Oral Sodium Bicarbonate and Bone Turnover in CKD: A Secondary Analysis of the BASE Pilot Trial.

SIGNIFICANCE STATEMENT: In CKD, metabolic acidosis is commonly treated with alkali in the hope that it will improve bone health. In a post hoc analysis of the Bicarbonate Administration to Stabilize eGFR Pilot Trial, we investigated whether sodium bicarbonate affects serum levels of bone turnover markers and other hormones related to bone health in individuals with CKD who have normal to slightly reduced total CO2 (20-28 mEq/L). Sodium bicarbonate increased serum levels of α-klotho but had no significant effect on other bone health markers, including intact fibroblast growth factor-23 (iFGF-23), intact parathyroid hormone (iPTH), and bone-specific alkaline phosphatase (B-SAP). Further study is needed to determine the effect of bicarbonate administration on clinical aspects of bone health. BACKGROUND: Treatment with alkali has been hypothesized to improve bone health in CKD by mitigating adverse effects of acid on bone mineral. We investigated the effect of treatment with sodium bicarbonate on bone turnover markers and other factors related to bone metabolism in CKD. METHODS: This is a post hoc analysis of the Bicarbonate Administration to Stabilize eGFR Pilot Trial in which 194 individuals with CKD and serum total CO2 20-28 mEq/L were randomly assigned to placebo or one of two doses of sodium bicarbonate (0.5 or 0.8 mEq/kg lean body weight per day) for 28 weeks. The following serum measurements were performed at baseline, week 12, and week 28: B-SAP, c-telopeptide, procollagen type I intact N-terminal propeptide, iPTH, iFGF-23, soluble klotho, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and tartrate-resistant acid phosphatase 5b. The difference (sodium bicarbonate versus placebo) in mean change of each bone biomarker from baseline was determined using linear mixed models. RESULTS: One hundred sixty-eight participants submitted samples for post hoc investigations. Mean eGFR was 37±10 ml/min per 1.73 m2 and mean total CO2 was 24±3 mEq/L at baseline. Sodium bicarbonate induced a dose-dependent increase in soluble klotho levels compared with placebo. There was no significant effect of treatment with either dose of sodium bicarbonate on any of the other bone biomarkers, including iFGF-23, iPTH, and B-SAP. Effects on bone biomarkers were similar in those with baseline serum total CO2 <24 mEq/L compared with those with total CO2 ≥24 mEq/L. CONCLUSIONS: In this pilot trial of individuals with CKD and total CO2 20-28 mEq/L, sodium bicarbonate treatment increased serum klotho levels but did not affect other bone health markers over 28 weeks. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, NCT02521181.

Race, Genetic Ancestry, and Estimating Kidney Function in CKD.

BACKGROUND: The inclusion of race in equations to estimate the glomerular filtration rate (GFR) has become controversial. Alternative equations that can be used to achieve similar accuracy without the use of race are needed. METHODS: In a large national study involving adults with chronic kidney disease, we conducted cross-sectional analyses of baseline data from 1248 participants for whom data, including the following, had been collected: race as reported by the participant, genetic ancestry markers, and the serum creatinine, serum cystatin C, and 24-hour urinary creatinine levels. RESULTS: Using current formulations of GFR estimating equations, we found that in participants who identified as Black, a model that omitted race resulted in more underestimation of the GFR (median difference between measured and estimated GFR, 3.99 ml per minute per 1.73 m2 of body-surface area; 95% confidence interval [CI], 2.17 to 5.62) and lower accuracy (percent of estimated GFR within 10% of measured GFR [P10], 31%; 95% CI, 24 to 39) than models that included race (median difference, 1.11 ml per minute per 1.73 m2; 95% CI, -0.29 to 2.54; P10, 42%; 95% CI, 34 to 50). The incorporation of genetic ancestry data instead of race resulted in similar estimates of the GFR (median difference, 1.33 ml per minute per 1.73 m2; 95% CI, -0.12 to 2.33; P10, 42%; 95% CI, 34 to 50). The inclusion of non-GFR determinants of the serum creatinine level (e.g., body-composition metrics and urinary excretion of creatinine) that differed according to race reported by the participants and genetic ancestry did not eliminate the misclassification introduced by removing race (or ancestry) from serum creatinine-based GFR estimating equations. In contrast, the incorporation of race or ancestry was not necessary to achieve similarly statistically unbiased (median difference, 0.33 ml per minute per 1.73 m2; 95% CI, -1.43 to 1.92) and accurate (P10, 41%; 95% CI, 34 to 49) estimates in Black participants when GFR was estimated with the use of cystatin C. CONCLUSIONS: The use of the serum creatinine level to estimate the GFR without race (or genetic ancestry) introduced systematic misclassification that could not be eliminated even when numerous non-GFR determinants of the serum creatinine level were accounted for. The estimation of GFR with the use of cystatin C generated similar results while eliminating the negative consequences of the current race-based approaches. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Calcium and Phosphate Disorders: Core Curriculum 2024.

