Factors associated with increased plasma homocysteine in patients using an amino acid peritoneal dialysis fluid.

BACKGROUND: Although amino acid peritoneal dialysate (AAPD) substitution is thought to improve protein-energy malnutrition in patients undergoing peritoneal dialysis (PD), it may also increase plasma homocysteine (Hcy) levels due to the methionine load in the dialysate. However, it is still unclear which factors are important for elevating Hcy in patients treated with AAPD. METHODS: Sixteen malnourished PD patients (age 48+/-18 years) were treated daily with one exchange of 1.1% AAPD for 3 months. The effects of AAPD on nutrition, Hcy, methionine, leptin and insulin resistance were studied. We also analysed factors that influenced plasma Hcy levels. RESULTS: We found a transient increase in serum albumin (P<0.01) after 1 month treatment, especially in patients with serum albumin < or = 3.5 g/dl. Total plasma Hcy increased markedly after AAPD (the peak at month 2, P<0.001) and returned to baseline after ceasing AAPD, despite no changes in dietary methionine intake and serum methionine levels. Eight patients with Hcy increments >5.65 microM (the median) had lesser dietary intakes of protein (P = 0.01) and methionine (P = 0.028), lower body fat mass (P = 0.05) and lower aspartate transaminase (AST) (P = 0.008) before AAPD treatment than patients with lower increments. DeltaHcy was inversely correlated with baseline dietary methionine intake (r = -0.61), protein intake (r = -0.54) and AST (r = -0.51) (all P<0.05). There was no change in leptin or insulin resistance. AAPD treatment significantly increased Kt/Vurea (P<0.001), weekly creatinine clearance (P<0.05) and peritoneal glucose transport (P<0.05). CONCLUSIONS: Treatment with 1.1% AAPD transiently increased serum albumin in malnourished PD patients. However, the methionine load from the dialysate in this study significantly elevated plasma Hcy levels, especially in patients with lower protein and methionine intakes, and lower AST levels. Further long-term studies will be needed to clarify potential nutritional benefits and adverse effects of AAPD.     

Improved insulin sensitivity is associated with restricted intake of dietary glycoxidation products in the db/db mouse

Advanced glycation end products (AGEs), known promoters of diabetic complications, form abundantly in heated foods and are ingested in bioreactive forms. To test whether dietary AGEs play a role in the progression of insulin resistance, C57/BL/KsJ db/db mice were randomly placed for 20 weeks on a diet with either a low AGE content (LAD) or a 3.4-fold higher content of AGE (high AGE diet [HAD]), including (epsilon)N-carboxymethyllysine (CML) and methylglyoxal (MG). LAD-fed mice showed lower fasting plasma insulin levels throughout the study (P = 0.01). Body weight was reduced by approximately 13% compared with HAD-fed mice (P = 0.04) despite equal food intake. LAD-fed mice exhibited significantly improved responses to both glucose (at 40 min, P = 0.003) and insulin (at 60 min, P = 0.007) tolerance tests, which correlated with a twofold higher glucose uptake by adipose tissue (P = 0.02). Compared with the severe hypertrophy and morphological disorganization of islets from HAD-fed mice, LAD-fed mice presented a better-preserved structure of the islets. LAD-fed mice demonstrated significantly increased plasma HDL concentrations (P < 0.0001). Consistent with these observations, LAD-fed mice exhibited twofold lower serum CML and MG concentrations compared with HAD-fed mice (P = 0.02). These results demonstrate that reduced AGE intake leads to lower levels of circulating AGE and to improved insulin sensitivity in db/db mice.     

Low prevalence of hyperphosphatemia independent of residual renal function in peritoneal dialysis patients.

