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BACKGROUND:The Systolic Blood Pressure Intervention Trial (SPRINT; ClinicalTrials.gov, NCT01206062) reported reduced cardiovascular events by intensive blood pressure (BP) control amongst hypertensive patients without diabetes. However, the risk-benefit profile of intensive BP control may differ across estimated glomerular filtration rate (eGFR) levels. METHODS:This is a post hoc analysis of the SPRINT. Nondiabetic hypertensive adults (n = 9361) with eGFR >20 mL per min per 1.73 m2 were enrolled from 102 US facilities between November 2010 and March 2013 and were followed up until August 2015 (median follow-up, 3.26 years). Patients were randomly assigned to either a systolic BP target of

BACKGROUND:The Systolic Blood Pressure Intervention Trial (SPRINT; ClinicalTrials.gov, NCT01206062) reported reduced cardiovascular events by intensive blood pressure (BP) control amongst hypertensive patients without diabetes. However, the risk-benefit profile of intensive BP control may differ across estimated glomerular filtration rate (eGFR) levels. METHODS:This is a post hoc analysis of the SPRINT. Nondiabetic hypertensive adults (n = 9361) with eGFR >20 mL per min per 1.73 m2 were enrolled from 102 US facilities between November 2010 and March 2013 and were followed up until August 2015 (median follow-up, 3.26 years). Patients were randomly assigned to either a systolic BP target of

Background In the general population, low serum magnesium levels are associated with poor outcomes and death. While limited data suggest that low baseline magnesium levels may be associated with higher mortality in hemodialysis (HD) patients, the impact of changes in magnesium levels over time is unknown. Study Design We examined the association of time-varying serum magnesium levels with all-cause mortality using multivariable time-varying survival models adjusted for clinical characteristics and other time-varying laboratory measures. Setting & Participants 9,359 maintenance HD patients treated in a large dialysis organization between 2007 and 2011. Predictor Time-varying serum magnesium levels across 5 magnesium increments (

Background In the general population, low serum magnesium levels are associated with poor outcomes and death. While limited data suggest that low baseline magnesium levels may be associated with higher mortality in hemodialysis (HD) patients, the impact of changes in magnesium levels over time is unknown. Study Design We examined the association of time-varying serum magnesium levels with all-cause mortality using multivariable time-varying survival models adjusted for clinical characteristics and other time-varying laboratory measures. Setting & Participants 9,359 maintenance HD patients treated in a large dialysis organization between 2007 and 2011. Predictor Time-varying serum magnesium levels across 5 magnesium increments (

Traditional risk factors of cardiovascular death in the general population, including body mass index (BMI), serum cholesterol, and blood pressure (BP), are also found to relate to outcomes in the geriatric population, but in an opposite direction. Some degrees of elevated BMI, serum cholesterols, and BP are reportedly associated with lower, instead of higher, risk of death among the elderly. This phenomenon is termed "reverse epidemiology" or "risk factor paradox" (such as obesity paradox) and is also observed in a variety of chronic disease states such as end-stage renal disease requiring dialysis, chronic heart failure, rheumatoid arthritis, and AIDS. Several possible causes are hypothesized to explain this risk factor reversal: competing short-term and long-term killers, improved hemodynamic stability in the obese, adipokine protection against tumor necrosis factor-α, lipoprotein protection against endotoxins, and lipophilic toxin sequestration by the adipose tissue. It is possible that the current thresholds for intervention and goal levels for such traditional risk factors as BMI, serum cholesterol, and BP derived based on younger populations do not apply to the elderly, and that new levels for such risk factors should be developed for the elderly population. Reverse epidemiology of conventional cardiovascular risk factors may have a bearing on the management of the geriatric population, thus it deserves further attention.

Traditional risk factors of cardiovascular death in the general population, including body mass index (BMI), serum cholesterol, and blood pressure (BP), are also found to relate to outcomes in the geriatric population, but in an opposite direction. Some degrees of elevated BMI, serum cholesterols, and BP are reportedly associated with lower, instead of higher, risk of death among the elderly. This phenomenon is termed "reverse epidemiology" or "risk factor paradox" (such as obesity paradox) and is also observed in a variety of chronic disease states such as end-stage renal disease requiring dialysis, chronic heart failure, rheumatoid arthritis, and AIDS. Several possible causes are hypothesized to explain this risk factor reversal: competing short-term and long-term killers, improved hemodynamic stability in the obese, adipokine protection against tumor necrosis factor-α, lipoprotein protection against endotoxins, and lipophilic toxin sequestration by the adipose tissue. It is possible that the current thresholds for intervention and goal levels for such traditional risk factors as BMI, serum cholesterol, and BP derived based on younger populations do not apply to the elderly, and that new levels for such risk factors should be developed for the elderly population. Reverse epidemiology of conventional cardiovascular risk factors may have a bearing on the management of the geriatric population, thus it deserves further attention.

