Search

Abstract The kidney tubules constitute two-thirds of the cells of the kidney and account for the majority of the organ’s metabolic energy expenditure. Acute tubular injury (ATI) is observed across various types of kidney diseases and may significantly contribute to progression to kidney failure. Non-invasive biomarkers of ATI may allow for early detection and drug development. Using the SomaScan proteomics platform on 434 patients with biopsy-confirmed kidney disease, we here identify plasma biomarkers associated with ATI severity. We employ regional transcriptomics and proteomics, single-cell RNA sequencing, and pathway analysis to explore biomarker protein and gene expression and enriched biological pathways. Additionally, we examine ATI biomarker associations with acute kidney injury (AKI) in the Kidney Precision Medicine Project (KPMP) (n = 44), the Atherosclerosis Risk in Communities (ARIC) study (n = 4610), and the COVID-19 Host Response and Clinical Outcomes (CHROME) study (n = 268). Our findings indicate 156 plasma proteins significantly linked to ATI with osteopontin, macrophage mannose receptor 1, and tenascin C showing the strongest associations. Pathway analysis highlight immune regulation and organelle stress responses in ATI pathogenesis.

Rationale & Objective: In 2021, the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) updated the creatinine-based estimated glomerular filtration rate (eGFR) equation and removed the coefficient for race. The development and validation of this equation involved binarizing race into African American and non-African American, involving few Asian participants. This study aimed to examine the difference between the 2021 equation and the previous 2009 equation on CKD prevalence estimates in 2 Asian populations. Study Design: Observational study using 2 national surveys. Setting & Participants: Participants from the 2019 Korea National Health and Nutrition Survey and participants self-reported as Asian from the 2011-2020 US National Health and Nutrition Survey. Exposure: eGFR using 2009 and 2021 CKD-EPI creatinine equation. Outcomes: Prevalence of CKD (eGFR

Rationale & Objective: The prevalence of chronic kidney disease (CKD) is known to increase with age; however, creatinine may be a less reliable filtration marker in older adults. Few studies have investigated the prevalence and progression of CKD using different filtration markers for estimating glomerular filtration rate (GFR). Study Design: A prospective observational cohort study. Setting & Participants: 6,393 White and African American participants aged 65-100 years from the Atherosclerosis Risk in Communities Study (ARIC) at Visit 5, followed longitudinally at Visits 6 and 7. Exposure and Outcome: The eGFR was estimated either by creatinine (eGFRcr), cystatin C (eGFRcys), creatinine and cystatin C (eGFRcr-cys), or using creatinine, cystatin C, and β-2-microglobulin (eGFRcr-cys-b2m). CKD progression was defined as 30% decline in eGFR at follow-up visits. Analytical Approach: Logistic regression models, adjusted for sex, race and study center, diabetes, blood pressure, body mass index, prevalent cardiovascular disease, and heart failure. Results: At Visit 5, the mean age in the study population was 75.8 years, and the mean eGFR ranged from 71.2 to 61.2 mL/min/1.73m2 using eGFRcr or eGFRcys, respectively. The proportion with eGFR

Background Patients with atrial fibrillation and severe chronic kidney disease have higher risks of bleeding, thromboembolism, and mortality. However, optimal anticoagulant choice in these high‐risk patients remains unclear. Methods and Results Using deidentified electronic health records from the Optum Labs Data Warehouse, adults with atrial fibrillation and severe chronic kidney disease (estimated glomerular filtration rate

Introduction: The kidney failure risk equation (KFRE) estimates a person’s risk of kidney failure and has great potential utility in clinical care. Methods: We used mixed methods to explore implementation of the KFRE in nephrology clinics. Results: KFRE scores were integrated into the electronic health record at Johns Hopkins Medicine and were displayed to nephrology providers. Documentation of KFRE scores increased over time, reaching 25% of eligible outpatient nephrology clinic notes at month 11. Three providers documented KFRE scores in >75% of notes, whereas 25 documented scores in

