Faculty Bibliography

Context:Mineral and bone disorders (MBDs) might be relevant in the etiology of infection. Objective:To determine whether MBD biomarkers were associated with the incidence of hospitalization with infection. We also assessed the cross-sectional association between MBD biomarker levels and kidney function. Design, Setting, Participants:Community-based cohort study of 11,218 participants with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m2 in the Atherosclerosis Risk in Communities study. We assessed the cross-sectional associations of five MBD markers-fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), calcium corrected for hypoalbuminemia, and phosphorus-with eGFR from 1990 to 1992 and their longitudinal associations with incident hospitalization with infection in 1990 to 2013. Main Outcome:Incident hospitalization with infection. Results:In age-, sex-, and race-adjusted models, lower eGFRs were significantly associated with greater levels of FGF23, PTH, and corrected calcium but not 25(OH)D or phosphorus. During follow-up, 5078 hospitalizations with infection occurred. In fully adjusted Cox models, with the second quartile as the reference, the hazard ratio (HR) was significantly greater in the highest quartile of FGF23 [HR, 1.12; 95% confidence interval (CI), 1.03 to 1.21], PTH (HR, 1.09; 95% CI, 1.01 to 1.18), and corrected calcium (HR, 1.11; 95% CI, 1.03 to 1.20), and lowest quartile for 25(OH)D (HR, 1.11; 95% CI, 1.03 to 1.21). The association with phosphorus was significant only when the outcome was restricted to primary diagnosis of infection. These findings were consistent across subgroups of age, sex, race, and eGFR (<60 vs ≥60 mL/min/1.73 m2). Conclusions:MBD biomarkers were associated with eGFR and the subsequent risk of infection, supporting MBD involvement in the etiology of infection.

While much emphasis, and some controversy, centers on recommendations for sodium intake, there has been considerably less interest in recommendations for dietary potassium intake, in both the general population and patients with medical conditions, particularly acute and chronic kidney disease. Physiology literature and cohort studies have noted that the relative balance in sodium and potassium intakes is an important determinant of many of the sodium-related outcomes. A noteworthy characteristic of potassium in clinical medicine is the extreme concern shared by many practitioners when confronted by a patient with hyperkalemia. Fear of this often asymptomatic finding limits enthusiasm for recommending potassium intake and often limits the use of renin-angiotensin-aldosterone system blockers in patients with heart failure and chronic kidney diseases. New agents for managing hyperkalemia may alter the long-term management of heart failure and the hypertension, proteinuria, and further function loss in chronic kidney diseases. In this jointly sponsored effort between the American Society of Hypertension and the National Kidney Foundation, 3 panels of researchers and practitioners from various disciplines discussed and summarized current understanding of the role of potassium in health and disease, focusing on cardiovascular, nutritional, and kidney considerations associated with both hypo- and hyperkalemia.

While much emphasis, and some controversy, centers on recommendations for sodium intake, there has been considerably less interest in recommendations for dietary potassium intake, in both the general population and patients with medical conditions, particularly acute and chronic kidney disease. Physiology literature and cohort studies have noted that the relative balance in sodium and potassium intakes is an important determinant of many of the sodium-related outcomes. A noteworthy characteristic of potassium in clinical medicine is the extreme concern shared by many practitioners when confronted by a patient with hyperkalemia. Fear of this often asymptomatic finding limits enthusiasm for recommending potassium intake and often limits the use of renin-angiotensin-aldosterone system blockers in patients with heart failure and chronic kidney diseases. New agents for managing hyperkalemia may alter the long-term management of heart failure and the hypertension, proteinuria, and further function loss in chronic kidney diseases. In this jointly sponsored effort between the American Society of Hypertension and the National Kidney Foundation, 3 panels of researchers and practitioners from various disciplines discussed and summarized current understanding of the role of potassium in health and disease, focusing on cardiovascular, nutritional, and kidney considerations associated with both hypo- and hyperkalemia.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Causes of CKD differ in prognosis and treatment. Metabolomic indicators of CKD cause may provide clues regarding the different physiologic processes underlying CKD development and progression. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS/METHODS:=423). RESULTS:<0.007), with all replicated metabolites exhibiting higher levels in polycystic kidney disease and lower levels in glomerular disease compared with CKD of other causes. CONCLUSIONS:Metabolomic profiling identified several metabolites strongly associated with cause of CKD.

