Emanuel Zitt

Vitamin D deficiency is associated with poor response to active hepatitis B immunisation in patients with chronic kidney disease

Vitamin D deficiency is highly prevalent in patients suffering from chronic kidney disease. At present it is not known whether this condition is associated with poor response to hepatitis B vaccination in these patients. We performed a retrospective analysis of 200 patients with chronic kidney disease stages 3-5D, who had undergone hepatitis B vaccination with three 40 μg recombinant hepatitis B vaccine doses in a single centre. Anti-HBs antibody titres and 25-hydroxyvitamin D (25(OH)D) levels were measured by chemiluminescence immunoassays. Vitamin D deficiency with serum levels <10 ng/mL was found in 35.5% of patients. These patients had a lower seroconversion rate than did patients with levels ≥10 ng/mL (45% vs 64%; P=0.011) and their median (25th, 75th percentile) anti-HBs antibody titres were lower (0 (0, 117)IU/L vs 48 (0, 236.5)IU/L). Non-responders had lower 25(OH)D concentrations than did responders (12.9±6.5 ng/mL vs 15.1±7.4 ng/mL; P=0.034). Treatment with a vitamin D receptor activator had no influence on the immune response. In a multiple logistic regression analysis vitamin D deficiency (OR 0.480; P=0.023) and diabetes (OR 0.496; P=0.038) remained independent and significant negative predictors of seroconversion. In conclusion, in patients with chronic kidney disease vitamin D deficiency is associated with a poor antibody formation upon hepatitis B vaccination.

Coumarins and survival in incident dialysis patients

BACKGROUND The benefit and risk of oral anticoagulation in dialysis patients are debated controversially. METHODS We prospectively followed 235 dialysis patients of the INVOR Study (Study of Incident Dialysis Patients in Vorarlberg) for up to 7 years and analysed the prevalence and incidence of atrial fibrillation (AF) and the impact of coumarin therapy on survival. Oral anticoagulation was monitored frequently. RESULTS A total of 748 person-years were recorded with a median follow-up of 2.84 years. Twelve patients (5.1%) had AF at the start of dialysis. During follow-up, 40 patients (17.0%) developed AF, representing an incidence of 5.85 per 100 person-years. AF was positively associated with mortality (P = 0.004). Forty-six (19.6%) of the 235 patients were treated with coumarins. The majority (93.7%) had a clear indication for oral anticoagulation. In 65% of our patients, AF was the indication for coumarins. Patients without coumarins and without AF represented our reference group. The mortality risk of the coumarin-treated patients with AF or an alternative indication for coumarins was slightly lower compared to the reference group [hazard ratio (HR) 95% confidence interval (CI): 0.80 (0.28-2.29), P = 0.679 and 0.42 (0.16-1.10), P = 0.078, respectively]. No patient under sufficient oral anticoagulation experienced a stroke or a fatal bleeding event. Patients with AF and a contraindication for coumarins had a significantly higher mortality risk compared to the reference group [HR (95% CI): 3.90 (2.16-7.04), P < 0.001]. CONCLUSIONS Our data suggest that coumarins might be less harmful than previously anticipated when clearly indicated and closely monitored.

Use of sodium thiosulphate in a multi-interventional setting for the treatment of calciphylaxis in dialysis patients

BACKGROUND Calciphylaxis is a life-threatening complication in patients with end-stage renal disease (ESRD). No established therapy exists so far. The aim of the present study was to determine the therapeutic response to a multi-interventional treatment regimen with consistent use of sodium thiosulphate (STS) in an Austrian cohort of calciphylaxis patients. METHODS We retrospectively collected demographic, clinical and laboratory data on 27 calciphylaxis patients treated with STS at seven Austrian dialysis centres between June 2004 and November 2010. RESULTS Twenty-seven dialysis patients (68 ± 12 years) were treated with STS for a median (25th, 75th percentile) of 96 (54, 133) days. Seven patients (26%) suffered from proximal-type, and 20 patients (74%) from distal-type calciphylaxis. Fourteen patients (52%) showed a complete remission, five patients (19%) a partial remission and eight patients (30%) progression that resulted in amputation in four patients. During a median follow-up of 101 (79, 273) days, 14 patients died (52%). Non-survivors were older (P = 0.04), showed higher CRP values (P = 0.04), presented more frequently with proximal-type calciphylaxis (P = 0.03), had a higher disease severity score at diagnosis (P = 0.01), were treated more often with antibiotics (P = 0.01) and cinacalcet (P = 0.03) and had a lower remission rate during treatment (P = 0.004) than did survivors. The use of antibiotics and cinacalcet, disease severity at diagnosis and remission rates were found to be significant survival predictors in logistic regression analysis. CONCLUSIONS Calciphylaxis remains a serious complication with high mortality. Early and consistent therapy including STS may help to improve the disease outcome.

