Long-term efficacy and safety profile of lanthanum carbonate: results for up to 6 years of treatment.

BACKGROUND/AIMS: Lanthanum carbonate (LC, FOSRENOL) is an effective phosphate binder for which tolerability and a safety profile have been reported in haemodialysis patients. Patients from previous studies entered a 2-year extension, enabling assessment of efficacy and safety for up to 6 years of LC monotherapy. METHODS: Patients from four previous trials entered this study. RESULTS: Ninety-three patients started the extension, with 22 entering a sixth year of LC treatment. Two-thirds of all patients received LC doses of 2,250 or 3,000 mg/day. Reductions in serum phosphate and calcium x phosphate product were maintained for up to 6 years. There were no new or unexpected adverse events (AEs), and no increase in the incidence of events with increasing treatment exposure. Over the complete duration of therapy, treatment-related AEs occurred in 25.8% of patients and were primarily gastrointestinal in nature. No clinically relevant changes in liver function tests were observed and there was no evidence of adverse effects on the liver, bone or the central nervous system. CONCLUSIONS: LC monotherapy was effective and well tolerated for up to 6 years with no evidence of safety concerns or increased frequency of AEs.

Partial Body UV Exposure in Chronic Kidney Disease and Extrarenal Vitamin D Metabolism.

BACKGROUND/AIM: Exposure of the skin to sunshine is the major natural source of vitamin D. In order to imitate this natural production of vitamin D for patients with chronic kidney disease, hemodialysis patients were exposed three times a week to radiation of the front part of both legs to normalize the vitamin D status. PATIENTS AND METHODS: Partial body UVB irradiation was performed during the routine dialysis session. Twenty-two patients took part, with a mean age of 61.7 (range=35-81) years. RESULTS: Serum levels of 25(OH)D3 and 1,25(OH)2D3 increased into the mid normal range. Intact parathyroid hormone decreased by 25% and osteocalcin by 45%. 24-Hour blood-pressure monitoring demonstrated decreases in systolic and diastolic blood pressure. CONCLUSION: Partial body exposure to UVB radiation normalized not only the serum level of 25(OH)D3, but also that of 1,25(OH)2D3, which resulted in a significant decrease in parathyroid hormone, osteocalcin levels, and also in blood pressure. Sunshine imitating UVB exposure utilizes the capacity of the skin to convert extrarenally vitamin D3 to 25(OH)D3 and 1,25(OH)2D3.

UV Irradiation and Pleiotropic Effects of Vitamin D in Chronic Kidney Disease - Benefits on Cardiovascular Comorbidities and Quality of Life.

BACKGROUND: Vitamin D3 can be metabolized in the skin to 25(OH)D and 1,25(OH)2D because the skin expresses vitamin D-25-hydroxylase, 25(OH)D-1-alpha-hydroxylase, and the vitamin D receptor. The aim of this review was to discuss the pleiotropic effects after serial suberythemal UVB irradiation with a sun-simulating UV spectrum in end-stage kidney disease patients. PATIENTS AND METHODS: Fourteen hemodialysis patients, with a mean age of 51 (range 41-57) years, were whole-body UV irradiated over 6 months. RESULTS: Patients demonstrated an increase in their hematocrit and required less erythropoietin. An increase in maximal oxygen uptake and workload capacity was associated with decreased lactic acid production. The patients demonstrated a decreased heart rate and systolic and diastolic blood pressure with an increase in the R-R-interval and the beat-to-beat-differences. CONCLUSION: Cardiovascular disease is the most important comorbidity. Exposure to simulated sunlight that contains both UVB and UVA reduce cardiovascular risk factors and improve quality of life.

Vitamin D Status in Chronic Kidney Disease - UVB Irradiation Is Superior to Oral Supplementation.

