The effect of high-dose vitamin D supplementation on hepcidin-25 and erythropoiesis in patients with chronic kidney disease.

BACKGROUND: Hepcidin is considered to play a central role in the pathophysiology of renal anemia. Recent studies in healthy individuals have demonstrated a suppressive effect of vitamin D (VD) on the expression of hepcidin. In this post-hoc analysis based on a randomized controlled study, we evaluated the effect of supplementing chronic kidney disease (CKD) patients (stage G3-G4) with a high daily dose of native VD on serum levels of hepcidin-25, the hepcidin/ferritin ratio, as well as on markers of erythropoiesis. METHODS: Patients with CKD stage G3-G4 included in a double blind, randomized, placebo (PBO) controlled study with available hepcidin measurements were analyzed. Study subjects received either 8000 international units (IU) of cholecalciferol daily or PBO for 12 weeks. We evaluated the change in markers of hepcidin expression, erythropoiesis, and iron status from baseline to week 12 and compared the change between the groups. RESULTS: Eighty five patients completed the study. Calcitriol, but not 25-hydroxyvitamin D (25(OH) D), was inversely correlated with serum levels of hepcidin-25 (rho = -0,38; p = < 0, 01 and rho = -0,02; p = 0, 89, respectively) at baseline. Supplementation with VD significantly raised the serum concentration of serum 25(OH)D in the treatment group (from 54 (39-71) to 156 (120-190) nmol/L; p = < 0, 01)) but had no effect on any of the markers of hepcidin, erythropoiesis, or iron status in the entire cohort. However, we did observe an increase in hemoglobin (HB) levels and transferrin saturation (TSAT) as compared to the PBO group in a subgroup of patients with low baseline 25(OH)D levels (< 56 nmol/L). In contrast, in patients with high baseline 25(OH)D values (≥ 56 nmol/L), VD supplementation associated with a decrease in HB levels and TSAT (p = 0,056) within the VD group in addition to a decrease in hepcidin levels as compared to the PBO group. CONCLUSION: High-dose VD supplementation had no discernible effect on markers of hepcidin or erythropoiesis in the entire study cohort. However, in patients with low baseline 25(OH)D levels, high-dose VD supplementation associated with beneficial effects on erythropoiesis and iron availability. In contrast, in patients with elevated baseline 25(OH)D levels, high-dose VD supplementation resulted in a decrease in hepcidin levels, most likely due to a deterioration in iron status.

Lower serum calcium is independently associated with CKD progression.

Disturbances in calcium metabolism are common in individuals with chronic kidney disease (CKD), but whether they are associated with subsequent kidney function decline is less clear. In a CKD 3-5 cohort of 15,755 adult citizens of Stockholm with creatinine tests taken during 2006-2011 and concurrent calcium testing at cohort entry, we investigated the association between baseline serum calcium and the subsequent change in estimated glomerular filtration rate (eGFR, by CKD-EPI) decline using linear mixed models. Mean (SD) baseline corrected serum calcium was 9.6 (0.5) mg/dL. Mean (95%-confidence interval [CI]) eGFR decline was -0.82 (-0.90; -0.74) mL/min/1.73 m2/year. In advanced CKD stages, higher baseline serum calcium was associated with less rapid kidney function decline. The adjusted change (95%-CI) in eGFR decline associated with each mg/dL increase in baseline serum calcium was -0.10 (-0.28; 0.26), 0.39 (0.07; 0.71), 0.34 (-0.02; 0.70) and 0.68 (0.36; 1.00) mL/min/1.73 m2/year for individuals in CKD stage 3a, 3b, 4, and 5, respectively. In a subgroup of patients using vitamin D supplements, the association between baseline serum calcium and CKD progression was eliminated, especially in CKD stage 3b and 4. To conclude, in individuals with CKD stage 3b to 5, lower baseline corrected serum calcium, rather than higher baseline serum calcium, associated with a more rapid CKD progression. Lower serum corrected calcium seems to be indicative for vitamin D deficiency.

Peritoneal dialysis impairs nitric oxide homeostasis and may predispose infants with low systolic blood pressure to cerebral ischemia.