Maintaining normal calcium and phosphate homeostasis is essential for optimal cellular, metabolic, and organ function. Parathyroid hormone, fibroblast growth factor 23, and 1,25-dihydroxyvitamin D regulate calcium and phosphate homeostasis via multiple interlinked feedback loops, receptors, ion channels, and transporters. Following an initial overview of the stimuli and effects of the different hormonal regulators, this installment of AJKD's Core Curriculum in Nephrology reviews the physiology and pathophysiology of calcium and phosphate disorders through the lens of a series of illustrative cases. The cases span clinical conundrums commonly encountered by nephrologists in their daily clinical practice and other less common disorders. Some of the cases present in the outpatient clinic setting and others in the inpatient hospital setting. Patients with normal kidney function, chronic kidney disease, kidney failure, and acute kidney injury are all represented. Some of the disorders are iatrogenic, and some are due to native disease. All demonstrate key aspects of pathophysiology that are essential knowledge for nephrology clinicians of all career stages.

Klotho and Clinical Outcomes in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Klotho deficiency may affect clinical outcomes in chronic kidney disease (CKD) through fibroblast growth factor-23 (FGF23)-dependent and -independent pathways. However, the association between circulating Klotho and clinical outcomes in CKD remains unresolved and was the focus of this study. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 1,088 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study with an estimated glomerular filtration rate (eGFR) of 20-70mL/min/1.73m2. EXPOSURE: Plasma Klotho level at the year-1 study visit. OUTCOMES: 5-year risks of all-cause mortality, heart failure hospitalization, atherosclerotic cardiovascular events, and a composite kidney end point that comprised a sustained 50% decrease in eGFR, dialysis, kidney transplant, or eGFR<15mL/min/1.73m2. ANALYTICAL APPROACH: We divided Klotho into 6 groups to account for its nonnormal distribution. We used Cox proportional hazards regression and subdistribution hazards models to compare survival and clinical outcomes, respectively, between Klotho groups. We sequentially adjusted for demographic characteristics, kidney function, cardiovascular risk factors, sample age, and FGF23. RESULTS: Mean eGFR was 42mL/min/1.73m2, and median Klotho concentration was 0.31ng/mL (IQR, 0.10-3.27ng/mL). When compared with the lowest Klotho group, survival (HR, 0.77; 95% CI, 0.32-1.89), heart failure hospitalization (HR, 1.10; 95% CI, 0.38-3.17), atherosclerotic cardiovascular events (HR, 1.19; 95% CI, 0.57-2.52), and CKD progression (HR, 1.05; 95% CI, 0.58-1.91) did not differ in the high Klotho group. In contrast, FGF23 was significantly associated with mortality and heart failure hospitalization independent of Klotho levels. LIMITATIONS: Despite adjustments, we cannot exclude the potential influence of residual confounding or sample storage on the results. A single measurement of plasma Klotho concentration may not capture Klotho patterns over time. CONCLUSIONS: In a large, diverse, well-characterized CKD cohort, Klotho was not associated with clinical outcomes, and Klotho deficiency did not confound the association of FGF23 with mortality or heart failure hospitalization. PLAIN-LANGUAGE SUMMARY: Klotho is a protein that is vital to mineral metabolism and aging and may protect against cardiovascular disease. Klotho levels decrease in chronic kidney disease (CKD), but the association between Klotho and clinical outcomes in CKD remains uncertain. In a prospective cohort study of more than 1,000 people with CKD, circulating Klotho levels were not associated with kidney disease progression, cardiovascular outcomes, or mortality. These results suggest that the decrease in circulating Klotho levels in CKD does not play a prominent role in the development of poor clinical outcomes.

Regulation and Effects of FGF23 in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a global health epidemic that accelerates cardiovascular disease, increases risk of infection, and causes anemia and bone disease, among other complications that collectively increase risk of premature death. Alterations in calcium and phosphate homeostasis have long been considered nontraditional risk factors for many of the most morbid outcomes of CKD. The discovery of fibroblast growth factor 23 (FGF23), which revolutionized the diagnosis and treatment of rare hereditary disorders of FGF23 excess that cause hypophosphatemic rickets, has also driven major paradigm shifts in our understanding of the pathophysiology and downstream end-organ complications of disordered mineral metabolism in CKD. As research of FGF23 in CKD has rapidly advanced, major new questions about its regulation and effects continuously emerge. These are promoting exciting innovations in laboratory, patient-oriented, and epidemiological research and stimulating clinical trials of new therapies and repurposing of existing ones to target FGF23.

Hypophosphataemia following ferric derisomaltose and ferric carboxymaltose in patients with iron deficiency anaemia due to inflammatory bowel disease (PHOSPHARE-IBD): a randomised clinical trial.

