Cholecalciferol supplementation to improve the hepatitis B vaccination response in hemodialysis patients: A first randomized open label pilot study (DeVitaHep).

BACKGROUND: Patients with advanced chronic kidney disease should be vaccinated against hepatitis B. In observational studies vitamin D insufficiency is associated with a reduced seroconversion rate. The effect of cholecalciferol supplementation on hepatitis B vaccination response in haemodialysis patients with vitamin D insufficiency is unknown. METHODS: In this randomized open label pilot study 40 unvaccinated haemodialysis patients with 25(OH)D insufficiency (<30 ng/mL) were enrolled. In the supplementation group, we administered cholecalciferol orally in a dose of 28,000 IU weekly for a maximum of 12 weeks. Hepatitis B vaccination (HBvaxPRO 40 µg i.m. months 0, 1, 6) was performed after achieving a 25(OH)D level >30 ng/mL or after completing three months of supplementation despite failure to achieve the target level. In the control group, patients were vaccinated immediately after randomization. Anti-hepatitis B-antibody titer (anti-HBs) was measured eight weeks after completing the vaccination course. RESULTS: Thirty-seven (26 male, 11 female) patients aged 65 (13.5) years underwent randomization with 17 patients allocated to the control group and 20 patients included in the supplementation group. After 12 weeks of cholecalciferol supplementation, mean (SD) 25(OH)D concentration increased from 15.0 (8.0) to 31.0 (7.1) ng/mL, but remained unchanged in the control group (14.0 (7.1) to 11.6 (7.5) mg/mL). Neither the number of patients with seroconversion (anti-HBs titer ≥ 10 IU/L; n = 6 (35.3%) vs n = 3 (27.3%), p = 0.704), nor the number of patients with seroprotection (anti-HBs titer >100 IU/L; n = 4 (23.5%) vs n = 2 (18.2%) differed between treatment groups. Cholecalciferol supplementation was safe without treatment-related adverse events. CONCLUSION: In this small pilot study, high-dose oral cholecalciferol supplementation did not improve the hepatitis B vaccination response in haemodialysis patients with vitamin D insufficiency. This clinical trial was registered within EudraCT (EudraCT number 2011-004621-26).

A randomized controlled trial of alanyl-glutamine supplementation in peritoneal dialysis fluid to assess impact on biomarkers of peritoneal health.

In early clinical testing, acute addition of alanyl-glutamine (AlaGln) to glucose-based peritoneal dialysis (PD) fluids restored peritoneal cellular stress responses and leukocyte function. This study was designed to test the effect of extended treatment with AlaGln-supplemented PD fluid on biomarkers of peritoneal health. In a double-blinded, randomized crossover design, stable PD patients were treated with AlaGln (8 mM) or placebo added to PD fluid for eight weeks. As primary outcome measures, dialysate cancer-antigen 125 (CA-125) appearance rate and ex vivo stimulated interleukin-6 (IL-6) release were assessed in peritoneal equilibration tests. In 8 Austrian centers, 54 patients were screened, 50 randomized, and 41 included in the full analysis set. AlaGln supplementation significantly increased CA-125 appearance rate and ex vivo stimulated IL-6 release. AlaGln supplementation also reduced peritoneal protein loss, increased ex vivo stimulated tumor necrosis factor (TNF)-α release, and reduced systemic IL-8 levels. No adverse safety signals were observed. All 4 peritonitis episodes occurred during standard PD fluid treatment. A novel AlaGln-supplemented PD fluid improves biomarkers of peritoneal membrane integrity, immune competence, and systemic inflammation compared to unsupplemented PD fluid with neutral pH and low-glucose degradation. A phase 3 trial is needed to determine the impact of AlaGln supplementation on hard clinical outcomes.

Efficacy and safety of body weight-adapted oral cholecalciferol substitution in dialysis patients with vitamin D deficiency.

BACKGROUND: Vitamin D deficiency is highly prevalent in dialysis patients. Whether substitution of native vitamin D in these patients is beneficial is a matter of ongoing discussion, as is the optimal dosing schedule. The purpose of this study was to investigate the efficacy and safety of a body-weight adapted oral dosing regimen of cholecalciferol in dialysis patients. METHODS: In a prospective single-center study 56 prevalent dialysis patients with a baseline 25OHD3 level <20 ng/mL received 100 IU of cholecalciferol per kg body weight once weekly orally for 26 weeks. 25OHD3 was measured at baseline and at study end, iPTH every three months, serum calcium and phosphorous monthly. Concurrent medication including phosphate binders, calcitriol and cinacalcet and dialysate calcium concentration remained unchanged throughout the study. RESULTS: Baseline 25OHD3 was 9.9 ± 4.1 ng/mL and increased to 26.1 ± 8.8 ng/mL (P = 0.01). Fourteen patients (27 %) achieved a level > 30 ng/mL and all others above 20 ng/mL. Cinacalcet therapy was positively associated with the increase in 25OHD3 (P = 0.024). The plasma iPTH level significantly decreased from median 362 pg/mL to 297 pg/mL (P = 0.01). This decline was more pronounced in patients with higher baseline iPTH levels (P < 0.01) and differed significantly dependent on concurrent calcitriol therapy. A significant iPTH decrease was observed in patients receiving calcitriol (P = 0.031). Serum calcium and phosphorous did not change significantly throughout the study period. Cholecalciferol substitution was well tolerated without adverse effects. CONCLUSION: The dosing regimen of oral cholecalciferol supplementation with 100 IU per kg body weight per week for 26 weeks in dialysis patients with vitamin D deficiency causes a significant increase in 25OHD3 close to the supposed target level of 30 ng/mL and a significant reduction in iPTH, without affecting serum calcium or phosphorous levels.

