Salem VA Medical Center

Mean plasma GH concentrations are controlled by the frequency, amplitude, and duration of underlying GH secretory bursts as well as by the half-life of endogenous GH. We investigated the specific mechanisms that subserve the clinically recognized negative effects of age and adiposity on mean serum GH concentrations. To this end, 21 healthy men, aged 21-71 yr, who were of nearly normal body weight underwent blood sampling at 10-min intervals for 24 h. Deconvolution analysis was used to estimate specific features of GH secretion and clearance. Compared to younger men, the older tertile of men had significant reductions in 1) GH secretory burst frequency, 2) the half-life of endogenous GH, and 3) the daily GH secretory rate, but not 4) GH secretory burst half-duration, amplitude, or mass. Linear regression analysis disclosed that age was a major negative statistical determinant of GH secretory burst frequency (r = -0.80; P = 0.005) and endogenous GH half-life (r = -0.70; P = 0.024). Body mass index, an indicator of relative obesity, was a significant negative correlate of GH half-life (P = 0.045) and GH secretory burst amplitude (P = 0.031). Age and body mass index each correlated negatively with the daily GH secretion rate (P = 0.0031 and P = 0.027, respectively), and together accounted for more than 60% of the variability in 24-h GH production rates (r = -0.78; P = 0.00056). On the average, for a normal body mass index, each decade of increasing age attenuated the GH production rate by 14% and the GH half-life by 6%. Conversely, each unit increase in body mass index, at a given age, reduced the daily GH secretion rate by 6%. We conclude that age and relative adiposity are distinct and specific correlates of individual attributes of GH secretion and clearance in men.

BACKGROUND: Patients with chronic kidney disease (stage 5) who undergo hemodialysis treatment have similarities to heart failure patients in that both populations retain fluid frequently and have excessively high mortality. Volume overload in heart failure is associated with worse outcomes. We hypothesized that in hemodialysis patients, greater interdialytic fluid gain is associated with poor all-cause and cardiovascular survival. METHODS AND RESULTS: We examined 2-year (July 2001 to June 2003) mortality in 34,107 hemodialysis patients across the United States who had an average weight gain of at least 0.5 kg above their end-dialysis dry weight by the time the subsequent hemodialysis treatment started. The 3-month averaged interdialytic weight gain was divided into 8 categories of 0.5-kg increments (up to > or =4.0 kg). Eighty-six percent of patients gained >1.5 kg between 2 dialysis sessions. In unadjusted analyses, higher weight gain was associated with better nutritional status (higher protein intake, serum albumin, and body mass index) and tended to be linked to greater survival. However, after multivariate adjustment for demographics (case mix) and surrogates of malnutrition-inflammation complex, higher weight-gain increments were associated with increased risk of all-cause and cardiovascular death. The hazard ratios (95% confidence intervals) of cardiovascular death for weight gain <1.0 kg and > or =4.0 kg (compared with 1.5 to 2.0 kg as the reference) were 0.67 (0.58 to 0.76) and 1.25 (1.12 to 1.39), respectively. CONCLUSIONS: In hemodialysis patients, greater fluid retention between 2 subsequent hemodialysis treatment sessions is associated with higher risk of all-cause and cardiovascular death. The mechanisms by which fluid retention influences cardiovascular survival in hemodialysis may be similar to those in patients with heart failure and warrant further research.

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.

We have examined the mechanisms underlying reduced circulating GH concentrations in the obese human. Computer-assisted (deconvolution) analysis was used to determine endogenous GH secretory and clearance rates quantitatively from entire 24-h plasma GH concentration profiles. These analyses revealed that the half-life (t 1/2) of endogenous GH was significantly shorter in obese (11.7 +/- 1.6 min) than in normal weight subjects (15.5 +/- 0.81 min; P less than 0.01). The accelerated blood disposal rate of GH was not due to decreased circulating concentrations of GH-binding protein, since the latter were similar in obese (25 +/- 1.0%) and normal weight (24 +/- 2.3%) men. However, obese men had significantly fewer GH secretory bursts (3.2 +/- 0.53 vs. 9.7 +/- 0.67/day; P less than 0.01). Among the rare GH secretory bursts that occurred in obese subjects, there were significantly prolonged mean intersecretory burst intervals (282 +/- 65 vs. 131 +/- 11 min; P less than 0.05). The resultant daily GH production rate in obese men was reduced to one fourth that in normal weight individuals. Both GH secretion rate and burst frequency were negatively correlated with the degree of obesity (ponderal index). The decreases in GH burst frequency and half-life were specific, since GH secretory pulse amplitude (maximal rate of GH release), the mass of GH released per burst, and the duration of computer-resolved GH secretory bursts were not different in obese and normal weight men. We conclude that obese men harbor a double defect in GH dynamics involving both GH secretion and clearance, and that the severity of the GH secretory deficiency is proportionate to the degree of obesity.