Background - In the general population, blacks experience higher mortality than their white peers, attributed in part to their lower socioeconomic status, reduced access to care, and possibly intrinsic biological factors. Patients with kidney disease are a notable exception, among whom blacks experience lower mortality. It is unclear if similar differences affecting outcomes exist in patients with no kidney disease but with equal or similar access to health care. Methods and Results - We compared all-cause mortality, incident coronary heart disease, and incident ischemic stroke using multivariable-adjusted Cox models in a nationwide cohort of 547 441 black and 2 525 525 white patients with baseline estimated glomerular filtration rate ≥60 mL·min-1·1.73 m-2 receiving care from the US Veterans Health Administration. In parallel analyses, we compared outcomes in black versus white individuals in the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. After multivariable adjustments in veterans, black race was associated with 24% lower all-cause mortality (adjusted hazard ratio, 0.76; 95% confidence interval, 0.75-0.77; P

Background - In the general population, blacks experience higher mortality than their white peers, attributed in part to their lower socioeconomic status, reduced access to care, and possibly intrinsic biological factors. Patients with kidney disease are a notable exception, among whom blacks experience lower mortality. It is unclear if similar differences affecting outcomes exist in patients with no kidney disease but with equal or similar access to health care. Methods and Results - We compared all-cause mortality, incident coronary heart disease, and incident ischemic stroke using multivariable-adjusted Cox models in a nationwide cohort of 547 441 black and 2 525 525 white patients with baseline estimated glomerular filtration rate ≥60 mL·min-1·1.73 m-2 receiving care from the US Veterans Health Administration. In parallel analyses, we compared outcomes in black versus white individuals in the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. After multivariable adjustments in veterans, black race was associated with 24% lower all-cause mortality (adjusted hazard ratio, 0.76; 95% confidence interval, 0.75-0.77; P

Rationale There is a paucity of large cohort studies examining the association of obstructive sleep apnoea (OSA) with clinical outcomes including all-cause mortality, coronary heart disease (CHD), strokes and chronic kidney disease (CKD). Objectives We hypothesised that a diagnosis of incident OSA is associated with higher risks of these adverse clinical outcomes. Methods, measurements In a nationally representative cohort of over 3 million (n=3 079 514) US veterans (93% male) with baseline estimated glomerular filtration rate (eGFR)≥60 mL/min/1.73 m2, we examined the association between the diagnosis of incident OSA, treated and untreated with CPAP, and: (1) all-cause mortality, (2) incident CHD, (3) incident strokes, (4) incident CKD defined as eGFR

Rationale There is a paucity of large cohort studies examining the association of obstructive sleep apnoea (OSA) with clinical outcomes including all-cause mortality, coronary heart disease (CHD), strokes and chronic kidney disease (CKD). Objectives We hypothesised that a diagnosis of incident OSA is associated with higher risks of these adverse clinical outcomes. Methods, measurements In a nationally representative cohort of over 3 million (n=3 079 514) US veterans (93% male) with baseline estimated glomerular filtration rate (eGFR)≥60 mL/min/1.73 m2, we examined the association between the diagnosis of incident OSA, treated and untreated with CPAP, and: (1) all-cause mortality, (2) incident CHD, (3) incident strokes, (4) incident CKD defined as eGFR

