Mechanisms of Crystalloid versus Colloid Osmosis across the Peritoneal Membrane.

Background Osmosis drives transcapillary ultrafiltration and water removal in patients treated with peritoneal dialysis. Crystalloid osmosis, typically induced by glucose, relies on dialysate tonicity and occurs through endothelial aquaporin-1 water channels and interendothelial clefts. In contrast, the mechanisms mediating water flow driven by colloidal agents, such as icodextrin, and combinations of osmotic agents have not been evaluated.Methods We used experimental models of peritoneal dialysis in mouse and biophysical studies combined with mathematical modeling to evaluate the mechanisms of colloid versus crystalloid osmosis across the peritoneal membrane and to investigate the pathways mediating water flow generated by the glucose polymer icodextrin.ResultsIn silico modeling and in vivo studies showed that deletion of aquaporin-1 did not influence osmotic water transport induced by icodextrin but did affect that induced by crystalloid agents. Water flow induced by icodextrin was dependent upon the presence of large, colloidal fractions, with a reflection coefficient close to unity, a low diffusion capacity, and a minimal effect on dialysate osmolality. Combining crystalloid and colloid osmotic agents in the same dialysis solution strikingly enhanced water and sodium transport across the peritoneal membrane, improving ultrafiltration efficiency over that obtained with either type of agent alone.Conclusions These data cast light on the molecular mechanisms involved in colloid versus crystalloid osmosis and characterize novel osmotic agents. Dialysis solutions combining crystalloid and colloid particles may help restore fluid balance in patients treated with peritoneal dialysis.

Can one long peritoneal dwell with icodextrin replace two short dwells with glucose?

Background: Due to the slower dissipation of the osmotic gradient, icodextrin-based solutions, compared to glucose-based solutions, can improve water removal. We investigated scenarios where one icodextrin-based long dwell (Extraneal) replaced two glucose-based exchanges. Methods: The three-pore model with icodextrin hydrolysis was used for numerical simulations of a single exchange to investigate the impact of different peritoneal dialysis schedules on fluid and solute removal in patients with different peritoneal solute transfer rates (PSTRs). We evaluated water removal (ultrafiltration, UF), absorbed mass of glucose (AbsGluc) and carbohydrates (AbsCHO, for glucose and glucose polymers), ultrafiltration efficiency (UFE = UF/AbsCHO) per exchange, and specified dwell time, and removed solute mass for sodium (ReNa), urea (ReU), and creatinine (ReCr) for a single peritoneal exchange with 7.5% icodextrin (Extraneal®) and glucose-based solutions (1.36% and 2.27%) and various dwell durations in patients with fast and average PSTRs. Results: Introducing 7.5% icodextrin for the long dwell to replace one of three or four glucose-based exchanges per day leads to increased fluid and solute removal and higher UF efficiency for studied transport groups. Replacing two glucose-based exchanges with one icodextrin exchange provides higher or similar water removal and higher daily sodium removal but slightly lower daily removal of urea and creatinine, irrespective of the transport type present in the case of reference prescription with three and four daily exchanges. Conclusion: One 7.5% icodextrin can replace two glucose solutions. Unlike glucose-based solutions, it resulted only in minor differences between PSTR groups in terms of water and solute removal with UFE remaining stable up to 16 h.

Genetic damage in patients with chronic kidney disease, peritoneal dialysis and haemodialysis: a comparative study.

Patients with chronic kidney disease (CKD) have signs of genomic instability and, as a consequence, extensive genetic damage, possibly due to accumulation of uraemic toxins, oxidative stress mediators and other endogenous substances with genotoxic properties. We explored factors associated with the presence and background levels of genetic damage in CKD. A cross-sectional study was performed in 91 CKD patients including pre-dialysis (CKD patients; n = 23) and patients undergoing peritoneal dialysis (PD; n = 33) or haemodialysis (HD; n = 35) and with 61 healthy subjects, divided into two subgroups with the older group being in the age range of the patients, serving as controls. Alkaline comet assay and cytokinesis-block micronucleus assay in peripheral blood lymphocytes were used to determine DNA and chromosome damage, respectively, present in CKD. Markers of oxidative stress [malondialdehyde (MDA), advanced glycation end products (AGEs), thiols, advanced oxidation protein products and 8-hydroxy-2'-deoxyguanosine] and markers of inflammation (C-reactive protein, interleukin-6 and tumour necrosis factor alpha) were also measured. Micronucleus (MN) frequency was significantly higher (P < 0.05) in the CKD group (46±4‰) when compared with the older control (oC) group (27.7±14). A significant increase in MN frequency (P < 0.05) was also seen in PD patients (41.9±14‰) versus the oC group. There was no statistically significant difference for the HD group (29.7±15.6‰; P = NS) versus the oC group. Comet assay data showed a significant increase (P < 0.001) of tail DNA intensity in cells of patients with CKD (15.6±7%) with respect to the total control (TC) group (11±1%). PD patients (14.8±7%) also have a significant increase (P < 0.001) versus the TC group. Again, there was no statistically significant difference for the HD group (12.5±3%) compared with the TC group. Patients with MN values in the upper quartile had increased cholesterol, triglycerides, AGEs and MDA levels and lower albumin levels. Multiple logistic regression analysis showed that male gender, diabetes and treatment modality were independently associated with higher levels of DNA damage. Our results suggest that oxidative stress, diabetes, gender and dialysis modality in CKD patients increased DNA and chromosome damage. To confirm these data, prospective clinical trials need to be performed.

