Michel Aparicio

Intradialytic Parenteral Nutrition Does Not Improve Survival in Malnourished Hemodialysis Patients: A 2-Year Multicenter, Prospective, Randomized Study

Although intradialytic parenteral nutrition (IDPN) is a method used widely to combat protein-calorie malnutrition in hemodialysis patients, its effect on survival has not been thoroughly studied. We conducted a prospective, randomized trial in which 186 malnourished hemodialysis patients received oral nutritional supplements with or without 1 year of IDPN. IDPN did not improve 2-year mortality (primary end point), hospitalization rate, Karnofsky score, body mass index, or laboratory markers of nutritional status. Instead, both groups demonstrated improvement in body mass index and the nutritional parameters serum albumin and prealbumin (P < 0.05). Multivariate analysis showed that an increase in prealbumin of >30 mg/L within 3 months, a marker of nutritional improvement, independently predicted a 54% decrease in 2-year mortality, as well as reduced hospitalizations and improved general well-being as measured by the Karnofsky score. Therefore, although we found no definite advantage of adding IDPN to oral nutritional supplementation, this is the first prospective study demonstrating that an improvement in prealbumin during nutritional therapy is associated with a decrease in morbidity and mortality in malnourished hemodialysis patients.

Eleven reasons to control the protein intake of patients with chronic kidney disease

For many years patients with chronic kidney disease have been advised to control the protein content of their diet. This advice has been given on the basis of a number of reported metabolic effects of lowering protein intake, such as lowering serum urea nitrogen levels, improving phosphocalcic metabolism and insulin resistance and, more recently, ameliorating proteinuria (independent of antiproteinuric medications). The effects on the progression of kidney disease, although spectacular in experimental studies, have been less convincing in humans. It is possible that flawed design of clinical trials is responsible for this discrepancy. In this Review, we comment on experimental findings that indicate that limiting protein intake protects the kidney and ameliorates uremic symptoms, outline how the body adapts to a reduction in protein intake, and describe the metabolic benefits to the patient. We then review the evidence from randomized controlled trials and meta-analyses that pertains to the effects of low-protein diets in adults with chronic kidney disease.

Plasma and Urinary Amino Acid Metabolomic Profiling in Patients with Different Levels of Kidney Function

BACKGROUND AND OBJECTIVES Patients with CKD display altered plasma amino acid profiles. This study estimated the association between the estimated GFR and urinary and plasma amino acid profiles in CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Urine and plasma samples were taken from 52 patients with different stages of CKD, and plasma samples only were taken from 25 patients on maintenance hemodialysis. Metabolic profiling was performed by liquid chromatography coupled with tandem mass spectrometry after phenylisothiocyanate derivatization. RESULTS Most plasma amino acid concentrations were decreased in hemodialysis patients, whereas proline, citrulline, asparagine, asymmetric dimethylarginine, and hydroxykynurenine levels were increased (P<0.05). Both plasma levels and urinary excretion of citrulline were higher in the group of patients with advanced CKD (CKD stages 2 and 3 versus CKD stages 4 and 5; in plasma: 35.9±16.3 versus 61.8±23.6 µmol/L, P<0.01; in urine: 1.0±1.2 versus 7.1±14.3 µmol/mol creatinine, P<0.001). Plasma asymmetric dimethylarginine levels were higher in advanced CKD (CKD stages 2 and 3, 0.57±0.29; CKD stages 4 and 5, 1.02±0.48, P<0.001), whereas urinary excretion was lower (2.37±0.93 versus 1.51±1.43, P<0.001). Multivariate analyses adjusting on estimated GFR, serum albumin, proteinuria, and other covariates revealed associations between diabetes and plasma citrulline (P=0.02) and between serum sodium and plasma asymmetric dimethylarginine (P=0.03). Plasma tyrosine to phenylalanine and valine to glycine ratios were lower in advanced CKD stages (P<0.01). CONCLUSION CKD patients have altered plasma and urinary amino acid profiles that are not corrected by dialysis. Depending on solutes, elevated plasma levels were associated with increased or decreased urinary excretion, depicting situations of uremic retention (asymmetric dimethylarginine) or systemic overproduction (citrulline). These results give some insight in the CKD-associated modifications of amino acid metabolism, which may help improve their handling.