Background In the general population, circulating adiponectin is associated with a favorable cardiovascular risk profile (eg, lower triglycerides and body fat) and decreased mortality. Hemodialysis (HD) patients have comparatively higher adiponectin concentrations, but prior studies examining the adiponectin-mortality association in this population have not accounted for body composition or shown a consistent relationship. Study Design Prospective cohort study. Settings & Participants We examined baseline serum adiponectin concentrations in 501 HD patients across 13 dialysis centers from the prospective MADRAD (Malnutrition, Diet, and Racial Disparities in Chronic Kidney Disease) cohort (entry period, October 2011 to February 2013; follow-up through August 2013). Predictor Serum adiponectin concentration in tertiles (tertiles 1, 2, and 3 defined as ≤16.1, 30.1, and ≥30.1-100.0 μg/mL, respectively). Adjustment variables included case-mix and laboratory test results (age, sex, race, ethnicity, vintage, diabetes, serum albumin, total iron-binding capacity, serum creatinine, white blood cell count, phosphate, hemoglobin, and normalized protein catabolic rate), body composition surrogates (subcutaneous, visceral, and total-body fat and lean body mass), and serum lipid levels (cholesterol, high-density lipoprotein cholesterol, and triglycerides). Outcomes All-cause mortality using survival (Cox) models incrementally adjusted for case-mix and laboratory test results. Results Among 501 HD patients, 50 deaths were observed during 631.1 person-years of follow-up. In case-mix- and laboratory-adjusted Cox analyses, the highest adiponectin tertile was associated with increased mortality versus the lowest tertile (HR, 3.35; 95% CI, 1.50-7.47). These associations were robust in analyses that additionally accounted for body composition (HR, 3.18; 95% CI, 1.61-8.24) and lipid levels (HR, 3.64; 95% CI, 1.34-7.58). Limitations Residual confounding cannot be excluded. Conclusions Higher adiponectin level is associated with a 3-fold higher death risk in HD patients independent of body composition and lipid levels. Future studies are needed to elucidate underlying mechanisms and determine therapeutic targets associated with improved outcomes in HD patients.

Background In the general population, circulating adiponectin is associated with a favorable cardiovascular risk profile (eg, lower triglycerides and body fat) and decreased mortality. Hemodialysis (HD) patients have comparatively higher adiponectin concentrations, but prior studies examining the adiponectin-mortality association in this population have not accounted for body composition or shown a consistent relationship. Study Design Prospective cohort study. Settings & Participants We examined baseline serum adiponectin concentrations in 501 HD patients across 13 dialysis centers from the prospective MADRAD (Malnutrition, Diet, and Racial Disparities in Chronic Kidney Disease) cohort (entry period, October 2011 to February 2013; follow-up through August 2013). Predictor Serum adiponectin concentration in tertiles (tertiles 1, 2, and 3 defined as ≤16.1, 30.1, and ≥30.1-100.0 μg/mL, respectively). Adjustment variables included case-mix and laboratory test results (age, sex, race, ethnicity, vintage, diabetes, serum albumin, total iron-binding capacity, serum creatinine, white blood cell count, phosphate, hemoglobin, and normalized protein catabolic rate), body composition surrogates (subcutaneous, visceral, and total-body fat and lean body mass), and serum lipid levels (cholesterol, high-density lipoprotein cholesterol, and triglycerides). Outcomes All-cause mortality using survival (Cox) models incrementally adjusted for case-mix and laboratory test results. Results Among 501 HD patients, 50 deaths were observed during 631.1 person-years of follow-up. In case-mix- and laboratory-adjusted Cox analyses, the highest adiponectin tertile was associated with increased mortality versus the lowest tertile (HR, 3.35; 95% CI, 1.50-7.47). These associations were robust in analyses that additionally accounted for body composition (HR, 3.18; 95% CI, 1.61-8.24) and lipid levels (HR, 3.64; 95% CI, 1.34-7.58). Limitations Residual confounding cannot be excluded. Conclusions Higher adiponectin level is associated with a 3-fold higher death risk in HD patients independent of body composition and lipid levels. Future studies are needed to elucidate underlying mechanisms and determine therapeutic targets associated with improved outcomes in HD patients.

Background: Protein–energy wasting (PEW) is a common condition in patients with chronic kidney disease (CKD) including dialysis and kidney transplant recipients (TX) and frequently assessed with malnutrition–inflammation score (MIS). We hypothesized that (1) the MIS and PEW parameters are correlated with kidney function and (2) the MIS and PEW parameters are more severe in TX than in non-dialysis (ND) CKD patients with similar eGFR. Methods: In this study, we matched 203 ND-CKD and 203 TX patients from two independently assembled cohorts of patients based on estimated glomerular filtration rate (eGFR) and compared various PEW parameters between the two groups using unadjusted and case-mix adjusted linear regression and conditional logistic regression analysis models. Results: In the combined cohort (n = 406) of patients, the mean ± SD age was 57 ± 12 years; included 55 % men and 35 % diabetics; and demonstrated a mean ± SD baseline eGFR of 29 ± 11 ml/min/1.73 m2. The eGFR correlated positively with serum albumin (ρ = 0.26, p