BACKGROUND: Higher muscle mass is associated with better outcomes and longevity in patients with chronic disease states. Imaging studies such as dual-energy X-ray absorptiometry (DEXA) are among the gold standard methods for assessing body fat and lean body mass (LBM), approximately half of which is comprised of skeletal muscle mass. Elaborate imaging devices, however, are not commonly available in routine clinical practice and therefore easily accessible and cost-effective, but reliable muscle mass biomarkers are needed. One such marker is serum creatinine, derived from muscle-based creatine, which is inexpensive and ubiquitously available, and it can serve as a biomarker of skeletal muscle mass in human subjects. METHODS AND RESULTS: In 118 hemodialysis patients, we found that the 3-month averaged serum creatinine concentration correlated well with DEXA-measured LBM. The recent literature regarding serum creatinine as a surrogate of muscle mass is summarized, as is the literature concerning the use of other measures of muscle mass, such as plasma gelsolin and actin, and urinary creatinine excretion. We have also reviewed the role of dietary meat intake in serum creatinine variability along with several biomarkers of dietary meat intake (creatine, carnitine, carnosine, ophidine, anserine, 3-methyl-L-histidine and 1-methylhistidine). CONCLUSION: In summary, none of these biomarkers was studied in CKD patients. We advance the hypothesis that in both health and disease, under steady state, serum creatinine can serve as a reliable muscle mass biomarker if appropriate adjustment for full or residual kidney function and dietary meat intake is undertaken.

Although treating anemia of chronic kidney disease by erythropoiesis-stimulating agents (ESA) may improve survival, most studies have examined associations between baseline hemoglobin values and survival and ignored variations in clinical and laboratory measures over time. It is not clear whether longitudinal changes in hemoglobin or administered ESA have meaningful associations with survival after adjustment for time-varying confounders. With the use of time-dependent Cox regression models, longitudinal associations were examined between survival and quarterly (13-wk averaged) hemoglobin values and administered ESA dose in a 2-yr (July 2001 to June 2003) cohort of 58,058 maintenance hemodialysis patients from a large dialysis organization (DaVita) in the United States. After time-dependent and multivariate adjustment for case mix, quarterly varying administered intravenous iron and ESA doses, iron markers, and nutritional status, hemoglobin levels between 12 and 13 g/dl were associated with the greatest survival. Among prevalent patients, the lower range of the recommended Kidney Disease Quality Outcomes Initiative hemoglobin target (11 to 11.5 g/dl) was associated with a higher death risk compared with the 11.5- to 12-g/dl range. A decrease or increase in hemoglobin over time was associated with higher or lower death risk, respectively, independent of baseline hemoglobin. Administration of any dose of ESA was associated with better survival, whereas among those who received ESA, requiring higher doses were surrogates of higher death risk. In this observational study, greater survival was associated with a baseline hemoglobin between 12 and 13 g/dl, treatment with ESA, and rising hemoglobin. Falling hemoglobin and requiring higher ESA doses were associated with decreased survival. Randomized clinical trials are required to examine these associations.