BACKGROUND: In chronic kidney disease (CKD) a deficiency of 1,25-dihydroxyvitamin D is common. The aim of this review was to compare vitamin D status after oral supplementation of vitamin D3 to that of serial suberythemal irradiation in end-stage kidney disease (ESKD) patients. PATIENTS AND METHODS: Ninety-five patients, with a mean age of 62 (range=35-82) years, were treated with a mean dose of 35,000 (20,000-60,000) IU vitamin D3 per week for a period of 18 months. Fourteen patients, with a mean age of 51 (range=41-57) years, were whole-body UVB irradiated for over 6 months. From 3 hemodialysis patients skin biopsies were performed. RESULTS: With oral supplementation 25(OH)D3 increased by 60%. With UV irradiation 25(OH)D3 increased by 400%. Gene expression analysis demonstrated an improvement in the vitamin D receptor (VDR) by 0.65 fold, in 1-alpha-hydroxylase (CYP27B1) by 1.0 fold, and in 25-hydroxylase (CYP2R) by 1.2 fold. CONCLUSION: Serial suberythemal UVB irradiation of patients with CKD on dialysis is capable to improve serum 25(OH)D3 and 1,25(OH)2D3 by enhancing the skin's ability to activate vitamin D.

Relaxin is an independent risk factor predicting death in male patients with end-stage kidney disease.

BACKGROUND: Patients with end-stage kidney disease (ESKD) have a reduced life expectancy mainly as the result of cardiovascular diseases. Relaxin has been implicated in the pathogenesis of cardiovascular diseases. We analyzed the impact of relaxin on death in patients with ESKD. METHODS AND RESULTS: Patients (n =245; 122 women, 123 men) on long-term hemodialysis were followed for 1140 days for death. Blood samples for analysis of relaxin, C-reactive protein, Troponin T, cholesterol, HDL, brain natriuretic peptide, and albumin were taken at study entry. Survival was compared by the Kaplan-Meier method and Cox regression analysis. One hundred seven patients died during the observation period; 66 died of cardiovascular diseases and 28 died of infectious diseases. Elevated serum relaxin concentrations (greater than median) predicted death in male but not in female patients with ESKD: All-cause death (men: relative risk, 2.63; 95% CI, 1.34 to 5.12; P=0.005; women: relative risk, 0.671; 95% CI, 0.33 to 1.35; P=0.262) and cardiovascular death (men: relative risk, 2.95; 95% CI, 1.20 to 7.21; P=0.018; women: relative risk, 0.639; 95% CI, 0.26 to 1.56; P=0.324). CONCLUSIONS: Relaxin is an independent risk factor predicting death in male patients with ESKD on chronic hemodialysis.

Vitamin D status and cancer prevalence of hemodialysis patients in Germany.

AIM: To describe Vitamin D (VitD) status and prevalence of cancer in a large cohort of ambulatory hemodialysis patients in Germany. PATIENTS AND METHODS: In a registry study adult patients starting dialysis between 2006 and 2012 were analyzed for VitD blood levels and International classification of diseases (ICD)-10 cancer diagnoses. RESULTS: Almost one third (32.7%) of patients initiating dialysis, had VitD levels<12.5 ng/ml and 79.7% had levels<30 ng/ml (n=8,377). Average VitD at dialysis initiation increased from 18.0 to 23.2 ng/ml between 2006 and 2012. Prevalence of cancer in this cohort was 22.1% with genital, renal and gastro-intestinal cancers being most common. Cancer frequencies were similar in patients with high and low vitamin D levels. CONCLUSION: Most chronic hemodialysis patients were vitamin D-deficient in spite of concurrent vitamin D supplementation. The burden of cancer was high in these patients. Future studies should address the role of vitamin D treatment on the course and progression of cancer in chronic kidney disease (CKD) patients.

A structured exercise programme during haemodialysis for patients with chronic kidney disease: clinical benefit and long-term adherence.

