Testosterone increases muscle mass and strength and regulates other physiological processes, but we do not know whether testosterone effects are dose dependent and whether dose requirements for maintaining various androgen-dependent processes are similar. To determine the effects of graded doses of testosterone on body composition, muscle size, strength, power, sexual and cognitive functions, prostate-specific antigen (PSA), plasma lipids, hemoglobin, and insulin-like growth factor I (IGF-I) levels, 61 eugonadal men, 18-35 yr, were randomized to one of five groups to receive monthly injections of a long-acting gonadotropin-releasing hormone (GnRH) agonist, to suppress endogenous testosterone secretion, and weekly injections of 25, 50, 125, 300, or 600 mg of testosterone enanthate for 20 wk. Energy and protein intakes were standardized. The administration of the GnRH agonist plus graded doses of testosterone resulted in mean nadir testosterone concentrations of 253, 306, 542, 1,345, and 2,370 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Fat-free mass increased dose dependently in men receiving 125, 300, or 600 mg of testosterone weekly (change +3.4, 5.2, and 7.9 kg, respectively). The changes in fat-free mass were highly dependent on testosterone dose (P = 0.0001) and correlated with log testosterone concentrations (r = 0.73, P = 0.0001). Changes in leg press strength, leg power, thigh and quadriceps muscle volumes, hemoglobin, and IGF-I were positively correlated with testosterone concentrations, whereas changes in fat mass and plasma high-density lipoprotein (HDL) cholesterol were negatively correlated. Sexual function, visual-spatial cognition and mood, and PSA levels did not change significantly at any dose. We conclude that changes in circulating testosterone concentrations, induced by GnRH agonist and testosterone administration, are associated with testosterone dose- and concentration-dependent changes in fat-free mass, muscle size, strength and power, fat mass, hemoglobin, HDL cholesterol, and IGF-I levels, in conformity with a single linear dose-response relationship. However, different androgen-dependent processes have different testosterone dose-response relationships.

In individuals with chronic kidney disease, high dietary phosphorus (P) burden may worsen hyperparathyroidism and renal osteodystrophy, promote vascular calcification and cardiovascular events, and increase mortality. In addition to the absolute amount of dietary P, its type (organic versus inorganic), source (animal versus plant derived), and ratio to dietary protein may be important. Organic P in such plant foods as seeds and legumes is less bioavailable because of limited gastrointestinal absorption of phytate-based P. Inorganic P is more readily absorbed by intestine, and its presence in processed, preserved, or enhanced foods or soft drinks that contain additives may be underreported and not distinguished from the less readily absorbed organic P in nutrient databases. Hence, P burden from food additives is disproportionately high relative to its dietary content as compared with natural sources that are derived from organic (animal and vegetable) food proteins. Observational and metabolic studies indicate nutritional and longevity benefits of higher protein intake in dialysis patients. This presents challenges to providing appropriate nutrition because protein and P intakes are closely correlated. During dietary counseling of patients with chronic kidney disease, the absolute dietary P content as well as the P-to-protein ratio in foods should be addressed. Foods with the least amount of inorganic P, low P-to-protein ratios, and adequate protein content that are consistent with acceptable palatability and enjoyment to the individual patient should be recommended along with appropriate prescription of P binders. Provision of in-center and monitored meals during hemodialysis treatment sessions in the dialysis clinic may facilitate the achievement of these goals.

Background The Malnutrition-Inflammation Score (MIS), a non-expensive and easy-to-assess score between 0 and 30 to examine protein-energy wasting (PEW) and inflammation, includes 7 components of the subjective global assessment, body mass index, and serum albumin and transferrin concentrations. We hypothesized that the MIS risk-stratification of chronic hemodialysis (HD) patients in predicting outcomes is better than its components or laboratory markers of inflammation. Study Design 5-year cohort study. Setting & Participants We examined 809 stable HD outpatients and followed them for up to 5 years (10/2001–12/2006). Predictors MIS and other nutritional and inflammatory markers. Outcomes & Measurements Prospective all-cause mortality, health-related quality of life via SF-36, and tests of body composition. Results The MIS was correlated with serum interleukin-6 (IL-6) (r=+0.26, p<0.001), C-reactive protein (CRP) (r=+0.16, p<0.001) and several measures of nutritional status. Patients with higher MIS had lower SF-36 scores. After multivariate adjustment for case-mix and other measures of PEW, the chronic HD patients in the second (3–4), third (5–7) and fourth (≥8) quartiles of MIS had worse survival rates than those in the first (0–2) quartile (p<0.001). Each 2 unit increase in MIS was associated with two-fold higher death risk, i.e., adjusted death hazard ratio of 2.03 (95% CI: 1.76–2.33, p<0.001). Cubic spline survival models confirmed linear trends. The areas under the receiver operating characteristic curves for the continuum of MIS in predicting 5-year mortality (0.67) was equal to IL-6 (0.67) and somewhat better than CRP (0.63). Limitations Selection bias and unknown confounders. Conclusions In chronic HD patients, the MIS is associated with inflammation, nutritional status, quality of life, and 5-year prospective mortality. The mortality-predictability of the MIS appears equal to serum IL-6 and somewhat greater than CRP. Controlled trials are warranted to examine whether interventions to improve MIS can also improve clinical outcomes in chronic HD patients.