Factors influencing survival in hemodialysis patients aged older than 75 years: 2.5-year outcome study

The incidence of malnutrition is widely held to be greater in the elderly, but this specific factor has not been extensively studied in elderly dialysis patients. In a 30-month follow-up prospective study, we evaluated the role of nutrition on the outcome of 290 stable hemodialysis (HD) outpatients aged older than 75 years followed up in 20 French HD centers (167 men, 123 women; age, 79.8 +/- 4.2 years; previous time on dialysis, 41 +/- 38 months). On the same day in January 1996, predialysis and postdialysis blood samples were collected according to recommended procedures for dialysis quantification. Normalized protein catabolic rate, dialysis adequacy parameters, and estimation of lean body mass (LBM; expressed as observed/expected LBM values [obs/exp LBM]) were computed from predialysis and postdialysis urea and creatinine levels. Overall survival rates were 80% and 65% after 1 and 2 years of follow-up, respectively, and were significantly less in patients with the lower quartile of obs/exp LBM. In univariate analysis using the Cox proportional hazards model, survival was significantly influenced by age, albumin level, prealbumin level, body mass index, and diabetes, but not by sex, Kt/V, duration of dialysis, cholesterol level, hemoglobin level, or obs/exp LBM. In multivariate analysis, no variable remained significant. Cardiovascular mortality accounted for 52.1% of the patient deaths. We conclude that in elderly HD patients, malnutrition influences overall survival despite adequate dialysis treatment.

ACID-BASE IN RENAL FAILURE: Acidosis and Nutritional Status in Hemodialyzed Patients

In a cross‐sectional study of more than 30% of French dialysis patients (N = 7,123), we evaluated the relationships between predialysis plasma bicarbonate concentration and nutritional markers. Data including age, gender, cause of end‐stage renal disease (ESRD), time on dialysis, body mass index (BMI), blood levels of midweek predialysis albumin, prealbumin, and bicarbonate were collected. Normalized protein catabolic rate (nPCR), dialysis adequacy parameters, and estimation of lean body mass (LBM) were computed from pre‐ and postbicarbonate‐dialysis urea and creatinine levels according to the classical formulas of Garred. Average values (±1 SD) were age 61 ± 16 years, BMI 23.3 ± 4.6 kg/m2, dialysis time 12.4 ± 2.7 h/week, HCO3 22.8 ± 3.5 mmol/L, albumin 38.7 ± 5.3 g/L, prealbumin 340 ± 90 mg/L, Kt/V 1.36 ± 0.36, nPCR 1.13 ± 0.32 g/kg BW/day, and LBM 0.86 ± 0.21% of ideal LBM. A highly significant negative correlation was observed between predialysis bicarbonate levels (within a range of 16–30 mmol/L, 95% of this population) and nPCR confirmed by analysis of variance using bicarbonate classes (p < 0.0001). Bicarbonate was also negatively correlated with albumin, prealbumin, BMI, and LBM. No relationship was noted between bicarbonate and Kt/V despite a positive correlation between Kt/V and nPCR. It is likely that a persistent acidosis observed despite standard bicarbonate dialysis was caused by a high dietary protein intake which results in an increased acid load, but also overcomes the usual catabolic effects of acidosis.

In Advanced Renal Failure, Dietary Phosphorus Restriction Reverses Hyperparathyroidism Independent of Changes in the Levels of Calcitriol

