Effect of an L-carnitine-containing peritoneal dialysate on insulin sensitivity in patients treated with CAPD: a 4-month, prospective, multicenter randomized trial.

BACKGROUND: In peritoneal dialysis, the high glucose load absorbed from dialysis fluid contributes to several metabolic abnormalities, including insulin resistance. We evaluate the efficacy of a peritoneal dialysis solution containing l-carnitine as an additive to improve insulin sensitivity. STUDY DESIGN: Multicenter parallel randomized controlled trial. SETTING & PARTICIPANTS: Nondiabetic uremic patients on continuous ambulatory peritoneal dialysis enrolled in 8 peritoneal dialysis centers. INTERVENTION: Patients were randomly assigned to receive peritoneal dialysis diurnal exchanges with either a standard glucose-based solution (1.5% or 2.5% according to the patient's need) or a glucose-based solution (identical glucose amount) enriched with l-carnitine (0.1%, weight/volume; 2 g/bag) for 4 months, the nocturnal exchange with icodextrin being unmodified. OUTCOMES & MEASUREMENTS: The primary outcome was insulin sensitivity, measured by the magnitude of change from baseline in glucose infusion rate (in milligrams per kilogram of body weight per minute) during a euglycemic hyperinsulinemic clamp. Secondary outcomes were safety and tolerability, body fluid management, peritoneal dialysis efficiency parameters, and biochemistry tests. RESULTS: 35 patients were randomly assigned, whereas 27 patients (standard solution, n=12; experimental solution, n = 15) were analyzed. Adverse events were not attributable to treatment. Glucose infusion rates in the l-carnitine-treated group increased from 3.8 ± 2.0 (SD) mg/kg/min at baseline to 5.0 ± 2.2 mg/kg/min at day 120 (P = 0.03) compared with 4.8 ± 2.4 mg/kg/min at baseline and 4.7 ± 2.4 mg/kg/min at day 120 observed in the control group (P = 0.8). The difference in glucose infusion rates between groups was 1.3 (95% CI, 0.0-2.6) mg/kg/min. In patients treated with l-carnitine-containing solution, urine volume did not change significantly (P = 0.1) compared to a significant diuresis reduction found in the other group (P = 0.02). For peritoneal function, no differences were observed during the observation period. LIMITATIONS: Small sample size. CONCLUSIONS: The use of l-carnitine in dialysis solutions may represent a new approach to improving insulin sensitivity in nondiabetic peritoneal dialysis patients.

[L-carnitine in peritoneal dialysis]. / La L-carnitina in dialisi peritoneale.

L-carnitine is an important compound involved both in the transfer of activated long-chain fatty acids across the mitochondrial membrane and in the modulation of the acyl coenzyme A/free coenzyme A ratio in various intracellular compartments. These processes activate several metabolic and cellular functions, and L-carnitine supplementation proved able to reduce insulin resistance and improve lipid metabolism, muscle tropism and erythrocyte rheology. Thus, L-carnitine may be considered a conditional drug rather than a conditional vitamin. Several studies examined the effects of L-carnitine supplementation in dialysis patients. Most of these studies were performed in hemodialysis patients, with controversial conclusions: positive results were countered by the finding of minimal or even no effects. The results were, moreover, often biased by the small number of patients, the lack of control groups, the difference in the measured biochemical data, and the lack of evaluation of patients' compliance and intestinal drug absorption. In addition, at present it is still uncertain what is the adequate level of plasma carnitine to be considered as the target of carnitine supplementation in dialysis patients. In peritoneal dialysis, the small number of published papers provided controversial results as well. Some authors observed significant lowering of apolipoprotein B without changes in cholesterol, triglycerides, free fatty acids, phospholipids and apoliporotein A after administration for short periods of high-dose oral L-carnitine to adult or, more often, pediatric patients. Others did not observe any positive effect. In vitro studies demonstrated that peritoneal dialysis solutions containing Lcarnitine cause less damage to mesothelial and endothelial cells than glucosebased- only peritoneal dialysis solutions. More recently, L-carnitine was used as an osmotic agent in experimental dialysis solutions for human use: the peritoneal ultrafiltration was similar to that induced by glucose solutions. In addition, intraperitoneal administration allows the measurement of absorbed carnitine, thus establishing a correct dose/effect ratio. Ongoing clinical studies in peritoneal dialysis patients on the metabolic effect of glucose plus carnitine solutions, as compared to standard solutions, seem to suggest positive results.