Background and objectives: Maintenance hemodialysis (MHD) patients with larger body or fat mass have greater survival than normal to low mass. We hypothesized that mid-arm muscle circumference (MAMC), a conveniently measured surrogate of lean body mass (LBM), has stronger association with clinical outcomes than triceps skinfold (TSF), a surrogate of fat mass.Design, settings, participants, & measurements: The associations of TSF, MAMC, and serum creatinine, another LBM surrogate, with baseline short form 36 quality-of-life scores and 5-year survival were examined in 792 MHD patients. In a randomly selected subsample of 118 subjects, LBM was measured by dual-energy x-ray absorptiometry.Results: Dual-energy x-ray absorptiometry-assessed LBM correlated most strongly with MAMC and serum creatinine. Higher MAMC was associated with better short form 36 mental health scale and lower death hazard ratios (HRs) after adjustment for case-mix, malnutrition-inflammation-cachexia syndrome, and inflammatory markers. Adjusted death HRs were 1.00, 0.86, 0.69, and 0.63 for the first to fourth MAMC quartiles, respectively. Higher serum creatinine and TSF were also associated with lower death HRs, but these associations were mitigated after multivariate adjustments. Using median values of TSF and MAMC to dichotomize, combined high MAMC with either high or low TSF (compared with low MAMC/TSF) exhibited the greatest survival, i.e., death HRs of 0.52 and 0.59, respectively.Conclusions: Higher MAMC is a surrogate of larger LBM and an independent predictor of better mental health and greater survival in MHD patients. Sarcopenia-correcting interventions to improve clinical outcomes in this patient population warrant controlled trials.

Background Hyperkalemia has been associated with higher mortality in long-term hemodialysis (HD) patients. There are little data concerning the relationship between dietary potassium intake and outcome. Study design Mortality-predictability of dietary potassium intake from reported food items, estimated from the Block Food Frequency Questionnaire (FFQ) at the start of the cohort, were examined in a 5-year (2001–06) cohort of 224 HD patients in Southern California using Cox proportional hazards regression. Setting and Participants 224 long-term hemodialysis patients from 8 DaVita dialysis clinics. Predictors Dietary potassium intake ranking using Block FFQ Outcomes 5-year survival Results HD patients with higher potassium intakes had greater dietary energy, protein and phosphorus intakes and higher predialysis serum potassium and phosphorus. Greater dietary potassium intake was associated with significantly increased death hazard ratios (HR) in the unadjusted models and after incremental adjustments for case-mix, nutritional factors (including 3-month averaged predialysis serum creatinine, potassium and phosphorus, body mass index, normalized protein nitrogen appearance, and energy, protein and phosphorus intake) and inflammatory markers. The HR (95% confidence intervals) of death across the 3 higher quartiles of dietary potassium intake in the fully adjusted model (compared to the lowest quartile) were 1.4 (0.6–3.0), 2.2 (0.9–5.4) and 2.4 (1.1–7.5), respectively (p for trend: 0.03). Restricted cubic spline analyses confirmed the incremental mortality-predictability of higher potassium intake. Limitations FFQs may underestimate individual potassium intake and should be used to rank dietary intake across population. Conclusions Higher dietary potassium intake is associated with increased death risk in long-term HD patients, even after adjustments for serum potassium and dietary protein, energy and phosphorus intake and nutritional and inflammatory markers. The potential role of dietary potassium in the high mortality rate of HD patients warrants clinical trials.

