Charles Chazot

Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population

Background. A number of US observational studies reported an increased mortality risk with higher intact parathyroid hormone (iPTH), calcium and/or phosphate. The existence of such a link in a European haemodialysis population was explored as part of the Analysing Data, Recognising Excellence and Optimising Outcomes (ARO) Chronic Kidney Disease (CKD) Research Initiative. Methods. The association between the markers of mineral and bone disease and clinical outcomes was examined in 7970 patients treated in European Fresenius Medical Care facilities over a median of 21 months. Baseline and time-dependent (TD) Cox regression were performed using Kidney Disease Outcomes Quality Initiative (KDOQI) target ranges as reference categories, adjusting for demographics, medical history, dialysis parameters, inflammation, medications and laboratory parameters. Fractional polynomial (FP) models were also used. Results. Hazard ratio (HR) estimates from baseline analysis for iPTH were U-shaped [>600 pg/mL, HR = 2.10, 95% confidence interval (CI) 1.62–2.73; <75 pg/mL, HR = 1.46, 95% CI 1.17–1.83]. TD analysis confirmed the results for iPTH. Baseline analysis showed that calcium >2.75 mmol/L increased risk of death (HR = 1.70, 95% CI 1.19–2.42). TD analysis showed that both low (HR = 1.19, 95% CI 1.04–1.37) and high calcium (HR = 1.74, 95% CI 1.30–2.34) increased risk of death. Baseline analysis for phosphate showed a U-shaped pattern (<1.13 mmol/L, HR = 1.18, 95% CI 1.01–1.37; >1.78 mmol/L, HR = 1.32, 95% CI 1.13–1.55). TD analysis confirmed the results for phosphate <1.13 mmol/L. HR estimates were higher in patients with diabetes versus those without diabetes for baseline analysis only (P-value = 0.014). FP analysis confirmed the results of baseline and TD analyses. Conclusion. Patients with iPTH, calcium and phosphate levels within the KDOQI target ranges have the lowest risk of mortality compared with those outside the target ranges.

High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients

BACKGROUND Fibroblast growth factor (FGF)-23, a novel bone-derived phosphaturic factor involved in mineral metabolism, is increased in chronic kidney disease (CKD); in dialysis patients, it has been linked to increased mortality rates and vascular calcification (VC). The present investigation aimed to study the factors associated with elevated serum FGF-23 levels in patients treated with long haemodialysis (LHD) sessions and to determine whether a relationship exists between serum FGF-23 levels and patient survival. METHODS All patients treated in one haemodialysis centre from September 2006 were included in the study. Standard laboratory values, medical history, cardiovascular events and risk factors, medication and FGF-23 levels [ELISA (C-Term) Immutopics] were recorded. Patients received haemodialysis three times a week, on a 5- to 8-h schedule. Patient data were analysed according to FGF-23 quartiles. The effect of FGF-23 on the 2-year survival rate was assessed using the Cox proportional hazard model, adjusted for confounding variables and according to the serum phosphate tertiles. RESULTS The study included 219 patients. Serum FGF-23 levels were high: 7060 +/- 13 500 RU/mL (median, 2740 RU/mL). In logistical regressions, only calcaemia (P = 0.002), phosphataemia (P = 0.008) and warfarin use (P = 0.04) were associated with the highest FGF-23 quartile. In the subgroup of patients with an estimated VC score, the third and fourth quartiles of the FGF-23 levels were associated with more severe VC. In multivariate linear regressions, only phosphataemia remained significantly correlated with FGF-23 (P = 0.04). The 2-year mortality rate was significantly higher for haemodialysis patients with serum FGF-23 levels in the higher quartile [P = 0.007; hazard ratio, 2.5 (1.3-5)] than in the first quartile, whereas within the phosphataemia tertiles, the lowest serum FGF-23 quartile was associated with lowered mortality. CONCLUSION This study demonstrated a high level of circulating FGF-23 in LHD patients, despite infrequent hyperphosphataemia. However, phosphataemia is still the main factor correlating with serum FGF-23. The association of higher serum FGF-23 levels with mortality and VC, regardless of the serum phosphate levels, has thus been confirmed.