Background: Protein–energy wasting (PEW) is a common condition in patients with chronic kidney disease (CKD) including dialysis and kidney transplant recipients (TX) and frequently assessed with malnutrition–inflammation score (MIS). We hypothesized that (1) the MIS and PEW parameters are correlated with kidney function and (2) the MIS and PEW parameters are more severe in TX than in non-dialysis (ND) CKD patients with similar eGFR. Methods: In this study, we matched 203 ND-CKD and 203 TX patients from two independently assembled cohorts of patients based on estimated glomerular filtration rate (eGFR) and compared various PEW parameters between the two groups using unadjusted and case-mix adjusted linear regression and conditional logistic regression analysis models. Results: In the combined cohort (n = 406) of patients, the mean ± SD age was 57 ± 12 years; included 55 % men and 35 % diabetics; and demonstrated a mean ± SD baseline eGFR of 29 ± 11 ml/min/1.73 m2. The eGFR correlated positively with serum albumin (ρ = 0.26, p

Niacin is the oldest drug available for the treatment of dyslipidemia. It has been studied extensively and tested in clinical trials of atherosclerotic cardiovascular disease prevention and regression in the general population, but not specifically in patients with chronic kidney disease (CKD), who are at extremely high residual risk despite current therapy. Despite the current controversy about recent trials with niacin, including their limitations, there may be a place for this agent in select patients with CKD with dyslipidemia. Niacin has a favorable unique impact on factors affecting the rate of glomerular filtration rate decline, including high-density lipoprotein (HDL) particle number and function, triglyceride levels, oxidant stress, inflammation and endothelial function, and lowering of serum phosphorus levels by reducing dietary phosphorus absorption in the gastrointestinal tract. These effects may slow glomerular filtration rate decline and ultimately improve CKD outcomes and prevent cardiovascular risk. This review presents the clinically relevant concept that niacin holds significant potential as a renoprotective therapeutic agent. In addition, this review concludes that clinical investigations to assess the effect of niacin (in addition to aggressive low-density lipoprotein cholesterol lowering) on reduction of cardiovascular events in patients with CKD with very low HDL cholesterol (or those with identified dysfunctional HDL) and elevated triglyceride levels need to be considered seriously to address the high residual risk in this population.

A significant number of dietary restrictions are imposed traditionally and uniformly on maintenance dialysis patients, whereas there is very little data to support their benefits. Recent studies indicate that dietary restrictions of phosphorus may lead to worse survival and poorer nutritional status. Restricting dietary potassium may deprive dialysis patients of heart-healthy diets and lead to intake of more atherogenic diets. There is little data about the survival benefits of dietary sodium restriction, and limiting fluid intake may inherently lead to lower protein and calorie consumption, when in fact dialysis patients often need higher protein intake to prevent and correct protein-energy wasting. Restricting dietary carbohydrates in diabetic dialysis patients may not be beneficial in those with burnt-out diabetes. Dietary fat including omega-3 fatty acids may be important caloric sources and should not be restricted. Data to justify other dietary restrictions related to calcium, vitamins, and trace elements are scarce and often contradictory. The restriction of eating during hemodialysis treatment is likely another incorrect practice that may worsen hemodialysis induced hypoglycemia and nutritional derangements. We suggest careful relaxation of most dietary restrictions and adoption of a more balanced and individualized approach, thereby easing some of these overzealous restrictions that have not been proven to offer major advantages to patients and their outcomes and which may in fact worsen patients' quality of life and satisfaction. This manuscript critically reviews the current paradigms and practices of recommended dietary regimens in dialysis patients including those related to dietary protein, carbohydrate, fat, phosphorus, potassium, sodium, and calcium, and discusses the feasibility and implications of adherence to ardent dietary restrictions and future research.

A significant number of dietary restrictions are imposed traditionally and uniformly on maintenance dialysis patients, whereas there is very little data to support their benefits. Recent studies indicate that dietary restrictions of phosphorus may lead to worse survival and poorer nutritional status. Restricting dietary potassium may deprive dialysis patients of heart-healthy diets and lead to intake of more atherogenic diets. There is little data about the survival benefits of dietary sodium restriction, and limiting fluid intake may inherently lead to lower protein and calorie consumption, when in fact dialysis patients often need higher protein intake to prevent and correct protein-energy wasting. Restricting dietary carbohydrates in diabetic dialysis patients may not be beneficial in those with burnt-out diabetes. Dietary fat including omega-3 fatty acids may be important caloric sources and should not be restricted. Data to justify other dietary restrictions related to calcium, vitamins, and trace elements are scarce and often contradictory. The restriction of eating during hemodialysis treatment is likely another incorrect practice that may worsen hemodialysis induced hypoglycemia and nutritional derangements. We suggest careful relaxation of most dietary restrictions and adoption of a more balanced and individualized approach, thereby easing some of these overzealous restrictions that have not been proven to offer major advantages to patients and their outcomes and which may in fact worsen patients' quality of life and satisfaction. This manuscript critically reviews the current paradigms and practices of recommended dietary regimens in dialysis patients including those related to dietary protein, carbohydrate, fat, phosphorus, potassium, sodium, and calcium, and discusses the feasibility and implications of adherence to ardent dietary restrictions and future research.

