Ashish Upadhyay

Multiple loci associated with indices of renal function and chronic kidney disease

Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m2) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10−8) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

Impact of Hospital-Associated Hyponatremia on Selected Outcomes

BACKGROUNDnHyponatremia is the most common electrolyte disorder encountered in hospitalized patients.nnnMETHODSnWe evaluated whether hospital-associated hyponatremia has an independent effect on all-cause mortality, hospital length of stay (LOS), and patient disposition. This cohort study included all adult hospitalizations at an academic medical center occurring between 2000-2007 for which an admission serum sodium concentration ([Na(+)]) was available (N = 53 236). We examined community-acquired hyponatremia (admission serum [Na(+)], <138 mEq/L [to convert to millimoles per liter, multiply by 1.0]), hospital-aggravated hyponatremia (community-acquired hyponatremia complicated by worsening in serum [Na(+)]), and hospital-acquired hyponatremia (nadir serum [Na(+)], <138 mEq/L with a normal admission serum [Na(+)]). The independent associations of these hyponatremic presentations with in-hospital mortality, LOS, and patient disposition were evaluated using generalized estimating equations adjusted for age, sex, race, admission service, and Deyo-Charlson Comorbidity Index score.nnnRESULTSnCommunity-acquired hyponatremia occurred in 37.9% of hospitalizations and was associated with adjusted odds ratios (ORs) of 1.52 (95% confidence interval [CI], 1.36-1.69) for in-hospital mortality and 1.12 (95% CI, 1.08-1.17) for discharge to a short- or long-term care facility and a 14% (95% CI, 11%-16%) adjusted increase in LOS. Hospital-acquired hyponatremia developed in 38.2% of hospitalizations longer than 1 day in which initial serum [Na(+)] was 138 to 142 mEq/L. Hospital-acquired hyponatremia was associated with adjusted ORs of 1.66 (95% CI, 1.39-1.98) for in-hospital mortality and 1.64 (95% CI, 1.55-1.74) for discharge to a facility and a 64% (95% CI, 60%-68%) adjusted increase in LOS. The strength of these associations tended to increase with hyponatremia severity.nnnCONCLUSIONSnHospital-associated hyponatremia is a common occurrence. All forms of hyponatremia are independently associated with in-hospital mortality and heightened resource consumption.

Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors

Background—Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD). Methods and Results—Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Womens Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10−8 to 2×10−242 in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 &mgr;mol/L; P=3×10−39) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Womens Genome Health Study. Conclusions—The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.

Epidemiology of Hyponatremia

Hyponatremia is the most common electrolyte abnormality encountered in clinical practice with wide-ranging prognostic implications in a variety of conditions. This review summarizes the available literature on the epidemiology of hyponatremia in both hospitalized and ambulatory-based patients. Particular attention is given to hyponatremia in the geriatric population, drug-induced hyponatremia, exercise-associated hyponatremia, and the medical costs of hyponatremia. The frequency and outcomes of hyponatremia in congestive heart failure, cirrhosis, pneumonia, and human immunodeficiency virus infection also are reviewed. Although the knowledge on hyponatremia has expanded in the past few decades, the disorder largely remains an underdiagnosed condition. Substantial additional work is needed to improve the awareness of hyponatremia among medical professionals. The advent of vasopressin-receptor antagonists as a plausible treatment option for some forms of euvolemic and hypervolemic hyponatremia now offers the opportunity to gain further insights into the prognostic impact of hyponatremia and its management in various clinical settings.