Intensive Hemodialysis Associates with Improved Survival Compared with Conventional Hemodialysis

Patients undergoing conventional maintenance hemodialysis typically receive three sessions per week, each lasting 2.5-5.5 hours. Recently, the use of more intensive hemodialysis (>5.5 hours, three to seven times per week) has increased, but the effects of these regimens on survival are uncertain. We conducted a retrospective cohort study to examine whether intensive hemodialysis associates with better survival than conventional hemodialysis. We identified 420 patients in the International Quotidian Dialysis Registry who received intensive home hemodialysis in France, the United States, and Canada between January 2000 and August 2010. We matched 338 of these patients to 1388 patients in the Dialysis Outcomes and Practice Patterns Study who received in-center conventional hemodialysis during the same time period by country, ESRD duration, and propensity score. The intensive hemodialysis group received a mean (SD) 4.8 (1.1) sessions per week with a mean treatment time of 7.4 (0.87) hours per session; the conventional group received three sessions per week with a mean treatment time of 3.9 (0.32) hours per session. During 3008 patient-years of follow-up, 45 (13%) of 338 patients receiving intensive hemodialysis died compared with 293 (21%) of 1388 patients receiving conventional hemodialysis (6.1 versus 10.5 deaths per 100 person-years; hazard ratio, 0.55 [95% confidence interval, 0.34-0.87]). The strength and direction of the observed association between intensive hemodialysis and improved survival were consistent across all prespecified subgroups and sensitivity analyses. In conclusion, there is a strong association between intensive home hemodialysis and improved survival, but whether this relationship is causal remains unknown.

Importance of normohydration for the long-term survival of haemodialysis patients

BACKGROUND Fluid overload and hypertension are among the most important risk factors for haemodialysis (HD) patients. The aim of this study was to analyse the impact of fluid overload for the survival of HD patients by using a selected reference population from Tassin. METHODS A positively selected HD population (n = 50) from Tassin (Lyon-France) was used as a reference for fluid status and all-cause mortality. This population was compared to one dialysis centre from Giessen (Germany) which was separated into a non-hyperhydrated (n = 123) and a hyperhydrated (n = 35) patient group. The hydration status (ΔHS) of all patients was objectively measured with whole-body bioimpedance spectroscopy in 2003. All-cause mortality was analysed after a 6.5-year follow-up. RESULTS Most of the reference patients from Tassin were normohydrated (ΔHS = 0.25 ± 1.15 L) at the start of the HD session. The hydration status of the Tassin patients was not different to the non-hyperhydrated Giessen patients (ΔHS = 0.8 ± 1.1 L) but significantly lower than in the hyperhydrated Giessen group (ΔHS = 3.5 ± 1.2 L). Multivariate adjusted all-cause mortality was significantly increased in the hyperhydrated patient group (hazard ratio = 3.41)- no difference in mortality could be observed between the Tassin and the non-hyperhydrated group from Giessen-even considering the fact that Tassin patients presented a significantly lower blood pressure. CONCLUSIONS Fluid overload has a very high predictive value for all-cause mortality and seems to be one of the major killers in the HD population. Patients might strongly benefit from active management of fluid overload.

Blood pressure in chronic kidney disease stage 5D-report from a Kidney Disease: Improving Global Outcomes controversies conference

Management of blood pressure (BP) in patients with chronic kidney disease receiving dialysis (stage 5D) provides a significant challenge for healthcare professionals. The association between BP and cardiovascular disease risk has been well studied in the general population; however, in dialysis patients, physiological and dialysis-related mechanisms influencing BP are complex, and the associated risk is poorly understood. In stage 5D, BP is determined by the complex interplay of fluid volume and prescription of post-dialysis target weight, sodium load, the renin-angiotensin and sympathetic nervous systems, and diverse exogenous factors, such as administration of erythropoiesis-stimulating agents, the type and timing of administration of antihypertensive drugs, and dialysate composition. Management of BP in this population requires both generally applicable plans and individualization in order to determine the BP target and the treatment regimen. This report summarizes the deliberations and recommendations of a conference sponsored by the Kidney Disease: Improving Global Outcomes (KDIGO) to address the following questions: (1) what is the optimal BP treatment target in relation to end-organ damage and outcomes in dialysis patients; (2) how should antihypertensive drugs be used in dialysis patients; and (3) what nonpharmacological therapies can be considered in achieving BP targets? The conference report will augment the KDIGO clinical practice guideline on blood pressure in chronic kidney disease stages 1-5, which is currently under development.

