Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD.

Modification of Association of Cystatin C With Kidney and Cardiovascular Outcomes by Obesity.

RATIONALE & OBJECTIVE: Cystatin C-based estimated glomerular filtration rate (eGFRcys) has stronger associations with adverse clinical outcomes than creatinine-based eGFR (eGFRcr). Obesity may be associated with higher cystatin C levels, independent of kidney function, but it is unknown whether obesity modifies associations of eGFRcys with kidney and cardiovascular outcomes. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 27,249 US adults in the Reasons for Geographic and Racial Differences in Stroke Study. PREDICTORS: eGFRcys, eGFRcr, waist circumference, and body mass index (BMI). OUTCOME: All-cause mortality, kidney failure, incident atherosclerotic cardiovascular disease (ASCVD), and incident heart failure (HF). ANALYTICAL APPROACH: Multivariable Cox and Fine-Gray models with multiplicative interaction terms were constructed to investigate whether waist circumference quartiles or BMI categories modified associations of eGFRcys with risks of 4 clinical outcomes. RESULTS: Participants had a mean age of 65 years; 54% were women, 41% were Black, and 21% had an eGFRcys<60mL/min/1.73m2. The baseline prevalence of abdominal obesity (waist circumference≥88cm for women or≥102cm for men) was 48% and obesity was 38%. In multivariable adjusted analyses, each 15mL/min/1.73m2 lower eGFRcys was associated with higher HR and 95% CI of mortality in each waist circumference quartile (first quartile, 1.19 [1.15-1.24]; second quartile, 1.22 [1.18-1.26]; third quartile, 1.20 [1.16-1.24]; fourth quartile, 1.19 [1.15-1.23]) as well as within each BMI category (BMI<24.9: 1.21 [1.17-1.25]; BMI 25.0-29.9: 1.21 [1.18-1.25]; BMI 30.0-34.9: 1.20 [1.16-1.25]; BMI≥35: 1.17, [1.12-1.22]). Neither waist circumference nor BMI modified the association of eGFRcys with mortality, kidney failure, incident ASCVD, or incident HF (all Pinteraction>0.05). LIMITATIONS: Included only Black and White persons in the United States. CONCLUSION: Obesity did not modify the association of eGFRcys with all-cause mortality, kidney failure, incident ASCVD, or incident HF. Among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes. PLAIN-LANGUAGE SUMMARY: Cystatin C is increasingly used in clinical practice to estimate kidney function, and cystatin C-based eGFR (eGFRcys) may be used to determine risk for adverse clinical outcomes. Adiposity may increase serum levels of cystatin C, independent of kidney function. This cohort study investigated whether associations of eGFRcys with adverse kidney and cardiovascular outcomes are modified by measures of obesity, waist circumference, and body mass index. We found that obesity does not modify associations of eGFRcys with 4 clinical outcomes and conclude that among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes.

Tubule dysfunction and injury and future risk of sepsis-associated acute kidney injury.

BACKGROUND: Novel biomarkers can quantify both kidney tubule function, including proximal tubule reabsorptive (urine α-1 microglobulin (uα1m)) and tubule protein synthesis capacities (urine uromodulin (uUMOD)), and tubular injury (urine neutrophil gelatinase-associated lipocalin (uNGAL)). In a blood pressure trial, we reported that lower reabsorptive and synthetic protein capacity at times of health predicted future risk of acute kidney injury (AKI), but most AKI was related to hemodynamic causes in this trial. Associations between tubular function and injury and future AKI related to other causes is unknown. MATERIALS AND METHODS: We performed a case-control study in REGARDS, a population-based cohort study, among participants who provided urine at the baseline visit. We matched each septic AKI case by age, sex, race, and time from baseline to hospital admission 1 : 1 to a participant with sepsis who did not develop AKI (controls). Using conditional logistic regression, we evaluated the associations of uα1m, uUMOD, urine ammonium, and uNGAL with septic AKI. RESULTS: Mean age was 69 ± 8 years, 44% were female, and 39% were Black participants. Median baseline eGFR among cases and controls was 73 (55, 90) and 82 (65, 92) mL/min/1.73m2, and median albuminuria was 19 (8, 87) vs. 9 (5, 22) mg/g, respectively. No independent associations were observed between the tubule function or injury markers and subsequent risk of septic AKI once models were adjusted for baseline albuminuria, estimated glomerular filtration rate, and other risk factors. CONCLUSION: Among community participants, tubule function and injury markers at times of health were not independently associated with future risk of septic AKI.