Rationale & Objective: While urine excretion of nitrogen estimates the total protein intake, biomarkers of specific dietary protein sources have been sparsely studied. Using untargeted metabolomics, this study aimed to identify serum metabolomic markers of 6 protein-rich foods and to examine whether dietary protein–related metabolites are associated with incident chronic kidney disease (CKD). Study Design: Prospective cohort study. Setting & Participants: A total of 3,726 participants from the Atherosclerosis Risk in Communities study without CKD at baseline. Exposures: Dietary intake of 6 protein-rich foods (fish, nuts, legumes, red and processed meat, eggs, and poultry), serum metabolites. Outcomes: Incident CKD (estimated glomerular filtration rate

Abstract Progression of chronic kidney disease (CKD) portends myriad complications, including kidney failure. In this study, we analyze associations of 4638 plasma proteins among 3235 participants of the Chronic Renal Insufficiency Cohort Study with the primary outcome of 50% decline in estimated glomerular filtration rate or kidney failure over 10 years. We validate key findings in the Atherosclerosis Risk in the Communities study. We identify 100 circulating proteins that are associated with the primary outcome after multivariable adjustment, using a Bonferroni statistical threshold of significance. Individual protein associations and biological pathway analyses highlight the roles of bone morphogenetic proteins, ephrin signaling, and prothrombin activation. A 65-protein risk model for the primary outcome has excellent discrimination (C-statistic[95%CI] 0.862 [0.835, 0.889]), and 14/65 proteins are druggable targets. Potentially causal associations for five proteins, to our knowledge not previously reported, are supported by Mendelian randomization: EGFL9, LRP-11, MXRA7, IL-1 sRII and ILT-2. Modifiable protein risk markers can guide therapeutic drug development aimed at slowing CKD progression.

Abstract Eicosanoids are biologically active derivatives of polyunsaturated fatty acids with broad relevance to health and disease. We report a genome-wide association study in 8406 participants of the Atherosclerosis Risk in Communities Study, identifying 41 loci associated with 92 eicosanoids and related metabolites. These findings highlight loci required for eicosanoid biosynthesis, including FADS1-3, ELOVL2, and numerous CYP450 loci. In addition, significant associations implicate a range of non-oxidative lipid metabolic processes in eicosanoid regulation, including at PKD2L1/SCD and several loci involved in fatty acyl-CoA metabolism. Further, our findings highlight select clearance mechanisms, for example, through the hepatic transporter encoded by SLCO1B1. Finally, we identify eicosanoids associated with aspirin and non-steroidal anti-inflammatory drug use and demonstrate the substantial impact of genetic variants even for medication-associated eicosanoids. These findings shed light on both known and unknown aspects of eicosanoid metabolism and motivate interest in several gene-eicosanoid associations as potential functional participants in human disease.

Abstract Background The pathophysiological causes of kidney disease are not fully understood. Here we show that the integration of genome-wide genetic, transcriptomic, and proteomic association studies can nominate causal determinants of kidney function and damage. Results Through transcriptome-wide association studies (TWAS) in kidney cortex, kidney tubule, liver, and whole blood and proteome-wide association studies (PWAS) in plasma, we assess for effects of 12,893 genes and 1342 proteins on kidney filtration (glomerular filtration rate (GFR) estimated by creatinine; GFR estimated by cystatin C; and blood urea nitrogen) and kidney damage (albuminuria). We find 1561 associations distributed among 260 genomic regions that are supported as putatively causal. We then prioritize 153 of these genomic regions using additional colocalization analyses. Our genome-wide findings are supported by existing knowledge (animal models for MANBA, DACH1, SH3YL1, INHBB), exceed the underlying GWAS signals (28 region-trait combinations without significant GWAS hit), identify independent gene/protein-trait associations within the same genomic region (INHBC, SPRYD4), nominate tissues underlying the associations (tubule expression of NRBP1), and distinguish markers of kidney filtration from those with a role in creatinine and cystatin C metabolism. Furthermore, we follow up on members of the TGF-beta superfamily of proteins and find a prognostic value of INHBC for kidney disease progression even after adjustment for measured glomerular filtration rate (GFR). Conclusion In summary, this study combines multimodal, genome-wide association studies to generate a catalog of putatively causal target genes and proteins relevant to kidney function and damage which can guide follow-up studies in physiology, basic science, and clinical medicine.