OBJECTIVE: Our objective was to evaluate serum phosphorus control in patients undergoing continuous ambulatory peritoneal dialysis, with and without residual renal function, by investigating the metabolic balance of phosphorus. METHODS: We assessed serum phosphorus levels in 205 patients undergoing continuous ambulatory peritoneal dialysis (CAPD). The clinical factors related to serum phosphorus were also examined, including dietary phosphate intake, dietary protein intake (DPI), phosphate removal through urine and dialysate, doses of phosphorus binder and vitamin D, and serum intact parathyroid hormone (PTH) levels. Nutritional indexes, including serum albumin (Alb), lean body mass (LBM), hand-grip strength (HGS), and subjective global assessment (SGA), were also assessed. Dialysis adequacy and residual renal function (RRF) were calculated by a standard technique. Patients with RRF <2 mL/min were viewed as having no significant RRF. Hyperphosphatemia was diagnosed in patients with serum phosphorus levels >1.78 mmol/L. RESULTS: The mean serum phosphorus level of all patients was 1.6 +/- 0.5 mmol/L (mean +/- SD). Only 58 of 205 patients (28%) had hyperphosphatemia. The average DPI was 0.8 +/- 0.3 g/kg/d, whereas the average dietary phosphorus intake was 691 +/- 201 mg/d. There were no differences in mean serum phosphorus levels or incidents of hyperphosphatemia between patients with and without RRF (1.6 +/- 0.4 mmol/L vs. 1.7 +/- 0.5 mmol/L, P = .256; 22% vs. 31%, P = .336). Although total phosphorus removal through urine and dialysate was lower in the 115 patients without RRF than in the 90 patients with RRF (270 +/- 106 mg vs. 333 +/- 129 mg, P = .000), they simultaneously had a lower dietary phosphorus intake (656 +/- 191 mg vs. 713 +/- 215 mg, P = .046). In addition, patients without RRF had significantly lower DPI, Alb, LBM, and right HGS levels than patients with RRF (P < .01-.05). In those without RRF, the 79 patients without hyperphosphatemia had significantly lower DPI, LBM, and HGS levels, and a higher prevalence of malnutrition diagnosed by SGA, than the 36 patients with hyperphosphatemia (P < .001-.05). However, in patients with RRF, there was no difference in nutritional index between patients with and without hyperphosphatemia (P > .05). CONCLUSION: A relatively lower prevalence of hyperphosphatemia existed in CAPD patients both with and without RRF, which may be associated with incremental dialysis, the correct administration of phosphorus binder, and a lower protein and phosphorus intake. However, patients without RRF, especially those without hyperphosphatemia, ran the risk of malnutrition, despite a well-controlled phosphorus intake.     

Fetal or neonatal low-glycotoxin environment prevents autoimmune diabetes in NOD mice

Advanced glycation end products (AGEs) are implicated in beta-cell oxidant stress. Diet-derived AGE (dAGE) are shown to contribute to end-organ toxicity attributed to diabetes. To assess the role of dAGE on type 1 diabetes, NOD mice were exposed to a high-AGE diet (H-AGE) and to a nutritionally similar diet with approximate fivefold-lower levels of N(epsilon)-carboxymethyllysine (CML) and methylglyoxal-derivatives (MG) (L-AGE). Suppression of serum CML and MG in L-AGE-fed mice was marked by suppression of diabetes (H-AGE mice >94% vs. L-AGE mice 33% in founder [F](0), 14% in F(1), and 13% in F(2) offspring, P < 0.006) and by a delay in disease onset (4-month lag). Survival for L-AGE mice was 76 vs. 0% after 44 weeks of H-AGE mice. Reduced insulitis in L-AGE versus H-AGE mice (P < 0.01) was marked by GAD- and insulin-unresponsive pancreatic interleukin (IL)-4-positive CD4+ cells compared with the GAD- and insulin-responsive interferon (IFN)-gamma-positive T-cells from H-AGE mice (P < 0.005). Splenocytes from L-AGE mice consisted of GAD- and insulin-responsive IL-10-positive CD4+ cells compared with the IFN-gamma-positive T-cells from H-AGE mice (P < 0.005). Therefore, high AGE intake may provide excess antigenic stimulus for T-cell-mediated diabetes or direct beta-cell injury in NOD mice; both processes are ameliorated by maternal or neonatal exposure to L-AGE nutrition.     

