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-alpha-hydroxylase capacity, but an extrarenal source of 1,25(OH)(2)D has been recognized. OBJECTIVE: The aim of this study was to assess the evolution of serum 1,25(OH)(2)D in hemodialysis (HD) patients with vitamin D deficiency after 6 months of 25(OH)D(3) supplementation, and to identify the factors associated with persistent 1,25(OH)(2)D 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 microg/day of oral 25(OH)D(3) based on the severity of their deficiency. The serum levels of 25(OH)D and 1,25(OH)(2)D evolution after 6 months were recorded. Responders were defined as patients with an increase in serum 1,25(OH)(2)D 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)(2)D 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)(2)D and serum 25(OH)D levels after 6 months of 25(OH)D(3) 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)(2)D production. These data confirm persistent renal or extra-renal production of 1,25(OH)(2)D in HD patients after 6 months of 25(OH)D(3) administration. Diabetes is the main factor associated with impaired 1,25(OH)(2)D production. 25(OH)D(3 )administration corrects vitamin D deficiency with few effects on mineral metabolism and stability of bone turnover markers.

Phenotypic and genotypic risk factors for cardiovascular events in an incident dialysis cohort.

Cardiovascular disease (CVD) remains the major cause of death in patients with end-stage renal disease (ESRD). Traditional risk factors do not explain the high prevalence of CVD in this population, and other non-traditional cardiovascular (CV) risk markers have now been described. Therefore, the potential relationship between CVD and phenotypic and genotypic risk markers was investigated prospectively in incident dialysis patients cohort. The 279 patients (244 on hemodialysis, 35 on peritoneal dialysis) within the Diamant Alpin Dialysis Cohort Study were investigated. Phenotypic and genotypic parameters were determined at dialysis initiation, patients monitored over a 2-year period, and CV events (morbidity and mortality) recorded. Globally, 82 CV events occurred and 26 patients (9.3%) died from CVD, whereas 28 (10%) died from non-CV causes. Previous CV events were strongly predictive of CV events occurrence, whatever patients had had one (hazard ratio (HR) 2, 95% confidence intervals (CI) 1.1-3.5) or more (HR 3.9, 95% CI 2.1-7.1) CV accidents before starting dialysis. Both lipoprotein(a) (HR 1.67, 95% CI 1-2.5) and total plasma homocysteine at cutoff 30 micromol/l (HR 1.7, 95% CI 1.1-2.8) were independent predictors of CV events outcome. In the subgroup of patients with homocysteine < 30 micromol/l, methylenetetrahydrofolate reductase (MTHFR) TT was the sole biological parameter predictive of CV event outcome (HR 2.5, 95% CI 1.1-10, P = 0.03). ESRD patients who enter chronic dialysis with a previous CV event, high total homocysteinemia levels, or MTHFR 677TT genotype must be considered at high risk of incident CV events.

Role of sodium in dialysis.

The total amount of sodium present in the body conditions the extracellular compartment volume. In advanced renal failure and in dialysis the sodium balance becomes positive and the extracellular volume inflates. This leads to hypertension and to direct cardiac and vascular changes that explain for a large part the excessive cardiovascular morbidity and mortality in dialysis patients. Controlling body sodium content and extracellular volume allows to reduce hypertension, cardiovascular changes and to improve dialysis patients survival. This can be achieved by reducing the sodium input (low sodium diet and reasonably low sodium dialysate) and/or by increasing sodium output (ultrafiltration by convection in hemodialysis or hemofiltration and osmotic drive in peritoneal dialysis). The intermittent nature of hemodialysis (and hemofiltration) conditions the saw-tooth volume fluctuations that drove to conceiving and implementing the concept of a dry weight, corresponding to normal extracellular volume and blood pressure.

Nutritional effects of carnitine supplementation in hemodialysis patients.