Pharmacological use of L-carnitine in uremic anemia: has its full potential been exploited?

Anemia is one of the most frequent complications of kidney failure and a common cause of morbidity in dialysis patients. A number of clinical studies have suggested that l-carnitine (LC), a naturally occurring compound involved in bioenergetic processes, may alleviate the anemia of hemodialysis patients. Since LC deficiency is commonly present in dialysis patients, LC has been described as a "conditional vitamin". However, the use of LC supplementation in dialysis remains controversial as well as its mode of action in preventing anemia. Recent literature shows that to fully exploit its pharmacological potential, LC may have to be administered at doses that achieve supra-physiological levels of LC in plasma and target organs. However, this concept has not been fully investigated in uremic patients. In this article, we will review the use of LC in dialysis patients, and provide a rationale for the anti-anemic action of LC based on biophysical, metabolic and antiapoptotic effects of this compound on erythropoiesis and the function of mature, circulating erythrocytes. The discussion will be focused on experimental and clinical data that support the concept that supra-physiological concentrations of LC may improve the anemic condition of dialysis patients, as would be expected from a "conditional drug" rather than a "conditional vitamin".

Free and total plasma malondialdehyde in chronic renal insufficiency and in dialysis patients.

BACKGROUND: Available data about oxidative status in patients with end-stage renal disease (ESRD) or on dialysis are contradictory. The present cross-sectional study aimed to investigate the role of renal insufficiency and dialysis on lipid peroxidation. To separate the effects of uraemia from dialysis-induced stress, we enrolled 26 patients with renal insufficiency on conservative treatment (ESRD), 23 on peritoneal dialysis (PD), 30 on haemodialysis (HD) and 30 controls. METHODS: Plasma malondialdehyde (MDA) levels, both total (tMDA) and free (fMDA), were measured as indexes of oxidative stress by gas chromatography-mass spectrometry. Bound MDA (bMDA) levels were calculated as the difference between tMDA and fMDA. RESULTS: Total and bMDA concentrations were significantly higher in patients than in controls (ESRD > HD > PD). In PD and HD patients, fMDA levels were similar and significantly higher than in ESRD. Multivariate analysis, with tMDA, fMDA and bMDA as dependent variables, showed similar and significant tMDA and bMDA relations with residual renal function (t = -2.160, P = 0.035) and albumin (t = -2.049, P = 0.045). Erythropoietin dose affected only fMDA values (t = -2.178, P = 0.034). CONCLUSIONS: Free and bMDA concentrations identified different MDA patterns. Bound MDA, not excreted by kidneys, accounts alone for high tMDA concentrations in ESRD patients, while both fMDA and bMDA contribute to tMDA values in dialysis patients. These findings show that increased tMDA could be indicative not only of recent lipid peroxidation, and they also highlight the importance of evaluating free, bound and total MDA in patients with reduced renal function in order to assess their oxidative status.

Two different modalities of iron gluconate i.v. administration: effects on iron, oxidative and inflammatory status in peritoneal dialysis patients.

BACKGROUND: Iron deficiency represents an important problem for dialysis patients. Oral iron administration is frequently ineffective, requiring parenteral administration, which may trigger severe side effects due to inflammation and/or peroxidation. The aim of the present study was to clarify the effects of parenteral iron administration on iron, inflammatory and oxidative status in peritoneal dialysis patients and compare two different modalities of injecting ferric gluconate intravenously. METHODS: Twenty peritoneal dialysis patients (10M/10F, mean age 60 +/- 16 years) were given i.v. iron gluconate (62.5 mg) both concentrated (1-2 min, PULSE) and diluted in 100 ml of glucose solution (30 min, SLOW). The interval between the first and second administration was 15-60 days. Blood cell count, serum iron, total iron binding capacity (TIBC), ferritin, C-reactive protein (CRP), reactive oxygen species (ROS) concentrations and total antioxidant capacity (TAC) were measured before iron infusion (T0), after 30 min (T1) and after 24 h (T2). RESULTS: No patient had clinical symptoms during or within an hour of iron administration. Serum transferrin was oversaturated in 25% of cases, no matter how iron was injected. Oxidative and inflammatory status parameters were not affected by iron administration: no difference in CRP, ROS concentrations or TAC was found at any time between PULSE and SLOW group. CONCLUSIONS: Our findings showed that neither inflammation nor peroxidation in peritoneal dialysis patients was clinically triggered by 62.5 mg i.v. iron infusion. Both modalities were equally safe. Therefore, in the absence of clinical side effects, PULSE intravenous administration, being cheaper and not so problematic for outpatients, is preferable to SLOW.

