Nishank Jain

Association of urinary sodium-to-potassium ratio with obesity in a multiethnic cohort

BACKGROUND Previous studies that reported an association of dietary Na(+) intake with metabolic syndrome were limited by the use of imprecise measures of obesity, Na(+) intake, or exclusion of multiethnic populations. The effect of dietary K(+) intake on obesity is less well described. OBJECTIVE We hypothesized that high dietary Na(+) and low K(+), based on the ratio of urinary Na(+) to K(+) (U[Na(+)]/[K(+)]) in a first-void morning urinary sample, is independently associated with total body fat. DESIGN In a prospective population-based cohort, 2782 participants in the community-dwelling, probability-sampled, multiethnic Dallas Heart Study were analyzed. The primary outcome established a priori was total-body percentage fat (TBPF) measured by dual-energy X-ray absorptiometry. The main predictor was U[Na(+)]/[K(+)]. Robust linear regression was used to explore an independent association between U[Na(+)]/[K(+)] and TBPF. The analyses were stratified by sex and race after their effect modifications were analyzed. RESULTS Of the cohort, 55.4% were female, 49.8% African American, 30.8% white, 17.2% Hispanic, and 2.2% other races. The mean (±SD) age was 44 ± 10 y, BMI (in kg/m(2)) was 30 ± 7, TBPF was 32 ± 10%, and U[Na(+)]/[K(+)] was 4.2 ± 2.6; 12% had diabetes. In the unadjusted and adjusted models, TBPF increased by 0.75 (95% CI: 0.25, 1.25) and 0.43 (0.15, 0.72), respectively (P = 0.003 for both), for every 3-unit increase in U[Na(+)]/[K(+)]. A statistically significant interaction was found between race and U[Na(+)] /[K(+)], so that the non-African American races had a higher TBPF than did the African Americans per unit increase in U[Na(+)]/[K(+)] (P-interaction < 0.0001 for both). No interaction was found between sex and U[Na(+)]/[K(+)]. CONCLUSIONS The ratio of dietary Na(+) to K(+) intake may be independently associated with TBPF, and this association may be more pronounced in non-African Americans. Future studies should explore whether easily measured spot U[Na(+)]/[K(+)] can be used to monitor dietary patterns and guide strategies for obesity management.

Effects of dietary interventions on incidence and progression of CKD

Traditional strategies for management of patients with chronic kidney disease (CKD) have not resulted in any change in the growing prevalence of CKD worldwide. A historic belief that eating healthily might ameliorate kidney disease still holds credibility in the 21st century. Dietary sodium restriction to <2.3 g daily, a diet rich in fruits and vegetables and increased water consumption corresponding to a urine output of 3–4 l daily might slow the progression of early CKD, polycystic kidney disease or recurrent kidney stones. Current evidence suggests that a reduction in dietary net acid load could be beneficial in patients with CKD, but the supremacy of any particular diet has yet to be established. More trials of dietary interventions are needed, especially in diabetic nephropathy, before evidence-based recommendations can be made. In the meantime, nephrologists should discuss healthy dietary habits with their patients and provide individualized care aimed at maximizing the potential benefits of dietary intervention, reducing the incidence of CKD and delaying its progression to end-stage renal disease. Keeping in mind the lack of data on hard outcomes, dietary recommendations should take into account barriers to adherence and be tailored to different cultures, ethnicities and geographical locations.

Rationale and Design of the Chronic Kidney Disease Antidepressant Sertraline Trial (CAST)

Major Depressive Disorder (MDD) affects one in five patients with Chronic Kidney Disease (CKD) and is an independent risk factor for hospitalization and death before and after dialysis initiation. However, it remains an under-recognized and under-treated problem, in part due to the lack of well-controlled studies that support or refute the efficacy and safety of antidepressant medications in CKD patients. Major trials of antidepressant treatment excluded patients with stages 3-5 CKD, precisely those at higher risk for both depression and increased mortality. The Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) is a randomized, double-blinded, placebo-controlled trial of sertraline, a selective serotonin reuptake inhibitor (SSRI). It will enroll 200 adults with stages 3-5 CKD and MDD excluding kidney transplant and chronic dialysis patients. Sertraline will be administered at an initial dose of 50mg once daily or matching placebo followed by a dose escalation strategy consisting of 50mg increments at 2week intervals (as tolerated) to a maximum dose of 200mg. The primary outcome is improvement in depression symptom severity measured by the Quick Inventory of Depressive Symptomatology scale. Secondary outcomes include safety endpoints and improvement in quality of life. Changes in cognitive function, adherence to medications, nutritional status, inflammation, and platelet function will be explored as potential mechanisms by which depression may mediate poor outcomes. We discuss the rationale and design of the CAST study, the largest placebo-controlled trial aimed to establish safety and efficacy of a SSRI in the acute phase treatment of CKD patients with MDD.