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.

Association of HbA1c Values with Mortality and Cardiovascular Events in Diabetic Dialysis Patients. The INVOR Study and Review of the Literature

Background Improved glycemic control reduces complications in patients with diabetes mellitus (DM). However, it is discussed controversially whether patients with diabetes mellitus and end-stage renal disease benefit from strict glycemic control. Methods We followed 78 patients with DM initiating dialysis treatment of the region of Vorarlberg in a prospective cohort study applying a time-dependent Cox regression analysis using all measured laboratory values for up to more than seven years. This resulted in 880 HbA1c measurements (with one measurement every 3.16 patient months on average) during the entire observation period. Non-linear P-splines were used to allow flexible modeling of the association with mortality and cardiovascular disease (CVD) events. Results We observed a decreased mortality risk with increasing HbA1c values (HR = 0.72 per 1% increase, p = 0.024). Adjustment for age and sex and additional adjustment for other CVD risk factors only slightly attenuated the association (HR = 0.71, p = 0.044). A non-linear P-spline showed that the association did not follow a fully linear pattern with a highly significant non-linear component (p = 0.001) with an increased risk of all-cause mortality for HbA1c values up to 6–7%. Causes of death were associated with HbA1c values. The risk for CVD events, however, increased with increasing HbA1c values (HR = 1.24 per 1% increase, p = 0.048) but vanished after extended adjustments. Conclusions This study considered the entire information collected on HbA1c over a period of more than seven years. Besides the methodological advantages our data indicate a significant inverse association between HbA1c levels and all-cause mortality. However, for CVD events no significant association could be found.

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.

Effect of cinacalcet on renal electrolyte handling and systemic arterial blood pressure in kidney transplant patients with persistent hyperparathyroidism.

Background. The calcimimetic cinacalcet has recently been increasingly used for persistent hyperparathyroidism after renal transplantation. The present study investigated the short-term effects of cinacalcet on urinary electrolyte concentration and arterial blood pressure in kidney transplant patients with persistent hyperparathyroidism. Methods. In a prospective controlled single-center cross-over study, we examined 10 stable kidney transplant patients (mean estimated glomerular filtration rate 51±10 mL/min/1.73 m2) who received cinacalcet daily for persistent hyperparathyroidism. Urine specimens were collected at baseline and every 2 hr for a total study period of 6 hr after ingestion of 30 mg cinacalcet and without cinacalcet. Intact parathyroid hormone was determined at baseline and 2 hr later. Using ambulatory blood pressure measurement, arterial blood pressure was determined every 15 min. Results. Intact parathyroid hormone was significantly reduced with cinacalcet as compared with controls (−37±27.7% vs. −9.6±10.3%, P=0.009). With cinacalcet, urinary calcium and magnesium concentration were increased (P=0.042 and P=0.007, respectively) and differed significantly as compared with the control phase without cinacalcet. After 4 hr, an increased urinary sodium concentration was also found compared with the control phase (P=0.039). Systolic blood pressure was reduced with cinacalcet (P<0.001) and differed significantly from control phase (−13.7±9.9 mm Hg vs. −3.2±5.2 mm Hg after 2 hr, P=0.009; −18.1±10.8 mm Hg vs. −1.9±5.2 mm Hg after 4 hr, P=0.001). Conclusions. In the short term, cinacalcet increases the urinary concentration of calcium, magnesium, and sodium. The observed antihypertensive effect might be beneficial in patients with a high cardiovascular risk after kidney transplantation.