Monthly cholecalciferol administration in haemodialysis patients: a simple and efficient strategy for vitamin D supplementation

BACKGROUND There is growing evidence of the usefulness of vitamin D supplementation in dialysis patients who are most often vitamin D deficient. Due to the long half-life of vitamin D, there is much interest in administering it intermittently for long-term adherence. However, there are no data to indicate which dosage would be most efficient. Objective. The aim was to assess the long-term efficiency and safety of a monthly oral dose of cholecalciferol (100 000 IU) in vitamin D-deficient haemodialysis (HD) patients. METHODS HD patients with a serum 25-hydroxyvitamin D (25(OH)D) level <75 nmol/L were enrolled in a 15-month prospective study. The exclusion criteria were as follows: use of any vitamin D derivatives, prescription of cinacalcet and bisphosphonates, uncontrolled hypercalcaemia (>2.55 mmol/L), hyperphosphataemia (>2 mmol/L) and severe secondary hyperparathyroidism (SHPT; serum PTH >600 pg/mL). Biological data were recorded in the following months: M-3, M0, M1, M3, M9 and M15. We aimed to maintain stable levels of the phosphate binder and oral and dialysate calcium during the course of the study. RESULTS Of the 250 patients screened, 161 were enrolled, and the results from 107 were recorded at the end of the study. Of these 107 patients, 56% were males, and the average age of the patient group was 66.4 +/- 15 years. Diabetics accounted for 36% of the total patients. The dialysis schedule ranged from 3 x 5 to 3 x 8 h, with a mean dialysate calcium concentration of 1.48 +/- 0.6 mmol/L. After 15 months, the mean serum 25(OH)D level increased from 32 +/- 13 to 105.8 +/- 27 nmol/L (P < 0.001) and plateaued after M3. Of the patients, 91% had a level higher than the target level (>75 nmol/L), while none had levels >200 nmol/L. The serum calcitriol (1,25(OH)(2)D) level increased from 13.7 +/- 14 to 45 +/- 13 pmol/L (P < 0.001) and plateaued after M9. The levels of serum PTH (median 295-190 pg/mL, P < 0.001), bone alkaline phosphatase (20.5 +/- 9-17.1 +/- 7 microg/L, P < 0.05) and beta-cross-laps (2.5 +/- 1-2.07 +/- 0.8 microg/L, P < 0.05) decreased significantly. No significant changes were observed in the values of the following: calcaemia, phosphataemia, blood pressure, serum albumin, haemoglobin and C-reactive protein. CONCLUSIONS Long-term monthly administration of oral cholecalciferol (100 000 IU) was a safe, effective, inexpensive and simple method for correcting vitamin D deficiency in almost 90% of the HD patients in this study and led to optimal compliance. The most evident consequences were a slight decrease in the levels of PTH and bone markers and an increase in the level of serum 1,25(OH)(2)D.

Diets and enteral supplements for improving outcomes in chronic kidney disease

Protein-energy wasting (PEW), which is manifested by low serum levels of albumin or prealbumin, sarcopenia and weight loss, is one of the strongest predictors of mortality in patients with chronic kidney disease (CKD). Although PEW might be engendered by non-nutritional conditions, such as inflammation or other comorbidities, the question of causality does not refute the effectiveness of dietary interventions and nutritional support in improving outcomes in patients with CKD. The literature indicates that PEW can be mitigated or corrected with an appropriate diet and enteral nutritional support that targets dietary protein intake. In-center meals or oral supplements provided during dialysis therapy are feasible and inexpensive interventions that might improve survival and quality of life in patients with CKD. Dietary requirements and enteral nutritional support must also be considered in patients with CKD and diabetes mellitus, in patients undergoing peritoneal dialysis, renal transplant recipients, and in children with CKD. Adjunctive pharmacological therapies, such as appetite stimulants, anabolic hormones, and antioxidative or anti-inflammatory agents, might augment dietary interventions. Intraperitoneal or intradialytic parenteral nutrition should be considered for patients with PEW whenever enteral interventions are not possible or are ineffective. Controlled trials are needed to better assess the effectiveness of in-center meals and oral supplements.