Optimal Care for Kidney Health: Development of a Merit-based Incentive Payment System (MIPS) Value Pathway.

The Merit-based Incentive Payment System (MIPS) is a mandatory pay-for-performance program through the Centers for Medicare & Medicaid Services (CMS) that aims to incentivize high-quality care, promote continuous improvement, facilitate electronic exchange of information, and lower health care costs. Previous research has highlighted several limitations of the MIPS program in assessing nephrology care delivery, including administrative complexity, limited relevance to nephrology care, and inability to compare performance across nephrology practices, emphasizing the need for a more valid and meaningful quality assessment program. This article details the iterative consensus-building process used by the American Society of Nephrology Quality Committee from May 2020 to July 2022 to develop the Optimal Care for Kidney Health MIPS Value Pathway (MVP). Two rounds of ranked-choice voting among Quality Committee members were used to select among nine quality metrics, 43 improvement activities, and three cost measures considered for inclusion in the MVP. Measure selection was iteratively refined in collaboration with the CMS MVP Development Team, and new MIPS measures were submitted through CMS's Measures Under Consideration process. The Optimal Care for Kidney Health MVP was published in the 2023 Medicare Physician Fee Schedule Final Rule and includes measures related to angiotensin-converting enzyme inhibitor and angiotensin receptor blocker use, hypertension control, readmissions, acute kidney injury requiring dialysis, and advance care planning. The nephrology MVP aims to streamline measure selection in MIPS and serves as a case study of collaborative policymaking between a subspecialty professional organization and national regulatory agencies.

Predicting pediatric kidney disease progression-are 3 variables all you need?

Accurate estimation of chronic kidney disease (CKD) progression risk is vital for clinical decision-making. Existing risk equations lack validation in pediatric CKD populations. Ng et al. developed new risk equations using the CKD in Children and European Study Consortium for Chronic Kidney Disorders Affecting Pediatric Patients cohorts. The elementary model, incorporating estimated glomerular filtration rate, urine protein-creatinine ratio, and diagnosis, exhibited excellent discrimination and calibration at external validation. External validation of enriched models is pending. The equations have the potential to aid pediatric CKD centers in patient counseling and care planning.

A genomic deep field view of hypertension.

Blood pressure is regulated by a complex neurohumoral system including the renin-angiotensin-aldosterone system, natriuretic peptides, endothelial pathways, the sympathetic nervous system, and the immune system. This review charts the evolution of our understanding of the genomic basis of hypertension at increasing resolution over the last 5 decades from monogenic causes to polygenic associations, spanning ∼30 monogenic rare variants and >1500 single nucleotide variants. Unexpected early wins from blood pressure genomics include deepening of our understanding of the complex causation of hypertension; refinement of causal estimates bidirectionally between blood pressure, risk factors, and outcomes through Mendelian randomization; risk stratification using polygenic risk scores; and opportunities for precision medicine and drug repurposing.

Uromodulin: more than a marker for chronic kidney disease progression.

PURPOSE OF REVIEW: Uromodulin, a protein that is highly conserved across several species through evolution, functions to maintain homeostasis and prevent disease development and progression. Historically, the role of uromodulin has been thought to be limited to the kidney and genitourinary tract. This review highlights developments indicating a broader role of uromodulin in human health. RECENT FINDINGS: Although initially discovered in the urine and found to have immunomodulatory properties, recent findings indicate that serum uromodulin (sUMOD) is distinct from urine uromodulin (uUMOD) in its structure, function, and regulation. uUMOD binds pathogenic bacteria in the urine preventing infection and is also upregulated in kidneys undergoing repair after injury. Uromodulin knockout mice exhibit higher mortality in the setting of sepsis which is also associated with upregulation of sUMOD. sUMOD lowers calcification risk but this may be influenced by presence of kidney disease. SUMMARY: Uromodulin is an evolutionarily conserved protein produced exclusively in the kidney tubule cells with evolving roles being reported both in the kidney and systemically. Further research should be focused at harnessing its use as a potential therapeutic.