Aggressive NIH is a common histopathological lesion found at the sites of venous stenosis in arteriovenous fistula (AVF) and arteriovenous grafts (AVG). Inflammatory mediators have been proposed to play a pathogenic role in NIH, but there is paucity of data evaluating this hypothesis in clinical studies or in animal models. Serum levels of inflammatory mediators can potentially identify patients at high risk of AVF and AVG dysfunction. In a cross-sectional cohort study of 754 HD patients who were part of the NIED study cohort, we examined the associations between inflammatory markers including serum interleukin (IL) 1β, IL-6, C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) and type of vascular access. Unadjusted and multivariate-adjusted linear regression models were used. In addition, time-dependent regression model was used to assess the association between inflammatory markers and mortality. We observed that in the multivariate-adjusted model, inflammatory mediators interleukin-6 (IL-6), interleukin-1L-ß (IL-1ß), and C-reactive protein (CRP), the predicted value in hemodialysis patients, are lowest in patients with AVF and highest in central venous catheter (CVC) and AVG even in case-mix and malnutrition-inflammation complex syndrome (MICS)-adjusted models. IL-6 and CRP levels fall consistently in the same patients when AVG or CVC is changed to AVF and increase if the same patient changes access from AVF to AVG or CVC. Obesity is a risk factor for fistula failure and fistulas are associated with the lowest mortality compared with CVC and AVG. We did not find any statistically significant association between tumor necrosis factor-α (TNF- α) and vascular access outcomes. Higher levels of inflammatory mediators seen in CVC and AVG compared with AVF could potentially explain the higher mortality seen in patients with CVC and AVG compared with AVF. © 2013 Wiley Periodicals, Inc.

The incidence of early stage renal cell carcinoma (RCC) is increasing and observational studies have shown equivalent oncological outcomes of partial versus radical nephrectomy for stage I tumours. Population studies suggest that compared with radical nephrectomy, partial nephrectomy is associated with decreased mortality and a lower rate of postoperative decline in kidney function. However, rates of chronic kidney disease (CKD) in patients who have undergone nephrectomy might be higher than in the general population. The risks of new-onset or accelerated CKD and worsened survival after nephrectomy might be linked, as kidney insufficiency is a risk factor for cardiovascular disease and mortality. Nephron-sparing approaches have, therefore, been proposed as the standard of care for patients with type 1a tumours and as a viable option for those with type 1b tumours. However, prospective data on the incidence of de novo and accelerated CKD after cancer nephrectomy is lacking, and the only randomized trial to date was closed prematurely. Intrinsic abnormalities in non-neoplastic kidney parenchyma and comorbid conditions (including diabetes mellitus and hypertension) might increase the risks of CKD and RCC. More research is needed to better understand the risk of CKD post-nephrectomy, to develop and validate predictive scores for risk-stratification, and to optimize patient management.

Aggressive NIH is a common histopathological lesion found at the sites of venous stenosis in arteriovenous fistula (AVF) and arteriovenous grafts (AVG). Inflammatory mediators have been proposed to play a pathogenic role in NIH, but there is paucity of data evaluating this hypothesis in clinical studies or in animal models. Serum levels of inflammatory mediators can potentially identify patients at high risk of AVF and AVG dysfunction. In a cross-sectional cohort study of 754 HD patients who were part of the NIED study cohort, we examined the associations between inflammatory markers including serum interleukin (IL) 1β, IL-6, C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) and type of vascular access. Unadjusted and multivariate-adjusted linear regression models were used. In addition, time-dependent regression model was used to assess the association between inflammatory markers and mortality. We observed that in the multivariate-adjusted model, inflammatory mediators interleukin-6 (IL-6), interleukin-1L-ß (IL-1ß), and C-reactive protein (CRP), the predicted value in hemodialysis patients, are lowest in patients with AVF and highest in central venous catheter (CVC) and AVG even in case-mix and malnutrition-inflammation complex syndrome (MICS)-adjusted models. IL-6 and CRP levels fall consistently in the same patients when AVG or CVC is changed to AVF and increase if the same patient changes access from AVF to AVG or CVC. Obesity is a risk factor for fistula failure and fistulas are associated with the lowest mortality compared with CVC and AVG. We did not find any statistically significant association between tumor necrosis factor-α (TNF- α) and vascular access outcomes. Higher levels of inflammatory mediators seen in CVC and AVG compared with AVF could potentially explain the higher mortality seen in patients with CVC and AVG compared with AVF. © 2013 Wiley Periodicals, Inc.