Antiplatelet Therapy in the Management of Cardiovascular Disease in Patients with CKD: What Is the Evidence?

Antiplatelet agents (APAs) are proven to reduce risk of major cardiovascular events in patients with cardiovascular disease and normal kidney function. With recent post hoc analyses of large trials questioning the safety and efficacy of APAs in CKD, major gaps exist in our understanding of platelet aggregability and the effects of APAs on thrombosis and bleeding in CKD. Clinical practice guidelines are ambiguous about use of such agents in CKD patients, because patients with moderate to advanced CKD were systematically excluded from clinical trials of APAs. CKD patients experience excessive rates of cardiovascular thrombotic events, yet paradoxically are at higher risk for major bleeding while receiving APAs. Furthermore, observational studies suggest that CKD patients may exhibit poor response to APAs. High residual platelet aggregability, as determined by inhibition of platelet aggregation, is associated with increased risk for cardiovascular events. In addition, metabolism of certain APAs may be altered in CKD patients. It is, therefore, imperative to explore the mechanisms responsible for poor response to APAs in CKD patients in order to use these drugs more safely and effectively. This review identifies the knowledge gaps and future trials needed to address those issues with the use of APAs in CKD patients.

Effect of Sertraline on Depressive Symptoms in Patients With Chronic Kidney Disease Without Dialysis Dependence: The CAST Randomized Clinical Trial

Importance Major depressive disorder (MDD) is prevalent among patients with chronic kidney disease (CKD) and is associated with morbidity and mortality. The efficacy and adverse events of selective serotonin reuptake inhibitors in these patients are unknown. Objective To determine whether treatment with sertraline improves depressive symptoms in patients with CKD and MDD. Design, Setting, and Participants The Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) was a randomized, double-blind, placebo-controlled trial involving 201 patients with stage 3, 4, or 5 non–dialysis-dependent CKD, who were enrolled at 3 US medical centers. The Mini Neuropsychiatric Interview was used to establish MDD. The first participant was randomized in March 2010 and the last clinic visit occurred in November 2016. Interventions After a 1-week placebo run-in, participants were randomized to sertraline (n = 102) for 12 weeks at an initial dose of 50 mg/d (escalated to a maximum dose of 200 mg/d based on tolerability and response) or matching placebo (n = 99). Main Outcomes and Measures The primary outcome was improvement in depressive symptom severity from baseline to 12 weeks determined by the 16-item Quick Inventory of Depression Symptomatology–Clinician Rated (QIDS-C16) (score range, 0-27; minimal clinically important difference, 2 points). Secondary outcomes included improvement in quality of life (Kidney Disease Quality of Life Survey–Short Form; score range, 0-100; higher scores indicate more favorable quality of life) and adverse events. Results There were 201 patients (mean [SD] age, 58.2 [13.2] years; 27% female) randomized. The primary analysis included 193 patients who had at least 1 outcome assessment after randomization. The mean (SD) baseline QIDS-C16 score was 14.0 (2.4) in the sertraline group (n = 97) and 14.1 (2.4) in the placebo group (n = 96). The median participation time was 12.0 weeks and the median achieved dose was 150 mg/d, which was not significantly different between the groups. The QIDS-C16 score changed by −4.1 in the sertraline group and by −4.2 in the placebo group (between-group difference, 0.1 [95% CI, −1.1 to 1.3]; P = .82). There was no significant between-group difference in change in patient-reported overall health on the Kidney Disease Quality of Life Survey (median score, 0 in the sertraline group vs 0 in the placebo group; between-group difference, 0 [95% CI, −10.0 to 0]; P = .61). Nausea or vomiting occurred more frequently in the sertraline vs placebo group (22.7% vs 10.4%, respectively; between-group difference, 12.3% [95% CI, 1.9% to 22.6%], P = .03), as well as diarrhea (13.4% vs 3.1%; between-group difference, 10.3% [95% CI, 2.7% to 17.9%], P = .02). Conclusions and Relevance Among patients with non–dialysis-dependent CKD and MDD, treatment with sertraline compared with placebo for 12 weeks did not significantly improve depressive symptoms. These findings do not support the use of sertraline to treat MDD in patients with non–dialysis-dependent CKD. Trial Registration clinicaltrials.gov Identifier: NCT00946998