Modelling of icodextrin hydrolysis and kinetics during peritoneal dialysis.

In peritoneal dialysis, ultrafiltration is achieved by adding an osmotic agent into the dialysis fluid. During an exchange with icodextrin-based solution, polysaccharide chains are degraded by α-amylase activity in dialysate, influencing its osmotic properties. We modelled water and solute removal taking into account degradation by α-amylase and absorption of icodextrin from the peritoneal cavity. Data from 16 h dwells with icodextrin-based solution in 11 patients (3 icodextrin-exposed, 8 icodextrin-naïve at the start of the study) on dialysate volume, dialysate concentrations of glucose, urea, creatinine and α-amylase, and dialysate and blood concentrations of seven molecular weight fractions of icodextrin were analysed. The three-pore model was extended to describe hydrolysis of icodextrin by α-amylase. The extended model accurately predicted kinetics of ultrafiltration, small solutes and icodextrin fractions in dialysate, indicating differences in degradation kinetics between icodextrin-naïve and icodextrin-exposed patients. In addition, the model provided information on the patterns of icodextrin degradation caused by α-amylase. Modelling of icodextrin kinetics using an extended three-pore model that takes into account absorption of icodextrin and changes in α-amylase activity in the dialysate provided accurate description of peritoneal transport and information on patterns of icodextrin hydrolysis during long icodextrin dwells.

Intima media thickness in children undergoing dialysis.

BACKGROUND: Uremic vasculopathy, including vascular calcification, increases the risk for cardiovascular disease and mortality in chronic kidney disease (CKD) patients. We have investigated the prevalence and factors associated with vasculopathy in children undergoing peritoneal dialysis (PD) or hemodialysis (HD) in a single center. METHODS: Common carotid intima media thickness (cIMT) and its relation with demographics, biochemical parameters and medication was analyzed in 60 patients (mean age 12.9 ± 3.4 years; 27 girls) treated with PD (n = 31) or HD (n = 29) for 34 ± 34 months. Patients were divided into two groups: normal cIMT and increased cIMT. RESULTS: Mean levels of calcium, phosphate and calcium/phosphate product were in the normal range, the but parathyroid hormone level, 729 ± 670 pg/mL, was higher than the National Kidney Foundation Kidney Disease Outcome Quality Iniative (K/DOQI) recommendations. Twenty-nine patients had increased cIMT, which was associated with time on dialysis of >2 years, hypercalcemia, higher daily dose of calcitriol and HD (vs. PD). In the multivariate analysis, accounting for time on dialysis, HD persisted as a risk for increased cIMT. CONCLUSIONS: The prevalence of increased cIMT in children on dialysis is similar to that reported in adults with CKD and increased with time on dialysis. HD was associated with increased cIMT, independently of time on dialysis; however, the results should be interpreted with caution due to the possible impact of confounding factors. These results underline the need to monitor and, if possible, prevent and treat increased cIMT in children on dialysis.

Sex Modulates Cardiovascular Effects of Icodextrin-Based Peritoneal Dialysis Solutions.