Rationale & Objective: Biomarkers of kidney disease progression have been identified in individuals with diabetes and underlying chronic kidney disease (CKD). Whether or not these markers are associated with the development of CKD in a general population without diabetes or CKD is not well established. Study Design: Prospective observational cohort. Setting & Participants: In the Atherosclerosis Risk in Communities) study, 948 participants were studied. Exposures: The baseline plasma biomarkers of kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein-1 (MCP-1), soluble urokinase plasminogen activator receptor (suPAR), tumor necrosis factor receptor 1 (TNFR-1), tumor necrosis factor receptor 2 (TNFR-2), and human cartilage glycoprotein-39 (YKL-40) measured in 1996-1998. Outcome: Incident CKD after 15 years of follow-up defined as ≥40% estimated glomerular filtration rate decline to

Rationale & Objective: Proteomics could provide pathophysiologic insight into the increased risk of mortality in patients with chronic kidney disease (CKD). This study aimed to investigate associations between the circulating proteome and all-cause mortality among patients with CKD. Study Design: Observational cohort study. Setting & Participants: Primary analysis in 703 participants in the African American Study of Kidney Disease and Hypertension (AASK) and validation in 1,628 participants with CKD in the Atherosclerosis Risk in Communities (ARIC) study who attended visit 5. Exposure: Circulating proteins. Outcome: All-cause mortality. Analytical Approach: Among AASK participants, we evaluated the associations of 6,790 circulating proteins with all-cause mortality using multivariable Cox proportional hazards models. Proteins with significant associations were further studied in ARIC Visit 5 participants with CKD. Results: In the AASK cohort, the mean age was 54.5 years, 271 (38.5%) were women, and the mean measured glomerular filtration rate (GFR) was 46 mL/min/1.73 m2. The median follow-up was 9.6 years, and 7 distinct proteins were associated with all-cause mortality at the Bonferroni-level threshold (P

Abstract Background Proteins and metabolites are essential for many biological functions and often linked through enzymatic or transport reactions. Individual molecules have been associated with all-cause mortality. Many of these are correlated and might jointly represent pathways or endophenotypes involved in diseases. Results We present an integrated analysis of proteomics and metabolomics via a local dimensionality reduction clustering method. We identified 224 modules of correlated proteins and metabolites in the Atherosclerosis Risk in Communities (ARIC) study, a general population cohort of older adults (N = 4046, mean age 75.7, mean eGFR 65). Many of the modules displayed strong cross-sectional associations with demographic and clinical characteristics. In comprehensively adjusted analyses, including fasting plasma glucose, history of cardiovascular disease, systolic blood pressure and kidney function among others, 60 modules were associated with mortality. We transferred the network structure to the African American Study of Kidney Disease and Hypertension (AASK) (N = 694, mean age 54.5, mean mGFR 46) and identified mortality associated modules relevant in this disease specific cohort. The four mortality modules relevant in both the general population and CKD were all a combination of proteins and metabolites and were related to diabetes / insulin secretion, cardiovascular disease and kidney function. Key components of these modules included N-terminal (NT)-pro hormone BNP (NT-proBNP), Sushi, Von Willebrand Factor Type A, EGF And Pentraxin (SVEP1), and several kallikrein proteases. Conclusion Through integrated biomarkers of the proteome and metabolome we identified functions of (patho-) physiologic importance related to diabetes, cardiovascular disease and kidney function.

Abstract Objective Newer antidiabetic medications such as sodium‐glucose co‐transporter 2 inhibitors (SGLT2i) and glucagon‐like peptide 1 receptor agonists (GLP1RA) result in weight loss in clinical trials. However, the real‐world effectiveness remains unclear. The magnitude of weight change associated with antidiabetic medication using real‐world data was examined. Methods Patients with diabetes who initiated SGLT2i (n = 906), GLP1RA (n = 782), dipeptidyl peptidase‐4 inhibitors (DPP4i, n = 1881), or sulfonylureas (n = 3255) in Geisinger Health System were identified. Outcomes were percent weight change per year and time to 5% weight loss. Propensity scores were used to account for differences across groups. Results The mean ± SD age of patients was 57.5 ± 14.1 years, 3381 (49.5%) were female, and 6450 (94.5%) had body mass index ≥25 kg/m2. Compared with sulfonylureas, newer antidiabetic medications were associated with significant weight loss (−3.2% [95% confidence interval: −3.8%, −2.6%] per year for SGLT2i; −2.9% [−3.6%, −2.3%] per year for GLP1RA; and −1.7% [−2.1%, −1.3%] per year for DPP4i). SGLT2i and GLP1RA were also associated with significant weight loss compared with DPP4i. Among patients with overweight or obesity, SGLT2i and GLP1RA users were more likely to achieve 5% weight loss compared with sulfonylureas and DPP4i. Conclusions In real‐world practice, SGLT2i and GLP1RA were associated with significant weight loss compared with sulfonylureas and DPP4i. These results may further motivate uptake of SGLT2i and GLP1RA, especially among patients who were overweight or had obesity.