Daily oral 25-hydroxycholecalciferol supplementation for vitamin D deficiency in haemodialysis patients: effects on mineral metabolism and bone markers

BACKGROUND Vitamin D deficiency is frequently observed in end-stage renal disease (ESRD) patients; however, the effects of vitamin D supplementation have rarely been reported. We aimed to assess the effects of daily 25(OH)D(3) supplementation on mineral metabolism, bone markers and Kidney Disease Outcomes Quality Initiative (KDOQI) targets in haemodialysis (HD) patients for a period of 6 months. METHODS HD patients were included in this study if their serum 25(OH)D level was <75 mmol/L. Oral 25(OH)D(3) was administered daily at 10-30 microg/day based on the severity of the deficiency. Characteristics of the patients were compared from the baseline to 6 months on the basis of their response to 25(OH)D(3) administration and the patients were divided into three groups. Patients who showed partial response [serum 25(OH)D <75 nmol/L] were placed in group 1, those who showed normal response [serum 25(OH)D ranging from 75 to 150 nmol/L] were placed in group 2 and those who showed excessive response [serum 25(OH)D >150 nmol/L] were placed in group 3. RESULTS Of the 253 HD patients, 225 (89%) showed vitamin D insufficiency or deficiency, 172 were included in the study and 149 patients completed the study. After 6 months of treatment [mean daily 25(OH)D(3): 16 +/- 5 microg/day], the serum 25(OH)D level increased (30 +/- 19 to 126 +/- 46 nmol/ L, P < 0.001), with 13% of patients in group 1, 57% in group 2 and 30% in group 3. The serum intact parathyroid hormone (iPTH) level decreased (235 +/- 186 to 189 +/- 137 pg/mL, P = 0.05), except in group 1. Bone alkaline phosphatase (BALP) showed a tendency to normalize (23 +/- 16 to 18.3 +/- 11 microg/L, P < 0.05), leading to a decrease in alfacalcidol administration from 66% to 43% (P < 0.05), except in group 1. The KDOQI targets achieved increased significantly for serum calcium (76% to 85%) and phosphate levels (66% to 77%) in all patients. The serum albumin level increased in all groups (34.6 +/- 4 to 36.8 +/- 4 g/L, P < 0.05), without any significant improvement in normalized protein catabolic rate (nPCR) or C-reactive proteins (CRP). CONCLUSION With a daily dose ranging from 10 to 30 microg, daily oral 25(OH)D(3) supplementation corrects most vitamin D deficiencies or insufficiencies in HD patients, without any evident toxicity. The main effects observed included correction of excessive bone turnover, despite less alfacalcidol administration, increase in serum albumin level and increase in the percentage of patients with serum calcium and phosphorus levels within the recommendation of the KDOQI guidelines.

Risk factor analysis for long-term tunneled dialysis catheter-related bacteremias

Infection, mainly related to vascular access, is one of the main causes of morbidity and a preventable cause of death in hemodialysis patients. From January 1994 to April 1998 we conducted a prospective study to assess the incidence and risk factors of catheter-related bacteremia. One hundred and twenty-nine tunneled dual-lumen hemodialysis catheters were inserted percutaneously into the internal jugular vein in 89 patients. Bacteremia (n = 56) occurred at least once with 37 (29%) of the catheters (an incidence of 1.1/1,000 catheter-days); local infection (n = 45, 1/1,000 catheter-days) was associated with bacteremia in 18 cases. Death in 1 case was directly related to Staphylococcus aureus (SA) septic shock, and septicemia contributed to deaths in 2 additional cases. Catheters were removed in 48% of the bacteremic episodes. Treatment comprised intravenous double antimicrobial therapy for 15–20 days. Bacteriological data of bacteremia showed 55% involvement of SA. Nasal carriage of SA was observed in 35% of the patients with catheters. Bacteremic catheters were more frequently observed in patients with diabetes mellitus (p = 0.03), peripheral atherosclerosis (p = 0.001), a previous history of bacteremia (p = 0.05), nasal carriage of SA (p = 0.0001), longer catheter survival time (p = 0.001), higher total intravenous iron dose (p = 0.001), more frequent urokinase catheter infusion (p < 0.01), and local infection (p < 0.001) compared with non-bacteremic catheters. Monovariate survival analysis showed that significant initial risk factors for bacteremia were nasal carriage of SA (p = 0.00001), previous bacteremia (p = 0.0001), peripheral atherosclerosis (p = 0.005), and diabetes (p = 0.04). This study confirms the relatively high incidence of bacteremia with tunneled double-lumen silicone catheters and its potential complications. Possible preventive actions are discussed according to the risk factors.