AIMS: Carnitine is involved in fatty acid metabolism and it is cleared by dialysis. As it plays a role in energy utilization and because malnutrition is a frequent complication of HD treatment, we studied the effects of carnitine supplementation on several nutritional parameters in HD patients. MATERIAL AND METHODS: The main selection criterion was a body mass index (BMI; body weight/(height)2) < 22 kg/m2. Fifty-three patients were enrolled to participate in this open and randomized study. For 6 months, 28 patients received 15 mg/kg of intravenous L-carnitine at the end of each hemodialysis (HD) treatment (Group A), the remaining 25 patients were controls (Group B). The measured parameters were the post-dialysis body weight, serum albumin concentration (nephelemetry), food intake assessed by a 3-day food questionnaire, nPNA (normalized protein equivalent of nitrogen appearance), creatinine generation, and anthropometry. RESULTS: Forty-five patients completed the study (Group A: 14 F/9 M, 66.7 years old; Group B: 11 F/11 M, 65.2 years old). At the beginning of the study, there were no differences between the groups for age, gender, HD duration, BMI, diabetes prevalence, plasma carnitine levels and measured nutritional parameters. 65.2% and 77.3% in each group were carnitine-deficient (plasma total carnitine level < 35 micromol/l). After 6 months of L-carnitine supplementation, none of the nutritional parameters had changed in either group, except that serum albumin concentration decreased in both groups. Dividing each group according to their respective median serum albumin concentrations, daily energy and protein intakes, creatinine generation or triceps skinfold thickness did not show any difference in the various nutritional parameters with or without carnitine supplementation. CONCLUSION: Carnitine supplementation, despite normalization of plasma carnitine levels, has no effect on the nutritional status of HD patients.

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.

Long-term outcome of permanent hemodialysis catheters: a controlled study.

AIMS: Hemodialysis tunneled catheters are widely used nowadays. However, their complications, infection and dysfunction, remain much too frequent. Different types of tunneled silicone hemodialysis catheters are available. We prospectively compared the long-term outcome of the two most popular devices, Permcath cuffed double catheter and TwinCath uncuffed twin catheter, both inserted percutaneously. METHODS: From January 1994 to April 1998, 125 tunneled catheters were inserted in the internal jugular vein of 86 chronic hemodialysis patients, 63 TwinCath MedComp (TC) and 62 Permcath Quinton (PC). They were prospectively followed looking for technical patency, infection and dysfunction rate. RESULTS: TC were used more often for iterative access (52 vs. 25%, p = 0.01) and were inserted more frequently in the left internal jugular vein (59 vs. 16% p < 0.001). Their median technical survival rate was longer (869 vs. 433 days for PC, p < 0.01) with a 1-year patency rate of 80 vs. 53% (p = 0.002). Total catheter extrusion was also slightly less frequent with TC (4.7 vs. 9.6%), but partial extrusion happened more frequently (43 vs. 16%, p = 0.02). No significant difference in infection rate was observed, 0.77 for TC vs. 1.3 local infection/1,000 catheter days; 1.08 vs. 1.30 bacteremia/1,000 catheter days. A persistent catheter thrombosis was observed in 7.9 vs. 20.9% in PC (p = 0.04), the number of dysfunction was 10.5 vs. 24/1,000 days in use (p = 0.0001) and the number of urokinase infusion was 4.4 vs. 12/1,000 days (p = 0.001). PC needed more radiological interventions for dysfunction with endolumenal brushes (4 vs. 0) or fibrin sleeve removal (4 vs. 0). The vena cava thrombosis incidence was not different (2 vs. 3). CONCLUSION: Although the study was not randomized, TC appears more efficient allowing for a longer patency with a lower dysfunction rate than PC. This was reinforced by less favorable conditions of TC including more left jugular side and more iterative catheters. The cuff does not offer a better bacteriological barrier or protection against extrusion, and the TC seems at a less risk of fibrin sleeves. However, a large randomized study is needed to definitively conclude.

Oxidants and antioxidants in long-term haemodialysis patients.