OBJECTIVE: Intravenous iron-a common treatment for anaemia and iron deficiency due to inflammatory bowel disease (IBD)-can cause hypophosphataemia. This trial compared the incidence of hypophosphataemia after treatment with ferric carboxymaltose (FCM) or ferric derisomaltose (FDI). DESIGN: This randomised, double-blind, clinical trial was conducted at 20 outpatient hospital clinics in Europe (Austria, Denmark, Germany, Sweden, UK). Adults with IBD and iron deficiency anaemia (IDA) were randomised 1:1 to receive FCM or FDI at baseline and at Day 35 using identical haemoglobin- and weight-based dosing regimens. The primary outcome was the incidence of hypophosphataemia (serum phosphate <2.0 mg/dL) at any time from baseline to Day 35 in the safety analysis set (all patients who received ≥1 dose of study drug). Markers of mineral and bone homeostasis, and patient-reported fatigue scores, were measured. RESULTS: A total of 156 patients were screened; 97 (49 FDI, 48 FCM) were included and treated. Incident hypophosphataemia occurred in 8.3% (4/48) FDI-treated patients and in 51.0% (25/49) FCM-treated patients (adjusted risk difference: -42.8% (95% CI -57.1% to -24.6%) p<0.0001). Both iron formulations corrected IDA. Patient-reported fatigue scores improved in both groups, but more slowly and to a lesser extent with FCM than FDI; slower improvement in fatigue was associated with greater decrease in phosphate concentration. CONCLUSION: Despite comparably effective treatment of IDA, FCM caused a significantly higher rate of hypophosphataemia than FDI. Further studies are needed to address the longer-term clinical consequences of hypophosphataemia and to investigate mechanisms underpinning the differential effects of FCM and FDI on patient-reported fatigue.

Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH.

BACKGROUND & AIMS: The LIVIFY trial investigated the safety, tolerability, and efficacy of vonafexor, a second-generation, non-bile acid farnesoid X receptor agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH). METHODS: This double-blind phase IIa study was conducted in two parts. Patients were randomised (1:1:1:1) to receive placebo, vonafexor 100 mg twice daily (VONA-100BID), vonafexor 200 mg once daily (VONA-200QD), or 400 mg vonafexor QD (VONA-400QD) in Part A (safety run-in, pharmacokinetics/pharmacodynamics) or placebo, vonafexor 100 mg QD (VONA-100QD), or VONA-200QD (1:1:1) in Part B. The primary efficacy endpoint was a reduction in liver fat content (LFC) by MRI-proton density fat fraction, while secondary endpoints included reduced corrected T1 values and liver enzymes, from baseline to Week 12. RESULTS: One hundred and twenty patients were randomised (Part A, n = 24; Part B, n = 96). In Part B, there was a significant reduction in least-square mean (SE) absolute change in LFC from baseline to Week 12 for VONA-100QD (-6.3% [0.9]) and VONA-200QD (-5.4% [0.9]), vs. placebo (-2.3% [0.9], p = 0.002 and 0.012, respectively). A >30% relative LFC reduction was achieved by 50.0% and 39.3% of patients in the VONA-100QD and VONA-200QD arms, respectively, but only in 12.5% in the placebo arm. Reductions in body weight, liver enzymes, and corrected T1 were also observed with vonafexor. Creatinine-based glomerular filtration rate improved in the active arms but not the placebo arm. Mild to moderate generalised pruritus was reported in 6.3%, 9.7%, and 18.2% of participants in the placebo, VONA-100QD, and VONA-200QD arms, respectively. CONCLUSIONS: In patients with suspected fibrotic NASH, vonafexor was safe and induced potent liver fat reduction, improvement in liver enzymes, weight loss, and a possible renal benefit. CLINICAL TRIAL NUMBER (EUDRACT): 2018-003119-22. GOV IDENTIFIER: NCT03812029. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) has become a leading cause of chronic liver disease worldwide. Affected patients are also at higher risk of developing chronic kidney disease. There are no approved therapies and only few options to treat this population. The phase IIa LIVIFY trial results show that single daily administration of oral vonafexor, an FXR agonist, leads in the short term to a reduction in liver fat, liver enzymes, fibrosis biomarkers, body weight and abdominal circumference, and a possible improvement in kidney function, while possible mild moderate pruritus (a peripheral FXR class effect) and an LDL-cholesterol increase are manageable with lower doses and statins. These results support exploration in longer and larger trials, with the aim of addressing the unmet medical need in NASH.

Supermarket Proximity and Risk of Hypertension, Diabetes, and CKD: A Retrospective Cohort Study.