The incidence of early stage renal cell carcinoma (RCC) is increasing and observational studies have shown equivalent oncological outcomes of partial versus radical nephrectomy for stage I tumours. Population studies suggest that compared with radical nephrectomy, partial nephrectomy is associated with decreased mortality and a lower rate of postoperative decline in kidney function. However, rates of chronic kidney disease (CKD) in patients who have undergone nephrectomy might be higher than in the general population. The risks of new-onset or accelerated CKD and worsened survival after nephrectomy might be linked, as kidney insufficiency is a risk factor for cardiovascular disease and mortality. Nephron-sparing approaches have, therefore, been proposed as the standard of care for patients with type 1a tumours and as a viable option for those with type 1b tumours. However, prospective data on the incidence of de novo and accelerated CKD after cancer nephrectomy is lacking, and the only randomized trial to date was closed prematurely. Intrinsic abnormalities in non-neoplastic kidney parenchyma and comorbid conditions (including diabetes mellitus and hypertension) might increase the risks of CKD and RCC. More research is needed to better understand the risk of CKD post-nephrectomy, to develop and validate predictive scores for risk-stratification, and to optimize patient management.

Background/aimsHyperphosphatemia is associated with higher mortality and increased incidence of end-stage renal disease in patients with non-dialysis dependent CKD (NDD-CKD), but there has not been a concomitant assessment of mortality and progressive kidney disease that would also account for cumulative effects of hyperphosphatemia.MethodsIn order to account for the cumulative effects of abnormal serum phosphorus we examined associations of not only baseline, but also time-averaged serum phosphorus levels with all-cause mortality, the composite of mortality or ESRD and the slopes of estimated glomerular filtration rate (eGFR), by using Cox models and mixed effects models in a contemporary cohort of 713 males with moderate and advanced NDD-CKD.ResultsHigher baseline and time-averaged serum phosphorus were both associated with mortality and with the composite outcome. A 1 mg/dl higher time-averaged serum phosphorus was associated with a multivariable adjusted hazard ratio of all-cause mortality (95% CI) of 1.56 (1.19 - 2.05), p = 0.001. Higher serum phosphorus was associated with a steeper slope of eGFR in unadjusted analyses, but this association became non-significant after multivariable adjustments.ConclusionThe cumulative burden of hyperphosphatemia is associated with increased mortality in patients with moderate and advanced NDD-CKD. Clinical trials are needed to determine if lowering serum phosphorus can result in improved mortality in this population.

Background/aimsHyperphosphatemia is associated with higher mortality and increased incidence of end-stage renal disease in patients with non-dialysis dependent CKD (NDD-CKD), but there has not been a concomitant assessment of mortality and progressive kidney disease that would also account for cumulative effects of hyperphosphatemia.MethodsIn order to account for the cumulative effects of abnormal serum phosphorus we examined associations of not only baseline, but also time-averaged serum phosphorus levels with all-cause mortality, the composite of mortality or ESRD and the slopes of estimated glomerular filtration rate (eGFR), by using Cox models and mixed effects models in a contemporary cohort of 713 males with moderate and advanced NDD-CKD.ResultsHigher baseline and time-averaged serum phosphorus were both associated with mortality and with the composite outcome. A 1 mg/dl higher time-averaged serum phosphorus was associated with a multivariable adjusted hazard ratio of all-cause mortality (95% CI) of 1.56 (1.19 - 2.05), p = 0.001. Higher serum phosphorus was associated with a steeper slope of eGFR in unadjusted analyses, but this association became non-significant after multivariable adjustments.ConclusionThe cumulative burden of hyperphosphatemia is associated with increased mortality in patients with moderate and advanced NDD-CKD. Clinical trials are needed to determine if lowering serum phosphorus can result in improved mortality in this population.