Iron supplementation and mortality in incident dialysis patients: an observational study.

BACKGROUND: Studies on the association between iron supplementation and mortality in dialysis patients are rare and conflicting. METHODS: In our observational single-center cohort study (INVOR study) we prospectively studied 235 incident dialysis patients. Time-dependent Cox proportional hazards models using all measured laboratory values for up to 7.6 years were applied to study the association between iron supplementation and all-cause mortality, cardiovascular and sepsis-related mortality. Furthermore, the time-dependent association of ferritin levels with mortality in patients with normal C-reactive protein (CRP) levels (<0.5 mg/dL) and elevated CRP levels (≧0.5 mg/dL) was evaluated by using non-linear P-splines to allow flexible modeling of the association. RESULTS: One hundred and ninety-one (81.3%) patients received intravenous iron, 13 (5.5%) patients oral iron, whereas 31 (13.2%) patients were never supplemented with iron throughout the observation period. Eighty-two (35%) patients died during a median follow-up of 34 months, 38 patients due to cardiovascular events and 21 patients from sepsis. Baseline CRP levels were not different between patients with and without iron supplementation. However, baseline serum ferritin levels were lower in patients receiving iron during follow up (median 93 vs 251 ng/mL, p<0.001). Iron supplementation was associated with a significantly reduced all-cause mortality [HR (95%CI): 0.22 (0.08-0.58); p = 0.002] and a reduced cardiovascular and sepsis-related mortality [HR (95%CI): 0.31 (0.09-1.04); p = 0.06]. Increasing ferritin concentrations in patients with normal CRP were associated with a decreasing mortality, whereas in patients with elevated CRP values ferritin levels>800 ng/mL were linked with increased mortality. CONCLUSIONS: Iron supplementation is associated with reduced all-cause mortality in incident dialysis patients. While serum ferritin levels up to 800 ng/mL appear to be safe, higher ferritin levels are associated with increased mortality in the setting of concomitant inflammation.

Medullary nephrocalcinosis in an adult patient with idiopathic infantile hypercalcaemia and a novel CYP24A1 mutation.

Idiopathic infantile hypercalcaemia (IIH) is an autosomal recessively inherited disease, presented in the first year of life with hypercalcaemia, precipitated by normal amounts of vitamin D supplementation. Recently loss-of-function mutations in the CYP24A1 gene, which encodes the vitamin D-metabolizing enzyme 24-hydroxylase, have been found in these patients. We describe a young man homozygous for a novel missense mutation (c.628T>C) of the CYP24A1 gene. He had suffered from severe hypercalcaemia in early childhood. At age 29 he presented with medullary nephrocalcinosis, chronic kidney disease (CKD) stage 2, microalbuminuria, mild hypertension and nephrogenic diabetes insipidus. He had mild hypercalcaemia and moderate hypercalciuria. As a novel finding, fibroblast growth factor 23 (FGF23) was elevated.

Interaction of time-varying albumin and phosphorus on mortality in incident dialysis patients.

BACKGROUND AND OBJECTIVES: Hypoalbuminemia and hyperphosphatemia have been shown to be strong predictors of mortality in dialysis patients that might not be independent from each other. We prospectively investigated the relationship and interaction between serum albumin and phosphorus with all-cause mortality in an inception cohort of incident dialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We followed 235 incident dialysis patients in a prospective single-center cohort study (INVOR study) applying a time-dependent Cox proportional hazards model using all measured laboratory values (2887 albumin and 10306 phosphorus values). RESULTS: Eighty-two patients (35%) died during a median follow-up of 35.1 months. Albumin was inversely associated with mortality (hazard ratio [95% confidence interval]: 0.23 [0.14 to 0.36]; P < 0.001), whereas higher phosphorus concentrations showed a trend to an increasing risk for mortality (hazard ratio 1.57 [95% confidence interval 0.97 to 2.54]; P = 0.07). Importantly, we observed a significant interaction between albumin and phosphorus (P = 0.01). The lowest risk was found with concurrent low phosphorus and high albumin values, whereas risk was increased with either concurrent low phosphorus and low albumin values or high phosphorus and high albumin values. CONCLUSIONS: In incident dialysis patients the associations of serum phosphorus and albumin concentrations with mortality are modified by each other over time. Phosphorus-lowering interventions that concomitantly can cause a fall in serum albumin level may be harmful and warrant additional studies. If confirmed, epidemiologic studies and therapeutic guidelines aiming for target values should consider this interplay.