Background and objectives: Epidemiologic studies show an association between higher predialysis serum phosphorus and increased death risk in maintenance hemodialysis (MHD) patients. The hypothesis that higher dietary phosphorus intake and higher phosphorus content per gram of dietary protein intake are each associated with increased mortality in MHD patients was examined.Design, setting, participants, & measurements: Food frequency questionnaires were used to conduct a cohort study to examine the survival predictability of dietary phosphorus and the ratio of phosphorus to protein intake. At the start of the cohort, Cox proportional hazard regression was used in 224 MHD patients, who were followed for up to 5 years (2001 to 2006).Results: Both higher dietary phosphorus intake and a higher dietary phosphorus to protein ratio were associated with significantly increased death hazard ratios (HR) in the unadjusted models and after incremental adjustments for case-mix, diet, serum phosphorus, malnutrition-inflammation complex syndrome, and inflammatory markers. The HR of the highest (compared with lowest) dietary phosphorus intake tertile in the fully adjusted model was 2.37. Across categories of dietary phosphorus to protein ratios of <12, 12 to <14, 14 to <16, and >16 mg/g, death HRs were 1.13, 1.00 (reference value), 1.80, and 1.99, respectively. Cubic spline models of the survival analyses showed similar incremental associations.Conclusions: Higher dietary phosphorus intake and higher dietary phosphorus to protein ratios are each associated with increased death risk in MHD patients, even after adjustments for serum phosphorus, phosphate binders and their types, and dietary protein, energy, and potassium intakes.

Background In maintenance hemodialysis (MHD) patients, a low serum transthyretin (prealbumin) is an indicator of protein-energy wasting. We hypothesized that baseline serum transthyretin correlates independently with health related quality of life (QoL) and death and that its change over time is a robust mortality predictor. Methods Associations and survival predictability of serum transthyretin at baseline and its changes over 6 months were examined in a 5-year (2001-06) cohort of 798 MHD patients. Results Patients with serum transthyretin ≥40 mg/dL had greater mid-arm muscle circumference but lower total body fat percentage. Both serum interleukin-6 and dietary protein intake correlated independently with serum transthyretin. Measures of QoL indicated better physical health, physical function and functionality in higher transthyretin levels. Although baseline transthyretin was not superior to albumin in predicting survival, in both all and normoalbuminemic (albumin≥3.5 g/dL, n=655) patients, transthyretin<20 mg/dL was associated with higher death risk in adjusted models, but further adjustments for inflammatory cytokines mitigated the associations. In 412 patients with baseline transthyretin between 20 and 40 mg/dl, whose serum transthyretin was remeasured after 6 months, a 10 mg/dL or greater fall resulted in death hazard ratio of 1.37 (95% confidence levels: 1.02, 1.85; p=0.03) after adjustment for baseline measures including inflammatory markers. Conclusions Even though baseline serum transthyretin may not be superior to albumin in predicting mortality in MHD patients, transthyretin levels below 20 mg/dL are associated with death risk even in normoalbuminemic patients, and a fall in serum transthyretin over 6 months is independently associated with increased death risk.

SummaryBackground and objectives Maintenance hemodialysis (MHD) patients often have protein-energy wasting, poor health-related quality of life (QoL), and high premature death rates, whereas African-American MHD patients have greater survival than non-African-American patients. We hypothesized that poor QoL scores and their nutritional correlates have a bearing on racial survival disparities of MHD patients.Design, setting, participants, & measurements We examined associations between baseline self-administered SF36 questionnaire-derived QoL scores with nutritional markers by multivariate linear regression and with survival by Cox models and cubic splines in the 6-year cohort of 705 MHD patients, including 223 African Americans.Results Worse SF36 mental and physical health scores were associated with lower serum albumin and creatinine levels but higher total body fat percentage. Spline analyses confirmed mortality predictability of worse QoL, with an almost strictly linear association for mental health score in African Americans, although the race-QoL interaction was not statistically significant. In fully adjusted analyses, the mental health score showed a more robust and linear association with mortality than the physical health score in all MHD patients and both races: death hazard ratios for (95% confidence interval) each 10 unit lower mental health score were 1.12 (1.05-1.19) and 1.10 (1.03-1.18) for all and African American patients, respectively.Conclusions MHD patients with higher percentage body fat or lower serum albumin or creatinine concentration perceive a poorer QoL. Poor mental health in all and poor physical health in non-African American patients correlate with mortality. Improving QoL by interventions that can improve the nutritional status without increasing body fat warrants clinical trials.