Genome-Wide Association Study of CKD Progression.

SIGNIFICANCE STATEMENT: Rapid progression of CKD is associated with poor clinical outcomes. Most previous studies looking for genetic factors associated with low eGFR have used cross-sectional data. The authors conducted a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD, focusing on longitudinal data. They identified three loci (two of them novel) associated with longitudinal eGFR decline. In addition to the known UMOD/PDILT locus, variants within BICC1 were associated with significant differences in longitudinal eGFR slope. Variants within HEATR4 also were associated with differences in eGFR decline, but only among Black/African American individuals without diabetes. These findings help characterize molecular mechanisms of eGFR decline in CKD and may inform new therapeutic approaches for progressive kidney disease. BACKGROUND: Rapid progression of CKD is associated with poor clinical outcomes. Despite extensive study of the genetics of cross-sectional eGFR, only a few loci associated with eGFR decline over time have been identified. METHODS: We performed a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD-defined by two outpatient eGFR measurements of <60 ml/min per 1.73 m 2 , obtained 90-365 days apart-from the Million Veteran Program and Vanderbilt University Medical Center's DNA biobank. The primary outcome was the annualized relative slope in outpatient eGFR. Analyses were stratified by ethnicity and diabetes status and meta-analyzed thereafter. RESULTS: In cross-ancestry meta-analysis, the strongest association was rs77924615, near UMOD / PDILT ; each copy of the G allele was associated with a 0.30%/yr faster eGFR decline ( P = 4.9×10 -27 ). We also observed an association within BICC1 (rs11592748), where every additional minor allele was associated with a 0.13%/yr slower eGFR decline ( P = 5.6×10 -9 ). Among participants without diabetes, the strongest association was the UMOD/PDILT variant rs36060036, associated with a 0.27%/yr faster eGFR decline per copy of the C allele ( P = 1.9×10 -17 ). Among Black participants, a significantly faster eGFR decline was associated with variant rs16996674 near APOL1 (R 2 =0.29 with the G1 high-risk genotype); among Black participants with diabetes, lead variant rs11624911 near HEATR4 also was associated with a significantly faster eGFR decline. We also nominally replicated loci with known associations with eGFR decline, near PRKAG2, FGF5, and C15ORF54. CONCLUSIONS: Three loci were significantly associated with longitudinal eGFR change at genome-wide significance. These findings help characterize molecular mechanisms of eGFR decline and may contribute to the development of new therapeutic approaches for progressive CKD.

Renin-angiotensin aldosterone inhibitor use at hospital discharge among patients with moderate to severe acute kidney injury and its association with recurrent acute kidney injury and mortality.

Recurrent episodes of acute kidney injury (AKI) are common among AKI survivors. Renin-angiotensin aldosterone inhibitors (RAASi) are often indicated for these patients but may increase the risk for recurrent AKI. Here, we examined whether RAASi associates with a higher risk for recurrent AKI and mortality among survivors of moderate to severe AKI in a retrospective cohort of Veterans who survived Stage II or III AKI. The primary exposure was RAASi at hospital discharge and the primary endpoint was recurrent AKI within 12 months. Cox proportional hazards models were fit on a propensity score-weighted cohort to compare time to recurrent AKI and mortality by RAASi exposure. Among 96,983 patients, 40% were on RAASi at discharge. Compared to patients who continued RAASi use, those discontinuing use experienced no difference in risk for recurrent AKI but had a significantly higher risk of mortality [hazard ratio 1.33 (95% confidence interval1.26-1.41)]. No differences in recurrent AKI risk was observed for non-users started or not on RAASi compared to prevalent users who continued RAASi. Subgroup analyses among those with diabetes, chronic kidney disease, heart failure, and malignancy were similar with exception of a modest reduction in recurrent AKI risk among RAASi discontinuers with chronic kidney disease. Thus, RAASi use among survivors of moderate to severe AKI was associated with little to no difference in risk for recurrent AKI but was associated with improved survival. Reinitiating or starting RAASi among patients with strong indications is warranted but should be balanced with individual overall risk for recurrent AKI and with adequate monitoring.