BACKGROUND Metabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into disease pathogenesis.METHODS We examined the association between blood metabolites and CKD progression, defined as the subsequent development of end-stage renal disease (ESRD) or estimated glomerular filtrate rate (eGFR) halving, in 1,773 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, 962 participants of the African-American Study of Kidney Disease and Hypertension (AASK), and 5,305 participants of the Atherosclerosis Risk in Communities (ARIC) study.RESULTS In CRIC, more than half of the measured metabolites were associated with CKD progression in minimally adjusted Cox proportional hazards models, but the number and strength of associations were markedly attenuated by serial adjustment for covariates, particularly eGFR. Ten metabolites were significantly associated with CKD progression in fully adjusted models in CRIC; 3 of these metabolites were also significant in fully adjusted models in AASK and ARIC, highlighting potential markers of glomerular filtration (pseudouridine), histamine metabolism (methylimidazoleacetate), and azotemia (homocitrulline). Our findings also highlight N-acetylserine as a potential marker of kidney tubular function, with significant associations with CKD progression observed in CRIC and ARIC.CONCLUSION Our findings demonstrate the application of metabolomics to identify potential biomarkers and causal pathways in CKD progression.FUNDING This study was supported by the NIH (U01 DK106981, U01 DK106982, U01 DK085689, R01 DK108803, and R01 DK124399).

Rationale & Objective: Novel metabolite biomarkers of kidney failure with replacement therapy (KFRT) may help identify people at high risk for adverse kidney outcomes and implicated pathways may aid in developing targeted therapeutics. Study Design: Prospective cohort. Setting & Participants: The cohort included 3,799 Atherosclerosis Risk in Communities study participants with serum samples available for measurement at visit 1 (1987-1989). Exposure: Baseline serum levels of 318 metabolites. Outcomes: Incident KFRT, kidney failure (KFRT, estimated glomerular filtration rate

Background Diltiazem, a moderate cytochrome P450 3A4 isozyme/P‐glycoprotein inhibitor, may potentiate the bleeding risk of direct oral anticoagulants (DOACs) through pharmacokinetic interactions. We evaluated the association between concomitant use of diltiazem with DOACs and bleeding among patients with atrial fibrillation, across varying degrees of kidney function. Methods and Results We identified 4544 patients with atrial fibrillation who were initiated on rivaroxaban (n=1583), apixaban (n=2373), or dabigatran (n=588), between 2010 and 2019 in Geisinger Health, with a mean age of 72 years and an estimated glomerular filtration rate of 70 mL/min per 1.73 m2. At the time of DOAC initiation, 15% patients were taking diltiazem and an additional 5% were initiated on diltiazem during follow‐up. Among DOAC users, using diltiazem concurrently (versus DOAC alone) was associated with an increased risk of any bleeding‐related hospitalization (unadjusted risk difference, 2.4; 95% CI, 0.6–4.2 events per 100 person‐years; adjusted hazard ratio, 1.56, 95% CI, 1.15–2.12), as well as major bleeding (unadjusted risk difference, 1.4 [95% CI, 0.1–2.6 events per 100 person‐years]; adjusted hazard ratio, 1.84 [95% CI, 1.18–2.85]). Increased risk of any/major bleeding with diltiazem was observed in both patients with and without CKD (estimated glomerular filtration rate

Summary: Background: The Endocrine Society Clinical Practice Guidelines recommend the avoidance of medications that may cause weight gain (i.e., obesogenic medications) in individuals with overweight or obesity. Obesity disproportionately affects people with lower socioeconomic status (SES); however, it is unknown whether the use of obesogenic medications differs by SES. Methods: We included adults with overweight or obesity and used prescription medications from 2009-2018 of the US National Health and Nutrition Examination Survey. We examined the associations between a composite measure of SES and use of obesogenic medications and anti-obesity medications. The composite SES included