BACKGROUND & PURPOSE: Infants on chronic peritoneal dialysis (PD) have an increased risk of developing neurological morbidities; however, the underlying biological mechanisms are poorly understood. In this clinical study, we investigated whether PD-mediated impairment of nitric oxide (NO) bioavailability and signaling, in patients with persistently low systolic blood pressure (SBP), can explain the occurrence of cerebral ischemia. METHODS & RESULTS: Repeated blood pressure measurements, serial neuroimaging studies, and investigations of systemic nitrate and nitrite levels, as well as NO signaling, were performed in ten pediatric patients on PD. We consistently observed the loss of both inorganic nitrate (-17 ± 3%, P < 0.05) and nitrite (-34 ± 4%, P < 0.05) during PD, which may result in impairment of the nitrate-nitrite-NO pathway. Indeed, PD was associated with significant reduction of cyclic guanosine monophosphate levels (-59.4 ± 15%, P < 0.05). This reduction in NO signaling was partly prevented by using a commercially available PD solution supplemented with l-arginine. Although PD compromised nitrate-nitrite-NO signaling in all cases, only infants with persistently low SBP developed ischemic cerebral complications. CONCLUSIONS: Our data suggests that PD impairs NO homeostasis and predisposes infants with persistently low SBP to cerebral ischemia. These findings improve current understanding of the pathogenesis of infantile cerebral ischemia induced by PD and may lead to the new treatment strategies to reduce neurological morbidities.

Determinants of fibroblast growth factor-23 and parathyroid hormone variability in dialysis patients.

BACKGROUND/AIMS: Treatment strategies for abnormal mineral metabolism in chronic kidney disease are largely based on achieving target ranges of biomarkers that vary considerably over time, yet determinants of their variability are poorly defined. METHODS: Observational study including 162 patients of three dialysis cohorts (peritoneal dialysis, n = 78; hemodialysis, n = 49; hemodiafiltration, n = 35). Clinical and biochemical determinants of parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) variability were analyzed in the peritoneal dialysis cohort. All cohorts were used for comparison of PTH and FGF23 intra-subject variability (intra-class correlation), and their intra-subject variability in different modes of dialysis was explored. RESULTS: High PTH variability was independently associated with lower 25-hydroxyvitamin D concentration and factors of lipid and glucose metabolism, whereas high FGF23 variability was mainly associated with lower baseline serum phosphorous. These results were consistent in multivariate and sensitivity analyses. The intra-subject variability of FGF23 was lower than for PTH irrespective of dialysis mode. CONCLUSIONS: Baseline vitamin D status and serum phosphorous are independent determinants of the longitudinal variation in PTH and FGF23, respectively. The clinical utility of FGF23 measurement remains unknown, yet it appears favorable based on its greater temporal stability than PTH in dialysis patients.

Iron isomaltoside 1000: a new intravenous iron for treating iron deficiency in chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) often suffer from iron deficiency anemia necessitating treatment with intravenous iron. This study was designed to assess the safety of iron isomaltoside 1000 (Monofer) in CKD patients. The secondary objective was to assess its effect on iron deficiency anemia. METHODS: This open-label, noncomparative, multicenter trial assigned 182 patients with CKD (n=161 in dialysis and n=21 in predialysis) to iron isomaltoside 1000 either as 4 intravenous bolus injections of 100-200 mg iron per dose or as a fast high-dose infusion at baseline. Patients were generally undergoing erythropoiesis-stimulating agent (ESA) treatment (82%), and the dosage was to be kept constant during the trial. They were either switched from an existing parenteral maintenance therapy (n=144) or were not currently being treated with parenteral iron (n=38). Frequency of adverse events (AEs) and changes in markers of iron deficiency anemia were measured during 8 weeks from baseline. RESULTS: Nineteen treatment-related AEs occurred in 13 patients (7.1%) and after 584 treatments (3.3%). No anaphylactic or delayed allergic reactions were observed. There were no clinically significant changes in routine clinical laboratory tests or vital signs. Hemoglobin increased from 99.2 g/L (SD=9.0) at baseline to 111.2 g/L (SD=14.7) at week 8 in patients not currently treated with parenteral iron (p<0.001) and increased slightly or stabilized in patients in maintenance therapy. S-Ferritin, s-iron and transferrin saturation increased significantly at all visits. CONCLUSIONS: Iron isomaltoside 1000 was clinically well tolerated, safe and effective. This new intravenous iron may offer a further valuable choice in treating the anemia of CKD.

Consequences of low plasma histidine in chronic kidney disease patients: associations with inflammation, oxidative stress, and mortality.

BACKGROUND: Histidine is considered as an antiinflammatory and antioxidant factor. Histidine deficiency may contribute to an impaired nutritional state in patients with chronic kidney disease (CKD). OBJECTIVE: We aimed to investigate the consequences of plasma histidine deficiency in CKD patients. DESIGN: CKD patients (n = 325; 203 M) with a median age of 54 y (range: 19-70 y) were evaluated shortly before the beginning of renal replacement therapy. The median glomerular filtration rate was 6.4 mL/min (range: 0.8-14.5 mL/min). Nutritional status was assessed by subjective global assessment. Survival was followed for up to 60 mo; 101 patients died. RESULTS: Plasma histidine concentrations were significantly lower in CKD patients with history of cardiovascular disease, presence of plaques, protein-energy wasting, and inflammation. Plasma histidine was negatively associated with age, C-reactive protein, interleukin-6, leukocytes, thrombocytes, fibrinogen, hepatocyte growth factor, adhesion molecules, insulin-like growth factor-1, and 8-hydroxy-2'-deoxyguanosine and was positively associated with handgrip strength, hemoglobin, S-albumin and fetuin-A. A multivariate regression analysis showed that histidine concentrations were independently associated with hepatocyte growth factor, hemoglobin, and fetuin-A. In unadjusted analysis, a low histidine concentration was associated with all-cause mortality (log rank chi-square test = 8.9; P = 0.002). After adjustment for age, sex, cardiovascular disease, inflammation, diabetes mellitus, serum S-albumin, and amino acid supplementation, the association between low histidine and mortality remained significant (hazard ratio: 1.55; 95% CI: 1.02, 2.40; P < 0.05). CONCLUSION: Low plasma concentrations of histidine are associated with protein-energy wasting, inflammation, oxidative stress, and greater mortality in CKD patients.

