Vitamin D status and clinical outcomes in incident dialysis patients: results from the NECOSAD study.

BACKGROUND: The majority of dialysis patients suffer from vitamin D deficiency, which might contribute to an adverse health outcome. We aimed to elucidate whether European dialysis patients with low 25-hydroxyvitamin D (25(OH)D) levels are at increased risk of mortality and specific fatal events. METHODS: This was a prospective cohort study of incident dialysis patients in the Netherlands (the NECOSAD). We selected all patients with measured 25(OH)D at 12 months after the start of dialysis, the baseline for our study. By Cox regression analyses, we assessed the impact of 25(OH)D levels on short-term (6 months of follow-up) as well as longer-term mortality (3 years of follow-up). Associations of 25(OH)D levels with cardiovascular and non-cardiovascular mortality were also determined. RESULTS: The data from 762 patients (39% females, age 59 ± 15 years, 25(OH)D = 18 ± 11 ng/mL) were available. Fifty-one and 213 patients died during a follow-up of 6 months and 3 years, respectively. After adjustments for possible confounders, the hazard ratio (HR) (with 95% CI) for mortality was 2.0 (1.0-3.8) for short-term and 1.5 (1.0-2.1) for longer-term mortality when comparing patients with 25(OH)D levels ≤ 10 ng/mL with those presenting with 25(OH)D levels > 10 ng/mL. Adjusted HRs for cardiovascular mortality were 2.7 (1.1-6.5) and 1.7 (1.1-2.7) for short- and longer-term mortality, respectively. For non-cardiovascular mortality, we observed no relevant association overall. The impact of 25(OH)D levels on clinical events was modified by parathyroid hormone (PTH) status, with low 25(OH)D levels meaningfully affecting outcomes only in patients with PTH levels above the median of 123 pmol/L. CONCLUSIONS: Vitamin D deficiency in dialysis patients is associated with an adverse health outcome, in particular with short-term cardiovascular mortality. Intervention studies are urgently needed to evaluate whether vitamin D supplementation improves health outcomes of dialysis patients.

Disordered mineral metabolism is not a risk factor for loss of residual renal function in dialysis patients.

BACKGROUND: Recent studies showed that mineral metabolism disorders are associated with renal function loss in pre-dialysis patients, but their effects in dialysis patients are less well established. We examined associations between parameters of mineral metabolism and loss of residual renal function (RRF) in dialysis patients. METHODS: We included 1468 incident haemodialysis (HD) and peritoneal dialysis (PD) patients who were not anuric at dialysis initiation from NECOSAD, a prospective multicentre cohort study. We studied the effects of plasma calcium, phosphorus, calcium-phosphorus product and intact PTH concentrations on loss of RRF. Cox regression models were applied to calculate relative risks of total loss of RRF, defined as anuria during the first 3 years of dialysis. The rate of decline of RRF over time was calculated using general linear mixed models. RESULTS: The mean (SD) age was 59 (15), 62% were men and 59% were treated with HD. We found that both HD and PD patients with the highest phosphorus (P < 0.0001) and calcium-phosphorus product (P < 0.0001) levels had the lowest baseline residual glomerular filtration rate (rGFR) values. During follow-up, 136 HD (15%) and 67 PD patients (12%) became anuric. After adjustment for baseline rGFR, there were no significant associations between parameters of mineral metabolism and the risk of becoming anuric. There were also no differences in the rate of decline in RRF between categories of plasma concentrations. CONCLUSION: Disordered mineral metabolism was neither associated with the risk of becoming anuric, nor with the rate of decline in RRF in dialysis patients. Differences in decline were mainly attributable to the baseline rGFR value.

Mineral metabolism and mortality in dialysis patients: a reassessment of the K/DOQI guideline.

BACKGROUND: Several studies found associations between higher plasma calcium and phosphorus and mortality in dialysis patients. However, different predefined categories and reference values were applied and the precise shape of these relationships remains unclear. METHODS: We evaluated 1,621 patients from NECOSAD, a prospective multicenter cohort study of incident dialysis patients (60 +/- 15 years, 61% male, 64% hemodialysis). We used multivariate Cox regression and restricted cubic spline regression to study the effects of time-updated plasma concentrations on mortality in a flexible manner. RESULTS: 486 patients (30%) died during follow-up. Elevated phosphorus concentration was associated with higher mortality (p = 0.0009). The association of high calcium with mortality was borderline significant (p = 0.07). Within the studied ranges, we could not identify a threshold where an appreciable change in mortality risk occurred. CONCLUSIONS: Mortality risk started to increase at a relatively low phosphorus concentration (4.5 mg/dl). Low-normal calcium combined with low-normal phosphorus concentration was associated with the lowest mortality.

Disturbed mineral metabolism is associated with muscle and skin complaints in a prospective cohort of dialysis patients.