The Impact of a Wearable Activity Tracker and Structured Feedback Program on Physical Activity in Hemodialysis Patients: The Step4Life Pilot Randomized Controlled Trial.

RATIONALE & OBJECTIVE: People with end-stage kidney disease (ESKD) have very low physical activity, and the degree of inactivity is strongly associated with morbidity and mortality. We assessed the feasibility and effectiveness of a 12-week intervention coupling a wearable activity tracker (FitBit) and structured feedback coaching versus wearable activity tracker alone on changes in physical activity in hemodialysis patients. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: 55 participants with ESKD receiving hemodialysis who were able to walk with or without assistive devices recruited from a single academic hemodialysis unit between January 2019 and April 2020. INTERVENTIONS: All participants wore a Fitbit Charge 2 tracker for a minimum of 12 weeks. Participants were randomly assigned 1:1 to a wearable activity tracker plus a structured feedback intervention versus the wearable activity tracker alone. The structured feedback group was counseled weekly on steps achieved after randomization. OUTCOME: The outcome was step count, and the main parameter of interest was the absolute change in daily step count, averaged per week, from baseline to completion of 12 weeks intervention. In the intention-to-treat analysis, mixed-effect linear regression analysis was used to evaluate change in daily step count from baseline to 12-weeks in both arms. RESULTS: Out of 55 participants, 46 participants completed the 12-week intervention (23 per arm). The mean age was 62 (± 14 SD) years; 44% were Black, and 36% were Hispanic. At baseline, step count (structured feedback intervention: 3,704 [1,594] vs wearable activity tracker alone: 3,808 [1,890]) and other participant characteristics were balanced between the arms. We observed a larger change in daily step count in the structured feedback arm at 12 weeks relative to use of the wearable activity tracker alone arm (Δ 920 [±580 SD] versus Δ 281 [±186 SD] steps; between-group difference Δ 639 [±538 SD] steps; P<0.05). LIMITATIONS: Single-center study and small sample size. CONCLUSION: This pilot randomized controlled trial demonstrated that structured feedback coupled with a wearable activity tracker led to a greater daily step count that was sustained over 12 weeks relative to a wearable activity tracker alone. Future studies are required to determine longer-term sustainability of the intervention and potential health benefits in hemodialysis patients. FUNDING: Grants from industry (Satellite Healthcare) and government (National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT05241171.

Changes in Natriuretic Peptide Levels and Subsequent Kidney Function Decline in SPRINT.