RATIONALE & OBJECTIVE: Living in environments with low access to food may increase the risk of chronic diseases. We investigated the association of household distance to the nearest supermarket (as a measure of food access) with the incidence of hypertension, diabetes, and chronic kidney disease (CKD) in a metropolitan area of the United States. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 777,994 individuals without hypertension, diabetes, or CKD at baseline within the HealthLNK Data Repository, which contains electronic health records from 7 health care institutions in Chicago, Illinois. EXPOSURE: Zip code-level average distance between households and nearest supermarket. OUTCOME: Incidence of hypertension, diabetes, and CKD based on presence of ICD-9 code and/or blood pressure≥140/90mm Hg, hemoglobin A1c≥6.5%, and eGFR<60mL/min/1.73m2, respectively. ANALYTICAL APPROACH: Average distance to nearest supermarket was aggregated from street-level metrics for 56 Chicagoland zip codes. The cumulative incidence of hypertension, diabetes, and CKD from 2007-2012 was calculated for each zip code in patients free of these diseases in 2006. Spatial analysis of food access and disease incidence was performed using bivariate local indicator of spatial association (BiLISA) maps and bivariate local Moran I statistics. The relationship between supermarket access and outcomes was analyzed using logistic regression. RESULTS: Of 777,994 participants, 408,608 developed hypertension, 51,380 developed diabetes, and 56,365 developed CKD. There was significant spatial overlap between average distance to supermarket and incidence of hypertension and diabetes but not CKD. Zip codes with large average supermarket distances and high incidence of hypertension and diabetes were clustered in southern and western neighborhoods. Models adjusted only for neighborhood factors (zip code-level racial composition, access to vehicles, median income) revealed significant associations between zip code-level average distance to supermarket and chronic disease incidence. Relative to tertile 1 (shortest distance), ORs in tertiles 2 and 3, respectively, were 1.27 (95% CI, 1.23-1.30) and 1.38 (95% CI, 1.33-1.43) for diabetes, 1.03 (95% CI, 1.02-1.05) and 1.04 (95% CI, 1.02-1.06) for hypertension, and 1.18 (95% CI, 1.15-1.21) and 1.33 (95% CI, 1.29-1.37) for CKD. Models adjusted for demographic factors and health insurance showed significant and positive association with greater odds of incident diabetes (tertile 2: 1.29 [95% CI, 1.26-1.33]; tertile 3: 1.35 [95% CI, 1.31-1.39]) but lesser odds of hypertension (tertile 2: 0.95 [95% CI, 0.94-0.97]; tertile 3: 0.91 [95% CI, 0.89-0.92]) and CKD (tertile 2: 0.80 [95% CI, 0.78-0.82]; tertile 3: 0.73 [95% CI, 0.72-0.76]). After adjusting for both neighborhood and individual covariates, supermarket distance remained significantly associated with greater odds of diabetes and lesser odds of hypertension, but there was no significant association with CKD. LIMITATIONS: Unmeasured neighborhood and social confounding variables, zip code-level analysis, and limited individual-level information. CONCLUSIONS: There are significant disparities in supermarket proximity and incidence of hypertension, diabetes, and CKD in Chicago, Illinois. The relationship between supermarket access and chronic disease is largely explained by individual- and neighborhood-level factors.

FGF23 AND ALTERED MINERAL HOMEOSTASIS IN KIDNEY DISEASE AND FOLLOWING INTRAVENOUS IRON.

Fibroblast growth factor 23 (FGF23) is an endocrine hormone that stimulates renal phosphate excretion and suppresses circulating concentrations of 1,25-dihydroxyvitamin D (1,25D). These effects of FGF23 are most evident in rare diseases that are characterized by FGF23-mediated hypophosphatemic rickets-osteomalacia. More commonly, elevated FGF23 is a ubiquitous, early consequence of chronic kidney disease (CKD) in which it helps to maintain normal serum phosphate levels but causes secondary hyperparathyroidism by suppressing 1,25D, and directly promotes cardiovascular disease and death. Elevated FGF23 is also a common complication of intravenous administration of ferric carboxymaltose (FCM), which is widely used to treat iron deficiency anemia. Among patients with normal kidney function who receive FCM, the resulting increase in FGF23 and subsequent FGF23-mediated reduction of 1,25D and secondary hyperparathyroidism promote hypophosphatemia that can be symptomatic, severe, and associated with musculoskeletal complications. Ongoing research is needed to design novel therapeutic approaches to mitigate FGF23-related illnesses.

Exploring US internal medicine resident career preferences: a Q-methodology study.

Career selection in medicine is a complex and underexplored process. Most medical career studies performed in the U.S. focused on the effect of demographic variables and medical education debt on career choice. Considering ongoing U.S. physician workforce shortages and the trilateral adaptive model of career decision making, a robust assessment of professional attitudes and work-life preferences is necessary. The objective of this study was to explore and define the dominant viewpoints related to career choice selection in a cohort of U.S. IM residents. We administered an electronic Q-sort in which 218 IM residents sorted 50 statements reflecting the spectrum of opinions that influence postgraduate career choice decisions. Participants provided comments that explained the reasoning behind their individual responses. In the final year of residency training, we ascertained participating residents' chosen career. Factor analysis grouped similar sorts and revealed four distinct viewpoints. We characterized the viewpoints as "Fellowship-Bound-Academic," "Altruistic-Longitudinal-Generalist," "Inpatient-Burnout-Aware," and "Lifestyle-Focused-Consultant." There is concordance between residents who loaded significantly onto a viewpoint and their ultimate career choice. Four dominant career choice viewpoints were found among contemporary U.S. IM residents. These viewpoints reflect the intersection of competing priorities, personal interests, professional identity, socio-economic factors, and work/life satisfaction. Better appreciation of determinants of IM residents' career choices may help address workforce shortages and enhance professional satisfaction.