Uromodulin (UMOD) is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is highly abundant in urine and related to chronic kidney disease, hypertension, and pathogen defense. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin using complementary antibody-based and aptamer-based assays. We detected 3 and 10 distinct significant loci, respectively. Integration of antibody-based results at the UMOD locus with functional genomics data (RNA-Seq, ATAC-Seq, Hi-C) of primary human kidney tissue highlighted an upstream variant with differential accessibility and transcription in uromodulin-synthesizing kidney cells as underlying the observed cis effect. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same pathway as UMOD. Experimental validation of the third antibody-based locus, B4GALNT2, showed that the p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase had a loss-of-function effect leading to higher serum uromodulin levels. Aptamer-based results pointed to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation, suggesting that this assay permits investigating uromodulin’s complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions.

Rationale & Objective: With a growing number of medications and therapies available to treat chronic kidney disease (CKD), risk-versus-benefit discussions are increasingly critical. Balancing risks and benefits requires assessing patients’ understanding of these, as well as incorporating patient preferences and tolerance for side effects into shared decision making. Study Design: A 26-question online survey was sent to people in the National Kidney Foundation patient email list and posted on associated social media pages to assess the respondents’ willingness and comfort with taking preventative medications during earlier-stage CKD to inform a December 2020 scientific workshop co-sponsored by the National Kidney Foundation and the US Food and Drug Administration on clinical trial considerations in developing treatments for individuals with early stages of CKD. Setting & Population: Online survey of CKD patients, including broad demographic data and responses to risk-benefit scenarios, with surveys emailed to 20,249 people not identified as currently receiving kidney replacement therapy. Analytical Approach: Survey results are presented as descriptive data. Results: Of 1,029 respondents, 45 self-identified as at risk for CKD, 566 had CKD, 267 had received kidney transplants, 51 were receiving dialysis, and 100 replied other or did not answer. Respondents reported being willing to assume some risk with the goal of preventing the progression of CKD, with a greater willingness to assume risk and treatment burdens the closer they came to late-stage disease. Clinician recommendations regarding kidney therapies and clinician willingness to work with patients to address any side effects were important in respondents’ willingness to initiate and persevere with a new medication. Limitations: Approximately 10% response rate with limited data on respondents. Conclusions: Risk-versus-benefit discussions appear key to patients and their care partners making well-informed decisions about taking a new medication that may or may not help the progression of their kidney disease. Future tools and strategies are needed to facilitate informed discussions of treatment in early-stage kidney disease.

Introduction: South Africa has the highest prevalence of HIV in the world. The epidemiology of kidney disease among people with HIV infections is well-described in the United States. However, there are limited data coming from South Africa, particularly that involve kidney biopsies. The purpose of this study was to determine what, if any, patient factors are predictive of HIV-associated nephropathy (HIVAN) on kidney biopsy in a South African kidney biopsy cohort. Methods: This study prospectively collected data of all patients infected with HIV referred to the Groote Schuur Hospital (GSH) renal unit for a kidney biopsy from 2002 to 2018. Results: There were 419 patients included in the study. Mean age was 36.5 years (SD, 9.4); 219 (52.3%) were women; and all were black. Seventy-nine patients (18.9%) were on dialysis at the time of biopsy; the mean estimated glomerular filtration rate among the remainder was 41.4 ml/min per 1.73 m2 (SD, 39.2). Only 163 patients (47.1%) were known to be taking antiretroviral therapy (ART) at the time of biopsy. There were 246 (58.7%) cases of HIVAN detected, and they were comparable on age, sex, kidney function, and kidney size to those with kidney disease of other causes but were less likely to be taking ART (P < 0.001). Biopsy confirmed HIVAN was associated with mortality (adjusted hazard ratio, 1.77; 95% confidence interval [CI]: 1.07–2.91; P = 0.025), and the use of ART at biopsy was protective (adjusted hazard ratio, 0.52; 95% CI, 0.32–0.84, P = 0.008). The proportion of HIVAN on biopsy decreased and the proportion taking ART increased from 2002 to 2018 (P for trend for both < 0.001). Conclusion: In summary, HIVAN was the most common etiology of kidney disease in this biopsy cohort from South Africa; however, the proportion with biopsy-proven HIVAN declined over time, perhaps in the setting of greater ART availability.