Serum phosphorus reduction in dialysis patients treated with cinacalcet for secondary hyperparathyroidism results mainly from parathyroid hormone reduction

Background The calcimimetic cinacalcet lowers parathyroid hormone (PTH), calcium (Ca) and phosphorus (P) in dialysis patients with secondary hyperparathyroidism (SHPT). We explored serum P changes in dialysis patients treated with cinacalcet, while controlling for vitamin D sterol and phosphate binder (PB) changes, based on data from the pan-European observational study ECHO. Methods Patients were categorized by serum P change (decreased/unchanged/increased) at 12 months after starting cinacalcet and subcategorized by vitamin D sterol and PB dose changes (decreased/unchanged/increased). The impact of PTH, Ca and P, and vitamin D sterol, PB and cinacalcet doses (absolute values and/or change) was evaluated. Predictors of P change were explored using univariate and multivariate general linear models (GLM) and logistic regression analysis. Results At Month 12, 661 (41%) of 1607 patients had decreased, 61 (4%) unchanged and 400 (25%) increased serum P, while 485 patients had missing data. In 45% of the patients with serum P reduction, vitamin D was either increased or unchanged and P binders decreased or unchanged. PTH was a key predictor of serum P reduction, with an estimated 3% decrease in P per 10% reduction in PTH. Changes in vitamin D sterol and PB doses were not generally significant factors in GLM and regression analyses. Conclusions The serum P reduction observed in a significant proportion of dialysis patients after adding cinacalcet to an existing therapeutic regimen for SHPT appears to result mainly from PTH reduction, rather than from changes in vitamin D sterol or PB doses. Financial support for the ECHO study was provided by Amgen.

Effectiveness of cinacalcet in patients with recurrent/persistent secondary hyperparathyroidism following parathyroidectomy: results of the ECHO study

BACKGROUND Progressive secondary hyperparathyroidism (sHPT) is characterized by parathyroid gland hyperplasia which may ultimately require parathyroidectomy (PTX). Although PTX is generally a successful treatment for those patients subjected to surgery, a significant proportion develops recurrent sHPT following PTX. ECHO was a pan-European observational study which evaluated the achievement of KDOQI(TM) treatment targets with cinacalcet use in patients on dialysis. Previously published results showed that cinacalcet plus flexible vitamin D therapy lowered serum PTH, phosphorus and calcium in the clinical practice with similar efficacy as seen in phase III trials. METHODS This subgroup analysis of ECHO describes the real-world cinacalcet treatment effect in patients with recurrent or persistent sHPT after PTX (n = 153) compared to sHPT patients without prior history of PTX (n = 1696). RESULTS Both groups of patients had substantially elevated serum PTH with comparable sHPT severity at baseline. After 12 months of cinacalcet treatment, 20.3% (26/128) of patients with prior PTX and 18.2% (253/1388) of patients without prior PTX achieved serum PTH and Ca × P values within the recommended KDOQI(TM) target ranges. CONCLUSIONS Our data support the successful use of cinacalcet in patients with recurrent/persistent sHPT after PTX.

The association of mid-regional pro-adrenomedullin and mid-regional pro-atrial natriuretic peptide with mortality in an incident dialysis cohort.

High levels of the plasma peptides mid-regional pro-adrenomedullin (MR-proADM) and mid-regional pro-atrial natriuretic peptide (MR-proANP) are associated with clinical outcomes in the general population. Data in patients with chronic kidney disease are sparse. We therefore investigated the association of MR-proANP and MR-proADM levels with all-cause and cardiovascular (CV) mortality, CV events and peripheral arterial disease in 201 incident dialysis patients of the INVOR-Study prospectively followed for a period of up to more than 7 years. The overall mortality rate was 43%, thereof 43% due to CV events. Both baseline MR-proANP and MR-proADM were associated with higher risk of all-cause (HR = 1.44, p = 0.001 and HR = 1.32, p = 0.002, respectively) and CV mortality (HR = 1.75, p<0.001 and HR = 1.41, p = 0.007, respectively) after adjustment for age, sex, previous CV events, diabetes mellitus and time-dependent type of renal replacement therapy. We then stratified patients in high risk (both peptides in the upper tertile), intermediate risk (only one of the two peptides in the upper tertile) and low risk (none in the upper tertile). Although demographic, clinical and laboratory variables were similar among the intermediate and high risk group, to be with both parameters in the upper tertile was associated with a 3-fold higher risk for all-cause (HR = 2.87, p<0.001) and CV mortality (HR = 3.58, p = 0.001). In summary, among incident dialysis patients MR-proANP and MR-proADM were shown to be associated with all-cause and CV mortality, with the highest risk when both parameters were in the upper tertiles.