Hungry bone syndrome

Purpose of review In the United States, the number of parathyroidectomies among patients with chronic dialysis has remained stable in the last decade. A fall in serum calcium concentration is common postparathyroidectomy in patients with hyperparathyroidism, which usually resolves in 2–4 days. A severe drop in serum total calcium concentration less than 2.1 mmol/L and/or prolonged hypocalcemia for more than 4 days postparathyroidectomy is called hungry bone syndrome (HBS). Concomitant hypophosphatemia, hypomagnesemia, and hyperkalemia can be seen. Hypocalcemia and hypophosphatemia can persist for months to years. In contemporary clinical practice, HBS may be more commonly seen in patients with secondary compared to primary hyperparathyroidism. Preoperative radiological changes in bone, elevated serum alkaline phosphatase and parathyroid hormone (PTH) levels, and high numbers of osteoclasts on bone biopsy may identify patients at risk. Treatment consists of high-dose oral calcium and calcitriol supplementation. A low-dose pamidronate infusion 1–2 days prior to surgery may prevent HBS. Recent findings Recent in-vitro studies reported net calcium movement into bone because of a sudden fall in serum PTH level after a prolonged period of elevation. This supports a previous hypothesis that a sudden drop in serum PTH level after surgery results in the unopposed action of osteoblasts and influx of calcium into bone. Summary Incidence of HBS and its association with morbidity and mortality remains unclear in contemporary clinical practice. It is more common to encounter HBS in chronic dialysis patients with secondary hyperparathyroidism than those with primary hyperparathyroidism that undergo parathyroidectomies. Use of bisphosphonates to prevent HBS should be explored in future studies.

Effect Modification of Chronic Kidney Disease on the Association of Circulating and Imaging Cardiac Biomarkers With Outcomes

Background Cardiac troponin T and brain natriuretic peptide (BNP) are elevated in >50% of dialysis patients and are associated with poor outcomes. Few data investigated these associations in earlier chronic kidney disease (CKD). Methods and Results We studied whether CKD modified associations of elevated BNP, N‐terminal‐pro‐BNP, high‐sensitivity cardiac troponin T, coronary artery calcification, and left ventricular hypertrophy with all‐cause death and cardiovascular death/events in 3218 multiethnic individuals followed for 12.5 years, and whether biomarkers added prognostic information to traditional cardiovascular risk factors in CKD. Of the cohort, 279 (9%) had CKD. There were 296 deaths and 218 cardiovascular deaths/events. Of non‐CKD individuals, 7% died and 6% had cardiovascular death/event versus 32% and 30% of CKD participants, P<0.001 for both. The interaction between BNP and CKD on death was significant (P=0.01): the adjusted hazard ratio in CKD was 2.05, 95% CI (1.34, 3.14), but not significant in non‐CKD, 1.04 (0.76, 1.41). CKD modified the association of high‐sensitivity cardiac troponin T with cardiovascular death/event, adjusted hazard ratio 3.34 (1.56, 7.18) in CKD versus 1.65 (1.16, 2.35) in non‐CKD, interaction P=0.09. There was an interaction between N‐terminal‐pro‐BNP and CKD for death in those without prior cardiovascular disease. Addition of each biomarker to traditional risk factors improved risk prediction, except coronary artery calcification was not discriminatory for cardiovascular death/event in CKD. Conclusions Cardiac biomarkers, with the exception of coronary artery calcification, prognosticated outcomes in early‐stage CKD as well as, if not better than, in non‐CKD individuals, even after controlling for estimated glomerular filtration rate, and added to information obtained from traditional cardiovascular risk factors alone.

Dietary phosphate: what do we know about its toxicity.

UNLABELLED Inorganic phosphate (Pi) is an essential mineral required for diverse cellular processes. Recent genetic and dietary experiments in animal models indicate that Pi may be toxic to a variety of biological processes. High dietary Pi load in such animal models resulted in an increase in oxidative stress, DNA damage that resulted in phenotypic expression of premature aging, and short life span. Further, high Pi load was reported to induce carcinogenesis in lung and skin cancer animal models. So far, translational research is limited to observational studies that show an independent association of Pi intake with morbidity and mortality across all strata of kidney function. Fast-food and processed-food consumption in an average American diet leads to large increases in daily phosphate intake. Whether such dietary patterns explain the epidemiology of disease processes in humans remains to be further investigated. CONCLUSION Phosphotoxicity is a novel concept with a potential for a large public health impact in future, but urgent studies are needed to prove reducing Pi intake to a certain target generates better clinical outcomes.