RATIONALE & OBJECTIVE: Novel approaches to the assessment of kidney disease risk during hypertension treatment are needed because of the uncertainty of how intensive blood pressure (BP) lowering impacts kidney outcomes. We determined whether longitudinal N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements during hypertension treatment are associated with kidney function decline. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 8,005 SPRINT (Systolic Blood Pressure Intervention Trial) participants with NT-proBNP measurements at baseline and 1 year. EXPOSURE: 1-year change in NT-proBNP categorized as a ≥25% decrease, ≥25% increase, or <25% change (stable). OUTCOME: Annualized change in estimated glomerular filtration rate (eGFR) and ≥30% decrease in eGFR. ANALYTICAL APPROACH: Linear mixed-effect and logistic regression models were used to evaluate the association of changes in NT-proBNP with subsequent annualized change in eGFR and ≥30% decrease in eGFR, respectively. Analyses were stratified by baseline chronic kidney disease (CKD) status. RESULTS: Compared with stable 1-year NT-proBNP levels, a ≥25% decrease in NT-proBNP was associated with a slower decrease in eGFR in participants with CKD (adjusted difference, 1.09%/y; 95% CI, 0.35-1.83) and without CKD (adjusted difference, 0.51%/y; 95% CI, 0.21-0.81; P = 0.4 for interaction). Meanwhile, a ≥25% increase in NT-proBNP in participants with CKD was associated with a faster decrease in eGFR (adjusted difference, -1.04%/y; 95% CI, -1.72 to -0.36) and risk of a ≥30% decrease in eGFR (adjusted odds ratio, 1.44; 95% CI, 1.06-1.96); associations were stronger in participants with CKD than in participants without CKD (P = 0.01 and P < 0.001 for interaction, respectively). Relationships were similar irrespective of the randomized BP arm in SPRINT (P > 0.2 for interactions). LIMITATIONS: Persons with diabetes and proteinuria >1 g/d were excluded. CONCLUSIONS: Changes in NT-proBNP during BP treatment are independently associated with subsequent kidney function decline, particularly in people with CKD. Future studies should assess whether routine NT-proBNP measurements may be useful in monitoring kidney risk during hypertension treatment. PLAIN-LANGUAGE SUMMARY: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker in the blood that reflects mechanical stress on the heart. Measuring NT-proBNP may be helpful in assessing the risk of long-term losses of kidney function. In this study, we investigated the association of changes in NT-proBNP with subsequent kidney function among individuals with and without chronic kidney disease. We found that increases in NT-proBNP are associated with a faster rate of decline of kidney function, independent of baseline kidney measures. The associations were more pronounced in individuals with chronic kidney disease. Our results advance the notion of considering NT-proBNP as a dynamic tool for assessing kidney disease risk.

Association of clinical characteristics with urine uromodulin in children with chronic kidney disease.

BACKGROUND: Uromodulin is the most abundant protein in the urine of healthy adults, and higher urine concentrations mark better tubular health. Greater kidney size and function are predictors of higher uromodulin levels in adults. Urine uromodulin has not yet been studied in children with chronic kidney disease (CKD). Thus, we sought to determine the relationship between age and kidney function with urine uromodulin levels in children with CKD. METHODS: In the CKD in Children (CKiD) cohort, we utilized multivariable linear regression to evaluate the relationship of age and eGFR with urine uromodulin levels. The primary outcome was uromodulin indexed to urine creatinine (Umod/Cr, mg/g), which was log2-transformed given its skewed distribution. RESULTS: Among 677 CKiD participants, the median age was 11.8 years (8.2-15.3), the median eGFR was 49 ml/min/1.73 m2 (37-63), the etiology of CKD was glomerular disease in 31%, and the median Umod/Cr level was 0.114 mg/g (0.045-0.226). In the multivariable models, each one-year older age was associated with 0.18 (12%) lower log2(Umod/Cr) and 0.20 (13%) lower log2(Umod/Cr) among those with non-glomerular and glomerular disease, respectively (p < 0.001). However, we did not find a statistically significant association between eGFR and Umod/Cr in either participants with non-glomerular or glomerular disease (p = 0.13 and p = 0.58, respectively). CONCLUSIONS: Among children with CKD, older age is significantly associated with lower Umod/Cr, independent of eGFR. Further studies are needed to comprehensively evaluate age-specific reference ranges for urine uromodulin and to evaluate the longitudinal relationship of uromodulin with both age and eGFR in children with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Markers of Kidney Tubular Secretion and Risk of Adverse Events in SPRINT Participants with CKD.