Risk Prediction Models for Atherosclerotic Cardiovascular Disease in Patients with Chronic Kidney Disease: The CRIC Study.

BACKGROUND: Individuals with CKD may be at high risk for atherosclerotic cardiovascular disease (ASCVD). However, there are no ASCVD risk prediction models developed in CKD populations to inform clinical care and prevention. METHODS: We developed and validated 10-year ASCVD risk prediction models in patients with CKD that included participants without self-reported cardiovascular disease from the Chronic Renal Insufficiency Cohort (CRIC) study. ASCVD was defined as the first occurrence of adjudicated fatal and nonfatal stroke or myocardial infarction. Our models used clinically available variables and novel biomarkers. Model performance was evaluated based on discrimination, calibration, and net reclassification improvement. RESULTS: Of 2604 participants (mean age 55.8 years; 52.0% male) included in the analyses, 252 had incident ASCVD within 10 years of baseline. Compared with the American College of Cardiology/American Heart Association pooled cohort equations (area under the receiver operating characteristic curve [AUC]=0.730), a model with coefficients estimated within the CRIC sample had higher discrimination (P=0.03), achieving an AUC of 0.736 (95% confidence interval [CI], 0.649 to 0.826). The CRIC model developed using clinically available variables had an AUC of 0.760 (95% CI, 0.678 to 0.851). The CRIC biomarker-enriched model had an AUC of 0.771 (95% CI, 0.674 to 0.853), which was significantly higher than the clinical model (P=0.001). Both the clinical and biomarker-enriched models were well-calibrated and improved reclassification of nonevents compared with the pooled cohort equations (6.6%; 95% CI, 3.7% to 9.6% and 10.0%; 95% CI, 6.8% to 13.3%, respectively). CONCLUSIONS: The 10-year ASCVD risk prediction models developed in patients with CKD, including novel kidney and cardiac biomarkers, performed better than equations developed for the general population using only traditional risk factors.

The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Secondary and Tertiary Renal Hyperparathyroidism.

OBJECTIVE: To develop evidence-based recommendations for safe, effective, and appropriate treatment of secondary (SHPT) and tertiary (THPT) renal hyperparathyroidism. BACKGROUND: Hyperparathyroidism is common among patients with chronic kidney disease, end-stage kidney disease, and kidney transplant. The surgical management of SHPT and THPT is nuanced and requires a multidisciplinary approach. There are currently no clinical practice guidelines that address the surgical treatment of SHPT and THPT. METHODS: Medical literature was reviewed from January 1, 1985 to present January 1, 2021 by a panel of 10 experts in SHPT and THPT. Recommendations using the best available evidence was constructed. The American College of Physicians grading system was used to determine levels of evidence. Recommendations were discussed to consensus. The American Association of Endocrine Surgeons membership reviewed and commented on preliminary drafts of the content. RESULTS: These clinical guidelines present the epidemiology and pathophysiology of SHPT and THPT and provide recommendations for work-up and management of SHPT and THPT for all involved clinicians. It outlines the preoperative, intraoperative, and postoperative management of SHPT and THPT, as well as related definitions, operative techniques, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Preoperative and Perioperative Care, Surgical Planning and Parathyroidectomy, Adjuncts and Approaches, Outcomes, and Reoperation. CONCLUSIONS: Evidence-based guidelines were created to assist clinicians in the optimal management of secondary and tertiary renal hyperparathyroidism.

Fibroblast growth factor-23 and subclinical markers of cardiac dysfunction: The coronary artery risk development in young adults (CARDIA) study.

BACKGROUND: Elevated Fibroblast Growth Factor-23 (FGF23) levels have been associated with greater left ventricular mass (LVM) and heart failure. Whether higher FGF23 is associated with higher LVH prevalence and longitudinal changes in LVM and myocardial strain in middle-aged adults without cardiovascular disease (CVD) or chronic kidney disease (CKD) is unknown. METHODS: We studied 3,113 adults without CVD at baseline participating in the Year 25 (2010-2011) follow-up exam of the Coronary Artery Risk Development in Young Adults (CARDIA) study. We studied the association of Year 25 c-terminal FGF23 concentrations with indexed LVM (LVMI=LVM/height2.7), LVH and myocardial strain as assessed by speckle tracking strain echocardiography. Among the 2,758 (88.6%) participants who returned for the Year 30 examination, we also investigated the association of Year 25 FGF23 with 5 Year change in LVMI, strain parameters and incident LVH. RESULTS: The mean age was 50.0 (±3.6) years, 56.8% were female, 45.7% were Black and 6.4% had CKD. There was 6.0% LVH prevalence at Year 25. Mean 5 Year change in LVMI was 5.3 (±7.7) grams/meter. In multivariable models, FGF23 in the highest quartile was associated with greater odds of LVH at Year 25 compared to lower quartiles. [Odds Ratio 95% CI: 1.81 (1.28, 2.58)] with similar findings after exclusion of participants with CKD. There was no interaction between FGF23 and race (P = .18) or sex (P = .80). There was no association between FGF23 and global longitudinal strain. There was no association between FGF23 and 5 Year change in LVMI. There was no association between higher FGF23 and 5 year incident LVH. CONCLUSIONS: In a middle-aged adult population without known CVD or CKD, higher FGF23 was associated with greater odds of LVH, but not with greater increases in LVM over time. Further study is needed to elucidate whether FGF23 is a risk marker for underlying LVH or a mechanism for increased LVM over time in younger and middle-aged adult populations without CKD.