Dr. M. Aparicio, Service de Néphrologie, Hôpital Pellegrin, F-33076 Bordeaux (France) Dear Sir, In patients with chronic renal failure (CRF), the restriction of dietary phosphorus results in serum phosphate reduction and improvement of secondary hyperparathyroidism. These data are usually ascribed to a concomitant increase in the production of calcitriol [1, 2]. However, it has been reported in patients with advanced renal failure [3] and in severe experimental renal failure [4, 5] that phosphorus restriction reversed hyperparathyroidism without significant change in plasma calcitriol levels. The aim of the present investigation was to examine the effects of phosphorus restriction on calcium phosphate metabolism and more especially on plasma calcitriol levels. Our study comprised 23 patients with advanced CRF (GFR: 11.63 ± 3.9 ml/min per 1.73 m2) receiving a diet providing daily, per kilogram body weight, 0.4 g protein of vegetable origin, 3-5 mg of inorganic phosphorus and 35 kcal. The diet was supplemented with ketoanalogues (CSW 20/4, Clintec, France) and with calcium carbonate to keep unchanged their habitual calcium intake: 758 ± 124 mg/day at the start of the study. No other phosphate binder was prescribed. The patients additionally received a multivitamin preparation providing 1,000 IU of vitamin D2 per day. Serum calcium, serum phosphorus, serum bicarbonate, PTH activity (intact hormone), calcitriol, alkaline phosphatase and osteocalcin were measured at the start of the study and 3 months later. The evolution of renal function was assessed by 5lCr-EDTA clearances. Results were expressed as mean ± standard deviation (SD). Student’s t test was used for paired data. Multiple regression analysis was applied to analyze the relationship between the concentrations of PTH and calcitriol and the different variables. At the start of the study, PTH concentration was directly correlated with GFR (r = 0.46; p = 0.04), with inorganic phosphorus (r = 0.59; p = 0.01) and with osteocalcin (r = 0.5; p = 0.02). On the other hand, PTH did not correlate with either calcitriol or calcium concentrations, no correlation was found between calcitriol and the other biochemical variables.

Granulocyte Activation and Adhesion Molecules During Hemodialysis With Cuprophane and a High-Flux Biocompatible Membrane

Hemodialysis with complement-activating membranes, such as cuprophane, induces neutropenia and expression of the granulocyte adhesion receptor Mac-1 (CD11b/CD18), while hemodialysis with noncomplement-activating membranes does not. Increased expression of CD11b by neutrophils may mediate cuprophane-induced leukopenia. However, the rebound granulocytosis that follows leukopenia is not fully understood. Ten patients on regular hemodialysis were included in a cross-over study. Hemodialysis was performed for 2 weeks with cuprophane and 2 weeks with polyamide, a high-flux noncomplement-activating membrane. At the end of each period, the following parameters were determined during a hemodialysis session: C5a concentration by enzyme immunoassay and the neutrophil expression of CD11b, LFA-1 (CD11a/CD18), and the antigen recognized by MoF11 (MoF11 Ag), a monoclonal antibody that recognizes activated neutrophils, by immunofluorescence flow cytometry. Hemodialysis with cuprophane induced an increase in C5a concentration and in the expression of CD11b and MoF11 Ag, which were maximal after 15 minutes of hemodialysis, at the nadir of neutropenia. CD11b expression was maintained throughout hemodialysis, despite the reversal of neutropenia. Conversely, after peak expression, C5a and MoF11 Ag decreased as the neutrophil count increased to baseline values. Polyamide hemodialysis did not induce variations in C5a concentration, nor in CD11b and MoF11 Ag expression. CD11a/CD18 expression remained stable during hemodialysis with both membrane types. Neutrophil activation, as determined by MoF11 Ag expression, was correlated with the evolution of neutrophil count and C5a concentration during cuprophane hemodialysis, while CD11b expression was not correlated with neutrophil count throughout dialysis. A decrease in neutrophil activation could explain in part the detachment of neutrophils previously bound to endothelium and, therefore, the reversal of neutropenia.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of red blood cell lipoperoxidation in hemodialysed patients during erythropoietin therapy supplemented or not with iron.

To investigate the effects of erythropoietin (rHuEPO) therapy supplemented or not with iron on hemolysis in hemodialysed patients (HD) we evaluated lipoperoxidation (LPO) by assaying (i) the red blood cell (RBC) antioxidant enzymatic system including superoxide dismutase (SOD), glutathione peroxidase, and catalase (Cat), (ii) RBC polyunsaturated fatty acids (PUFA) and (iii) malondialdehyde (MDA). Group 1 included 12 HD patients, group 2 had 7 HD patients with iron supplementation, group 3 comprised 12 HD patients with rHuEPO therapy and group 4 included 9 HD patients with both iron and rHuEPO therapies. No LPO was found in group 1 as regards MDA and PUFA levels. However, SOD and Cat activities were significantly elevated as compared to controls (p < 0.001). In the second group, a significant decrease in PUFA percentage was observed, particularly in 20:4(n-6) and 22:4(n-6) (the main ones involved in LPO) as compared to the other groups, whereas total MDA level was higher than that of the other groups. Similarly a decreased SOD activity was observed as compared to group 1 (p < 0.001), indicating its inactivation subsequent to an hyperproduction of reactive oxygen species through iron injection. In groups 3 and 4 no change was observed in MDA levels or PUFA percentages indicating no LPO. However, marked differences were observed in the enzymatic defense system. Particularly in group 3, SOD and Cat activities decreased when compared to group 1 (p < 0.001) whereas the association of erythropoietin and iron (group 4) increased the three enzymatic activities (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Antioxidant Effects of a Supplemented Very Low Protein Diet in Chronic Renal Failure