How should clinicians interpret cardiac troponin values in patients with ESRD

Division of Nephrology, Department of Medicine, Veterans Affairs North Texas Health CareSystem, Dallas, TexasCardiovascular (CV) mortality is the predominant cause of death in patients with end-stagerenal disease (ESRD). The cause-specific hospitalization rates for CV events and coronaryrevascularization remain high in chronic dialysis patients (1). Chest pain or anginalequivalents are frequently encountered symptoms in the dialysis unit, and early riskstratification for acute coronary syndrome (ACS) is required, as early intervention such asimmediate reperfusion therapy improves outcomes. The American College of Cardiologyand the American Heart Association guidelines incorporated cardiac-specific troponin T(cTnT) and troponin I (cTnI) in the definition of acute myocardial infarction (AMI) anddeemed troponins as the preferred marker for myocardial injury and early risk stratificationof patients who present with suspected ACS (2). The European Society of Cardiologydefines AMI as “detection of rise and or fall of cardiac biomarkers (preferably troponins)with at least one value above the 99th percentile of the upper reference limits (URL),together with evidence of myocardial ischemia with at least one of the following: symptomsof ischemia, EKG changes indicative of new ischemia, development of pathological Qwaves on EKG, or imaging evidence of new loss of viable myocardium or new regional wallmotion abnormality (3).” The diagnostic utility of troponins in patients with ESRD,however, is challenging because the URL were initially derived in subjects without kidneydisease.It is important to understand the unique biochemical and analytical differences in cTnT andcTnI assays to better interpret these diagnostic tests in patients with ESRD. Sufficientdissimilarity between the amino acid sequences of the skeletal and cardiac isoforms of bothTnT and TnI has allowed development of monoclonal antibody-based immunoassays fortheir detection. cTnT and cTnI have different release kinetics after myocardial injury(biphasic vs. monophasic) because of differential compartmentation in the cardiac myocyte,and it was proposed that the kinetics may be altered in dialysis patients (4). Free cTnT is thepredominant form of released TnT as compared to binary/ternary complexes released withcTnI. Some cTnI is also released in oxidized, phosphorylated, or reduced forms. This mayalter the epitope conformation recognized by the monoclonal antibodies in the assays andaccount for low TnI levels in the serum (4). cTnI assays have been developed using differentmonoclonal/polyclonal antibodies directed to various epitopes or isoforms. Anotherchallenge for developing cTnI assays arises from its instability and high susceptibility toproteolysis. Therefore, standardization is lacking in cTnI assays as compared to cTnT (5).

Differences in Whole Blood Platelet Aggregation at Baseline and in Response to Aspirin and Aspirin Plus Clopidogrel in Patients With Versus Without Chronic Kidney Disease.

Thrombotic events while receiving antiplatelet agents (APAs) are more common in subjects with versus without chronic kidney disease (CKD). Data on antiplatelet effects of APA in CKD are scarce and limited by lack of baseline platelet function before APA treatment. We hypothesized subjects with stages 4 to 5 CKD versus no CKD have greater baseline platelet aggregability and respond poorly to aspirin and clopidogrel. In a prospective controlled study, we measured whole blood platelet aggregation (WBPA) in 28 CKD and 16 non-CKD asymptomatic stable outpatients not on APA, frequency-matched for age, gender, obesity, and diabetes mellitus. WBPA was remeasured after 2 weeks of each aspirin and aspirin plus clopidogrel. The primary outcome was percent inhibition of platelet aggregation (IPA) from baseline. The secondary outcome was residual platelet aggregability (RPA; proportion with <50% IPA). Baseline platelet aggregability was similar between groups except adenosine diphosphate-induced WBPA, which was higher in CKD versus non-CKD; median (interquartile range) = 13.5 (9.5 to 16.0) versus 9.0 (6.0 to 12.0) Ω, p = 0.007. CKD versus non-CKD participants had lower clopidogrel-induced IPA, 38% versus 72%, p = 0.04. A greater proportion of CKD versus non-CKD participants had RPA after clopidogrel treatment (56% vs 8.3%, p = 0.01). There were no significant interactions between CKD and the presence of cytochrome P450 2C19 polymorphisms for platelet aggregability in clopidogrel-treated participants. In conclusion, CKD versus non-CKD subjects exhibited similar platelet aggregation at baseline, similar aspirin effects and greater RPA on clopidogrel, which was independent of cytochrome P450 2C19 polymorphisms.