Survival for decades is now possible in end-stage renal disease patients (ESRD) treated with haemodialysis (HD). Long-term survivors may present dialysis-related pathology (DRP). Alterations in lipid metabolism and oxidative stress are recognized as important risk factors that could be prevented or reduced by optimal therapy. We have studied markers of oxidative stress in patients receiving HD treatment for more than 20 years. In order to evaluate a preventive intervention against oxidative damage we measured the factors implied for the prooxidative and antioxidative mechanisms in haemodialysis patients. Ten long-term HD survivors (HD duration: 274.2 months) and ten patients with recent onset of HD (HD duration: 17.8 months), had blood drawn for plasma vitamins A and E, malondialdehyde (MDA), plasma and RBC glutathione peroxidase (GPx), RBC superoxide dismutase (SOD), plasma and erythrocyte glutathione reductase (GSSG-R), oxidized and reduced glutathione (GSH) assessment. Despite normal levels of antioxidant vitamins, an usual finding in this setting, increased MDA, and oxidized GSH, and decreased plasma GPx and reduced GSH show that oxidant stress is markedly present in both recent onset and long-term HD patients. It would appear highly advantageous to reduce complications of long-term dialysis patients with preventing modalities.

Rat small intestine is an insulin-sensitive gluconeogenic organ.

At variance with the current view that only liver and kidney are gluconeogenic organs, because both are the only tissues to express glucose-6-phosphatase (Glc6Pase), we have recently demonstrated that the Glc6Pase gene is expressed in the small intestine in rats and humans and that it is induced in insulinopenic states such as fasting and diabetes. We used a combination of arteriovenous balance and isotopic techniques, reverse transcription-polymerase chain reaction, Northern blot analysis, and enzymatic activity assays. We report that rat small intestine can release neosynthesized glucose in mesenteric blood in insulinopenia, contributing 20-25% of total endogenous glucose production. Like liver glucose production, small intestine glucose production is acutely suppressed by insulin infusion. In the small intestine, glutamine and, to a much lesser extent, glycerol are the precursors of glucose, whereas alanine and lactate are the main precursors in liver. Accounting for these metabolic fluxes: 1) the phosphoenolpyruvate carboxykinase gene (required for the utilization of glutamine) is strongly induced at the mRNA and enzyme levels in insulinopenia; 2) the glycerokinase gene is expressed, but not induced; 3) the pyruvate carboxylase gene (required for the utilization of alanine and lactate) is repressed by 80% at the enzyme level in insulinopenia. These studies identify small intestine as a new insulin-sensitive tissue and a third gluconeogenic organ, possibly involved in the pathophysiology of diabetes.

Diabetes mellitus in Tassin, France: remarkable transformation in incidence and outcome of ESRD in diabetes.

The incidence and prevalence of diabetes mellitus (DM) in the dialysis population in Europe, and more especially in France, have been lagging behind the impressive United States and Japanese rates. For a decade, things have been changing, and the incidence of DM in hemodialysis (HD) reached almost 40 in Tassin, France in 1999. The prevalence has followed the same trend but increased more slowly. The increase in incidence and prevalence is almost totally accounted for by type 2 DM explosive outbreak and development. The morbidity on dialysis (hypotensive episodes, hospitalization number, and duration) was significantly worse in diabetic patients (without difference between type 1 and 2) than in nondiabetic patients. The mortality rate was higher in diabetic patients than in nondiabetic patients (mean half-life 3 and 13 years, respectively), even after adjustment for age and comorbidity. The mortality rate was higher in type 2 than in type 1 (mean half-life 2.7 and 5.2 years, respectively), a difference which disappears when adjusting for age and comorbidity. Specific causes of death were different in diabetic and nondiabetic HD patients; in diabetics there was a six-fold higher cardiovascular (CV) and three-fold higher infectious mortality, but there was the same mortality from cancer. A strong difference was observed between type 1 and type 2 DM: in type 1 there was no increased infectious mortality and a moderately increased CV mortality compared with nondiabetic patients. Type 2 diabetic patients had a four-fold increased infectious and an eight-fold increased CV mortality. Altogether, the eruption of DM in our unit over the last decade has drastically increased the crude mortality, but the standardized mortality ratio using the USRDS mortality table remained unchanged, about 45 of expected mortality.