Timing of Recovery From Moderate to Severe AKI and the Risk for Future Loss of Kidney Function.

RATIONALE & OBJECTIVE: The extent of recovery of kidney function following acute kidney injury (AKI) is known to be associated with future chronic kidney disease. Less is known about how the timing of recovery affects the rate of future loss of kidney function. STUDY DESIGN: We performed a retrospective cohort study examining the independent association between the timing of recovery from moderate to severe AKI and future loss of kidney function. SETTING & PARTICIPANTS: 47,903 adult US veterans with stage 2 or 3 AKI who recovered to within 120% of baseline creatinine level within 90 days of peak injury. EXPOSURE: The timing of recovery of kidney function from peak inpatient serum creatinine level grouped into 1 to 4, 5 to 10, 11 to 30, and 31 to 90 days. OUTCOME: A sustained 40% decline in estimated glomerular filtration rate below that calculated from the last serum creatinine level available during the 90-day recovery period or kidney failure (2 outpatient estimated glomerular filtration rates<15mL/min/1.73m2, dialysis procedures > 90 days apart, kidney transplantation, or registry within the US Renal Data System). ANALYTICAL APPROACH: Time to the primary outcome was examined using multivariable Cox proportional hazards regression. RESULTS: Among 47,903 patients, 29,316 (61%), 10,360 (22%), 4,520 (9%), and 3,707 (8%) recovered within 1 to 4, 5 to 10, 11 to 30, and 31 to 90 days, respectively. With a median follow-up of 42 months, unadjusted incidence rates for the kidney outcome were 2.01, 3.55, 3.86, and 3.68 events/100 person-years, respectively. Compared with 1 to 4 days, recovery within 5 to 10, 11 to 30, and 31 to 90 days was associated with increased rates of the primary outcome: adjusted HRs were 1.33 (95% CI, 1.24-1.43), 1.41 (95% CI, 1.28-1.54), and 1.58 (95% CI, 1.43-1.75), respectively. LIMITATIONS: Predominately male population, residual confounding, and inability to make causal inferences because of the retrospective observational study design. CONCLUSIONS: The timing of recovery provides an added dimension to AKI phenotyping and prognostic information regarding the future occurrence of loss of kidney function. Studies to identify effective interventions on the timing of recovery from AKI are warranted.

Development of Portable Electronic Health Record Based Algorithms to Identify Individuals with Diabetic Retinopathy.

Objectives: To develop, validate and implement algorithms to identify diabetic retinopathy (DR) cases and controls from electronic health care records (EHR)s. Methods : We developed and validated EHR-based algorithms to identify DR cases and individuals with type I or II diabetes without DR (controls) in three independent EHR systems: Vanderbilt University Medical Center Synthetic Derivative (VUMC), the VA Northeast Ohio Healthcare System (VANEOHS), and Massachusetts General Brigham (MGB). Cases were required to meet one of three criteria: 1) two or more dates with any DR ICD-9/10 code documented in the EHR, or 2) at least one affirmative health-factor or EPIC code for DR along with an ICD9/10 code for DR on a different day, or 3) at least one ICD-9/10 code for any DR occurring within 24 hours of an ophthalmology exam. Criteria for controls included affirmative evidence for diabetes as well as an ophthalmology exam. Results: The algorithms, developed and evaluated in VUMC through manual chart review, resulted in a positive predictive value (PPV) of 0.93 for cases and negative predictive value (NPV) of 0.97 for controls. Implementation of algorithms yielded similar metrics in VANEOHS (PPV=0.94; NPV=0.86) and lower in MGB (PPV=0.84; NPV=0.76). In comparison, use of DR definition as implemented in Phenome-wide association study (PheWAS) in VUMC, yielded similar PPV (0.92) but substantially reduced NPV (0.48). Implementation of the algorithms to the Million Veteran Program identified over 62,000 DR cases with genetic data including 14,549 African Americans and 6,209 Hispanics with DR. Conclusions/Discussion: We demonstrate the robustness of the algorithms at three separate health-care centers, with a minimum PPV of 0.84 and substantially improved NPV than existing high-throughput methods. We strongly encourage independent validation and incorporation of features unique to each EHR to enhance algorithm performance for DR cases and controls.

