44 with UACR 30-299; or eGFR 30-59 with UACR ≥300). Corresponding hazard ratios for all-cause mortality were 1.42 (95% CI, 1.08-1.88) and 14.75 (95% CI, 9.97-21.82). Although CVD associations were attenuated after adjustment for mediating CVD risk factors, all-cause mortality associations remained statistically significant. Conclusions Among young to middle-aged adults, progression to higher CKD risk category was common. Routine monitoring eGFR and UACR holds promise for prevention of CVD and total mortality.