Background/Aims: Some previous observations have noted that after six months of peritoneal dialysis (PD) treatment with icodextrin solutions, blood pressure (BP) and NT-proBNP tend to return to baseline values. This may be due to accumulation of icodextrin products that exert a colloid osmotic effect, which drives water into the bloodstream, causing the rise in blood pressure. Since icodextrin is metabolized by α-Amylase and its gene copies are lower in females than in males, we hypothesized icodextrin metabolites reach higher concentrations in females and that cardiovascular effects of icodextrin are influenced by sex. Methods: Secondary analysis of a RCT comparing factors influencing fluid balance control in diabetic PD patients with high or high average peritoneal transport receiving icodextrin (n = 30) or glucose (n = 29) PD solutions. Serum icodextrin metabolites, osmolality, body composition and Inferior Vena Cava (IVC) diameter were measured at baseline, and at 6 and 12 months of follow-up. Results: After six months of treatment, icodextrin metabolites showed higher levels in females than in males, particularly G5-7 and >G7, serum osmolality was lower in females. In spite of reduction in total and extracellular body water, ultrafiltration (UF) was lower and IVC diameter and BP increased in females, suggesting increment of blood volume. Conclusion: Females undergoing PD present with higher levels of icodextrin metabolites in serum that may exert an increased colloid-osmotic pressure followed by less UF volumes and increment in blood volume and blood pressure. Whether this could be due to the lesser number of α-Amylase gene copies described in diabetic females deserves further investigation.

Long Peritoneal Dialysis Dwells With Icodextrin: Kinetics of Transperitoneal Fluid and Polyglucose Transport.

Background and objective: During peritoneal dialysis (PD), the period of effective net peritoneal ultrafiltration during long dwells can be extended by using the colloidal osmotic agent icodextrin but there are few detailed studies on ultrafiltration with icodextrin solution exceeding 12 h. We analyzed kinetics of peritoneal ultrafiltration in relation to icodextrin and its metabolites for 16-h dwells with icodextrin. Design, setting, participants, and measurements: In 20 clinically stable patients (mean age 54 years; 8 women; mean preceding time on PD 26 months), intraperitoneal dialysate volume (VD) was estimated from dilution of 125I-human serum albumin during 16-h dwell studies with icodextrin 7.5% solution. Sodium was measured in dialysate and plasma. In 11 patients, fractional absorption of icodextrin from dialysate, dialysate, and plasma amylase and high and low (Mw <2 kDa) Mw icodextrin fractions were analyzed. Results: Average VD increased linearly with no difference between transport types. At 16 h, the cumulative net ultrafiltration was 729 ± 337 ml (range -18 to 1,360 ml) and negative in only one patient. Average transcapillary ultrafiltration rate was 1.40 ± 0.36 ml/min, and peritoneal fluid absorption rate was 0.68 ± 0.38 ml/min. During 16 h, 41% of the initial mass of icodextrin was absorbed. Plasma sodium decreased from 138.7 ± 2.4 to 136.5 ± 3.0 mmol/L (p < 0.05). Dialysate glucose G2-G7 oligomers increased due to increase of G2-G4 metabolites while G6-G7 metabolites and higher Mw icodextrin fractions decreased. In plasma maltose and maltotriose (G2-G3 metabolites) increased while higher Mw icodextrin oligomers were almost undetectable. Dialysate amylase increased while plasma amylase decreased. Conclusions: Icodextrin resulted in linear increase of VD with sustained net UF lasting 16 h and with no significant difference between peritoneal transport types. In plasma, sodium and amylase declined, G2-G3 increased whereas larger icodextrin fractions were not detectable. In dialysate, icodextrin mass declined due to decrease of high Mw icodextrin fractions while low Mw metabolites, especially G2-G3, increased. The ability of icodextrin to provide sustained UF during very long dwells - which is usually not possible with glucose-based solutions - is especially important in anuric patients and in patients with fast peritoneal transport.

Longitudinal relationships between fluid status, inflammation, urine volume and plasma metabolites of icodextrin in patients randomized to glucose or icodextrin for the long exchange.