Arterial Stiffness in Mild-to-Moderate CKD

Whether arterial stiffness correlates with mild-to-moderate CKD and albuminuria in the community is unclear. We studied the association between arterial stiffness and mild-to-moderate CKD and albuminuria in the Framingham Heart Study. CKD was present in 6.7% (181 of 2682) of participants and microalbuminuria was present in 8.2% (479 of 5818). The measures of arterial stiffness were the carotid femoral pulse wave velocity, forward pressure wave amplitude, central pulse pressure, augmentation pressure, augmentation index, and mean arterial pressure. In cross-sectional analyses, arterial stiffness did not associate with CKD (defined by estimated GFR <60 ml/min/1.73 m(2)) in either age- and gender-adjusted or multivariable-adjusted linear regression models. Carotid femoral pulse wave velocity associated with both urinary albumin-to-creatinine ratio and microalbuminuria (P < 0.0001 after multivariable adjustment). In longitudinal analyses, we used logistic regression models to examine the associations between baseline arterial stiffness measures (exposure variables) and incident CKD or microalbuminuria (n = 1675 for CKD analyses and n = 1252 for microalbuminuria analyses). Baseline arterial measures did not associate with incident CKD or incident microalbuminuria. In summary, arterial stiffness correlates with albuminuria but not with mild-to-moderate CKD.

Single-Use versus Reusable Dialyzers: The Known Unknowns

The practice of reusing dialyzers has been widespread in the United States for decades, with single use showing signs of resurgence in recent years. Reprocessing of dialyzers has traditionally been acknowledged to improve blood-membrane biocompatibility and prevent first-use syndromes. These proposed advantages of reuse have been offset by the introduction of more biocompatible membranes and favorable sterilization techniques. Moreover, reuse is associated with increased health hazard from germicide exposure and disposal. Some observational studies have also pointed to an increased mortality risk with dialyzer reuse, and the potential for legal liability is another concern. The desire to save cost is the major driving force behind the continued practice of dialyzer reuse in the United States. It is imperative that future research focus on the environmental consequences of dialysis, including the need for more optimal management of disinfectant-related waste with reuse, and solid waste with single use. The dialysis community has a responsibility to explore ways to mitigate environmental consequences before single-use and a more frequent dialysis regimen becomes a standard practice in the United States.

Renal artery calcium, cardiovascular risk factors, and indexes of renal function.

Vascular calcium is well studied in the coronary and peripheral arteries, although there are limited data focusing on calcium deposits specific to renal arteries. The associations among renal artery calcium (RAC), cardiovascular disease risk factors, and indexes of renal function are unknown. We examined 2,699 Framingham Heart Study participants who were part of a multidetector computed tomography substudy from 2008 to 2011. RAC was measured as a calcified plaque of >130 HU and an area of >3 contiguous pixels. Detectable RAC was defined as an Agatston score >0. Chronic kidney disease was defined as an estimated glomerular filtration rate of <60 ml/min/1.73 m(2). Microalbuminuria was defined as an albumin/creatinine ratio of ≥17 mg/g for men and ≥25 mg/g for women. Multivariable adjusted logistic regression models were used to evaluate the associations between RAC, cardiovascular disease risk factors, and renal function. The associations were secondarily adjusted for coronary artery calcium (CAC) that was used as a marker of nonrenal systemic vascular calcium. The prevalence of RAC was 28.2%; this was similar in women (28.8%) and men (27.5%). Patients with RAC had a higher odds of microalbuminuria (odds ratio [OR] 1.79, 95% confidence interval [CI] 1.22 to 2.61, p = 0.003), hypertension (OR 2.11, 95% CI 1.69 to 2.64, p <0.001), and diabetes (OR 1.60, 95% CI 1.14 to 2.24, p = 0.01) but not chronic kidney disease (OR 0.87, 95% CI 0.58 to 1.32). After adjustment for CAC, the association with microalbuminuria and hypertension persisted, but the association with diabetes became nonsignificant. In conclusion, RAC is common and independently associated with microalbuminuria and hypertension after adjustment for nonrenal vascular calcium. RAC may be uniquely associated with these markers of renal end-organ damage.