BACKGROUND: Disturbed mineral metabolism is associated with increased morbidity and mortality, however, its influence on physical symptoms is less clear. We explored the effects of disordered plasma calcium, phosphorus, calcium-phosphorus (Ca x P) product and intact parathyroid hormone (iPTH) concentrations according to the K/DOQI guideline for bone metabolism and disease on the risk of muscle and skin complaints in dialysis patients. METHODS: As part of NECOSAD, a prospective multicentre study in the Netherlands, we included 1469 consecutive patients who started haemodialysis or peritoneal dialysis between 1997 and 2004. Muscle pain, cramps and itching (pruritus) and dry (xerosis) skin were repeatedly measured using the Kidney Disease Quality of Life-Short Form questionnaire. Odds ratios (OR) for the risk of complaints over time were calculated by generalized estimating equations (GEE) models. RESULTS: Mean age was 59 +/- 15 years, 61% of the patients were male and 63% were on haemodialysis. At baseline >65% of the patients had muscle and skin complaints. Compared with patients who met the target, the risk of muscle pain was increased in patients with hyperphosphataemia [OR: 1.2; 95% confidence interval (CI): 1.1-1.5] iPTH concentrations below the target range were associated with lower risk of cramps (OR 0.8, 95%CI: 0.6-0.9). The risk of pruritus was increased in patients with severely elevated plasma calcium (OR 1.4; 95%CI: 1.1-1.7), phosphorus (OR 1.4; 95%CI: 1.1-1.7) and Ca x P product levels (OR 1.6; 95%CI: 1.3-2.0). Finally, increased plasma calcium concentrations were associated with an elevated risk of xerosis (OR 1.4; 95%CI: 1.1-1.9). CONCLUSIONS: Disturbed mineral metabolism according to the K/DOQI guideline is associated with more muscle and skin complaints in dialysis patients. These findings emphasize the importance of keeping mineral metabolism in dialysis patients in tight control.

Mineral metabolism and cardiovascular morbidity and mortality risk: peritoneal dialysis patients compared with haemodialysis patients.

BACKGROUND: The K/DOQI guideline for bone metabolism and disease in chronic kidney disease is predominantly based on studies in haemodialysis (HD) patients. However, in clinical practice, this guideline is also applied to peritoneal dialysis (PD) patients. To validate the implementation of this guideline in PD patients, we evaluated the associations between plasma concentrations outside the K/DOQI-targets and the risk of cardiovascular morbidity and mortality in incident PD patients compared with HD patients. METHODS: In a large prospective multicentre study in the Netherlands (The Netherlands Cooperative Study on the Adequacy of Dialysis, NECOSAD), we included patients starting PD or HD between 1997 and 2004. Relative risk of cardiovascular morbidity and mortality were estimated using time-dependent Cox regression modelling. RESULTS: We included 586 PD patients with mean age 52 +/- 15 years (66% males) and 1043 HD patients with mean age 63 +/- 14 years (58% males). Cardiovascular disease (CVD) was the reason for hospitalization in 102 PD and 271 HD patients. In HD patients, the relative risk of CVD-related hospitalization increased with elevated plasma calcium concentrations (hazard ratio: 1.4; 95% CI: 1.1-1.9). Cardiovascular mortality was significantly higher for phosphorus concentrations above the K/DOQI-threshold in PD (2.4; 95% CI: 1.3-4.2) and HD patients (1.5; 95% CI: 1.1-2.1), and for elevated Ca x P in PD (2.2; 95% CI: 1.3-3.8) and HD patients (1.5; 95% CI: 1.1-2.1). CONCLUSIONS: Plasma calcium concentrations above the K/DOQI-threshold increase the relative risk of CVD-related hospitalization in HD patients. Associations with cardiovascular mortality were more pronounced. Both in PD and HD patients with elevated plasma phosphorus and Ca x P concentrations, the cardiovascular mortality risk is increased. Therefore, it seems appropriate to adopt the current guideline in PD patients.

The Kidney Disease Outcomes Quality Initiative (K/DOQI) Guideline for Bone Metabolism and Disease in CKD: association with mortality in dialysis patients.