Rationale & Objective: Retinopathy and chronic kidney disease (CKD) are typically considered microvascular complications of diabetes, and cardiovascular and cerebrovascular diseases are considered macrovascular complications; however, all may share common pathological mechanisms. This study quantified the association of retinopathy with risk of kidney disease and compared with the association with cardiovascular disease in persons with diabetes. Study Design: Retrospective cohort study. Setting & Participants: 1,759 participants in the ARIC study who had diabetes at visit 4 and underwent retinal examination at visit 3. Exposure: Retinopathy. Outcome: Prevalent CKD (estimated glomerular filtration rate [eGFR] 30 mg/g), incident CKD, incident end-stage kidney disease (ESKD), incident coronary heart disease (CHD), and incident stroke. Analytical Approach: The cross-sectional association of retinopathy with prevalent CKD and albuminuria was assessed by logistic regression. The associations between retinopathy, incident CKD, incident ESKD, incident CHD, and incident stroke were examined using Cox proportional hazards models. Seemingly unrelated regression was used to compare the strength of association between retinopathy and outcomes. Results: During the median follow-up period of 14.2 years, 723 participants developed CKD, and there were 109 ESKD events, 399 CHD events, and 196 stroke events. Compared with the participants without retinopathy, participants with retinopathy were more likely to have reduced eGFR (OR, 1.56 [95% CI, 1.09-2.23]) and UACR > 30 mg/g (OR, 1.61 [95% CI, 1.24-2.10]). Retinopathy was associated with risk of incident CKD (HR, 1.22 [95% CI, 1.02-1.46]), ESKD (HR, 1.69 [95% CI, 1.11-2.58]), CHD (HR, 1.46 [95% CI, 1.15-1.84]), and stroke (HR, 1.43 [95% CI, 1.03-1.97]). A stronger relationship was found between retinopathy and CHD when compared with retinopathy and CKD (P = 0.03); all other associations were similar. Limitations: Retinal examination and kidney measurements were taken at different visits. Conclusions: The presence of retinopathy was associated with higher prevalence of kidney disease and higher risk of incident CKD, ESKD, and CHD. These results may suggest that a similar mechanism underlies the development of retinopathy and other adverse outcomes in diabetes.

Rationale & Objective: Evaluation of glomerular filtration rate (GFR) is challenging in adults undergoing bariatric surgery because creatinine and cystatin C levels are influenced by changes in muscle and fat mass. Additionally, indexing of GFR by body surface area (BSA) may by affected by decreases in BSA. Study Design: Prospective observational study. Setting & Participants: 27 adults with body mass index (BMI) ≥ 35 kg/m2 who underwent measurement of GFR before and after bariatric surgery. Outcomes: Indexed and nonindexed GFRs measured (mGFRs) using plasma iohexol clearance, indexed and nonindexed estimated GFR (eGFR) based on levels of creatinine, cystatin C, or both from Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. Analytic Approach: Bias and percent of estimates within 20% and 30% of mGFR (P20 and P30) for estimating equations were examined. Results: Mean presurgery BMI was 49.5 (SD, 9.4) kg/m2, BSA was 2.42 (SD, 0.27) m2, nonindexed mGFR was 117.3 (SD, 34.1) mL/min, and indexed mGFR was 84.1 (SD, 22.0) mL/min/1.73 m2. After 6 months, mean BMI changed by –13.8 (95% CI, −15.9 to −11.8) kg/m2, BSA by −0.30 (95% CI, −0.33 to −0.27) m2, and nonindexed mGFR by −9.2 (95% CI, −17.2 to −1.1) mL/min, while indexed mGFR was unchanged at 5.1 (95% CI, −0.1 to 10.4) mL/min/1.73 m2. Nonindexed eGFRcr was unbiased (median bias, 5.0 [95% CI, −4.3 to 11.6] mL/min) before surgery, but overestimated mGFR (8.8 [95% CI, 1.8 to 16.9] mL/min) after surgery. Nonindexed eGFRcys underestimated mGFR before (median bias, −12.1 [95% CI, −21.4 to −1.2] mL/min) and after surgery (−11.2 [95% CI, −21.8 to −7.3] mL/min). Nonindexed eGFRcr-cys was unbiased before (median bias, −6.0 [95% CI, −11.0 to 1.0] mL/min) and after surgery (−2.0 [95% CI, −8.8 to 4.9] mL/min). Findings were similar for indexed eGFR compared with indexed mGFR. Limitations: Small, mostly white sample. Conclusions: Changes in indexed and nonindexed GFRs may be discordant after bariatric surgery in adults because of decreases in BSA. Indexed and nonindexed eGFRcr-cys may be less biased than indexed or nonindexed eGFRcr or eGFRcys because of opposite biases in estimating mGFR.