BACKGROUND: Kidney tubular secretion is an essential mechanism for clearing many common antihypertensive drugs and other metabolites and toxins. It is unknown whether novel measures of tubular secretion are associated with adverse events (AEs) during hypertension treatment. METHODS: Among 2089 SPRINT (Systolic Blood Pressure Intervention Trial) participants with baseline eGFR <60 ml/min per 1.73 m2, we created a summary secretion score by averaging across the standardized spot urine-to-plasma ratios of ten novel endogenous tubular secretion measures, with lower urine-to-plasma ratios reflecting worse tubular secretion. Multivariable Cox proportional hazards models were used to evaluate associations between the secretion score and risk of a composite of prespecified serious AEs (hypotension, syncope, bradycardia, AKI, electrolyte abnormalities, and injurious falls). The follow-up protocol for SPRINT routinely assessed two laboratory monitoring AEs (hyperkalemia and hypokalemia). RESULTS: Overall, 30% of participants experienced at least one AE during a median follow-up of 3.0 years. In multivariable models adjusted for eGFR and albuminuria, lower (worse) secretion scores at baseline were associated with greater risk of the composite AE outcome (hazard ratio per 1-SD lower secretion score, 1.16; 95% confidence interval, 1.04 to 1.27). In analyses of the individual AEs, lower secretion score was associated with significantly greater risk of AKI, serious electrolyte abnormalities, and ambulatory hyperkalemia. Associations were similar across randomized treatment assignment groups. CONCLUSION: Among SPRINT participants with CKD, worse tubular secretion was associated with greater risk of AEs, independent of eGFR and albuminuria.

Kidney Tubulointerstitial Fibrosis and Tubular Secretion.

RATIONALE & OBJECTIVE: Tubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of kidney function decline. We evaluated whether histopathologic quantification of interstitial fibrosis and tubular atrophy (IFTA) is associated with lower tubular secretory clearance in persons undergoing kidney biopsy. STUDY DESIGN: Cross-sectional. SETTINGS & PARTICIPANTS: The Boston Kidney Biopsy Cohort is a study of persons undergoing native kidney biopsies for clinical indications. EXPOSURES: Semiquantitative score of IFTA reported by 2 trained pathologists. OUTCOMES: We measured plasma and urine concentrations of 9 endogenous secretory solutes using a targeted liquid chromatography/mass spectrometry assay. We used linear regression to test associations of urine-to-plasma ratios (UPRs) of these solutes with IFTA score after controlling for estimated glomerular filtration rate (eGFR) and albuminuria. RESULTS: Among 418 participants, mean age was 53 years, 51% were women, 64% were White, and 18% were Black. Mean eGFR was 50mL/min/1.73m2, and median urinary albumin-creatinine ratio was 819mg/g. Compared with individuals with≤25% IFTA, those with>50% IFTA had 12%-37% lower UPRs for all 9 secretory solutes. Adjusting for age, sex, race, eGFR, and urine albumin and creatinine levels attenuated the associations, yet a trend of lower secretion across groups remained statistically significant (P<0.05 for trend) for 7 of 9 solutes. A standardized composite secretory score incorporating UPR for all 9 secretory solutes using the min-max method showed similar results (P<0.05 for trend). LIMITATIONS: Single time point and spot measures of secretory solutes. CONCLUSIONS: Greater IFTA severity is associated with lower clearance of endogenous secretory solutes even after adjusting for eGFR and albuminuria.

Kidney tubule health, mineral metabolism and adverse events in persons with CKD in SPRINT.

BACKGROUND: Measures of kidney tubule health are risk markers for acute kidney injury (AKI) in persons with chronic kidney disease (CKD) during hypertension treatment, but their associations with other adverse events (AEs) are unknown. METHODS: Among 2377 Systolic Blood Pressure Intervention Trial (SPRINT) participants with CKD, we measured at baseline eight urine biomarkers of kidney tubule health and two serum biomarkers of mineral metabolism pathways that act on the kidney tubules. Cox proportional hazards models were used to evaluate biomarker associations with risk of a composite of pre-specified serious AEs (hypotension, syncope, electrolyte abnormalities, AKI, bradycardia and injurious falls) and outpatient AEs (hyperkalemia and hypokalemia). RESULTS: At baseline, the mean age was 73 ± 9 years and mean estimated glomerular filtration rate (eGFR) was 46 ± 11 mL/min/1.73 m2. During a median follow-up of 3.8 years, 716 (30%) participants experienced the composite AE. Higher urine interleukin-18, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin (NGAL) and monocyte chemoattractant protein-1 (MCP-1), lower urine uromodulin (UMOD) and higher serum fibroblast growth factor-23 were individually associated with higher risk of the composite AE outcome in multivariable-adjusted models including eGFR and albuminuria. When modeling biomarkers in combination, higher NGAL [hazard ratio (HR) = 1.08 per 2-fold higher biomarker level, 95% confidence interval (CI) 1.03-1.13], higher MCP-1 (HR = 1.11, 95% CI 1.03-1.19) and lower UMOD (HR = 0.91, 95% CI 0.85-0.97) were each associated with higher composite AE risk. Biomarker associations did not vary by intervention arm (P > 0.10 for all interactions). CONCLUSIONS: Among persons with CKD, several kidney tubule biomarkers are associated with higher risk of AEs during hypertension treatment, independent of eGFR and albuminuria.