OBJECTIVE: Long-term studies regarding the effect of a structured physical exercise programme (SPEP) during haemodialysis (HD) assessing compliance and clinical benefit are scarce. STUDY DESIGN: A single-centre clinical trial, non-randomised, investigating 46 patients with HD (63.2 ± 16.3 years, male/female 24/22, dialysis vintage 4.4 years) performing an SPEP over 5 years. The SPEP (twice/week for 60 min during haemodialysis) consisted of a combined resistance (8 muscle groups) and endurance (supine bicycle ergometry) training. Exercise intensity was continuously adjusted to improvements of performance testing. Changes in endurance and resistance capacity, physical functioning and quality of life (QoL) were analysed over 1 year in addition to long-term adherence and economics of the programme over 5 years. Average power per training session, maximal strength tests (maximal exercise repetitions/min), three performance-based tests for physical function, SF36 for QoL were assessed in the beginning and every 6 months thereafter. RESULTS: 78% of the patients completed the programme after 1 year and 43% after 5 years. Participants were divided--according to adherence to the programme--into three groups: (1) high adherence group (HA, >80% of 104 training sessions within 12 months), (2) moderate adherence (MA, 60-80%), and 3. Low adherence group (LA, <60%)) with HA and MA evaluated quantitatively. One-year follow-up data revealed significant (p<0.05) improvement for both groups in all measured parameters: exercise capacity (HA: 55%, MA: 45%), strength (HA: >120%, MA: 40-50%), QoL in three scores of SF36 subscales and physical function in the three tests taken between 11% and 31%. Moreover, a quantitative correlation analysis revealed a close association (r=0.8) between large improvement of endurance capacity and weak physical condition (HA). CONCLUSIONS: The exercise programme described improves physical function significantly and can be integrated into a HD routine with a high long-term adherence.

Vitamin D and UV exposure in chronic kidney disease.

With loss of renal function and decreasing glomerula filtration rate the serum levels of 25-hydroxyvitamin D [25(OH)D] as well as 1,25-dihydroxyvitamin D [1,25 (OH)2 D] often decrease simultaneously. In representative groups of German patients on renal replacement therapy (hemodialysis, peritoneal dialysis, kidney transplantation) our group retrospectively analyzed the vitamin D status over a period of 12 y (1995‒2006). Only 11% of patients had a serum level of 25(OH)D that was > 30 ng/ml, more than 70% had a level of 25(OH)D < 20 ng/ml. In clinical trials we used sun-simulating artificial lamps to produce vitamin D3 in the skin. Partial-body irradiation (15% of body surface) was used during the routine hemodialysis treatment. Whole-body UV exposure was done in a standing position three times a week before the hemodialysis treatment. With both procedures we observed an increase of the serum level of 25(OH)2D3 by approx. 35-50% over a period of 2‒3 mo, maintenance of trabecular bone mineral density and a normalization of systolic and diastolic blood pressure. Heart rate variability improved during the whole-body radiation intervention period by 20‒25%. Patients who continued the whole-body irradiation regularly two or three times before starting the routine hemodialysis session had maintained normal levels of circulating 25(OH)D3 and of 1,25(OH)2D3. Therefore, from our data it can be recommended that intermittent suberythemal UVB exposure with a sun-simulation spectrum is effective to treat and/or protect against vitamin D deficiency in chronic and end-stage kidney disease patients.

Vitamin D status and mortality of German hemodialysis patients.

AIM: The goal was to analyze the link between blood levels of calcidiol and all-cause, cardiac and infectious diseases, and mortality due to cancer in hemodialysis patients. PATIENTS AND METHODS: This study retrospectively evaluated a representative sub-cohort (n=6,518) of German hemodialysis patients from the incidence cohorts 1997-2006. RESULTS: Most (58.8%) were found to be vitamin D deficient (25(OH)D<20 ng/ml), with 41.2% being severely deficient (25(OH)D<12.5 ng/ml). All-cause mortality risk more than doubled in patients with severe deficiency (adjusted odds ratio (aOR)=2.67; 95% confidence interval (CI)=2.30-3.10; p<0.0001). Comparable data were obtained for mortality from cardiac disease (aOR=1.57; 95% CI=1.30-1.88; p<0.0001), infectious disease (aOR=1.48; 95% CI=1.15-1.90; p=0.0026), and cancer (aOR=1.51; 95% CI=1.09-2.08; p=0.0121), respectively. CONCLUSION: These data highlight the need to ensure primarily adequate 25(OH)D levels in dialysis patients for an advantage of survival.