Skin autofluorescence, a measure of cumulative metabolic stress and advanced glycation end products, predicts mortality in hemodialysis patients

Tissue advanced glycation end products (AGE) are a measure of cumulative metabolic stress and trigger cytokines driven inflammatory reactions. AGE are thought to contribute to the chronic complications of diabetes and ESRD. Tissue autofluorescence is related to the accumulation of AGE. Therefore, skin autofluorescence (AF) may provide prognostic information on mortality in hemodialysis (HD) patients. Skin AF was measured noninvasively with an AF reader at baseline in 109 HD patients. Overall and cardiovascular mortality was monitored prospectively during a period of 3 yr. The AF reader was validated against AGE contents in skin biopsies from 29 dialysis patients. Forty-two of the 109 (38.5%) HD patients died. Cox regression analysis showed that AF was an independent predictor of overall and cardiovascular mortality (for overall mortality odds ratio [OR] 3.9), as were pre-existing cardiovascular disease (CVD; OR 3.1), C-reactive protein (OR 1.1), and serum albumin (OR 0.3). Multivariate analysis revealed that 65% of the variance in AF could be attributed to the independent effects of age, dialysis and renal failure duration, presence of diabetes, triglycerides levels, and C-reactive protein. AF was also independently linked to the presence of CVD at baseline (OR 8.8; P < 0.001). AF correlated with collagen-linked fluorescence (r = 0.71, P < 0.001), pentosidine (r = 0.75, P < 0.001), and carboxy(m)ethyllysine (both r = 0.45, P < 0.01). Skin AF is a strong and independent predictor of mortality in ESRD. This supports a role for AGE as a contributor to mortality and CVD and warrants interventions specifically aimed at AGE accumulation.     

Differential effects of advanced glycation end-products on renal tubular cell inflammation

Aim: The authors recently showed that advanced glycation end‐products (AGE) in the form of glycated albumin (GA) upregulated renal tubular expression of interleukin (IL)‐8 and soluble intercellular adhesion molecule‐1 (sICAM‐1), but not other important cytokines known to mediate diabetic nephropathy. This implies that other molecules such as the carbonyl intermediates of AGE or other modified protein lysine‐albumin may participate in diabetic tubular injury. Methods: Human proximal tubular epithelial cells (PTEC) were growth‐arrested and exposed to methylglyoxal (MG), MG‐bovine serum albumin (BSA)‐AGE, carboxymethyllysine (CML)‐BSA, AGE‐BSA or BSA with or without prior addition of rosiglitazone that was previously shown to attenuate the pro‐inflammatory effect of GA alone. Results: MG‐BSA‐AGE and AGE‐BSA upregulated tubular expression of connective tissue growth factor (CTGF), transforming growth factor (TGF)‐β, and vascular endothelial growth factor (VEGF), whereas CML‐BSA stimulated expression of IL‐6, CCL‐2, CTGF, TGF‐β and VEGF. These AGE compounds also activated nuclear factor (NF)‐κB and their effects were attenuated by pre‐incubation with anti‐RAGE antibody. MG and BSA did not affect the expression of any of these molecules. Rosiglitazone did not affect the in vitro biological effects of MG, MG‐BSA‐AGE, AGE‐BSA or CML‐BSA on PTEC. Conclusion: AGE exhibit differential inflammatory and fibrotic effects on PTEC via RAGE activation and NF‐κB signal transduction. Rosiglitazone had no effect on these responses. Further investigations on compounds that nullify the downstream effects of these AGE are warranted.     