Chronic kidney disease (CKD) is defined by reduced estimated glomerular filtration rate (eGFR). Previous genetic studies have implicated regulatory mechanisms contributing to CKD. Here we present epigenome-wide association studies of eGFR and CKD using whole-blood DNA methylation of 2264 ARIC Study and 2595 Framingham Heart Study participants to identify epigenetic signatures of kidney function. Of 19 CpG sites significantly associated (P < 1e-07) with eGFR/CKD and replicated, five also associate with renal fibrosis in biopsies from CKD patients and show concordant DNA methylation changes in kidney cortex. Lead CpGs at PTPN6/PHB2, ANKRD11, and TNRC18 map to active enhancers in kidney cortex. At PTPN6/PHB2 cg19942083, methylation in kidney cortex associates with lower renal PTPN6 expression, higher eGFR, and less renal fibrosis. The regions containing the 243 eGFR-associated (P < 1e-05) CpGs are significantly enriched for transcription factor binding sites of EBF1, EP300, and CEBPB (P < 5e-6). Our findings highlight kidney function associated epigenetic variation.

Background/UNASSIGNED:Reduced kidney function is a common public health problem that increases risk for a wide variety of adverse outcomes, making the identification of potentially modifiable factors associated with the development of incident chronic kidney disease (CKD) important. Alterations in the hypothalamic-pituitary-thyroid axis have been linked to reduced kidney function, but the association of thyroid function with the development of incident CKD is largely uncharacterized. Methods/UNASSIGNED:Concentrations of thyroid stimulating hormone (TSH), free thyroxine (FT4), triiodothyronine (T3) and thyroid peroxidase antibody (TPOAb) were quantified in 12 785 black and white participants of the ongoing community-based prospective Atherosclerosis Risk in Communities study. Thyroid markers and clinical categories of thyroid dysfunction (euthyroidism, combined subclinical and overt hypothyroidism, combined subclinical and overt hyperthyroidism) were also evaluated for their association with reduced kidney function (estimated glomerular filtration rate <60 mL/min/1.73 m2) at study baseline and with incident CKD over a median follow-up time of 19.6 years. Results/UNASSIGNED:Higher TSH and FT4 as well as lower T3 concentrations were strongly and independently associated with reduced kidney function at study baseline. The clinical entities hypothyroidism and hyperthyroidism were also associated with higher odds of baseline reduced kidney function, but this was not significant. However, none of the markers of thyroid function nor different clinical categories of thyroid dysfunction (hypothyroidism, hyperthyroidism or TPOAb positivity) were associated with incident CKD in adjusted analyses. Conclusions/UNASSIGNED:Elevated TSH, FT4 and reduced T3 concentrations were associated with reduced kidney function cross-sectionally. The lack of association with the development of incident CKD suggests that altered thyroid function in the general population is not causally related to CKD development, but screening for thyroidal status may be especially relevant in persons with reduced kidney function.

Endothelin-1, a marker of endothelial dysfunction, is a potent vasoconstrictor released by endothelial cells and an important regulator of renal physiology. It is not known whether elevated serum levels of endothelin-1 indicate future risk of kidney disease in the general population. In participants in the Jackson Heart Study, a community-based observational study of cardiovascular risk in black adults, we measured serum endothelin-1 level at baseline (2000-2004; n=3538). We defined incident CKD as eGFR<60 ml/min per 1.73 m² and ≥30% eGFR decline at the third visit (2009-2013) relative to baseline among those participants with baseline eGFR ≥60 ml/min per 1.73 m² At baseline, mean age was 55 years old, 37% of participants were men, and mean eGFR was 94 ml/min per 1.73 m² Over a median follow-up of 8 years, 228 (6.4%) cases of incident CKD occurred in participants. Participants with baseline endothelin-1 levels in higher quartiles had a greater incidence of CKD in the fully adjusted model (odds ratio for fourth versus first quartile, 1.81; 95% confidence interval, 1.11 to 2.96; P