Background: Chronic kidney disease (CKD) measures (estimated glomerular filtration rate [eGFR] and albuminuria) are frequently assessed in clinical practice and improve the prediction of incident cardiovascular disease (CVD), yet most major clinical guidelines do not have a standardized approach for incorporating these measures into CVD risk prediction. “CKD Patch” is a validated method to calibrate and improve the predicted risk from established equations according to CKD measures. Methods: Utilizing data from 4,143,535 adults from 35 datasets, we developed several “CKD Patches” incorporating eGFR and albuminuria, to enhance prediction of risk of atherosclerotic CVD (ASCVD) by the Pooled Cohort Equation (PCE) and CVD mortality by Systematic COronary Risk Evaluation (SCORE). The risk enhancement by CKD Patch was determined by the deviation between individual CKD measures and the values expected from their traditional CVD risk factors and the hazard ratios for eGFR and albuminuria. We then validated this approach among 4,932,824 adults from 37 independent datasets, comparing the original PCE and SCORE equations (recalibrated in each dataset) to those with addition of CKD Patch. Findings: We confirmed the prediction improvement with the CKD Patch for CVD mortality beyond SCORE and ASCVD beyond PCE in validation datasets (Δc-statistic 0.027 [95% CI 0.018–0.036] and 0.010 [0.007–0.013] and categorical net reclassification improvement 0.080 [0.032–0.127] and 0.056 [0.044–0.067], respectively). The median (IQI) of the ratio of predicted risk for CVD mortality with CKD Patch vs. the original prediction with SCORE was 2.64 (1.89–3.40) in very high-risk CKD (e.g., eGFR 30–44 ml/min/1.73m2 with albuminuria ≥30 mg/g), 1.86 (1.48–2.44) in high-risk CKD (e.g., eGFR 45–59 ml/min/1.73m2 with albuminuria 30–299 mg/g), and 1.37 (1.14–1.69) in moderate risk CKD (e.g., eGFR 60–89 ml/min/1.73m2 with albuminuria 30–299 mg/g), indicating considerable risk underestimation in CKD with SCORE. The corresponding estimates for ASCVD with PCE were 1.55 (1.37–1.81), 1.24 (1.10–1.54), and 1.21 (0.98–1.46). Interpretation: The “CKD Patch” can be used to quantitatively enhance ASCVD and CVD mortality risk prediction equations recommended in major US and European guidelines according to CKD measures, when available. Funding: US National Kidney Foundation and the NIDDK.

Introduction: Patients with chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR)

Genome-wide association studies of kidney function show enrichment of associated genetic variants in regulatory regions. Here, the authors perform epigenome-wide association studies of kidney function and disease, identifying 19 CpG sites significantly associated with these.

Widely regarded as safe and effective, PPIs are among the most commonly used medications in the world today. However, a spate of observational studies suggest an association between PPI use and adverse events, including infection, bone fracture, and dementia. This review details evidence linking the use of PPI therapy to the development of kidney disease, including early case reports of acute interstitial nephritis and subsequent large observational studies of AKI, CKD, and ESRD. The majority of studies showed higher risk of kidney outcomes among persons prescribed PPI medications, with effect sizes that were slightly higher for AKI (∼2- to 3-fold) compared with CKD and ESRD (1.2- to 1.8-fold). Although observational pharmacoepidemiology studies are limited by the possibility of residual confounding and confounding by indication, many of the described studies conducted rigorous sensitivity analyses aimed at minimizing these biases, including new-user design, comparison to similar agents (e.g., histamine2 receptor antagonists), and evaluation for a dose response, with robust results. Given the widespread use of PPIs, even a small effect on kidney outcomes could result in large public health burden. Timely cessation of PPI therapy when there is no clear indication for use might reduce the population burden of kidney disease.