Secondary hyperparathyroidism is associated with mortality in patients undergoing maintenance dialysis treatment. We studied 515 male US veterans with chronic kidney disease, who were not yet on dialysis, to see what outcomes were associated with secondary hyperparathyroidism in this population. Relationships between intact parathyroid hormone levels and all-cause mortality along with the composite of mortality or incidence of dialysis were measured in unadjusted and adjusted Cox models for case-mix and laboratory variables. Elevated parathyroid hormone levels above the upper limit compared to the lower limit of the normal range were significantly associated with mortality after adjustments. Higher intact parathyroid hormone levels in the upper limit of normal were significantly associated with higher mortality overall and showed similar trends in subgroups of patients with stage 3 and stage 4-5 chronic kidney disease and with higher and lower serum calcium and phosphorus levels. Similar associations were found with the composite outcome of mortality or dialysis. Our study shows that secondary hyperparathyroidism is independently associated with higher mortality in patients with chronic kidney disease but not yet on dialysis.

Replacement of activated vitamin D has been the cornerstone of therapy for secondary hyperparathyroidism (SHPT). Recent findings from several large observational studies have suggested that the benefits of vitamin D receptor activators (VDRA) may extend beyond the traditional parathyroid hormone (PTH)-lowering effect, and could result in direct cardiovascular and metabolic benefits. The advent of several new analogs of the activated vitamin D molecule has widened our therapeutic armamentarium, but has also made therapeutic decisions more complicated. Treatment of SHPT has become even more complex with the arrival of the first calcium-sensing receptor (CSR) agonist (cinacalcet hydrochloride) and with the uncovering of novel mechanisms responsible for SHPT. We provide a brief overview of the physiology and pathophysiology of SHPT, with a focus on vitamin D metabolism, and discuss various practical aspects of VDRA therapy and its reported association with survival in recent observational studies. A detailed discussion of the available agents is aimed at providing the practicing physician with a clear understanding of the advantages or disadvantages of the individual medications. A number of open questions are also analyzed, including the present and future roles of CSR agonists and 25(OH) vitamin D replacement.

Secondary hyperparathyroidism is associated with mortality in patients undergoing maintenance dialysis treatment. We studied 515 male US veterans with chronic kidney disease, who were not yet on dialysis, to see what outcomes were associated with secondary hyperparathyroidism in this population. Relationships between intact parathyroid hormone levels and all-cause mortality along with the composite of mortality or incidence of dialysis were measured in unadjusted and adjusted Cox models for case-mix and laboratory variables. Elevated parathyroid hormone levels above the upper limit compared to the lower limit of the normal range were significantly associated with mortality after adjustments. Higher intact parathyroid hormone levels in the upper limit of normal were significantly associated with higher mortality overall and showed similar trends in subgroups of patients with stage 3 and stage 4-5 chronic kidney disease and with higher and lower serum calcium and phosphorus levels. Similar associations were found with the composite outcome of mortality or dialysis. Our study shows that secondary hyperparathyroidism is independently associated with higher mortality in patients with chronic kidney disease but not yet on dialysis.

Replacement of activated vitamin D has been the cornerstone of therapy for secondary hyperparathyroidism (SHPT). Recent findings from several large observational studies have suggested that the benefits of vitamin D receptor activators (VDRA) may extend beyond the traditional parathyroid hormone (PTH)-lowering effect, and could result in direct cardiovascular and metabolic benefits. The advent of several new analogs of the activated vitamin D molecule has widened our therapeutic armamentarium, but has also made therapeutic decisions more complicated. Treatment of SHPT has become even more complex with the arrival of the first calcium-sensing receptor (CSR) agonist (cinacalcet hydrochloride) and with the uncovering of novel mechanisms responsible for SHPT. We provide a brief overview of the physiology and pathophysiology of SHPT, with a focus on vitamin D metabolism, and discuss various practical aspects of VDRA therapy and its reported association with survival in recent observational studies. A detailed discussion of the available agents is aimed at providing the practicing physician with a clear understanding of the advantages or disadvantages of the individual medications. A number of open questions are also analyzed, including the present and future roles of CSR agonists and 25(OH) vitamin D replacement.

