Juan Jesús Carrero

Comparative Associations of Muscle Mass and Muscle Strength with Mortality in Dialysis Patients

BACKGROUND AND OBJECTIVESnReduced muscle mass and strength are prevalent conditions in dialysis patients. However, muscle strength and muscle mass are not congruent; muscle strength can diminish even though muscle mass is maintained or increased. This study addresses phenotype and mortality associations of these muscle dysfunction entities alone or in combination (i.e., concurrent loss of muscle mass and strength/mobility, here defined as sarcopenia).nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnThis study included 330 incident dialysis patients (203 men, mean age 53±13 years, and mean GFR 7±2 ml/min per 1.73 m(2)) recruited between 1994 and 2010 and followed prospectively for up to 5 years. Low muscle mass (by dual-energy x-ray absorptiometry appendicular mass index) and low muscle strength (by handgrip) were defined against young reference populations according to the European Working Group on Sarcopenia in Older People.nnnRESULTSnWhereas 20% of patients had sarcopenia, low muscle mass and low muscle strength alone were observed in a further 24% and 15% of patients, respectively. Old age, comorbidities, protein-energy wasting, physical inactivity, low albumin, and inflammation associated with low muscle strength, but not with low muscle mass (multivariate ANOVA interactions). During follow-up, 95 patients (29%) died and both conditions associated with mortality as separate entities. When combined, individuals with low muscle mass alone were not at increased risk of mortality (adjusted hazard ratio [HR], 1.23; 95% confidence interval [95% CI], 0.56 to 2.67). Individuals with low muscle strength were at increased risk, irrespective of their muscle stores being appropriate (HR, 1.98; 95% CI, 1.01 to 3.87) or low (HR, 1.93; 95% CI, 1.01 to 3.71).nnnCONCLUSIONSnLow muscle strength was more strongly associated with aging, protein-energy wasting, physical inactivity, inflammation, and mortality than low muscle mass. Assessment of muscle functionality may provide additional diagnostic and prognostic information to muscle-mass evaluation.

Prevalence and clinical implications of testosterone deficiency in men with end-stage renal disease

BACKGROUNDnAbnormally low serum testosterone levels were recently associated with an increased mortality risk in male dialysis patients. However, the prevalence of testosterone deficiency in end-stage renal disease (ESRD) is not well defined. We hereby explore the prevalence and correlates of clinical testosterone deficiency in a large cohort of ESRD male patients.nnnMETHODSnTwo hundred and sixty ESRD men [median age 59 (25th-75th percentile 48-67)u2009 years] were included. Testosterone concentration and testosterone deficiency (<10 nmol/L) were studied in relation to clinically evident cardiovascular disease and markers of inflammation at baseline as well as deaths registered during the following 36 months.nnnRESULTSnTestosterone deficiency was present in 44% of the patients, while 33% showed testosterone insufficiency (10-14 nmol/L), and only 23% had normal testosterone values (>14 nmol/L). Testosterone was strongly and inversely correlated to inflammatory markers (CRP, IL-6 and fibrinogen), even after correction for age and sex hormone-binding globulin. In a crude spline curve, low testosterone concentrations were associated with worse outcome. A clinical condition of testosterone deficiency was independently associated with cardiovascular co-morbidity [odds ratio (OR) 2.51; 95% confidence interval (CI) 1.32-4.76] and death (OR 2.00; 95% CI 1.01-3.97) in logistic regression analyses.nnnCONCLUSIONSnTestosterone deficiency is a common finding among male ESRD patients, and it is independently associated with inflammation, cardiovascular co-morbidity and outcome. Future studies are needed to determine the potential adverse effects of male hypogonadism in ESRD and the possibility of improving risk profile, quality of life, and ultimately outcome with testosterone supplementation in these patients.