Increased peroxidation of lipids in red blood cells (RBC) in patients with advanced chronic renal failure (CRF) reflects increased generation of reactive oxygen species (ROS), which may contribute to the metabolic damage induced by CRF and to its progression. We have evaluated parameters indicative of lipoperoxidation (LPO) of RBC at baseline in patients with CRF compared to controls, and the effects of a very low protein diet supplemented with amino and keto acids and vitamins A, C, E (VLPD) over a 6-month period. The presence of peroxidation damage in CRF patients before the administration VLPD was demonstrated by elevated levels of free malondialdehyde (MDA) (p < .0003) and decreased levels of polyunsaturated fatty acids (PUFA), particularly C20:4 (p < .001), C22:4 (p < .0001) and C22:5 (p < .0001) when compared to controls. Similarly, RBC vitamin E content was significantly decreased (p < .0001) while enzymatic activities were unalterated. VLPD reduced erythrocyte LPO as suggested by (a) decreased levels of free and total RBC MDA (p < .003 and p < .03, respectively), (b) increased levels of PUFA, particularly C22:4 and C22:5 (p < .003 and p < .03, respectively), and (c) increased levels of vitamins A and E (p < .001 and p < .04, respectively) as compared to prediet results. Antioxidant enzyme activities were not modified. These results suggest that VLPD has a protective role against LPO of erythrocytes in patients with CRF.

Keto Acid Therapy in Predialysis Chronic Kidney Disease Patients: Final Consensus

*Department of Nephrology, Centre Hospitalier Universitaire et Universitea Bordeaux II, Bordeaux, France.†Nephrology Dialysis and Renal Transplantation Unit, University Hospital ‘‘S. Giovanni di Dio e Ruggi d’Aragona’’, Salerno, Italy.‡Department of Nephrology, Hopital Pellegrin, Bordeaux, France.§Aurad-Aquitaine, Gradignan, France.{Nephrology Unit, Department of Internal Medicine, University of Pisa, Pisa, Italy.**Division of Nephrology, Department of Internal Medicine, Istanbul School of Medicine, Istanbul University, Capa, Istanbul, Turkey.††Departement de Nephrologie, H^opital E. Herriot, Lyon Cedex, France.‡‡‘‘Dr. Carol Davila’’ Teaching Hospital of Nephrology, Bucharest, Romania.§§Chinese Society of Nephrology, International Society of Nephrology, and Division of Nephrology, Huashan Hospital, Fudan University,Shanghai, People’s Republic of China.{{Division of Nephrology, Baylor College of Medicine, Houston, Texas.***Department of Nephrology, Institute for Clinical and Experimental Medicine and Institute for Postgradual Education, Prague, CzechRepublic.‡‡‡Dialysis Center No. 9, Health Care Service PLC, Euro Care Hungary, Szekesfehervar, Hungary.§§§The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China.FinancialDisclosure:TheauthorsbelongtotheFreseniusKabiKetoanalogueAdvisoryBoardandparticipatedinthe5thInternationalAdvisoryBoardMeeting,Vevey,Switzerland,May29,2010.ConsultancyfeesandtravelgrantswerereceivedfromFreseniusKabi.Thearticleswerepub-lished as part of a supplement sponsored by an unrestricted educational grant from Fresenius Kabi.AddressreprintrequeststoPhilippeChauveau,ServicedeNephrologie,HopitalPellegrin,CHUdeBordeaux,PlaceAmelieRabaLeon,33000,Bordeaux, France.