Serum-free insulin-like growth factor I correlates with clearance in patients with chronic renal failure

Serum-free insulin-like growth factor I correlates with clearance in patients with chronic renal failure. BACKGROUND: Chronic renal failure (CRF) results in major changes in the circulating growth hormone (GH)/insulin-like growth factor (IGF) system. However, there are only limited data on changes in free IGF-I in CRF. METHODS: Matched groups of nondiabetic, nondialyzed patients with CRF (N = 25) and healthy controls (N = 13) were compared. The creatinine clearance (CCr) based on a 24-hour urine collection ranged from 3 to 59 and 89 to 148 ml/min/1.73 m2 in patients and controls, respectively. Overnight fasting serum samples were analyzed for free and total IGF-I and -II, and IGF-binding protein (IGFBP)-1, -2, and -3. Additionally, intact as well as proteolyzed IGFBP-3 was determined. RESULTS: The patients had reduced serum-free IGF-I (-53%) and increased levels of total IGF-II (40%), IGFBP-1 (546%), and IGFBP-2 (270%, P < 0.05). Serum total IGF-I and free IGF-II were normal. Also, serum levels of immunoreactive IGFBP-3 were elevated (33%, P < 0.05), but this could be explained by an increased abundance of IGFBP-3 fragments, as ligand blotting showed no difference in levels of intact IGFBP-3. Accordingly, patients had an increased proteolysis of IGFBP-3 in vivo (17%) and in vitro (7%, P < 0.05). In patients, free IGF-I levels correlated positively with CCr (r2 = 0.38, P < 0.002) and inversely with IGFBP-1 (r2 = 0.69, P < 0. 0001) and IGFBP-2 (r2 = 0.41, P < 0.0007), whereas CCr was inversely correlated with levels of IGFBP-1 (r2 = 0.48, P < 0.0001) and IGFBP-2 (r2 = 0.63, P < 0.0001). CONCLUSIONS: These data strongly support the hypothesis that CRF-related growth failure and tissue catabolism are caused by an increased concentration of circulating IGFBP-1 and -2, resulting in low serum levels of free IGF-I and thus IGF-I bioactivity. In addition, low levels of free IGF-I may explain the increased secretion of GH in CRF.     

Peritoneal clearance of leptin in CAPD patients: impact of local insulin administration.

INTRODUCTION: The ob gene product leptin is secreted by fat cells and the serum leptin levels reflects the body fat content. Markedly elevated serum leptin levels have been reported in patients with chronic renal failure. The aim of the present study was to assess if the dialysate leptin levels in peritoneal dialysate are similar to what can be expected from passive diffusion or if intraperitoneal synthesis of leptin may occur. METHODS: We studied 39 patients (20 males), mean age 54+/-12 years, who had been treated with peritoneal dialysis for 17+/-12 months. Ten of the patients were diabetics of which seven used intraperitoneal insulin. A 24-h collection of dialysate was performed and dialysate and fasting blood samples were analysed for leptin, albumin and beta2-microglobulin, and the peritoneal clearances (PCl) were calculated for these solutes. RESULTS: Serum leptin (mean 47+/-76, range 3-350 ng/ml) was related to body mass index (r=0.35, P<0.05). In multiple regression analysis, serum leptin also correlated to serum TNF-alpha. Although dialysate leptin levels correlated to serum leptin, they were higher than expected from the molecular weight of 16 kD. PCl of leptin was 1.3 ml/min (range 0.2-5.9 ml/min), which was 1.6 times higher than expected from the molecular weight of leptin and PCl for albumin and beta2-microglobulin, not taking the protein binding of leptin into account. A strong correlation was found between PCI for albumin and beta2-microglobulin (r = 0.68, P < 0.0001) but neither PCl albumin, nor PCl beta2-microglobulin correlated to PCI leptin. The PCl of leptin was markedly higher in diabetics using intraperitoneal insulin (n = 7) compared to the other 32 patients (2.6+/-2.0 vs 1.1+/-0.7 ml/min, P<0.05). CONCLUSION: Serum leptin is locally produced in the peritoneal cavity, and intraperitoneal insulin enhances local production of leptin.     

Influence of haemodialysis on plasma total homocysteine concentration.