Erythrocyte ferritin concentration: analytical performance of the immunoenzymatic IMx-Ferritin (Abbott) assay.

Together with serum ferritin, erythrocyte ferritincan be a valuable diagnostic tool for evaluating the degree of impaired iron metabolism in different diseases. We collected peripheral blood samples from 64 subjects (22 healthy volunteers, 20 patients with hereditary hemochromatosis, and 22 patients on regular hemodialysis with secondary anemia) to evaluate whether an immunoenzymatic method generally used for serum ferritin can also be used to determine erythrocyte ferritin levels under various conditions of body iron status. Serum and erythrocyte ferritin levels were assayed in parallel using a microparticle enzyme immunoassay (MEIA) IMx-Ferritin kit and an IMx analyzer. The inter-assay imprecision of the serum and erythrocyte ferritin assays was 4.9% and 5.05%, the intra-assay imprecision was 2.2% and 2.3%, and the mean recovery was 102% (range 96-105%) and 101% (range 99-105%), respectively. Both serum and erythrocyte ferritin assays showed a detection limit of 1 microg/L and good linearity (R(2) = 0.99) in the intervals 13.9-443 and 3.9-135.6 microg/L, respectively. Our findings demonstrate that the IMx-Ferritin assay currently used to measure serum ferritin levels can also be adopted to measure erythrocyte ferritin insofar as it clearly discriminates high and low erythrocyte ferritin levels in cases of both iron overload and deficiency.

The efficacy and safety of once-weekly and once-fortnightly subcutaneous epoetin beta in peritoneal dialysis patients with chronic renal anaemia.

BACKGROUND: Reducing the dosage frequency of subcutaneous epoetin in peritoneal dialysis (PD) patients is convenient and should improve patient satisfaction and, possibly, compliance. We investigated if a weekly dosage of epoetin beta in PD patients safely maintained haemoglobin (Hb) concentrations equivalent to those obtained with previous twice- or thrice-weekly administration. In addition, we investigated if a fortnightly dosage of epoetin beta was safe and as effective as previous weekly administration. METHODS: After a 4 week run-in period, PD patients were switched to either weekly or fortnightly epoetin beta administration, depending on their previous treatment schedules, for 25 weeks. RESULTS: The per-protocol cohort included 128 patients, of whom 54 received epoetin beta once weekly and 74 once fortnightly. The mean change in Hb concentration from baseline over weeks 13-25 and the 90% confidence intervals (CIs) remained within the target range (10-12 g/dl) and specified equivalence (+/-0.75 g/dl) limits in the weekly (-0.34 g/dl; 90% CI: -0.14 to -0.54 g/dl) and fortnightly (-0.39 g/dl; 90% CI: -0.24 to -0.55 g/dl) cohorts. The mean change from baseline in the epoetin beta dose was 1.4 IU/kg/week (90% CI: -3.8 to 6.6 IU/kg/week; 2%) in the weekly cohort and 4.4 IU/kg/week (90% CI: 1.7-7.2 IU/kg/week; 13%) in the fortnightly cohort. Both treatment regimens were well tolerated. CONCLUSIONS: In stable PD patients switched from twice- or thrice-weekly to weekly epoetin beta treatment, Hb concentrations could be maintained within the specified range over 25 weeks without significant change in their mean epoetin beta doses. In patients switched from weekly to fortnightly treatment, Hb concentrations could also be maintained over 25 weeks. There was a small increase in the mean dose during this period, but >/=50% of patients could be maintained without dose increase. Reducing dosage frequency may improve compliance in PD patients who self-administer their epoetin.

The self-locating catheter: clinical experience and follow-up.

BACKGROUND: The self-locating catheter invented by Nicola Di Paolo has been used increasingly in Italy and elsewhere since 1994, with about a thousand patients currently implanted every year. Twelve grams of tungsten inserted into the tip of the conventional Tenckhoff catheter during extrusion does not significantly change its form, but suffices to keep the tip firmly in the Douglas cavity. OBJECTIVE: The aim of the present study was to confirm our preliminary results in a large population of peritoneal dialysis patients. SETTING: 16 Italian nephrology departments. RESULTS: In addition to confirming the validity of the new catheter, the present results show that patients with the new catheter have fewer episodes of peritonitis, tunnel infection, cuff extrusion, catheter malfunction, obstruction, and leakage. CONCLUSION: The present multicenter control study confirms preliminary results and demonstrates that complications of peritoneal dialysis, such as cuff extrusion, infection, peritonitis, early leakage, and obstruction, are statistically less frequent in patients with self-locating catheters than in patients with classic Tenckhoff catheters.