Mediterranean Diet, Kidney Function, and Mortality in Men with CKD

BACKGROUND AND OBJECTIVESnAdherence to a Mediterranean diet may link to a better preserved kidney function in the community as well as a favorable cardiometabolic profile and reduced mortality risk in individuals with manifest CKD.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnDietary habits were determined by 7-day dietary records in a population-based cohort of 1110 Swedish men (age 70 years) from 1991 to 1995, 506 of whom were considered to have CKD because of a GFR<60 ml/min per 1.73 m(2). A Mediterranean Diet Score was calculated, and participants were categorized as having low, medium, or high adherence. Adequate dietary reporters were identified with Goldberg cutoffs (n=597). Deaths were registered during a median follow-up of 9.9 years.nnnRESULTSnCompared with low adherents, medium and high adherents were 23% and 42% less likely to have CKD, respectively (adjusted odds ratio [95% confidence interval]=0.77 [0.57 to 1.05] and 0.58 [0.38 to 0.87], respectively, P for trend=0.04). Among those individuals with CKD, phosphate intake and net endogenous acid production were progressively lower across increasing adherence groups. No differences were observed regarding other cardiometabolic risk factors across adherence groups. As many as 168 (33%) CKD individuals died during follow-up. Compared with low adherents, proportional hazards regression associated medium and high adherents to a 25% and 23% lower mortality risk, respectively (adjusted hazard ratio [95% confidence interval]=0.75 [0.52 to 1.06] and 0.77 [0.44 to 1.36], respectively, P for trend=0.10). Sensitivity analyses showed significant and stronger associations when only adequate dietary reporters were considered.nnnCONCLUSIONSnAdherence to a Mediterranean dietary pattern is associated with lower likelihood of CKD in elderly men. A greater adherence to this diet independently predicted survival in those patients with manifest CKD. Clinical trials are warranted to test the hypothesis that following such a diet could improve outcomes (independent of other healthy lifestyles) in CKD patients.

Prolactin Levels, Endothelial Dysfunction, and the Risk of Cardiovascular Events and Mortality in Patients with CKD

BACKGROUND AND OBJECTIVESnBoth prolactin clearance and production are altered in CKD. In nonrenal populations, emerging evidence suggests that prolactin participates in the atherosclerotic process. Given the elevated cardiovascular risk of CKD, this study examined links between prolactinemia, vascular derangements, and outcomes.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnThis observational study was conducted in two cohorts: one with 457 nondialyzed CKD patients (mean age 52±12 years; 229 men) with measurements of flow-mediated dilation (FMD) and carotid intima-media thickness and one with 173 hemodialysis patients (65±12 years; 111 men) with measurements of pulse wave velocity (PWV). Patients were followed for cardiovascular events (n=146, nondialyzed cohort) or death (n=79, hemodialysis cohort).nnnRESULTSnProlactin levels increased along with reduced kidney function. Prolactin significantly and independently contributed to explain the variance of both FMD (in nondialyzed patients) and PWV (in hemodialysis patients), but not intima-media thickness. In Cox analyses, the risk of cardiovascular events in nondialyzed patients increased by 27% (hazard ratio [HR], 1.27; 95% confidence interval [95% CI], 1.17-1.38) for each 10 ng/ml increment of prolactin. Similarly, the risk for all-cause and cardiovascular mortality in hemodialysis patients increased by 12% (HR, 1.12; 95% CI, 1.06-1.17) and 15% (HR, 1.15; 95% CI, 1.08-1.21), respectively. This was true after multivariate adjustment for confounders and after adjustment within the purported causal pathway (FMD or PWV).nnnCONCLUSIONSnProlactin levels directly associated with endothelial dysfunction/stiffness and with increased risk of cardiovascular events and mortality in two independent cohorts of CKD patients.

Visfatin is increased in chronic kidney disease patients with poor appetite and correlates negatively with fasting serum amino acids and triglyceride levels

OBJECTIVEnAnorexia is a common complication of chronic kidney disease (CKD), while novel animal and human data suggest a role for visfatin in regulating feeding behavior. We hypothesized that increased visfatin levels in CKD patients may be involved in the regulation of appetite and nutrient homeostasis.nnnMETHODSnThis is a cross-sectional study where circulating visfatin levels were analysed in 246 incident CKD stage 5 patients starting dialysis therapy. The associations between visfatin (enzyme-linked immunosorbent assay, ELISA) and anthropometric and biochemical nutritional status, self-reported appetite, fasting serum amino acids (high-performance liquid chromatography) and circulating cytokine levels (ELISAs) were assessed. We also performed genotyping (Pyrosequencing(R)) of two polymorphisms (rs1319501 and rs9770242) in the visfatin gene.nnnRESULTSnSerum visfatin concentrations were not associated with either body mass index or serum leptin. Across groups with worsening appetite, median visfatin levels were incrementally higher (P < 0.05). With increasing visfatin tertiles, patients proved to be more often anorectic (P < 0.05) and to have incrementally lower serum albumin, cholesterol and triglycerides as well as lower essential and non-essential serum amino acids (P < 0.05 for all). A polymorphism in the visfatin gene was associated with increased circulating visfatin levels and, at the same time, a higher prevalence of poor appetite (P < 0.05 for both).nnnCONCLUSIONnOur study suggests novel links between visfatin and anorexia in CKD patients. Based on recent studies, we speculate that high visfatin in CKD patients may constitute a counter-regulatory response to central visfatin resistance in uremia. Future studies should examine a putative role of visfatin as a regulator of nutrient homeostasis in uremia.