Evidence for Persistent Vitamin D 1-Alpha-Hydroxylation in Hemodialysis Patients: Evolution of Serum 1,25-Dihydroxycholecalciferol after 6 Months of 25-Hydroxycholecalciferol Treatment

Background: End-stage renal disease (ESRD) patients are thought to have impaired 1-α-hydroxylase capacity, but an extrarenal source of 1,25(OH)2D has been recognized. Objective: The aim of this study was to assess the evolution of serum 1,25(OH)2D in hemodialysis (HD) patients with vitamin D deficiency after 6 months of 25(OH)D3 supplementation, and to identify the factors associated with persistent 1,25(OH)2D production. Methods: HD patients in a HD center with vitamin D deficiency (i.e. 25(OH)D <75 nmol/l) who were not receiving any vitamin D derivatives or calcimimetics were studied. Patients who had previously undergone parathyroidectomy or nephrectomy or those with uncontrolled hypercalcemia or hyperphosphatemia were excluded from this study. The patients were administrated a dose of 10–30 µg/day of oral 25(OH)D3 based on the severity of their deficiency. The serum levels of 25(OH)D and 1,25(OH)2D evolution after 6 months were recorded. Responders were defined as patients with an increase in serum 1,25(OH)2D levels greater than the median value. Changes in mineral metabolism parameters were compared with those in the nonresponders. Results: Of the 253 patients, 225 (89%) were vitamin D-deficient, and 43 met the inclusion criteria. The patients were 72.6 ± 10 years old and had been on dialysis for 71 ± 70 months; 39% of the patients were female and 45% were diabetics. From baseline to 6 months of treatment, serum 25(OH)D levels increased from 27.8 ± 18 to 118 ± 34 nmol/l (p < 0.001) and serum 1,25(OH)2D levels increased from 7.7 ± 5 to 30.5 ± 15 pmol/l (p < 0.001) with a median increase of 20 pmol/l. The mean serum calcium level increased from 2.19 ± 0.1 to 2.25 ± 0.1 mmol/l (p = 0.009), the intact parathyroid hormone (iPTH) level decreased from 144 ± 108 to 108 ± 63 pg/ml (p = 0.05), and the bone alkaline phosphatase (BALP) level remained unchanged. The serum phosphate level increased slightly from 1.22 ± 0.3 to 1.34 ± 0.2 mmol/l (p = 0.04) with reduced hypophosphatemia. Compared with the responders (n = 24), most of the nonresponders (n = 19) were diabetic (63 vs. 29%, p = 0.02) and had a lesser increase of their 25(OH)D serum level. The serum level of FGF-23 was not significant. A positive correlation was observed between serum 1,25(OH)2D and serum 25(OH)D levels after 6 months of 25(OH)D3 treatment (p = 0.02). Conclusion: The Kidney Disease Outcomes Quality Improvement (KDOQI) guidelines do not recommend checking and treating vitamin D deficiency in chronic kidney disease (CKD) stage 5 patients due to the supposed lack of 1,25(OH)2D production. These data confirm persistent renal or extra-renal production of 1,25(OH)2D in HD patients after 6 months of 25(OH)D3 administration. Diabetes is the main factor associated with impaired 1,25(OH)2D production. 25(OH)D3 administration corrects vitamin D deficiency with few effects on mineral metabolism and stability of bone turnover markers.