Glutathione S-transferase mu 1 (GSTM1) encodes an enzyme that catalyzes the conjugation of electrophilic compounds with glutathione to facilitate their degradation or excretion. The loss of one or both copies of GSTM1 is common in many populations and has been associated with CKD progression. With the hypothesis that the loss of GSTM1 is also associated with incident kidney failure and heart failure, we estimated GSTM1 copy number using exome sequencing reads in the Atherosclerosis Risk in Communities (ARIC) Study, a community-based prospective cohort of white and black participants. Overall, 51.2% and 39.8% of white participants and 25.6% and 48.5% of black participants had zero or one copy of GSTM1, respectively. Over a median follow-up of 24.6 years, 256 kidney failure events occurred in 5715 participants without prevalent kidney failure, and 1028 heart failure events occurred in 5368 participants without prevalent heart failure. In analysis adjusted for demographics, diabetes, and hypertension, having zero or one copy of GSTM1 associated with higher risk of kidney failure and heart failure (adjusted hazard ratio [95% confidence interval] for zero or one versus two copies of GSTM1: kidney failure, 1.66 [1.27 to 2.17]; heart failure, 1.16 [1.04 to 1.29]). Risk did not differ significantly between participants with zero and one copy of GSTM1 (P>0.10). In summary, the loss of GSTM1 was significantly associated with incident kidney and heart failure, independent of traditional risk factors. These results suggest GSTM1 function is a potential treatment target for the prevention of kidney and heart failure.

BACKGROUND:Reduced lung function is associated with clinical outcomes such as cardiovascular disease. However, little is known about its association with incident end-stage renal disease (ESRD) and chronic kidney disease (CKD). STUDY DESIGN/METHODS:Prospective cohort study. SETTING & PARTICIPANTS/METHODS:14,946 participants aged 45 to 64 years at baseline (1987-1989) in the Atherosclerosis Risk in Communities (ARIC) Study (45.0% men and 25.2% black), with follow-up through 2012. PREDICTORS/METHODS:/FVC) at baseline determined with spirometry. OUTCOMES/RESULTS:, or CKD-related hospitalizations/deaths) as the secondary outcome. RESULTS:/FVC 70%-<75%; 44.3% of participants) at 1.21 (95% CI, 0.94-1.55). Similar associations were seen with incident CKD. LIMITATIONS/CONCLUSIONS:Limited number of participants with moderate/severe lung dysfunction and spirometry only at baseline. CONCLUSIONS:Reduced lung function, particularly lower percent-predicted FVC, is independently associated with CKD progression. Our findings suggest a potential pathophysiologic contribution of reduced lung function to the development of CKD and a need for monitoring kidney function in persons with reduced lung function.

OBJECTIVE:Sodium-glucose cotransporter-2 (SGLT2) inhibitors are new medications that improve cardiovascular and renal outcomes in patients with type 2 diabetes (T2D). However, the Food and Drug Administration has issued alerts regarding increased acute kidney injury (AKI) risk with canagliflozin and dapagliflozin. We aimed to assess the real-world risk of AKI in new SGLT2 inhibitor users in two large health care utilization cohorts of patients with T2D. RESEARCH DESIGN AND METHODS:). We performed 1:1 nearest-neighbor propensity matching and calculated unadjusted hazard ratios (HRs) and adjusted HRs (aHRs; accounting for covariates poorly balanced) for AKI in primary and sensitivity analyses. RESULTS:= 0.09). These estimates did not qualitatively change across several sensitivity analyses. CONCLUSIONS:Our findings do not suggest an increased risk of AKI associated with SGLT2 inhibitor use in patients with T2D in two large health systems.