Efficacy and safety of lipid lowering by alirocumab in chronic kidney disease

Individuals with chronic kidney disease are at increased risk of premature cardiovascular disease. Among them, many with elevated low-density lipoprotein cholesterol (LDL-C) are unable to achieve optimal LDL-C on statins and require additional lipid-lowering therapy. To study this, we compared the LDL-C-lowering efficacy and safety of alirocumab in individuals with hypercholesterolemia with impaired renal function, defined as eGFR 30-59 ml/min/1.73 m2, to those without impaired renal function eGFR ≥60xa0ml/min/1.73 m2. A total of 4629 hypercholesterolemic individuals without or with impaired renal function, pooled from eight phase 3 ODYSSEY trials (double-blind treatments of 24-104 weeks), were on alirocumab 150 mg or 75/150 mg every two weeks vs. placebo or ezetimibe. Overall, 10.1% had impaired renal function and over 99% were receiving statin treatment. Baseline LDL-C in alirocumab and control groups was comparable in subgroups analyzed. LDL-C reductions at week 24 ranged from 46.1 to 62.2% or 48.3 to 60.1% with alirocumab among individuals with or without impaired renal function, respectively. Similar reductions were observed for lipoprotein (a), non-high-density lipoprotein cholesterol, apolipoprotein B, and triglycerides. Safety data were similar in both treatment subgroups, regardless of the degree of CKD. Renal function did not change over time in response to alirocumab. This post hoc efficacy analysis is limited by evaluation of alirocumab treatment effects on renal and lipid parameters by serum biochemistry. Thus, alirocumab consistently lowered LDL-C regardless of impaired renal function, with safety comparable to control, among individuals with hypercholesterolemia who nearly all were on statin treatment.

Statins in chronic kidney disease: what do meta-analyses tell us?

AbstractnDyslipidemia is common in patients with chronic kidney disease (CKD), and previous reports indicate that a significant number of CKD patients with dyslipidemia do not receive statin therapy. This article reviews two recent meta-analyses on statin therapy in CKD which summarize results from randomized controlled trials that have reported on hard clinical outcomes and major adverse events. Despite differences in methodology, both meta-analyses show that statin therapy is safe and effective in preventing mortality and major cardiovascular events in non-dialysis-dependent CKD patients. However, there is very limited evidence to support the use of statins in patients on dialysis, and statin therapy was not found to be effective in reducing the risk of kidney failure or decline in kidney function.

Program Characteristics Influencing Allopathic Students' Residency Selection.

CONTEXTnMedical students must consider many overt variables when entering the National Resident Matching Program. However, changes with the single graduate medical education accreditation system have caused a gap in knowledge about more subtle considerations, including what, if any, influence the presence of osteopathic physician (ie, DO) and international medical graduate (IMG) house officers has on allopathic students residency program preferences. Program directors and selection committee members may assume students implicit bias without substantiating evidence.nnnOBJECTIVEnTo reexamine which program characteristics affect US-trained allopathic medical students residency selection, and to determine whether the presence of DO and IMG house officers affects the program choices of allopathic medical students.nnnMETHODSnFourth-year medical students from 4 allopathic medical schools completed an online survey. The Pearson χ(2) statistic was used to compare demographic and program-specific traits that influence ranking decisions and to determine whether school type (private vs public), valuing a residency programs prestige, or interest in a competitive specialty dictated results. Qualitative data were analyzed using the Pandit variation of the Glaser and Strauss constant comparison.nnnRESULTSnSurveys were completed by 323 of 577 students (56%). Students from private vs public institutions were more likely to value a programs prestige (160 [93%] vs 99 [72%]; P<.001) and research opportunities (114 [66%] vs 57 [42%]; P<.001), and they were less likely to consider their prospects of being accepted (98 [57%] vs 111 [81%]; P<.001). A total of 33 (10%) and 52 (16%) students reported that the presence of DO or IMG trainees, respectively, would influence their final residency selection, and these percentages were largely unchanged among students interested in programs prestige or in entering a competitive specialty. Open-ended comments were generally optimistic about diversification of the physician workforce, and 4 of the 709 student comments expressed cynicism or hostility to the presence of DOs or IMGs.nnnCONCLUSIONnBoth overt and subtle variables influence students perceptions of residency programs in the United States, but the presence of DO and IMG house officers seems relevant to a small percentage of them.