Dietary Fiber, Kidney Function, Inflammation, and Mortality Risk

BACKGROUND AND OBJECTIVESnIn the United States population, high dietary fiber intake has been associated with a lower risk of inflammation and mortality in individuals with kidney dysfunction. This study aimed to expand such findings to a Northern European population.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnDietary fiber intake was calculated from 7-day dietary records in 1110 participants aged 70-71 years from the Uppsala Longitudinal Study of Adult Men (examinations performed during 1991-1995). Dietary fiber was adjusted for total energy intake by the residual method. Renal function was estimated from the concentration of serum cystatin C, and deaths were registered prospectively during a median follow-up of 10.0 years.nnnRESULTSnDietary fiber independently and directly associated with eGFR (adjusted difference, 2.6 ml/min per 1.73 m(2) per 10 g/d higher; 95% confidence interval [95% CI], 0.3 to 4.9). The odds of C-reactive protein >3 mg/L were lower (linear trend, P=0.002) with higher fiber quartiles. During follow-up, 300 participants died (incidence rate of 2.87 per 100 person-years at risk). Multiplicative interactions were observed between dietary fiber intake and kidney dysfunction in the prediction of mortality. Higher dietary fiber was associated with lower mortality in unadjusted analysis. These associations were stronger in participants with kidney dysfunction (eGFR<60 ml/min per 1.73 m(2)) (hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.98) than in those without (HR, 1.30; 95% CI, 0.76 to 2.22; P value for interaction, P=0.04), and were mainly explained by a lower incidence of cancer-related deaths (0.25; 95% CI, 0.10 to 0.65) in individuals with kidney dysfunction versus individuals with an eGFR≥60 ml/min per 1.73 m(2) (1.61; 95% CI, 0.69 to 3.74; P value for interaction, P=0.01).nnnCONCLUSIONSnHigh dietary fiber was associated with better kidney function and lower inflammation in community-dwelling elderly men from Sweden. High dietary fiber was also associated with lower (cancer) mortality risk, especially in individuals with kidney dysfunction.

Validation of insulin sensitivity surrogate indices and prediction of clinical outcomes in individuals with and without impaired renal function

As chronic kidney disease (CKD) progresses with abnormalities in glucose and insulin metabolism, commonly used insulin sensitivity indices (ISIs) may not be applicable in individuals with CKD. Here we sought to validate surrogate ISIs against the glucose disposal rate by the gold-standard hyperinsulinemic euglycemic glucose clamp (HEGC) technique in 1074 elderly men of similar age (70 years) of whom 495 had and 579 did not have CKD (estimated glomerular filtration rate (eGFR) under 60u2009ml/min per 1.73u2009m(2) (median eGFR of 46u2009ml/min per 1.73u2009m(2))). All ISIs provided satisfactory (weighted κ over 0.6) estimates of the glucose disposal rate in patients with CKD. ISIs derived from oral glucose tolerance tests (OGTTs) agreed better with HEGC than those from fasting samples (higher predictive accuracy). Regardless of CKD strata, all ISIs allowed satisfactory clinical discrimination between the presence and absence of insulin resistance (glucose disposal rate under 4u2009mg/kg/min). We also assessed the ability of both HEGC and ISIs to predict all-cause and cardiovascular mortality during a 10-year follow-up. Neither HEGC nor ISIs independently predicted mortality. Adjustment for renal function did not materially change these associations. Thus, ISIs can be applied in individuals with moderately impaired renal function for diagnostic purposes. For research matters, OGTT-derived ISIs may be preferred. Our data do not support the hypothesis of kidney function mediating insulin sensitivity (IS)-associated outcomes nor a role for IS as a predictor of mortality.