BACKGROUND: Randomized trials have shown that icodextrin reduces the volume of extra-cellular fluid (ECFv) with variable effects on residual renal function. To explore this fluid shift and its possible mechanisms in more detail, prospectively collected data from one such trial, including measures of inflammation (C-reactive protein, tumour necrosis factor-alpha, albumin and low and high molecular weight hyaluronan) ANP (atrial naturetic peptide), an indirect marker of intra-vascular volume, plasma concentrations of icodextrin metabolites and alpha-amylase activity were analysed. METHODS: 50 patients were randomized to either 2.27% glucose or icodextrin (n = 28) for a long exchange following a month run in. Blood samples were obtained at -1, 0, 3 and 6 months, coincident with measurements of urine volume and fluid status. RESULTS: In both randomized groups, a significant correlation between the fall in ECFv and the decline in urine volume was observed (P = 0.001), although the relative drop in urine volume for patients randomized to icodextrin tended to be less. At baseline, ANP was higher in patients with proportionately more ECFv for a given body water or height. Icodextrin patients had non-significantly higher ANP levels at baseline, whereas by 3 (P = 0.026) and 6 months (P = 0.016) these differed between groups due to divergence. There was a correlation between increasing ANP and reduced ECF at 3 months, r = -0.46, P = 0.007, in patients randomized to icodextrin, but not glucose. There were no relationships between fluid status and any inflammatory markers at any point of the study, with the exception of albumin at baseline, r = -0.39, P = 0.007. Amylase activities at -1 month and baseline were highly correlated, r = 0.89, P < 0.0001. Within patients, concentrations of icodextrin metabolites were highly correlated; the only predictor of between-patient variability on multivariate analysis was body weight. There was no relationship between plasma concentrations of icodextrin metabolites and any of the other clinical parameters, including change in daily ultrafiltration, urine volume, fluid or inflammatory status. CONCLUSIONS: This analysis supports observational data that changes in fluid status are associated with changes in urine volume. Icodextrin was not associated with a greater fall in urine output despite its larger effect on ECFv. Changes in fluid status could not be explained or did not appear to influence systemic inflammation. Nor can they be explained by individual variability in plasma concentrations of icodextrin that are in turn inversely proportional to the volume of distribution.

Rate of synthetic oligosaccharide degradation as a novel measure of amylase activity in peritoneal dialysis patients.

BACKGROUND: Plasma alpha-amylase activity is elevated in uremic patients but lower in peritoneal dialysis (PD) patients using icodextrin in comparison to healthy controls. We studied the rate by which an exogenous oligosaccharide (maltoheptaose; G7) is degraded ex vivo by amylase in plasma from PD patients treated with glucose or icodextrin PD solutions. METHODS: Plasma amylase (pancreatic and total) activity and concentration were measured in 11 controls and in PD patients treated with glucose (n = 11) and icodextrin (n = 19). The plasma was spiked with G7 and/or synthetic amylase and the metabolites formed were measured by HPLC following incubation at 37 degrees C for 4 hours. RESULTS: The relationship between amylase activity and amylase concentration was similar in all patients and controls. The G7 degradation rate was slower in plasma from icodextrin patients but it was also reduced in patients using glucose compared with the controls, in spite of the higher amylase activity in the glucose group. Normalization (by spiking) of patient plasma with porcine amylase increased but did not normalize the speed of G7 degradation. At a given endogenous amylase activity level, the efficiency of G7 degradation was similar for both patient groups. CONCLUSIONS: An ex vivo model to study the relationship between amylase activity and the actual rate of carbohydrate (represented by G7) breakdown was developed and showed that PD patients using glucose and icodextrin degrade G7 at a slower speed than controls. This suggests that amylase-mediated carbohydrate metabolism is reduced in PD patients. Further clinical studies are needed to confirm if these findings hold true also in other groups of uremic patients with varying degrees of kidney failure, as well as in patients undergoing hemodialysis.

Copeptin Plasma Levels are Associated with Decline of Renal Function in Patients with Type 2 Diabetes Mellitus.

BACKGROUND: Chronic kidney disease (CKD) is a leading complication of type 2 diabetes mellitus (T2DM) and is considered as a public health problem. Copeptin is a surrogate marker of arginine vasopressin (AVP) system and is proposed as a biomarker of decline renal function. OBJECTIVE: Evaluate whether plasma copeptin levels may be used as a biomarker of decline renal function in patients with T2DM. RESEARCH DESIGN AND METHODS: A total of 480 patients with T2DM and different stages of CKD were included. Plasma levels of copeptin, cystatin-C, and other biochemical parameters were measured. The correlation between copeptin and glomerular filtration rate (GFR), estimated based on plasma cystatin-C levels, was investigated. RESULTS: Plasma copeptin levels were gradually increased from the stage 1-5 of CKD in the patients with T2DM. In univariate linear regression analysis, high plasma levels of copeptin were associated with lower GFR (Standardized ß = -0.535, R2 = 0.287, p <0.0001). This association remained significant even after being adjusted for glucose levels and years of T2DM diagnosis, mean blood pressure, pharmacological treatment, gender, and age. CONCLUSIONS: The results show that high plasma copeptin levels are associated with the decline of renal function in patients with T2DM and, therefore, copeptin may be considered as a biomarker of renal function. Further evaluation of plasma copeptin levels to predict morbidity and mortality of T2DM patients, with or without CKD, has been taken into our consideration.

Risk factors for cardiovascular disease in patients undergoing peritoneal dialysis.