BACKGROUND: In 2003, the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (K/DOQI) published a guideline recommending tight control of serum calcium, phosphorus, calcium-phosphorus product (Ca x P), and intact parathyroid hormone levels in patients with chronic kidney disease. Within the context of this guideline, we explored associations of these plasma concentrations with all-cause mortality risk in incident dialysis patients in The Netherlands. METHODS: In a large, prospective, multicenter, cohort study (Netherlands Cooperative Study on the Adequacy of Dialysis), we included 1,629 patients new on hemodialysis or peritoneal dialysis therapy between 1997 and 2004. Multivariate Cox regression models containing calcium level, phosphorus level, intact parathyroid hormone level, age, comorbidity, primary kidney disease, nutritional status, albumin level, dialysis dose, and hemoglobin level were used to examine mortality risks. RESULTS: Mean age was 60 +/- 15 (SD) years, 61% were men, and 64% were treated with hemodialysis. In adjusted time-dependent survival analysis, all-cause mortality risk increased in hemodialysis patients by 40% (hazard ratio [HR], 1.4; 95% confidence interval [CI], 1.1 to 1.7) and in peritoneal dialysis patients by 60% (HR, 1.6; 95% CI, 1.1 to 2.4) for plasma phosphorus levels greater than the target. In addition, having elevated plasma Ca x P product levels increased mortality risk by 40% (HR, 1.4; 95% CI, 1.1 to 1.8) in hemodialysis patients and 50% in peritoneal dialysis patients (HR, 1.5; 95% CI, 1.0 to 2.2). In both patient groups, no significant effects were observed for plasma levels less than the targets. CONCLUSION: In time-dependent survival analysis, the presence of plasma phosphorus and Ca x P product concentrations greater than K/DOQI targets increased all-cause mortality risk in hemodialysis and peritoneal dialysis patients.

Acute effects of high-dose furosemide on residual renal function in CAPD patients.

BACKGROUND: High doses of furosemide can increase urine volume in chronic peritoneal dialysis (CAPD) patients. However, no information is available about effects on urinary solute excretion in relation to residual glomerular filtration rate (GFR), urinary furosemide excretion, and peritoneal solute kinetics. METHODS: Diuretic response and the effect on peritoneal fluid and solute transport parameters were investigated in 7 stable CAPD patients with residual renal function (median urine volume 350 mL/24 hours, range 140- 1900 mL/24 hours). Comparisons were made during two clearance periods of 24 hours: one without (P1) and one during 2 g furosemide (P2). RESULTS: The median increase in urine volume was 400 mL (range 270 - 910 mL, p < 0.02) and the increase in sodium excretion was 54 mmol (range 25 - 118 mmol, p < 0.02). No change in GFR was found between P1 (2.4 mL/ minute, range 0.6 - 5.7 mL/min) and P2 (2.0 mL/min, range 1.0 - 4.8 mL/min). An increase in fractional clearance was found for volume, sodium, potassium, and osmolality (p < 0.02). No change was found in the fractional clearance of urea and electrolyte-free water. Furosemide excretion in urine was 8.7 mg/24 hours (range 2.1 - 38 mg/24 hours) and in dialysate 4.9 mg/24 hours (range 1.9 - 7.8 mg/ 24 hours). Plasma furosemide concentration was 29.5 mg/L (range 6.2 - 43.9 mg/L). A positive correlation was found between residual GFR and total urine furosemide excretion (r = 0.93, p < 0.005). Efficiency, expressed as the increase in fractional sodium clearance (percent) per milligram of furosemide excreted per 24 hours, was 1.2%/mg (range 0.3% - 11.3%/mg). CONCLUSION: High-dose furosemide is effective in CAPD patients in increasing urine volume and electrolyte excretion without affecting urea and creatinine clearance. In CAPD patients, the individual response to an identical high dose of furosemide is dependent on the magnitude of residual GFR.

Renal function and nutritional status at the start of chronic dialysis treatment.

Early start of dialysis has been hypothesized to prevent deterioration of nutritional status and to lead to a better clinical outcome. According to the National Kidney Foundation/Dialysis Outcomes Quality Initiative guidelines, dialysis should be started when renal Kt/V(urea) falls below 2.0/wk or the protein equivalent of total nitrogen appearance normalized to body weight (nPNA) falls below 0.8 g/kg per d. The present study was performed 0 to 4 wk before the start of dialysis treatment in 114 incident Dutch patients with chronic renal failure who all had received pre-end-stage renal disease care. The objectives were (1) to analyze the relationship of different levels of residual renal function with parameters of nutritional status and (2) to investigate the relationship of renal Kt/V(urea) and nPNA in this population. The mean GFR at the start of dialysis treatment was 6.2 ml/min per 1.73 m(2), and the Kt/V(urea) was 1.3/wk. Only 10% of the patients fulfilled the Dialysis Outcomes Quality Initiative criterion of Kt/V(urea) > 2.0/wk. In contrast, 69% met the nPNA norm of 0.8 g/kg per d. Seventy-one percent of these patients had a normal nutritional status as scored by subjective global assessment and also other parameters of nutritional status, such as body mass index, and serum albumin fell within the normal range in the majority of the patients. Dutch predialysis patients reached a higher nPNA with the same level of Kt/V(urea) compared with U.S. predialysis patients. Implications of these findings are that guidelines on the initiation of dialysis treatment derived from one population are not necessarily valid in other populations.