Epidemiology of GB virus c/hepatitis g virus infection in patients on peritoneal dialysis.

BACKGROUND: A new genus in the family Flaviviridae has recently been discovered; it has provisionally been designated GBV-C/HGV. As determined by virologic techniques [reverse-transcription polymerase chain reaction (RT-PCR)], infection with GBV-C/HGV is frequent in renal transplant (RT) recipients and in patients on chronic hemodialysis (HD). The epidemiology of GBV-C/HGV infection in patients on peritoneal dialysis is scarce and mostly based on RT-PCR technology. PURPOSE: We report on the prevalence (as detected by serologic and virologic techniques) and the risk factors for GBV-C/HGV infection in a cohort of patients on continuous ambulatory peritoneal dialysis (CAPD). We also tested a control group of blood donors. METHODS: Infection by GBV-C/HGV was assessed by serologic and virologic techniques. Cases of GBV-C/HGV viremia (GBV-C/HGV RNA) were detected by RT-PCR. Antibodies to the envelope protein of GBV-C/HGV (anti-E2 GBV-C/HGV antibody) were analyzed by serologic methods. RESULTS: We found a high frequency [17/85 (20%)] of GBV-C/HGV. The rates of GBV-C/HGV viremia and anti-E2 GBV-C/HGV positivity were 10.5% (9/85) and 10.5% (9/85) respectively. In most patients [17/18 (94%)], the presence of anti-E2 GBV-C/HGV antibody was associated with clearance of GBV-C/HGV from serum. No relationship was noted between anti-E2 GBV-C/HGV antibody (or GBV-C/ HGV viremia) and age, sex, race, time on dialysis, anti-HCV antibody, HBsAg status, and anti-HIV positivity. The frequency of GBV-C/HGV infection in CAPD patients was much higher than that in blood donors, even if the difference did not approach statistical significance. No associations between GBV-C/HGV positivity and biochemical liver tests [aminotransferase and gamma glutamyl transpeptidase (GGT)] were apparent. CONCLUSIONS: Infection by GBV-C/HGV as detected by RT-PCR and anti-E2 antibody was common in patients on CAPD and in controls alike. No association was seen between GBV-C/HGV and various demographic or clinical factors. The clinical significance of GBV-C/HGV in CAPD remains unclear. Larger investigations are in progress.

Outcome of peritoneal dialysis in cirrhotic patients with chronic renal failure.

BACKGROUND: Results of peritoneal dialysis (PD) in cirrhotic patients with renal failure are debated. The aim of the present study is to assess the outcome of PD patients with liver cirrhosis. METHODS: A retrospective study based on clinical records was performed in 21 cirrhotic and 41 PD patients without liver disease followed up at our PD unit. RESULTS: Five-year patient and technique survival were similar in the two groups. Seven cirrhotic patients (33%) died of liver failure (5 patients), liver cancer (1 patient), and peritonitis (1 patient). Ten controls (24%) died of cardiovascular complications (6 patients), pneumonia (1 patient), cachexia (1 patient), and unknown reasons (2 patients). Six cirrhotic patients discontinued PD therapy after 44.3 +/- 24.7 months because of inadequate dialysis (2 patients), sclerosing peritonitis (2 patients), dementia (1 patient), or patient choice (1 patient). Twelve controls discontinued PD therapy after 33 +/- 25.9 months because of peritonitis (6 patients), exit-site infection (1 patient), inadequate peritoneal clearance (3 patients), catheter malfunction (1 patient), and patient request (1 patient). The peritonitis rate was 0.31 episodes/y in cirrhotic patients and 0.53 episodes/y in controls (P = not significant). The hospitalization rate was similar (16.5 d/y in cirrhotic patients, 15.4 d/y in controls). In cirrhotic patients, complications were leakage (3 patients), symptomatic hypotension (5 patients), anemia (5 patients), severe malnutrition (14 patients), sclerosing peritonitis (2 patients), and hepatic encephalopathy (3 patients). CONCLUSION: The outcome of PD and risk for bacterial peritonitis or other dialysis complications are not worsened by the presence of liver cirrhosis.