Time-Updated Changes in Estimated GFR and Proteinuria and Major Adverse Cardiac Events: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Evaluating repeated measures of estimated glomerular filtration rate (eGFR) and urinary protein-creatinine ratio (UPCR) over time may enhance our ability to understand the association between changes in kidney parameters and cardiovascular disease risk. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Annual visit data from 2,438 participants in the Chronic Renal Insufficiency Cohort (CRIC). EXPOSURES: Average and slope of eGFR and UPCR in time-updated, 1-year exposure windows. OUTCOMES: Incident heart failure, atherosclerotic cardiovascular disease events, death, and a composite of incident heart failure, atherosclerotic cardiovascular disease events, and death. ANALYTICAL APPROACH: A landmark analysis, a dynamic approach to survival modeling that leverages longitudinal, iterative profiles of laboratory and clinical information to assess the time-updated 3-year risk of adverse cardiovascular outcomes. RESULTS: Adjusting for baseline and time-updated covariates, every standard deviation lower mean eGFR (19mL/min/1.73m2) and declining slope of eGFR (8mL/min/1.73m2 per year) were independently associated with higher risks of heart failure (hazard ratios [HRs] of 1.82 [95% CI, 1.39-2.44] and 1.28 [95% CI, 1.12-1.45], respectively) and the composite outcome (HRs of 1.32 [95% CI, 1.11-1.54] and 1.11 [95% CI, 1.03-1.20], respectively). Every standard deviation higher mean UPCR (136mg/g) and increasing UPCR (240mg/g per year) were also independently associated with higher risks of heart failure (HRs of 1.58 [95% CI, 1.28-1.97] and 1.20 [95% CI, 1.10-1.29], respectively) and the composite outcome (HRs of 1.33 [95% CI, 1.17-1.50] and 1.12 [95% CI, 1.06-1.18], respectively). LIMITATIONS: Limited generalizability of annual eGFR and UPCR assessments; several biomarkers for cardiovascular disease risk were not available annually. CONCLUSIONS: Using the landmark approach to account for time-updated patterns of kidney function, average and slope of eGFR and proteinuria were independently associated with 3-year cardiovascular risk. Short-term changes in kidney function provide information about cardiovascular risk incremental to level of kidney function, representing possible opportunities for more effective management of patients with chronic kidney disease.

A Comparative Study of Serum Phosphate and Related Parameters in Chronic Kidney Disease between the USA and Japan.

INTRODUCTION: Recent studies have suggested a higher incidence of cardiovascular disease (CVD) among patients with chronic kidney disease (CKD) in the USA than in Japan. Hyperphosphatemia, a possible risk for CVD, may explain this difference; however, international differences in phosphate parameters in CKD have not been well elaborated. METHODS: By using the baseline data from the USA and the Japanese nation-wide, multicenter, CKD cohort studies; the Chronic Renal Insufficiency Cohort Study (CRIC, N = 3,870) and the Chronic Kidney Disease-Japan Cohort Study (CKD-JAC, N = 2,632), we harmonized the measures and compared clinical parameters regarding phosphate metabolism or serum phosphate, fibroblast growth factor-23 (FGF23), and parathyroid hormone (PTH), in the cross-sectional model. RESULTS: Multivariable linear regression analyses revealed that serum phosphate levels were significantly higher in CRIC across all levels of estimated glomerular filtration rate (eGFR) with the greatest difference being observed at lower levels of eGFR. Serum FGF23 and 25-hydroxy vitamin D (25OHD) levels were higher in CRIC, while PTH levels were higher in CKD-JAC at all levels of eGFR. Adjustments for demographics, 25OHD, medications, dietary intake or urinary excretion of phosphate, PTH, and FGF23 did not eliminate the difference in serum phosphate levels between the cohorts (0.43, 0.46, 0.54, 0.64, and 0.78 mg/dL higher in CRIC within eGFR strata of >50, 41-50, 31-40, 21-30, and ≤20 mL/min/1.73 m2, respectively). These findings were consistent when only Asian CRIC participants (N = 105) were included in the analysis. CONCLUSION: Serum phosphate levels in CRIC were significantly higher than those of CKD-JAC across all stages of CKD, which may shed light on the international variations in phosphate parameters and thus in cardiovascular risk among CKD patients. The key mechanisms for the substantial differences in phosphate parameters need to be elucidated.

Iron status, fibroblast growth factor 23 and cardiovascular and kidney outcomes in chronic kidney disease.