BACKGROUND AND OBJECTIVES: Controlling serum potassium is an important goal in maintenance hemodialysis patients. We examined the achievement of potassium balance through hemodialysis treatments and the associated fluctuations in serum potassium. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A 3-yr (July 2001 to June 2004) cohort of 81,013 maintenance hemodialysis patients from all DaVita dialysis clinics across the United States were studied. Nine quarterly-averaged serum potassium groups (< 4.0, > or = 6.3 mEq/L and seven increments in-between) and four dialysate potassium concentration groups were created in each of the 12 calendar quarters. The death risk associated with predialysis potassium level and dialysate potassium concentration was examined using unadjusted, case-mix adjusted, and malnutrition-inflammation-adjusted time-dependent survival models. RESULTS: Serum potassium correlated with nutritional markers. Serum potassium between 4.6 and 5.3 mEq/L was associated with the greatest survival, whereas potassium < 4.0 or > or = 5.6 mEq/L was associated with increased mortality. The death risk of serum potassium > or = 5.6 mEq/L remained consistent after adjustments. Higher dialysate potassium concentration was associated with increased mortality in hyperkalemic patients with predialysis serum potassium > or = 5.0 mEq/L. CONCLUSIONS: A predialysis serum potassium of 4.6 to 5.3 mEq/L is associated with the greatest survival in maintenance hemodialysis patients. Hyperkalemic patients who undergo maintenance hemodialysis against lower dialysate bath may have better survival. Limitations of observational studies including confounding by indication should be considered when interpreting these results.

Gangliosides are carbohydrate-containing sphingolipids that are widely expressed in normal tissues, making most subtypes unsuitable as targets for cancer therapy. However, the disialoganglioside GD2 subtype has limited expression in normal tissues but is overexpressed across a wide range of tumors. Disialoganglioside GD2 can be considered a tumor-associated antigen and well-suited as a target for cancer therapy. Disialoganglioside GD2 is implicated in tumor development and malignant phenotypes through enhanced cell proliferation, motility, migration, adhesion, and invasion, depending on the tumor type. This provides a rationale for targeting disialoganglioside GD2 in cancer therapy with the development of anti-GD2 monoclonal antibodies and other therapeutic approaches. Anti-GD2 monoclonal antibodies target GD2-expressing tumor cells, leading to phagocytosis and destruction by means of antibody-dependent cell-mediated cytotoxicity, lysis by complement-dependent cytotoxicity, and apoptosis and necrosis through direct induction of cell death. Anti-GD2 monoclonal antibodies may also prevent homing and adhesion of circulating malignant cells to the extracellular matrix. Disialoganglioside GD2 is highly expressed by almost all neuroblastomas, by most melanomas and retinoblastomas, and by many Ewing sarcomas and, to a more variable degree, by small cell lung cancer, gliomas, osteosarcomas, and soft tissue sarcomas. Successful treatment of disialoganglioside GD2-expressing tumors with anti-GD2 monoclonal antibodies is hindered by pharmacologic factors such as insufficient antibody affinity to mediate antibody-dependent cell-mediated cytotoxicity, inadequate penetration of antibody into the tumor microenvironment, and toxicity related to disialoganglioside GD2 expression by normal tissues such as peripheral sensory nerve fibers. Nonetheless, anti-GD2 monoclonal antibody dinutuximab (ch14.18) has been approved by the U.S. Food and Drug Administration and dinutuximab beta (ch14.18/CHO) has been approved by the European Medicines Agency for the treatment of high-risk neuroblastoma in pediatric patients. Clinical trials of anti-GD2 therapy are currently ongoing in patients with other types of disialoganglioside GD2-expressing tumors as well as neuroblastoma. In addition to anti-GD2 monoclonal antibodies, anti-GD2 therapeutic approaches include chimeric antigen receptor T-cell therapy, disialoganglioside GD2 vaccines, immunocytokines, immunotoxins, antibody-drug conjugates, radiolabeled antibodies, targeted nanoparticles, and T-cell engaging bispecific antibodies. Clinical trials should clarify further the potential of anti-GD2 therapy for disialoganglioside GD2-expressing malignant tumors.