[Prevalence of stenosis and thrombosis of central veins in hemodialysis after a tunneled jugular catheter]. / Prévalence des sténoses et thromboses des veines centrales chez les hémodialysés après un cathéter jugulaire tunnellisé.

Central venous stenosis (ST) and thrombosis (TB) related to catheter (KT) had been reported mostly for the subclavian vein. We performed a systematic cavographic study to evaluate the prevalence of these complications in 51 hemodialysis patients with present or previous history of tunneled internal jugular catheter. Each of them had used one or several KT (1.8 +/- 1.4 KT) for a mean 28 +/- 26 month cumulative time (i.e. 43,584 days total exposure time). Fifty percent of the KT were PermCath Quinton and 50% were Twincath (uncuffed) or CS 100 (cuffed) Medcomp. Twenty-seven had no ST (53%, group I), 24 had one or several significant ST (47%, group II) of superior Vena Cava (SVC, n = 4), inferior Vena Cava (IVC, n = 1), Brachio-cephalic Vein (BCV, n = 5) and subclavian vein (SC, n = 10), or a TB of SVC (n = 1), IVC (n = 3), BCV (n = 3), SC (n = 2). This accounts for an incidence of 0.55 ST or TB/1000 patient-days. Five of the twelve subclavian ST and TB had no history of previous subclavian catheter. Comparison between the two groups showed no differences according to age, time on dialysis, diabetes, hematocrit, CRP, cumulative time with catheter, catheter-related infections, type of catheter and anticoagulant treatment. IVC catheter tip's position is an important risk factor for TB and ST (4/6). Twelve group II patients had ST or TB-related symptoms, with a functional AV fistula in 9 cases. Eleven patients underwent repeated percutaneous angioplasty with 4 additional Wallstents and in 2 cases an AV fistula need to be closed. Central venous ST and TB after a jugular KT is extremely frequent, mostly without any symptoms. Consequences on peripheral or central vascular access, cost and poor long-term patency rate of angioplasty are of major importance. These results incite us to further reduce the catheter use in dialysis patients.

Acetate-free biofiltration for acute renal failure.

The characteristics of acetate-free biofiltration (AFB) are now well documented in patients with chronic renal failure: hemodynamic tolerance, correction of acid-base imbalance, buffer-free dialysate (without acetate) and absence of backfiltration. This hemodialysis technique can be beneficial to patients with acute renal failure (ARF). In our intensive care unit, we prospectively studied 29 patients with isolated ARF or ARF associated with failure of other organs. All eligible patients were randomly assigned to undergo dialysis with bicarbonate hemodialysis (BH) or with (AFB). All used the same high flux biocompatible dialysis membranes. Effectiveness and hemodynamic tolerance of hemodialysis sessions and evolution of patients were analyzed. Correction of metabolic disorders, although better in the AFB group was not statistically different from that in the BH group. Re-equilibration of acid-base balance was also similar, with or without mechanical ventilation. Heparin consumption was significantly higher in the AFB group, with no effect on haemorrhagic complications. Analysis of hypo- and hypertensive episodes, defined as arterial pressure (AP) variations 20% greater than initial pressure, showed no difference in terms of number or degree of AP variation. However, weight loss and the rate of ultrafiltration led to a higher hypotensive risk in the BH group (p < 0.05). Finally, the clinical course and prognosis was similar in both groups. In summary, AFB may be considered as effective a hemodialysis technique as BH in patients with ARF. Weight loss was better tolerated in the AFB group and can be a favorable factor considering the deleterious effect of overhydration in patients admitted to an intensive care unit. This study invites a comparison of longer dialysis session of AFB therapy and continuous hemodiafiltration.