Photoacoustic monitoring of angiogenesis predicts response to therapy in healing wounds.

Chronic wounds are a major health problem that cause the medical infrastructure billions of dollars every year. Chronic wounds are often difficult to heal and cause significant discomfort. Although wound specialists have numerous therapeutic modalities at their disposal, tools that could three dimensional-map wound bed physiology and guide therapy do not exist. Visual cues are the current standard but are limited to surface assessment; clinicians rely on experience to predict response to therapy. Photoacoustic (PA) ultrasound (US) is a non-invasive, hybrid imaging modality that can solve these major limitations. PA relies on the contrast generated by haemoglobin in blood which allows it to map local angiogenesis, tissue perfusion and oxygen saturation-all critical parameters for wound healing. This work evaluates the use of PA-US to monitor angiogenesis and stratify patients responding versus not-responding to therapy. We imaged 19 patients with 22 wounds once a week for at least 3 weeks. Our findings suggest that PA imaging directly visualises angiogenesis. Patients responding to therapy showed clear signs of angiogenesis and an increased rate of PA increase (p = 0.002). These responders had a significant and negative correlation between PA intensity and wound size. Hypertension was correlated to impaired angiogenesis in non-responsive patients. The rate of PA increase and hence the rate of angiogenesis was able to predict healing times within 30 days from the start of monitoring (power = 88%, alpha = 0.05). This early response detection system could help inform management and treatment strategies while improving outcomes and reducing costs.

Lipid accumulation product, visceral adiposity index and risk of chronic kidney disease.

BACKGROUND: Lipid accumulation product (LAP) and visceral adiposity index (VAI) are novel, non-imaging markers of visceral adiposity that are calculated by using body mass index (BMI), waist circumference (WC) and serum lipid concentrations. We hypothesized that LAP and VAI are more strongly associated with adverse kidney outcomes than BMI and WC. METHODS: Using data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, we used multivariable logistic regression to evaluate associations of LAP, VAI, BMI and WC with incident chronic kidney disease (CKD), (incident eGFR < 60 ml/min/1.73m2 and > 25% decline). RESULTS: Among the overall cohort of 27,550 participants, the mean baseline age was 65 years; 54% were women; and 41% were African American. After a median of 9.4 years (IQR 8.6, 9.9) of follow-up, a total of 1127 cases of incident CKD were observed. Each two-fold higher value of VAI (OR 1.12, 95% CI 1.04, 1.20), LAP (OR 1.21, 95% CI 1.13, 1.29), WC (OR 2.10, 95% CI 1.60, 2.76) and BMI (OR: 2.66, 95% CI 1.88, 3.77), was associated with greater odds of incident CKD. CONCLUSIONS: LAP and VAI as measures of visceral adiposity are associated with higher odds of incident CKD but may not provide information beyond WC and BMI.

Marathon Runners' Knowledge and Strategies for Hydration.