OBJECTIVE: The mechanisms mediating hypercortisolemia in depression remain controversial. Adopting the biomarker strategy, we studied adrenocorticotropin (ACTH) and cortisol dynamics in hypercortisolemic and non-hypercortisolemic depressed in-patients, and in normal volunteers. METHOD: Deconvolution analysis of 24-h pulsatile secretion, approximate entropy (ApEn) estimation of secretory regularity, cross-ApEn quantitation of forward and reverse ACTH-cortisol synchrony, and cosine regression of 24-h rhythmicity. RESULTS: Hypercortisolemia was strongly associated with melancholic and psychotic depressive subtypes. Hypercortisolemic patients had elevated ACTH and cortisol secretion, mediated chiefly by increased burst masses. Basal ACTH secretion was increased, ACTH half-life was reduced, and mean 24-h ACTH concentration was normal. Cortisol secretion was increased in a highly irregular pattern (high ApEn), with high ACTH --> cortisol cross-ApEn (impaired feedforward coupling). Cortisol-mediated feedback on the secretory pattern of ACTH was normal. Hypercortisolemic depressed patients had normal programming of the central hypothalamo-pituitary-adrenal (HPA) axis pulse generator: ACTH pulse frequency, cortisol pulse frequency, circadian acrophases, and ApEn of ACTH secretion were normal. Responsiveness of the adrenal cortex to endogenous ACTH was normal. Non-hypercortisolemic patients resembled hypercortisolemic patients on ACTH regulatory parameters but had low total cortisol secretion. CONCLUSION: Increased ACTH secretion occurs in depressed in-patients regardless of cortisolemic status, confirming central HPA axis overdrive in severe depression. Depressive hypercortisolemia results from an additional change in the adrenal cortex that causes ACTH-independent, disorderly basal cortisol release, a sign of physiological stress in melancholic/psychotic depression.

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: Hyponatremia is common in patients with conditions such as congestive heart failure and is associated with increased mortality in hospitalized patients. Congestive heart failure is common in patients with chronic kidney disease, but the association of serum sodium concentration with mortality in such patients is not well characterized. METHODS AND RESULTS: We examined the association of serum sodium concentration with all-cause mortality in a nationally representative cohort of 655 493 US veterans with non-dialysis-dependent chronic kidney disease (95 961 [15%] of them with congestive heart failure). Associations were examined in time-dependent Cox models with adjustment for potential confounders. During a median follow-up of 5.5 years, a total of 193 956 patients died (mortality rate, 62.5/1000 patient-years; 95% confidence interval, 62.2-62.8). The association of serum sodium level with mortality was U-shaped, with the lowest mortality seen in patients with sodium level of 140 mEq/L and with both lower and higher levels showing significant associations with increased mortality. Patients with serum sodium levels of <130, 130 to 135.9, 145.1 to 150, and ≥150 mEq/L compared with 136 to 145 mEq/L had multivariable-adjusted mortality hazard ratios (95% confidence interval) of 1.93 (1.83-2.03), 1.28 (1.26-1.30), 1.33 (1.28-1.38), and 1.56 (1.33-1.83) (P<0.001 for all). The associations remained consistent in subgroups of patients with and without congestive heart failure. CONCLUSIONS: Both lower and higher serum sodium levels are independently associated with higher mortality in patients with non-dialysis-dependent chronic kidney disease, irrespective of the presence or absence of congestive heart failure.

OBJECTIVE: To evaluate the cost of lost productivity in the workplace due to allergic rhinitis compared to other selected medical conditions from an employer perspective. SETTING AND PARTICIPANTS: A total of 8267 US employees at 47 employer locations who volunteered to participate in health/wellness screenings. MEASUREMENTS: The Work Productivity Short Inventory was used to assess the impact of a predefined group of health conditions on workplace productivity for the previous 12 months. Both absenteeism and presenteeism (lost productivity while at work) were recorded. Costs were calculated using a standard hourly wage. RESULTS: Allergic rhinitis was the most prevalent of the selected conditions; 55% of employees reported experiencing allergic rhinitis symptoms for an average of 52.5 days, were absent 3.6 days per year due to the condition, and were unproductive 2.3 h per workday when experiencing symptoms. The mean total productivity (absenteeism + presenteeism) losses per employee per year were 593 US dollars for allergic rhinitis, 518 US dollars for high stress, 277 US dollars for migraine, 273 US dollars for depression, 269 US dollars for arthritis/rheumatism, 248 US dollars for anxiety disorder, 181 US dollars for respiratory infections, 105 US dollars for hypertension or high blood pressure, 95 US dollars for diabetes, 85 US dollars for asthma, and 40 US dollars for coronary heart disease. The mean total productivity loss per employee per year due to caregiving was 102 US dollars for pediatric respiratory infections, 85 US dollars for pediatric allergies, 49 US dollars for Alzheimer's disease, and 42 US dollars for otitis media/earache. CONCLUSIONS: Allergies are major contributors to the total cost of health-related absenteeism and presenteeism. Payers and employers need to consider this when determining health benefits for employees.