Two year comparison of sevelamer and calcium carbonate effects on cardiovascular calcification and bone density.

BACKGROUND: Calcium-based phosphate binders may induce tissue calcification, and little is known about their effects on bone density. We compared the effects of a calcium with a non-calcium phosphate binder on both arterial calcification and bone density measured by computed tomography. METHODS: Seventy-two adult haemodialysis patients were randomized to treatment with calcium carbonate (CC) or sevelamer (SEV) for 2 years. Electron beam CT scans were performed at baseline and at 6, 12 and 24 months. Serum phosphorus, calcium, calcium x phosphorus product and intact parathyroid hormone (iPTH) were measured and other routine laboratory tests were also carried out. RESULTS: The average calcium x phosphorus product was similar in the two treatment groups. However, patients receiving CC had significantly lower average iPTH (P<0.01), were more likely to have hypercalcaemic episodes (P = 0.03) and had significantly greater increases in coronary artery (CC median 484, P<0.0001, SEV median 37, P = 0.3118, between-group P = 0.0178) and aortic (CC median 610, P = 0.0003, SEV median 0, P = 0.5966, between-group P = 0.0039) calcification scores. The CC group also had a significant decrease in trabecular bone density (CC median -6%, P = 0.0049, SEV median +3%, P = 0.0296, between-group P = 0.0025). However, there was no significant difference in cortical bone density between the two groups. CONCLUSIONS: This 2 year study shows that calcium carbonate use is continuously associated with progressive arterial calcification in haemodialysis patients. In addition, it suggests that it is also associated with decreased trabecular bone density. However, this latter finding requires confirmation by a study specifically devoted to this issue.

Different impact of biomarkers as mortality predictors among diabetic and nondiabetic patients undergoing hemodialysis.

Diabetic patients undergoing hemodialysis demonstrate much worse survival rates than do nondiabetic patients undergoing hemodialysis. To search for risk predictors, a prospective cohort study was performed with 245 hemodialysis patients, including 84 with diabetes mellitus, for 2 yr. C-reactive protein, troponin T (TnT), total, HDL, LDL, and lipoprotein(a) cholesterol, apoA2, apoB, triglyceride, fibrinogen, D-dimer, albumin, and creatinine levels and clinical characteristics at the time of entry were recorded. Survival rates were compared with Kaplan-Meier and Cox regression analyses. Forty-three diabetic patients and 30 nondiabetic patients died. Among diabetic patients, oliguria (<200 ml/d) (relative risk, 3.24; 95% confidence interval, 1.63 to 6.41; P = 0.001), elevated C-reactive protein levels (relative risk, 2.57; 95% confidence interval, 1.06 to 6.18; P = 0.035), and elevated D-dimer levels (relative risk, 2.36; 95% confidence interval, 1.11 to 5.01; P = 0.025) predicted all-cause mortality rates. Oliguria was by far the most important predictor, particularly for infectious disease-related death (relative risk, 23.35; 95% confidence interval, 2.60 to 209.97; P = 0.005). Among nondiabetic patients, elevated TnT levels (relative risk, 4.00; 95% confidence interval, 1.58 to 10.10; P = 0.003), elevated D-dimer levels (relative risk, 3.45; 95% confidence interval, 1.27 to 9.33; P = 0.015), and low cholesterol levels (relative risk, 3.61; 95% confidence interval, 1.34 to 9.71; P = 0.011) predicted all-cause mortality rates. Subdivision of the causes of death among nondiabetic patients revealed that TnT levels predicted cardiovascular mortality rates (relative risk, 5.38; 95% confidence interval, 1.11 to 26.10; P = 0.037) and infectious disease-related mortality rates (relative risk, 12.02; 95% confidence interval, 1.42 to 191.96; P = 0.023). In conclusion, mortality predictors among patients undergoing hemodialysis differed substantially between diabetic and nondiabetic patients. Strategies to reduce mortality rates should consider these differences.