A Proinflammatory Diet Is Associated with Systemic Inflammation and Reduced Kidney Function in Elderly Adults

BACKGROUNDnDiet can affect kidney health through its effects on inflammation.nnnOBJECTIVEnWe tested whether the Adapted Dietary Inflammatory Index (ADII) is associated with kidney function and whether effects of diet on chronic low-grade inflammation explain this association.nnnMETHODSnThis was an observational analysis in 1942 elderly community-dwelling participants aged 70-71 y from 2 independent cohorts: the Uppsala Longitudinal Study of Adult Men (n = 1097 men) and the Prospective Investigation of Vasculature in Uppsala Seniors (n = 845 men and women). The ADII was calculated from 7-d food records, combining putatively proinflammatory and anti-inflammatory effects of nutrients, vitamins, and trace elements. The ADII was validated against serum C-reactive protein (CRP) concentrations. The estimated glomerular filtration rate (eGFR) was assessed from serum cystatin C (cys) and creatinine (crea). Associations between the ADII and eGFR were investigated, and CRP was considered to be a mediator.nnnRESULTSnIn adjusted analysis, a 1-SD higher ADII was associated with higher CRP (β: 6%; 95% CI: 1%, 10%; P = 0.01) and lower eGFR [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)cys: -2.1%; 95% CI: -3.2%, -1.1%; CKD-EPIcys+crea: -1.8%; 95% CI: -2.7%, -0.9%; both P < 0.001]. CRP was also inversely associated with eGFR. Mediation analyses showed that of the total effect of the ADII on kidney function, 15% and 17% (for CKD-EPIcys+crea and CKD-EPIcys equations, respectively) were explained/mediated by serum CRP. Findings were similar when each cohort was analyzed separately.nnnCONCLUSIONSnA proinflammatory diet was associated with systemic inflammation as well as with reduced kidney function in a combined analysis of 2 community-based cohorts of elderly individuals. Our results also suggest systemic inflammation to be one potential pathway through which this dietary pattern is linked to kidney function.

Serum fatty acid patterns, insulin sensitivity and the metabolic syndrome in individuals with chronic kidney disease

The causes of the multiple metabolic disorders of individuals with chronic kidney disease (CKD) are not fully known. We investigated the relationships between dietary fat quality, the metabolic syndrome (MetS), insulin sensitivity and inflammation in individuals with CKD.

Estimated Dietary Acid Load Is Not Associated with Blood Pressure or Hypertension Incidence in Men Who Are Approximately 70 Years Old

BACKGROUNDnDietary acid load affects acid-base homeostasis, which may be associated with blood pressure (BP). Previous research on dietary acid load and BP in the community has provided conflicting results, which may be confounded by underlying kidney function with inability to eliminate acid excess.nnnOBJECTIVEnThe objective of this study was to determine whether dietary acid load is associated with blood pressure or the incidence of hypertension in older men taking into account each individuals kidney function.nnnMETHODSnWe included 673 men aged 70-71 y and not receiving antihypertensive medication from the Uppsala Longitudinal Study of Adult Men. Of those, 378 men were re-examined after 7 y. Dietary acid load was estimated at baseline by potential renal acid load (PRAL) and net endogenous acid production (NEAP), based on nutrient intake assessed by 7-d food records at baseline. Ambulatory blood pressure monitoring (ABPM) was performed at both visits. Cystatin C-estimated kidney function allowed identification of underlying chronic kidney disease.nnnRESULTSnMedian estimated PRAL and NEAP were 3.3 and 40.7 mEq/d, respectively. In cross-section, PRAL was in general not associated with ABPM measurements (all P > 0.05, except for the 24-h diastolic BP). During follow-up, PRAL did not predict ABPM changes (all P > 0.05). When individuals with baseline hypertension (ABPM ≥ 130/80 mm Hg) or nondippers (with nighttime-to-daytime systolic BP ratio > 0.9) were excluded, PRAL was not a predictor of incident cases (P > 0.30). Kidney function did not modify these null relations. Similar findings were obtained with the use of NEAP as the exposure.nnnCONCLUSIONnOur analyses linking estimated dietary acid load with BP outcome measurements both cross-sectionally and after 7 y in community-based older Swedish men of similar age did not reveal an association between dietary acid load and BP.