Wasting/cachexia is prevalent among patients with chronic kidney disease (CKD). It is to be distinguished from malnutrition, which is defined as the consequence of insufficient food intake or an improper diet. Malnutrition is characterized by hunger, which is an adaptive response, whereas anorexia is prevalent in patients with wasting/cachexia. Energy expenditure decreases as a protective mechanism in malnutrition whereas it remains inappropriately high in cachexia/wasting. In malnutrition, fat mass is preferentially lost and lean body mass and muscle mass is preserved. In cachexia/wasting, muscle is wasted and fat is relatively underutilized. Restoring adequate food intake or altering the composition of the diet reverses malnutrition. Nutrition supplementation does not totally reverse cachexia/wasting. The diagnostic criteria of cachexia/protein-energy wasting in CKD are considered. The association of wasting surrogates, such as serum albumin and prealbumin, with mortality is strong making them robust outcome predictors. At the patient level, longevity has consistently been observed in patients with CKD who have more muscle and/or fat, who report better appetite and who eat more. Although inadequate nutritional intake may contribute to wasting or cachexia, recent evidence indicates that other factors, including systemic inflammation, perturbations of appetite-controlling hormones from reduced renal clearance, aberrant neuropeptide signaling, insulin and insulin-like growth factor resistance, and metabolic acidosis, may be important in the pathogenesis of CKD-associated wasting. A number of novel therapeutic approaches, such as ghrelin agonists and melanocortin receptor antagonists are currently at the experimental level and await confirmation by randomized controlled clinical trials in patients with CKD-associated cachexia/wasting syndrome.

An increased circulating level of fibroblast growth factor 23 (FGF23) is an independent risk factor for mortality, cardiovascular disease, and progression of chronic kidney disease (CKD), but its role in transplant allograft and patient survival is unknown. We tested the hypothesis that increased FGF23 is an independent risk factor for all-cause mortality and allograft loss in a prospective cohort of 984 stable kidney transplant recipients. At enrollment, estimated GFR (eGFR) was 51 ± 21 ml/min per 1.73 m(2) and median C-terminal FGF23 was 28 RU/ml (interquartile range, 20 to 43 RU/ml). Higher FGF23 levels independently associated with increased risk of the composite outcome of all-cause mortality and allograft loss (full model hazard ratio: 1.46 per SD increase in logFGF23, 95% confidence interval: 1.28 to 1.68, P<0.001). The results were similar for each component of the composite outcome and in all sensitivity analyses, including prespecified analyses of patients with baseline eGFR of 30 to 90 ml/min per 1.73 m(2). In contrast, other measures of phosphorus metabolism, including serum phosphate and parathyroid hormone (PTH) levels, did not consistently associate with outcomes. We conclude that a high (or elevated) FGF23 is an independent risk factor for death and allograft loss in kidney transplant recipients.

BACKGROUND: Although it has been shown that human immunodeficiency virus (HIV)-infected adults are at greater risk for aging-associated events, it remains unclear as to whether these events happen at similar, or younger ages, in HIV-infected compared with uninfected adults. The objective of this study was to compare the median age at, and risk of, incident diagnosis of 3 age-associated diseases in HIV-infected and demographically similar uninfected adults. METHODS: The study was nested in the clinical prospective Veterans Aging Cohort Study of HIV-infected and demographically matched uninfected veterans, from 1 April 2003 to 31 December 2010. The outcomes were validated diagnoses of myocardial infarction (MI), end-stage renal disease (ESRD), and non-AIDS-defining cancer (NADC). Differences in mean age at, and risk of, diagnosis by HIV status were estimated using multivariate linear regression models and Cox proportional hazards models, respectively. RESULTS: A total of 98 687 (31% HIV-infected and 69% uninfected) adults contributed >450 000 person-years and 689 MI, 1135 ESRD, and 4179 NADC incident diagnoses. Mean age at MI (adjusted mean difference, -0.11; 95% confidence interval [CI], -.59 to .37 years) and NADC (adjusted mean difference, -0.10 [95% CI, -.30 to .10] years) did not differ by HIV status. HIV-infected adults were diagnosed with ESRD at an average age of 5.5 months younger than uninfected adults (adjusted mean difference, -0.46 [95% CI, -.86 to -.07] years). HIV-infected adults had a greater risk of all 3 outcomes compared with uninfected adults after accounting for important confounders. CONCLUSIONS: HIV-infected adults had a higher risk of these age-associated events, but they occurred at similar ages than those without HIV.