Disordered iron and mineral homeostasis are interrelated complications of chronic kidney disease that may influence cardiovascular and kidney outcomes. In a prospective analysis of 3747 participants in the Chronic Renal Insufficiency Cohort Study, we investigated risks of mortality, heart failure, end-stage kidney disease (ESKD), and atherosclerotic cardiovascular disease according to iron status, and tested for mediation by C-terminal fibroblast growth factor 23 (FGF23), hemoglobin and parathyroid hormone. Study participants were agnostically categorized based on quartiles of transferrin saturation and ferritin as "Iron Replete" (27.1% of participants; referent group for all outcomes analyses), "Iron Deficiency" (11.1%), "Functional Iron Deficiency" (7.6%), "Mixed Iron Deficiency" (iron indices between the Iron Deficiency and Functional Iron Deficiency groups; 6.3%), "High Iron" (9.2%), or "Non-Classified" (the remaining 38.8% of participants). In multivariable-adjusted Cox models, Iron Deficiency independently associated with mortality (hazard ratio 1.28, 95% confidence interval 1.04-1.58) and heart failure (1.34, 1.05- 1.72). Mixed Iron Deficiency associated with mortality (1.61, 1.27-2.04) and ESKD (1.33, 1.02-1.73). High Iron associated with mortality (1.54, 1.24-1.91), heart failure (1.58, 1.21-2.05), and ESKD (1.41, 1.13-1.77). Functional Iron Deficiency did not significantly associate with any outcome, and no iron group significantly associated with atherosclerotic cardiovascular disease. Among the candidate mediators, FGF23 most significantly mediated the risks of mortality and heart failure conferred by Iron Deficiency. Thus, alterations in iron homeostasis associated with adverse cardiovascular and kidney outcomes in patients with chronic kidney disease.

Mineral bone disease in autosomal dominant polycystic kidney disease.

Mice with disruption of Pkd1 in osteoblasts demonstrate reduced bone mineral density, trabecular bone volume and cortical thickness. To date, the bone phenotype in adult patients with autosomal dominant polycystic kidney disease (ADPKD) with stage I and II chronic kidney disease has not been investigated. To examine this, we characterized biochemical markers of mineral metabolism, examined bone turnover and biology, and estimated risk of fracture in patients with ADPKD. Markers of mineral metabolism were measured in 944 patients with ADPKD and other causes of kidney disease. Histomorphometry and immunohistochemistry were compared on bone biopsies from 20 patients with ADPKD with a mean eGFR of 97 ml/min/1.73m2 and 17 healthy individuals. Furthermore, adults with end stage kidney disease (ESKD) initiating hemodialysis between 2002-2013 and estimated the risk of bone fracture associated with ADPKD as compared to other etiologies of kidney disease were examined. Intact fibroblast growth factor 23 was higher and total alkaline phosphatase lower in patients with compared to patients without ADPKD with chronic kidney disease. Compared to healthy individuals, patients with ADPKD demonstrated significantly lower osteoid volume/bone volume (0.61 vs. 1.21%) and bone formation rate/bone surface (0.012 vs. 0.026 µm3/µm2/day). ESKD due to ADPKD was not associated with a higher risk of fracture as compared to ESKD due to diabetes (age adjusted incidence rate ratio: 0.53 (95% confidence interval 0.31, 0.74) or compared to other etiologies of kidney disease. Thus, individuals with ADPKD have lower alkaline phosphatase, higher circulating intact fibroblast growth factor 23 and decreased bone formation rate. However, ADPKD is not associated with higher rates of bone fracture in ESKD.

Design and Rationale of HiLo: A Pragmatic, Randomized Trial of Phosphate Management for Patients Receiving Maintenance Hemodialysis.

RATIONALE & OBJECTIVE: Hyperphosphatemia is a risk factor for poor clinical outcomes in patients with kidney failure receiving maintenance dialysis. Opinion-based clinical practice guidelines recommend the use of phosphate binders and dietary phosphate restriction to lower serum phosphate levels toward the normal range in patients receiving maintenance dialysis, but the benefits of these approaches and the optimal serum phosphate target have not been tested in randomized trials. It is also unknown if aggressive treatment that achieves unnecessarily low serum phosphate levels worsens outcomes. STUDY DESIGN: Multicenter, pragmatic, cluster-randomized clinical trial. SETTING & PARTICIPANTS: HiLo will randomize 80-120 dialysis facilities operated by DaVita Inc and the University of Utah to enroll 4,400 patients undergoing 3-times-weekly, in-center hemodialysis. INTERVENTION: Phosphate binder prescriptions and dietary recommendations to achieve the "Hi" serum phosphate target (≥6.5 mg/dL) or the "Lo" serum phosphate target (<5.5 mg/dL). OUTCOMES: Primary outcome: Hierarchical composite outcome of all-cause mortality and all-cause hospitalization. Main secondary outcomes: Individual components of the primary outcome. RESULTS: The trial is currently enrolling. LIMITATIONS: HiLo will not adjudicate causes of hospitalizations or mortality and does not protocolize use of specific phosphate binder classes. CONCLUSIONS: HiLo aims to address an important clinical question while more generally advancing methods for pragmatic clinical trials in nephrology by introducing multiple innovative features including stakeholder engagement in the study design, liberal eligibility criteria, use of electronic informed consent, engagement of dietitians to implement the interventions in real-world practice, leveraging electronic health records to eliminate dedicated study visits, remote monitoring of serum phosphate separation between trial arms, and use of a novel hierarchical composite outcome. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT04095039.