Patients on peritoneal dialysis (PD) are at high cardiovascular risk. Although some risk factors are unmodifiable (for example, age, sex, genetics), others are exacerbated in the unfriendly uremic milieu (inflammation, oxidative stress, mineral disturbances) or contribute per se to kidney disease and cardiovascular progression (diabetes mellitus, hypertension). Moreover, several factors associated with PD therapy may both increase (by altered lipid profile, hyperinsulinemia, and formation of advanced glycation end-products) and decrease (by better blood pressure control and anemia management) cardiovascular risk. The present review discusses recent findings and therapy trends in cardiovascular research on the PD population, with emphasis on the roles of inflammation, insulin resistance, homocysteinemia, dyslipidemia, vascular calcification, and genetics/epigenetics.

Icodextrin metabolism and alpha-amylase activity in nonuremic rats undergoing chronic peritoneal dialysis.

OBJECTIVE: To study the metabolism of icodextrin and alpha-amylase activity following daily exposure to dialysis solutions containing either glucose or icodextrin as osmotic agent in rats. METHODS: Male Wistar rats with implanted peritoneal catheters were infused twice daily for 3 weeks with 20 mL 7.5% icodextrin-based peritoneal dialysis fluid (IPDF; ICO group, n = 12) or 3.86% glucose-based peritoneal dialysis fluid (GLU group, n = 11). A 4-hour dwell study using 30 mL IPDF was performed on day 10 (D1) and day 21 (D2) in both the ICO and the GLU groups. Radiolabeled serum albumin (RISA) was used as a macromolecular volume marker. Dialysate samples were collected at 3, 15, 30, 60, 90, 120, and 240 minutes. Blood samples were drawn before the start and at the end of the dwell. RESULTS: During all dwell studies, the dialysate concentrations of total icodextrin decreased due to decrease in high molecular weight (MW) fractions, whereas there was a marked increase in icodextrin low MW metabolites. alpha-Amylase activity increased in dialysate and decreased in plasma. About 60% of the total icodextrin was absorbed from the peritoneal cavity during the 4-hour dwells. Low MW icodextrin metabolites were present in the dialysate already at 3 minutes, and maltose (G2), maltotriose (G3), maltotetraose (G4), and maltopentaose (G5) increased progressively, reaching maximum concentrations at 60 minutes. Maltohexaose (G6) and maltoheptaose (G7) were also detected already at 3 minutes but did not change significantly during the dwells. During the two 4-hour dwell studies (D1 and D2), the concentrations of total icodextrin and icodextrin metabolites and alpha-amylase activity in dialysate did not differ between the ICO and GLU groups, during either D1 or D2. No icodextrin metabolites were detected in plasma at the end of the dwells. alpha-Amylase activity in the dialysate increased six- to eightfold whereas plasma alpha-amylase activity decreased by 21% - 26% during the two 4-hour dwells in both the ICO and the GLU groups; there were no significant differences between the ICO and the GLU groups during either D1 or D2. alpha-Amylase activity in the dialysate correlated strongly with the disappearance rate of icodextrin from the peritoneal cavity during the 4-hour dwells, and with the concentrations of G2, G3, G6, and G7 in dialysate. CONCLUSIONS: The decline in the dialysate concentrations of high MW fractions and the increase in low MW metabolites of icodextrin suggest intraperitoneal alpha-amylase mediated the metabolism of icodextrin and the transport of predominantly the smaller icodextrin metabolites from dialysate. However, no icodextrin could be detected in plasma, suggesting that it was metabolized and excreted by the kidney in these nonuremic rats. In contrast to uremic peritoneal dialysis patients, chronic exposure to IPDF did not seem to further affect alpha-amylase activity or icodextrin metabolism. The much higher alpha-amylase activity in plasma and dialysate in rats than in humans explains the much more rapid metabolism of icodextrin in rats compared with peritoneal dialysis patients.

Use of icodextrin during nocturnal automated peritoneal dialysis allows sustained ultrafiltration while reducing the peritoneal glucose load: a randomized crossover study.