BACKGROUND: Metabolic acidosis, usually manifested by low serum bicarbonate level, is common in chronic kidney disease (CKD) and appears to be associated with higher mortality in dialysis patients. It is not known whether a similar association is present in patients with non-dialysis-dependent CKD (NDD-CKD). METHODS: We used multivariable-adjusted Cox models to examine the association between baseline and time-variable serum bicarbonate (measured as total CO2) with the outcomes of all-cause mortality and the composite of pre-dialysis mortality or end-stage renal disease in 1240 male patients with moderate and advanced NDD-CKD. RESULTS: Serum bicarbonate showed a significant U-shaped association with all-cause mortality, with the highest mortality rate observed in patients with baseline serum bicarbonate levels <22 mmol/L [multivariable-adjusted hazard ratio (95% confidence interval) for patients with serum bicarbonate <22 mmol/L versus > or =22 mmol/L: 1.33 (1.05-1.69), P = 0.02] and the lowest mortality observed in patients with baseline serum bicarbonate of 26-29 mmol/L. The associations between lower serum bicarbonate level and mortality were more accentuated in subgroups of patients with better nutritional status and lower inflammation. CONCLUSIONS: Both lower and higher serum bicarbonates are associated with increased all-cause mortality in patients with moderate and advanced NDD-CKD. Clinical trials are needed to determine if therapeutic interventions aimed at optimizing serum bicarbonate can result in improved outcomes in this population.

BACKGROUND: Treatment of secondary hyperparathyroidism (SHPT) with activated vitamin D analogues is associated with better survival in patients receiving dialysis. It is unclear whether such a benefit is present in patients with predialysis chronic kidney disease (CKD). METHODS: We examined the association of oral calcitriol treatment with mortality and the incidence of dialysis in 520 male US veterans (mean [SD] age, 69.8 [10.3] years; 23.5% black) with CKD stages 3 to 5 and not yet receiving dialysis (mean [SD] estimated glomerular filtration rate, 30.8 [11.3]). Associations were examined by the Kaplan-Meier method and in Poisson regression models with adjustment for age, race, comorbidities, smoking, blood pressure, body mass index, use of phosphate binders, estimated glomerular filtration rate, proteinuria, white blood cell count, percentage of lymphocytes, and levels of parathyroid hormone, calcium, phosphorus, albumin, bicarbonate, and hemoglobin. RESULTS: Two hundred fifty-eight of 520 subjects received treatment with calcitriol, 0.25 to 0.5 microg/d, for a median duration of 2.1 years (range, 0.06-6.0 years). The incidence rate ratios for mortality and combined death and dialysis initiation were significantly lower in treated vs untreated patients (P < .001 for both in the fully adjusted models). Treatment with calcitriol was associated with a trend toward a lower incidence of dialysis. These results were consistent across different subgroups. CONCLUSIONS: Treatment with the activated vitamin D analogue calcitriol appears to be associated with significantly greater survival in patients with CKD not yet receiving dialysis. Randomized clinical trials are required to verify the causality of these associations and to examine whether similar associations are seen with different activated vitamin D analogues.