Change in Cardiac Biomarkers and Risk of Incident Heart Failure and Atrial Fibrillation in CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Circulating cardiac biomarkers may signal potential mechanistic pathways involved in heart failure (HF) and atrial fibrillation (AF). Single measures of circulating cardiac biomarkers are strongly associated with incident HF and AF in chronic kidney disease (CKD). We tested the associations of longitudinal changes in the N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), galectin-3, growth differentiation factor 15 (GDF-15), and soluble ST-2 (sST-2) with incident HF and AF in patients with CKD. STUDY DESIGN: Observational, case-cohort study design. SETTING & PARTICIPANTS: Adults with CKD enrolled in the Chronic Renal Insufficiency Cohort study. EXPOSURES: Biomarkers were measured at baseline and 2 years later among those without kidney failure. We created 3 categories of absolute change in each biomarker: the lowest quartile, the middle 2 quartiles, and the top quartile. OUTCOMES: The primary outcomes were incident HF and AF. ANALYTICAL APPROACH: Cox proportional hazards regression models were used to test the associations of the change categories of each cardiac biomarker with each outcome (with the middle 2 quartiles of change as the referent group), adjusting for potential confounders and baseline concentrations of each biomarker. RESULTS: The incident HF analysis included 789 participants (which included 138 incident HF cases), and the incident AF analysis included 774 participants (123 incident AF cases). In multivariable models, the top quartile of NT-proBNP change (>232pg/mL over 2years) was associated with increased risk of incident HF (HR, 1.79 [95% CI, 1.06-3.04]) and AF (HR, 2.32 [95% CI, 1.37-3.93]) compared with the referent group. Participants in the top quartile of sST2 change (>3.37ng/mL over 2years) had significantly greater risk of incident HF (HR, 1.89 [95% CI, 1.13-3.16]), whereas those in the bottom quartile (≤-3.78ng/mL over 2years) had greater risk of incident AF (HR, 2.43 [95% CI, 1.39-4.22]) compared with the 2 middle quartiles. There was no association of changes in hsTnT, galectin-3, or GDF-15 with incident HF or AF. LIMITATIONS: Observational study. CONCLUSIONS: In CKD, increases in NT-proBNP were significantly associated with greater risk of incident HF and AF, and increases in sST2 were associated with HF. Further studies should investigate whether these markers of subclinical cardiovascular disease can be modified to reduce the risk of cardiovascular disease in CKD.

Novel Risk Factors for Progression of Diabetic and Nondiabetic CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Identification of novel risk factors for chronic kidney disease (CKD) progression may inform mechanistic investigations and improve identification of high-risk subgroups. The current study aimed to characterize CKD progression across levels of numerous risk factors and identify independent risk factors for CKD progression among those with and without diabetes. STUDY DESIGN: The Chronic Renal Insufficiency Cohort (CRIC) Study is a prospective cohort study of adults with CKD conducted at 7 US clinical centers. SETTING & PARTICIPANTS: Participants (N=3,379) had up to 12.3 years of follow-up; 47% had diabetes. PREDICTORS: 30 risk factors for CKD progression across sociodemographic, behavioral, clinical, and biochemical domains at baseline. OUTCOMES: Study outcomes were estimated glomerular filtration rate (eGFR) slope and the composite of halving of eGFR or initiation of kidney replacement therapy. ANALYTICAL APPROACH: Stepwise selection of independent risk factors was performed stratified by diabetes status using linear mixed-effects and Cox proportional hazards models. RESULTS: Among those without and with diabetes, respectively, mean eGFR slope was-1.4±3.3 and-2.7±4.7mL/min/1.73m2 per year. Among participants with diabetes, multivariable-adjusted hazard of the composite outcome was approximately 2-fold or greater with higher levels of the inflammatory chemokine CXCL12, the cardiac marker N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the kidney injury marker urinary neutrophil gelatinase-associated lipocalin (NGAL). Among those without diabetes, low serum bicarbonate and higher high-sensitivity troponin T, NT-proBNP, and urinary NGAL levels were all significantly associated with a 1.5-fold or greater rate of the composite outcome. LIMITATIONS: The observational study design precludes causal inference. CONCLUSIONS: Strong associations for cardiac markers, plasma CXCL12, and urinary NGAL are comparable to that of systolic blood pressure≥140mm Hg, a well-established risk factor for CKD progression. This warrants further investigation into the potential mechanisms that these markers indicate and opportunities to use them to improve risk stratification.