BACKGROUND: Optimization of ultrafiltration and preservation of the peritoneal membrane are desirable objectives in peritoneal dialysis (PD) patients. Mixtures of glucose- and non-glucose-based solutions may help to meet both targets simultaneously. AIM: To analyze the effects, in terms of ultrafiltration and peritoneal glucose load, of including icodextrin-based dialysate in the nocturnal schedule of patients undergoing automated PD (APD). METHOD: Following a randomized crossover design, 17 APD patients underwent two 10-day study periods under identical prescription (including amino acid-based solution for the night schedule), except for the substitution of 2 L glucose-based dialysate in the nocturnal mixture (control) by a similar amount of icodextrin-based dialysate (icodextrin phase) in one period. Dependent variables included ultrafiltration, sodium removal, peritoneal glucose load, and residual renal function. We measured serum and urine levels of icodextrin metabolites at the end of each phase. RESULTS: Ultrafiltration was marginally higher during the icodextrin phase (median 815 vs 763 mL/day, p = 0.07), while peritoneal sodium removal was similar in both phases (74 vs 71 mmol/L/day). Peritoneal glucose load (median 67.5 vs 104.0 g/day, p < 0.005) and absorption (14.0 vs 35.6 g/day, p < 0.005) were lower during the icodextrin phase. Diuresis was also modestly lower during the icodextrin phase (500 vs 600 mL/day, p < 0.05). Serum levels of icodextrin metabolites were moderately higher in the icodextrin phase (p < 0.005) in patients both on and off diurnal icodextrin. CONCLUSION: Inclusion of amino acid- and icodextrin-based solutions in the nocturnal schedule of APD patients may allow sustained ultrafiltration and sodium removal while significantly reducing the peritoneal glucose load in these patients.

Low triiodothyronine is associated with elevation of N-terminal pro-brain natriuretic peptide (NT-proBNP) and mortality in dialysis patients. / La disminución de triyodotironina se asocia con la elevación del péptido natriurético cerebral N-terminal y con la mortalidad en pacientes en diálisis.

BACKGROUND: Low thyroid hormone (TH) levels and myocardial damage are common in dialysis patients and are associated with mortality. However, little is known about the role of THs on myocardial damage as has been described in primary thyroid diseases. The aim of this study was to explore the potential relationship between low total triiodothyronine (total T3) and biomarkers of myocardial damage and the effect of their interaction on mortality, to ascertain if cardiovascular damage is the link between low THs and the risk of death in dialysis patients with CKD. MATERIAL AND METHODS: TH plasma levels, nutritional markers, inflammation and myocardial damage were studied in 296 patients undergoing peritoneal dialysis or haemodialysis, who were followed up for 16 months to ascertain the association between biochemical variables and mortality. RESULTS: Low total T3 levels were found in 45% of patients, which was inversely correlated with C-reactive protein (CRP) and NT-proBNP, and directly correlated with albumin and transferrin. Diabetes, CRP and total T3 were risk factors for all-cause mortality, and CRP, NT-proBNP and total T3 for cardiovascular mortality. CONCLUSIONS: Low total T3 levels are common in dialysis patients and are associated with inflammation, malnutrition and myocardial damage. The latter may be the link between low THs and all-cause and cardiovascular mortality.

J-shaped mortality relationship for uric acid in CKD.

BACKGROUND: Hyperuricemia is a common feature in patients with chronic kidney disease (CKD). Hyperuricemia has been associated with increased cardiovascular mortality in the general population, but less is known about this association in patients with CKD. METHODS: To explore possible associations of serum uric acid with all-cause mortality and comorbidity in patients with CKD, we studied 294 incident patients with CKD stage 5 (185 men; age, 53 +/- 12 years) starting renal replacement therapy with a median glomerular filtration rate of 6.4 mL/min/1.73 m(2) (0.11 mL/s/1.73 m(2); range, 0.8 to 14.3 mL/min/1.73 m(2) [0.01 to 0.24 mL/s/1.73 m(2)]). Survival was determined from the day of examination and during a mean follow-up period of 27 months (range, 3 to 72 months); 94 patients died. Patients were divided into 3 groups based on serum uric acid levels (low quintile, 3 middle quintiles, and high quintile). RESULTS: In a nonadjusted analysis, patients in the high quintile, followed by patients in the low quintile, had greater all-cause mortality compared with patients in the 3 middle quintiles (log-rank test chi-square, 6.8; P = 0.03). After adjusting for age, sex, glomerular filtration rate, cholesterol level, phosphate level, C-reactive protein level, cardiovascular disease, diabetes mellitus, diuretics, and allopurinol treatment, the association showed a "J-shaped" association with hazard ratios of 1.96 (confidence interval, 1.10 to 3.48; P = 0.02) for the high quintile and 1.42 (confidence interval, 0.76 to 2.66; P = not significant) for the low quintile. Moreover, uric acid levels correlated positively with levels of triglycerides, phosphate, C-reactive protein, and intracellular adhesion molecule 1 and negatively with levels of calcium, high-density lipoprotein cholesterol, and apolipoprotein A. CONCLUSION: Serum uric acid levels showed a J-shaped association with all-cause mortality, with the lowest risk in the 3 middle quintiles. Moreover, uric acid level was associated with calcium/phosphate metabolism, dyslipidemia, and inflammation.