OBJECTIVE: To study hydration plans and understanding of exercise-associated hyponatremia (EAH) among current marathon runners. DESIGN: Cross-sectional study. SETTING: Southern California 2018 summer marathon. PARTICIPANTS: Two hundred ten marathon runners. INTERVENTIONS: Survey administered 1 to 2 days before the race. Race times were obtained from public race website. MAIN OUTCOME MEASURES: Planned frequency of hydration; awareness of, understanding of, and preventative strategies for dehydration and EAH; resources used to create hydration plans; drink preferences. RESULTS: When the participants were split into 3 equal groups by racing speed, the slower tertile intended to drink at every mile/station (60%), whereas the faster tertile preferred to drink every other mile or less often (60%), although not statistically significant. Most runners (84%) claimed awareness of EAH, but only 32% could list a symptom of the condition. Both experienced marathoners and the faster tertile significantly had greater understanding of hyponatremia compared with first-time marathoners and the slower tertile, respectively. Less than 5% of marathoners offered "drink to thirst" as a prevention strategy for dehydration or EAH. CONCLUSION: Slower runners plan to drink larger volumes compared with their faster counterparts. Both slower and first-time marathoners significantly lacked understanding of EAH. These groups have plans and knowledge that may put them at higher risk for developing EAH. Most marathon runners did not know of the guidelines to "drink to thirst," suggesting the 2015 EAH Consensus statement may not have had the desired impact.

Central and peripheral arterial diseases in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Chronic kidney disease (CKD) affects about 10% of all populations worldwide, with about 2 million people requiring dialysis. Although patients with CKD are at high risk of cardiovascular disease and events, they are often underrepresented or excluded in clinical trials, leading to important knowledge gaps about how to treat these patients. KDIGO (Kidney Disease: Improving Global Outcomes) convened the fourth clinical Controversies Conference on the heart, kidney and vasculature in Dublin, Ireland, in February 2020, entitled Central and Peripheral Arterial Diseases in Chronic Kidney Disease. A global panel of multidisciplinary experts from the fields of nephrology, cardiology, neurology, surgery, radiology, vascular biology, epidemiology, and health economics attended. The objective was to identify key issues related to the optimal detection, management, and treatment of cerebrovascular diseases, central aortic disease, renovascular disease, and peripheral artery disease in the setting of CKD. This report outlines the common pathophysiology of these vascular processes in the setting of CKD, describes best practices for their diagnosis and management, summarizes areas of uncertainty, addresses ongoing controversial issues, and proposes a research agenda to address key gaps in knowledge that, when addressed, could improve patient care and outcomes.

Biomarkers of Kidney Tubule Health, CKD Progression, and Acute Kidney Injury in SPRINT (Systolic Blood Pressure Intervention Trial) Participants.

RATIONALE & OBJECTIVE: The Systolic Blood Pressure Intervention Trial (SPRINT) compared the effect of intensive versus standard systolic blood pressure targets on cardiovascular morbidity and mortality. In this ancillary study, we evaluated the use of exploratory factor analysis (EFA) to combine biomarkers of kidney tubule health in urine and plasma and then study their role in longitudinal estimated glomerular filtration rate (eGFR) change and risk of acute kidney injury (AKI). STUDY DESIGN: Observational cohort nested in a clinical trial. SETTING & PARTICIPANTS: 2,351 SPRINT participants with eGFR < 60 mL/min/1.73 m2 at baseline. EXPOSURE: Levels of neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), chitinase-3-like protein (YKL-40), kidney injury molecule 1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), α1-microglobulin (A1M) and ß2-microglobulin (B2M), uromodulin (UMOD), fibroblast growth factor 23 (FGF-23), and intact parathyroid hormone (PTH). OUTCOME: Longitudinal changes in eGFR and risk of AKI. ANALYTICAL APPROACH: We performed EFA to capture different tubule pathophysiologic processes. We used linear mixed effects models to evaluate the association of each factor with longitudinal changes in eGFR. We evaluated the association of the tubular factors scores with AKI using Cox proportional hazards regression. RESULTS: From 10 biomarkers, EFA generated 4 factors reflecting tubule injury/repair (NGAL, IL-18, and YKL-40), tubule injury/fibrosis (KIM-1 and MCP-1), tubule reabsorption (A1M and B2M), and tubule reserve/mineral metabolism (UMOD, FGF-23, and PTH). Each 1-SD higher tubule reserve/mineral metabolism factor score was associated with a 0.58% (95% CI, 0.39%-0.67%) faster eGFR decline independent of baseline eGFR and albuminuria. Both the tubule injury/repair and tubule injury/fibrosis factors were independently associated with future risk of AKI (per 1 SD higher, HRs of 1.18 [95% CI, 1.10-1.37] and 1.23 [95% CI, 1.02-1.48], respectively). LIMITATIONS: The factors require validation in other settings. CONCLUSIONS: EFA allows parsimonious subgrouping of biomarkers into factors that are differentially associated with progressive eGFR decline and AKI. These subgroups may provide insights into the pathological processes driving adverse kidney outcomes.