Abnormalities of mineral metabolism are associated with increased mortality in patients with ESRD, but their effects in predialysis chronic kidney disease (CKD) are less well characterized. In this study, the associations between levels of serum phosphorus, calcium, and calcium-phosphorus product and progression of CKD were examined. Historical data were collected on 985 male US veterans (age 67.4 +/- 10.9; 23.9% black) with CKD stages 1 through 5. Unadjusted and multivariable-adjusted relative risks for progressive CKD (defined as the composite of ESRD or doubling of serum creatinine) were calculated for categories of serum phosphorus, calcium, and calcium-phosphorus product using Cox proportional hazards models. Higher phosphorus was associated with a higher risk for the composite end point (adjusted hazard ratio [HR] [95% confidence interval (CI)] for phosphorus levels 3.3 to 3.8, 3.81 to 4.3, and >4.3 versus <3.3 mg/dl 0.83 [0.54 to 1.27], 1.24 [0.82 to 1.88], and 1.60 [1.06 to 2.41]; P = 0.001 for trend). A 1-mg/dl higher phosphorus level was associated with an adjusted HR (95% CI) of 1.29 (1.12 to 1.48; P < 0.001). Higher calcium-phosphorus product also was associated with higher risk for progressive CKD (adjusted HR [95% CI] for calcium-phosphorus products 30 to 35, 36 to 40, and >40 versus <30 mg2/dl2 0.58 [0.36 to 0.94], 0.87 [0.57 to 1.34], and 1.37 [0.91 to 2.07]; P = 0.002 for trend). A 10-mg2/dl2 higher calcium-phosphorus product was associated with an adjusted HR (95% CI) of 1.29 (1.11 to 1.51; P = 0.001). Lower serum calcium showed a trend toward higher risk for progressive CKD but without statistical significance. Higher serum phosphorus and higher calcium-phosphorus product are associated with progression of CKD.

Several observational studies have demonstrated that serum levels of minerals and parathyroid hormone (PTH) have U- or J-shaped associations with mortality in maintenance hemodialysis patients, but the relationship between serum alkaline phosphatase (AlkPhos) and risk for all-cause or cardiovascular death is unknown. In this study, a 3-yr cohort of 73,960 hemodialysis patients in DaVita outpatient dialysis were studied, and the hazard ratios for all-cause and cardiovascular death were higher across 20-U/L increments of AlkPhos, including within the various strata of intact PTH and serum aspartate aminotransferase. In the fully adjusted model, which accounted for demographics, comorbidity, surrogates of malnutrition and inflammation, minerals, PTH, and aspartate aminotransferase, AlkPhos > or =120 U/L was associated with a hazard ratio for death of 1.25 (95% confidence interval 1.21 to 1.29; P < 0.001). This association remained among diverse subgroups of hemodialysis patients, including those positive for hepatitis C antibody. A rise in AlkPhos by 10 U/L during the first 6 mo was incrementally associated with increased risk for death during the subsequent 2.5 yr. In summary, high levels of serum AlkPhos, especially >120 U/L, are associated with mortality among hemodialysis patients. Prospective controlled trials will be necessary to test whether serum AlkPhos measurements could be used to improve the management of renal osteodystrophy.

BACKGROUND: Our investigation involved a quantitative literature review technique known as meta-analysis to compare the efficacy of three newer antidepressants and imipramine. METHOD: We examined seven major journals in psychiatry from 1980 through 1990, inclusive, and selected those investigations of imipramine, trazodone, bupropion, and fluoxetine that met our minimal criteria for interpretability. These criteria included: (1) the presence of a placebo control, (2) double-blind status, (3) the use of the Hamilton Rating Scale for Depression as a dependent variable measure, (4) the use of nongeriatric adults with a diagnosis of major depression by DSM or RDC standards, and (5) the presence of reported means and standard deviations in the investigation, or sufficient data that allowed such to be computed. Each study of four antidepressants was analyzed for an effect size of the drug investigated. The effect size allows for a determination of the efficacy of a particular drug as compared with placebo, measured in standard deviation units. RESULTS: The data indicated that all four agents are effective as compared with placebo. Furthermore, there is no evidence that the newer heterocyclic agents are less effective than imipramine, as an ANOVA showed no statistically significant difference between the effect sizes of the four antidepressants. CONCLUSION: These data are discussed in terms of characteristics of the various investigations and the need for further research comparing the efficacy of psychopharmacologic agents.