Homocysteine-lowering is not a primary target for cardiovascular disease prevention in chronic kidney disease patients.

The homocysteine (Hcy) theory states that total homocysteine (tHcy) is a risk factor for atherosclerosis. Chronic kidney disease (CKD) is one of the most frequent causes of hyperhomocysteinemia in the presence of high prevalence of cardiovascular disease (CVD). However, there is not yet any conclusive answer to the question whether Hcy may contribute to, or predict, cardiovascular events or mortality in CKD patients or whether it is just an innocent bystander biologically related to other potential risk factors for CVD. Moreover, tHcy levels in CKD are influenced by several commonly occurring confounding factors, such as inflammation and protein-energy wasting (PEW). These factors are also associated with morbidity and mortality and altogether this may explain why Hcy does not show up as a cardiovascular risk but in fact is reversely associated with clinical outcome. Thorough evaluation of such reverse association may not necessarily imply that the principles of Hcy being a contributor to vascular pathophysiology are different in CKD patients but rather indicate that other superimposed factors, such as PEW and inflammation, are more important. These confounders contribute significantly to the unacceptably high mortality rate in this patient population and may require nutritional and anti-inflammatory interventions to improve clinical outcome. So far, the results of recent folic acid intervention trials do not support the use of folic acid supplementation for lowering tHcy and improving survival in CKD patients. Although we are still waiting for the results from several ongoing controlled randomized trials in this area, future studies are needed to evaluate if thiol-exchange agents, besides folic acid, as part of a future multifactorial intervention regime targeting inflammation, PEW, oxidative stress as well as hyperhomocysteinemia may decrease CVD risk in this high-risk patient population.

Plasma sulfur amino acids in relation to cardiovascular disease, nutritional status, and diabetes mellitus in patients with chronic renal failure at start of dialysis therapy.

Sulfur amino acids (sAAs) are potential candidates as risk factors for cardiovascular disease (CVD). However, we recently reported that chronic hemodialysis patients with CVD had a greater prevalence of malnutrition, hypoalbuminemia, and lower plasma total homocysteine (tHcy) levels than those without CVD. In this cross-sectional study, we examined the relationship of plasma sAAs to CVD and nutritional status in 151 patients with chronic renal failure (CRF) close to the start of regular dialysis treatment (33 +/- 7 days before the first dialysis treatment). Clinical signs of CVD were present in 32% of patients with CRF, 41% had malnutrition assessed by subjective global nutritional assessment (SGNA) score, and 26% had diabetes mellitus (DM). Plasma tHcy levels were high in 91% of patients, as were plasma total cysteine (tCys) levels, whereas plasma methionine (Met) and taurine (Tau) levels were normal. Patients with CRF who had CVD were older, more often malnourished, and had lower tHcy and serum albumin (s-albumin) levels and a greater frequency of DM than those without CVD. Plasma tCys, Met, and Tau levels did not differ between patients with CRF with and without CVD. The tCys-tHcy ratio was higher in patients with CVD and related to SGNA score and DM. Moreover, this ratio, but not tHcy or tCys level, correlated with age and triglyceride, total cholesterol, and apolipoprotein B levels. Malnutrition and hypoalbuminemia were associated with low plasma sAA levels (tHcy, Met, and Tau); tCys was related to s-albumin level, but not SGNA score. Among patients with diabetes, sAA levels did not differ between patients with and without CVD or between malnourished and well-nourished patients. In conclusion, patients with CRF at the start of dialysis treatment with CVD were more often diabetic, malnourished, and had lower s-albumin and tHcy levels and a higher tCys-tHcy ratio than patients with no CVD. tCys-tHcy ratio, but not tHcy or tCys levels per se, was related to cardiovascular risk factors, suggesting that cysteine may have a role in the development of CVD. Malnutrition, hypoalbuminemia, and DM in patients with CRF influence sAA levels, mainly plasma tHcy, which should be considered when evaluating hyperhomocysteinemia as a cardiovascular risk factor.