Although renal osteodystrophy and vitamin D analogs may be related to survival in maintenance hemodialysis (MHD) patients, most studies have examined associations between baseline values and survival without accounting for variations in clinical and laboratory measures over time. We examined associations between survival and quarterly laboratory values and administered paricalcitol in a 2-year (July 2001-June 2003) cohort of 58,058 MHD patients from all DaVita dialysis clinics in USA using both time-dependent Cox models with repeated measures and fixed-covariate Cox models with only baseline values. Whereas hypercalcemia and hyperphosphatemia were robust predictors of higher death risk in all models, the association between serum calcium and mortality was different in time-varying models. Changes in baseline calcium and phosphorus values beyond the Kidney Disease Outcome Quality Initiative recommended targets were associated with increased mortality. Associations between high serum parathyroid hormone and increased death risk were masked by case-mix characteristics of MHD patients. Time-varying serum alkaline phosphatase had an incremental association with mortality. Administration of any dose of paricalcitol was associated with improved survival in time-varying models. Controlling for nutritional markers may introduce overadjustment bias owing to their strong collinearity with osteodystrophy surrogates. Whereas both time-dependent and fixed-covariate Cox models result in similar associations between osteodystrophy indicators and survival, subtle but potentially clinically relevant differences between the two models exist, probably because fixed models do not account for variations of osteodystrophy indices and changes in medication dose over time.

Although renal osteodystrophy and vitamin D analogs may be related to survival in maintenance hemodialysis (MHD) patients, most studies have examined associations between baseline values and survival without accounting for variations in clinical and laboratory measures over time. We examined associations between survival and quarterly laboratory values and administered paricalcitol in a 2-year (July 2001-June 2003) cohort of 58,058 MHD patients from all DaVita dialysis clinics in USA using both time-dependent Cox models with repeated measures and fixed-covariate Cox models with only baseline values. Whereas hypercalcemia and hyperphosphatemia were robust predictors of higher death risk in all models, the association between serum calcium and mortality was different in time-varying models. Changes in baseline calcium and phosphorus values beyond the Kidney Disease Outcome Quality Initiative recommended targets were associated with increased mortality. Associations between high serum parathyroid hormone and increased death risk were masked by case-mix characteristics of MHD patients. Time-varying serum alkaline phosphatase had an incremental association with mortality. Administration of any dose of paricalcitol was associated with improved survival in time-varying models. Controlling for nutritional markers may introduce overadjustment bias owing to their strong collinearity with osteodystrophy surrogates. Whereas both time-dependent and fixed-covariate Cox models result in similar associations between osteodystrophy indicators and survival, subtle but potentially clinically relevant differences between the two models exist, probably because fixed models do not account for variations of osteodystrophy indices and changes in medication dose over time.

Anemia is a common complication of chronic kidney disease (CKD), but the outcomes associated with lower hemoglobin (Hgb) levels in patients with CKD not yet on dialysis are not well characterized. Analyses exploring outcomes associated with a single baseline Hgb value also do not account for the longitudinal variation of this measure. After collecting all Hgb measurements (N=17 194, median (range): 12 (1-168)) over a median follow-up period of 2.1 years in a historical prospective cohort of 853 male US veterans with CKD Stages 3-5 not yet on dialysis, we examined the association of time-averaged Hgb levels with predialysis all-cause mortality, end-stage renal disease (ESRD), and a composite end point of both. Kaplan-Meier survival analysis and Cox models adjusted for age, race, body mass index, smoking status, blood pressure, diabetes mellitus, cardiovascular disease, categories of estimated glomerular filtration rate, serum concentrations of albumin and cholesterol, and proteinuria were examined. Lower time-averaged Hgb was associated with significantly higher hazard of the composite end point (hazard ratio (95% confidence interval) in the adjusted model for time-averaged Hgb of 130 g/l: 2.57 (1.85-3.58), 1.97 (1.45-2.66), 1.19 (0.86-1.63), P(trend)

Anemia is a common complication of chronic kidney disease (CKD), but the outcomes associated with lower hemoglobin (Hgb) levels in patients with CKD not yet on dialysis are not well characterized. Analyses exploring outcomes associated with a single baseline Hgb value also do not account for the longitudinal variation of this measure. After collecting all Hgb measurements (N=17 194, median (range): 12 (1-168)) over a median follow-up period of 2.1 years in a historical prospective cohort of 853 male US veterans with CKD Stages 3-5 not yet on dialysis, we examined the association of time-averaged Hgb levels with predialysis all-cause mortality, end-stage renal disease (ESRD), and a composite end point of both. Kaplan-Meier survival analysis and Cox models adjusted for age, race, body mass index, smoking status, blood pressure, diabetes mellitus, cardiovascular disease, categories of estimated glomerular filtration rate, serum concentrations of albumin and cholesterol, and proteinuria were examined. Lower time-averaged Hgb was associated with significantly higher hazard of the composite end point (hazard ratio (95% confidence interval) in the adjusted model for time-averaged Hgb of 130 g/l: 2.57 (1.85-3.58), 1.97 (1.45-2.66), 1.19 (0.86-1.63), P(trend)