Proteinuria and nocturnal blood pressure dipping in hypertensive children and adolescents.

BACKGROUND: The absence of nocturnal blood pressure dipping is associated with adverse cardiovascular outcomes in adults, and proteinuria is a risk factor for non-dipping in this population. Risk factors for non-dipping in children are largely unknown. METHODS: We retrospectively identified patients aged 5-19 years who underwent 24-h ambulatory blood pressure monitoring (ABPM) from August 2018 to January 2019 and had a spot urine protein-to-creatinine ratio (PCR) within 1 year of their ABPM. Dipping was defined as ≥10% reduction in systolic and diastolic blood pressure from day to night. Multivariable logistic and linear regression models evaluated the association of proteinuria with non-dipping. RESULTS: Among 77 children identified, 27 (35.1%) were non-dippers. Each two-fold higher urine PCR was associated with 38% higher odds of non-dipping, after adjusting for body mass index (BMI). Higher urine PCR was also associated with a lower diastolic dipping percentage by 1.33 (95% confidence interval 0.31-2.34), after adjusting for BMI, age, and estimated glomerular filtration rate. CONCLUSIONS: Limitations of this study include its retrospective design and the time lapse between urine PCR and ABPM. Proteinuria appears to be associated with blood pressure non-dipping in children. This finding needs to be confirmed in prospective studies. IMPACT: Our study demonstrates the association of proteinuria with non-dipping of blood pressure in children. This association has been explored in adults, but to our knowledge, this is the first time it is evaluated in children referred for evaluation of elevated blood pressure. Non-dipping is a modifiable risk factor for kidney function decline and cardiovascular disease in adulthood, and thus early identification in children is important. The association between proteinuria and non-dipping in children will allow us to more readily identify those at risk, with a future focus on interventions to modify blood pressure dipping patterns.

Prevalence and risk factors of peripheral artery disease in a population with chronic kidney disease in Australia: A systematic review and meta-analysis.

There is a lack of clarity and guidance for screening peripheral artery disease (PAD) in persons with chronic kidney disease (CKD) and end stage kidney disease (ESKD) despite this group being at excess risk of cardiovascular disease (CVD). In this current study, we performed a systematic review and meta-analysis to examine the prevalence and risk factors for PAD in persons with CKD in Australian cohorts. We used the inverse variance heterogeneity meta-analysis with double arcsine transformation to summarize the prevalence of PAD (with 95% CIs). Nine studies and 18 reports from the Australia and New Zealand dialysis and transplant registry with 36 cohorts were included in the review. We found a substantially higher PAD prevalence in cohorts based on an ankle-brachial index (ABI) or toe systolic pressure (TBI) than cohorts based on self-reported history. Higher PAD prevalence was observed in ESKD persons than CKD persons without dialysis (PAD diagnosis based on ABI or TBI: 31% in ESKD persons and 23% in CKD persons, PAD diagnosis based on self-reported history: 17% in ESKD persons and 10% in CKD persons). Older age, Caucasian race, cerebrovascular disease and haemodialysis were associated with the presence of PAD in ESKD persons. Our findings indicated a considerable proportion of PAD in CKD and ESKD persons particularly in those with ESKD. To develop and provide an adequate plan to clinically manage CKD patients with PAD, evidence of cost-effectiveness and clinical benefit of early detection of PAD in persons with CKD in Australia is recommended for future studies.