Serum markers of low-turnover bone disease in Mexican children with chronic kidney disease undergoing dialysis.

BACKGROUND: The frequency of low-turnover bone disease (LTBD) in patients with chronic kidney disease (CKD) has increased in past years. This change is important because LTBD is associated with bone pain, growth delay, and higher risk for bone fractures and extraosseous calcifications. LTBD is a histological diagnosis. However, serum markers such as parathyroid hormone (PTH) and calcium levels offer a noninvasive alternative for diagnosing these patients. OBJECTIVE: To describe the prevalence of LTBD in pediatric patients with renal failure undergoing some form of renal replacement therapy, using serum calcium and intact PTH levels as serum markers. METHODS: In this cross-sectional study, 41 children with CKD undergoing dialysis treatment (31 on continuous ambulatory peritoneal dialysis and 10 on hemodialysis) were included. There were no inclusion restrictions with respect to gender, cause of CKD, or dialysis modality. The children were studied as outpatients. The demographic data, CKD course, time on dialysis, phosphate-binding agents, and calcitriol prescription were registered, as well as weight, height, Z-score for height, linear growth rate, and Z-score for body mass index. Serum calcium, phosphorus, aluminum, PTH, alkaline phosphatase, osteocalcin, glucose, creatinine, urea, cholesterol, and triglycerides were measured. RESULTS: There were 20 (48.8%) children with both PTH < 150 pg/mL and corrected total calcium >10 mg/dL who were classified as having LTBD[(+)]; the remaining 21 (51.2%) children were classified as having no LTBD[(-)]. The LTBD(+) patients were younger (11.2 +/- 2.7 vs 13.2 +/- 2.4 years, p < 0.01) but they had no differences regarding Z-scores for height. Linear growth in 6 months was less than expected in both groups (-0.15 +/- 0.23 cm/month), but the difference between expected and observed growth was higher in the LTBD(+) group (-0.24 +/- 0.14 vs -0.07 +/- 0.28 cm/mo, p < 0.03). LTBD(+) patients also had lower serum creatinine (8.69 +/- 2.75 vs 11.19 +/- 3.17 mg/dL, p < 0.01), higher serum aluminum levels [median (range) 38.4 (9 - 106) vs 28.1 (9 - 62) microLg/L, p < 0.05], and lower systolic blood pressure (112.0 +/- 10.3 vs 125.0 +/-1 2.9 mmHg, p < 0.015) and diastolic blood pressure (76.0 +/- 9.7 vs 84.5 +/- 8.2 mmHg, p < 0.017). A significant correlation was found between PTH and alkaline phosphatase (r = 0.68, p < 0.001), but not between PTH and aluminum. CONCLUSION: The LTBD(+) biochemical profile was found in 48.8% of the children and was associated with impaired linear growth. Aluminum contamination, evidenced by higher serum aluminum levels, may have had a pathogenic role in these disorders. Higher systolic and diastolic blood pressure levels may be related to higher serum PTH levels.

Determination of high and low molecular weight molecules of icodextrin in plasma and dialysate, using gel filtration chromatography, in peritoneal dialysis patients.

OBJECTIVE: The aim of this study was to apply high performance liquid chromatography (HPLC) with modern gel filtration media to determine high molecular weight (HMW) icodextrin fractions and low molecular weight (LMW) icodextrin metabolites in dialysate and plasma in peritoneal dialysis (PD) patients on treatment with icodextrin, and to explore the potential relationships between these compounds, alpha-amylase activity, and glomerular filtration rate. DESIGN: Retrospective study of dialysate and plasma samples from PD patients. SETTING: Samples were collected at one PD center. PATIENTS: Blood and dialysate samples were obtained from PD patients who were subdivided into three groups: patients using only glucose-based peritoneal dialysis fluid (GPDF; GLU group, n = 23), patients studied after the first long dwell with icodextrin-based peritoneal dialysis fluid (IPDF; 1st ICO group, n = 24), and patients who were regular users of IPDF for the long dwells (ICO group, n = 9). METHODS: LMW icodextrin metabolites [i.e., maltose (G2), maltotriose (G3), maltotetraose (G4), maltopentaose (G5), maltohexaose (G6), and maltoheptaose (G7)] and HMW fractions were determined in plasma and dialysate using two different gel filtration HPLC methods. Enzymatic hydrolysis with amyloglucosidase to glucose yielded the total carbohydrate content and this was used to validate the HPLC results. alpha-Amylase activity was determined using a routine method. RESULTS: The results obtained by gel filtration HPLC yielded values of LMW metabolites and HMW fractions in plasma and dialysate in agreement with results obtained with enzymatic hydrolysis. HMW fractions were not detectable in plasma. Absorption of icodextrin from the peritoneal cavity during the long dwell (10 - 16 hours) was, on average, 39% of the amount instilled. During the long dwell, there was a relative decrease in the dialysate concentration of the largest HMW fractions (>21.4 kDa). Plasma concentration of the LMW icodextrin metabolites G2-G7 was highest in the ICO group (2.65+/-0.54 mg/mL) but also higher in the 1st ICO group (1.97+/-0.57 mg/mL) compared with the GLU group (0.52+/-0.23 mg/mL). Plasma alpha-amylase activity was significantly lower in the 1st ICO group and in the ICO group compared with the GLU group. CONCLUSIONS: Accurate analysis of HMW icodextrin fractions in dialysate and LMW icodextrin metabolites in plasma and dialysate in PD patients can be achieved by gel filtration HPLC with two different columns. This method can be used to study the complex pattern of changes in icodextrin and its metabolites in plasma and dialysate. The finding that HMW icodextrin fractions were not detected in plasma was unexpected, and differs from results of previous studies by other researchers.