The prevalence of severe obesity in both the general and the chronic kidney disease (CKD) populations continues to rise, with more than one-fifth of CKD patients in the United States having a body mass index of ≥35 kg/m2. Severe obesity has significant renal consequences, including increased risk of end-stage renal disease (ESRD) and nephrolithiasis. Bariatric surgery represents an effective method for achieving sustained weight loss, and evidence from randomized controlled trials suggests that bariatric surgery is also effective in improving blood pressure, reducing hyperglycemia, and even inducing diabetes remission. There is also observational evidence suggesting that bariatric surgery may diminish the long-term risk of kidney function decline and ESRD. Bariatric surgery appears to be relatively safe in patients with CKD, with postoperative complications only slightly higher than in the general bariatric surgery population. The use of bariatric surgery in patients with CKD might help prevent progression to ESRD or enable selected ESRD patients with severe obesity to become candidates for kidney transplantation. However, there are also renal risks in bariatric surgery, namely, acute kidney injury, nephrolithiasis, and, in rare cases, oxalate nephropathy, particularly in types of surgery involving higher degrees of malabsorption. Although bariatric surgery may improve long-term kidney outcomes, this potential benefit remains unproved and must be balanced with potential adverse events.

Background There are no available lifetime risk estimates of lower‐extremity peripheral artery disease (PAD). Methods and Results Using data from 6 US community‐based cohorts and the vital statistics, we estimated the prevalence and incidence of PAD, defined as an ankle‐brachial index

Background In patients with myocardial infarction (MI), reduced kidney function is recognized as an important predictor of poor prognosis, but the impact of albuminuria, a representative measure of kidney damage, has not been extensively evaluated. Methods and Results In the SCREAM (Stockholm Creatinine Measurements) project (2006–2012), we identified 2469 patients with incident MI with dipstick proteinuria measured within a year before MI (427 patients also had urine albumin to creatinine ratio [ACR] measured concurrently) and obtained estimates for ACR with multiple imputation in participants with data solely on dipstick proteinuria. We quantified the association of ACR with the post‐MI composite and individual outcomes of all‐cause mortality, cardiovascular mortality, recurrent MI, ischemic stroke, or heart failure using Cox models and then evaluated the improvement in C statistic. During a median follow‐up of 1.0 year after MI, 1607 participants (65.1%) developed the post‐MI composite outcome. Higher ACR levels were independently associated with all outcomes except for ischemic stroke. Per 8‐fold higher ACR (eg, 40 versus 5 mg/g), the hazard ratio of composite outcome was 1.21 (95% CI, 1.08–1.35). The addition of the ACR improved the C statistic of the post‐MI composite by 0.040 (95% CI, 0.030–0.051). Largely similar results were obtained regardless of diabetic status and when ACR or dipstick was separately analyzed without imputation. Conclusions In patients with MI, albuminuria was a potent predictor of subsequent outcomes, suggesting the importance of paying attention to the information on albuminuria, in addition to kidney function, in this high‐risk population.

BackgroundAlthough hypokalemia has been viewed as a significant concern among patients with heart failure (HF), recent advances in HF management tend to increase the risk of hyperkalemia.ObjectiveTo characterize contemporary data regarding correlates and prognostic values of dyskalemia in patients with HF.Design, setting, and participantsIn cross-sectional and longitudinal analyses, we studied 142,087 patients with newly diagnosed HF in US nationwide Veterans Administration database from 2005 through 2013.ExposuresDemographic characteristics, laboratory variables, comorbidities, and medication use for the analysis of correlates of dyskalemia as well as potassium level in the analysis of mortality.Main outcomes and measuresDyskalemia and mortality.ResultsHypokalemia (50% of measurements), intermittent (>1 occurrence but ≤50%), and transient (1 occurrence) hypo- and hyperkalemia were also related to increased mortality in a graded fashion regardless of the aforementioned thresholds for dyskalemia. These dyskalemic patterns were also related to other clinical actions and demands such as emergency room visit.ConclusionsPotassium levels below 4 mmol/L and above 5 mmol/L at and after HF diagnosis were associated with poor prognosis and the clinical actions. HF patients (particularly with risk factors for dyskalemia like black race and kidney dysfunction) may require special attention for both hypo- and hyperkalemia.