Adaptive selection at G6PD and disparities in diabetes complications.

Diabetes complications occur at higher rates in individuals of African ancestry. Glucose-6-phosphate dehydrogenase deficiency (G6PDdef), common in some African populations, confers malaria resistance, and reduces hemoglobin A1c (HbA1c) levels by shortening erythrocyte lifespan. In a combined-ancestry genome-wide association study of diabetic retinopathy, we identified nine loci including a G6PDdef causal variant, rs1050828 -T (Val98Met), which was also associated with increased risk of other diabetes complications. The effect of rs1050828 -T on retinopathy was fully mediated by glucose levels. In the years preceding diabetes diagnosis and insulin prescription, glucose levels were significantly higher and HbA1c significantly lower in those with versus without G6PDdef. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, participants with G6PDdef had significantly higher hazards of incident retinopathy and neuropathy. At the same HbA1c levels, G6PDdef participants in both ACCORD and the Million Veteran Program had significantly increased risk of retinopathy. We estimate that 12% and 9% of diabetic retinopathy and neuropathy cases, respectively, in participants of African ancestry are due to this exposure. Across continentally defined ancestral populations, the differences in frequency of rs1050828 -T and other G6PDdef alleles contribute to disparities in diabetes complications. Diabetes management guided by glucose or potentially genotype-adjusted HbA1c levels could lead to more timely diagnoses and appropriate intensification of therapy, decreasing the risk of diabetes complications in patients with G6PDdef alleles.

Association of Apparent Treatment-Resistant Hypertension With Differential Risk of End-Stage Kidney Disease Across Racial Groups in the Million Veteran Program.

[Figure: see text].

Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

Risk of Hypoglycemia Following Hospital Discharge in Patients With Diabetes and Acute Kidney Injury.

OBJECTIVE: Hypoglycemia is common in patients with diabetes. The risk of hypoglycemia after acute kidney injury (AKI) is not well defined. The purpose of this study was to compare the risk for postdischarge hypoglycemia among hospitalized patients with diabetes who do and do not experience AKI. RESEARCH DESIGN AND METHODS: We performed a propensity-matched analysis of patients with diabetes, with and without AKI, using a retrospective national cohort of veterans hospitalized between 2004 and 2012. AKI was defined as a 0.3 mg/dL or 50% increase in serum creatinine from baseline to peak serum creatinine during hospitalization. Hypoglycemia was defined as hospital admission or an emergency department visit for hypoglycemia or as an outpatient blood glucose <60 mg/dL. Time to incident hypoglycemia within 90 days postdischarge was examined using Cox proportional hazards models. Prespecified subgroup analyses by renal recovery, baseline chronic kidney disease, preadmission drug regimen, and HbA1c were performed. RESULTS: We identified 65,151 propensity score-matched pairs with and without AKI. The incidence of hypoglycemia was 29.6 (95% CI 28.9-30.4) and 23.5 (95% CI 22.9-24.2) per 100 person-years for patients with and without AKI, respectively. After adjustment, AKI was associated with a 27% increased risk of hypoglycemia (hazard ratio [HR] 1.27 [95% CI 1.22-1.33]). For patients with full recovery, the HR was 1.18 (95% CI 1.12-1.25); for partial recovery, the HR was 1.30 (95% CI 1.23-1.37); and for no recovery, the HR was 1.48 (95% CI 1.36-1.60) compared with patients without AKI. Across all antidiabetes drug regimens, patients with AKI experienced hypoglycemia more frequently than patients without AKI, though the incidence of hypoglycemia was highest among insulin users, followed by glyburide and glipizide users, respectively. CONCLUSIONS: AKI is a risk factor for hypoglycemia in the postdischarge period. Studies to identify risk-reduction strategies in this population are warranted.