Determination of alpha-amylase activity in serum and dialysate from patients using icodextrin-based peritoneal dialysis fluid.

OBJECTIVE: Low serum activity of alpha-amylase has been reported in peritoneal dialysis (PD) patients following treatment with icodextrin-based peritoneal dialysis fluid (IPDF). However, these results have been questioned because icodextrin interferes with the polysaccharide reagent included in the assay as a substrate for alpha-amylase in the sample. DESIGN: We adapted a routine method using p-nitrophenol maltoheptaoside as substrate for the analysis of total alpha-amylase in serum and dialysate from 27 patients using IPDF. Serum from 12 healthy volunteers and serum and dialysate from 19 PD patients using glucose-based peritoneal dialysis fluid (GPDF) were used as controls. For the PD patients, time on dialysis ranged from 1 to 24 months (mean 5.7 months) and time of exposure to IPDF ranged from 1 to 52 weeks. RESULTS: To test for interference and recovery, and thus to validate the alpha-amylase assay, samples were spiked with IPDF and synthetic alpha-amylase. This revealed that addition of up to 75% IPDF did not interfere with the assay. Furthermore, alpha-amylase was fully recovered when spiked in serum from patients treated with IPDF. We show that total alpha-amylase activity is considerably lower in the serum of IPDF patients (20.3 +/- 16.5 U/L, p < 0.001) than GPDF patients (85.5 +/- 51.7 U/L) and healthy persons (55.1 +/- 13.6 U/L). CONCLUSIONS: We have shown that the IL method (ILTest; Instrumentation Laboratory, Lexington, MA, USA) measures alpha-amylase activity in samples containing icodextrin metabolites. The clinical significance of reduced plasma alpha-amylase activity, as well as the relative importance of pancreatic versus salivary and tissue-bound alpha-amylase, in PD patients using IPDF is not known.

Dialysis adequacy indices and body composition in male and female patients on peritoneal dialysis.

OBJECTIVES: Creatinine clearance scaled to body surface area (BSA) and urea KT/V normalized to total body water (TBW) are used as indices for peritoneal dialysis (PD) adequacy. We investigated relationships of indices of dialysis adequacy (including KT/V, KT, clearance, dialysate over plasma concentration ratio) and anthropometric and body composition parameters (BSA, TBW, body mass index (BMI), weight, height, fat mass (FM), and fat-free mass (FFM)) in male and female patients on continuous ambulatory peritoneal dialysis. METHODS: Ninety-nine stable patients (56 males) performed four 24-hr collections of drained dialysate for four dialysis schedules with three daily exchanges of glucose 1.36% and one night exchange of either: 1) glucose 1.36%, 2) glucose 2.27%, 3) glucose 3.86% or 4) icodextrin 7.5%. RESULTS: KT and dialysate over plasma concentration ratio, CD/CP, for urea and creatinine were similar for males and females and, in general, did not depend on body-size parameters including V (= TBW), which means that the overall capacity of the transport system in females and males is similar. However, after normalization of KT to V or 1.73/BSA yielding KT/V and creatinine clearance, Cl(1.73/BSA), respectively, the normalized indices were substantially higher in females than in males and correlated inversely with body-size parameters, especially in males. CONCLUSIONS: As KT/V depends strongly on body size, treatment target values for KT/V should take body size and therefore also gender into account. As KT is less influenced by body size, body composition and gender, KT should be considered as a potential auxiliary index in PD.