BACKGROUND: The high prevalence of hyperhomocysteinaemia in uraemic patients is of interest because of the cardiovascular risk associated with increased plasma total homocysteine (tHcy) concentration. Treatment with folic acid lowers tHcy in haemodialysis patients, however, in most patients not to normohomocysteinaemic levels. With possible tHcy-lowering modifications in mind, we studied the influence of standard haemodialysis on tHcy. METHODS: In 56 folate-loaded haemodialysis patients, tHcy and parameters of dialysis adequacy were measured. In six patients, interdialytic curves of tHcy and serum creatinine concentrations were obtained and in five patients, the amount of homocysteine (Hcy) in dialysate was determined. RESULTS: tHcy (21.8+/-14.4 micromol/l) correlated significantly with Kt/V (r=0.32, P<0.05), total Kt/V (r=0.29, P<0.05), nPCR (r=0.30, P<0.05) and serum concentrations of albumin (r=0.28, P<0.05) and cobalamines (r=-0.27, P<0.05). In a multiple linear regression analysis, only serum albumin concentrations significantly predicted tHcy (r=0.34, P < 0.05). During dialysis, tHcy decreased by 28% and remained constant for at least 8 h after treatment. The amount of Hcy recovered in dialysate was 63 micromol (12-158 micromol). There was no difference in tHcy between those who had residual renal function and those who had not. CONCLUSIONS: The direct relationship between tHcy and Kt/V seemed to be mediated by the serum albumin concentration. The shape of the interdialytic tHcy curve suggested facilitated Hcy removal for at least 8 h after dialysis possibly due to reduced levels of inhibitory activities against relevant enzyme(s). The dialysed amount of Hcy did not seem to contribute significantly to Hcy removal. Thus, modifications of standard dialytic regimens are not likely to be effective from a tHcy-lowering point of view whereas convective procedures such as haemofiltration or haemodiafiltration might be more effective.     

The interaction of PTH and dietary phosphorus and calcium on serum calcitriol levels in the rat with experimental renal failure

BACKGROUND.: Renal failure results in decreased calcitriol production, akey factor in the development of secondary hyperparathyroidism.Phosphorus accumulation and high parathyroid hormone (PTH) levels,both inherent to renal failure, have different effects on calcitriolproduction; moreover, dietary calcium loading may have a separateinhibitory effect on calcitriol production. This study was designedto evaluate the relative effects of PTH and dietary phosphorusand calcium on serum calcitriol levels. METHODS.: Renal failure was surgically induced and rats were divided intonormal, moderate renal failure, and advanced renal failure basedon the serum creatinine. Each group was subdivided and receivedeither a highphosphorusdiet (HPD, 0.6% Ca, 1.2% P) or highcalcium diet (HCaD, 1.2% Ca, 0.6% P) for 14–16 days to determinethe relative effects of dietary calcium andphosphorus loadingon serum calcitriol. In addition the effect of PTH and phosphoruson calcitriol stimulation was determined with a 48-h PTH infusioncombined with either a low (0.16%) or high (1%) phosphorus dietsboth diets had negligible calcium (<0.05%) RESULTS.: With decreasing renal function, PTH increased and was greaterin rats fed the HPD than the HCaD; serum calcitriol decreasedas renal function decreased and was lower in normal rats andrats with moderate renal failure fed a HCaD (P < 0.01). Thecalcitriol response to a PTH infusion decreased as renal functiondecreased (P <0.05) but was greater on a low- (0.16%) thana high- (1%) phosphorus diet (P<0.05) CONCLUSION.: Dietary calcium loading either directly decreases serum calcitriolor acts by modifying the stimulatory effect of PTH; the stimulatoryeffect of PTH on serum calcitriol is modified by dietary phosphorus;in moderate renal failure, serum calcitriol levels depend ona complex interaction between PTH and dietary calcium and phosphorus;and in advanced renal failure, serum calcitriol levels are lowand are difficult to stimulate, presumably because of the lossof renal mass.     

含糖透析液对维持性血液透析患者血糖、血压及代谢的影响

目的 探讨含糖透析液对维持性血液透析(maintenance hemodialysis,MHD)患者血糖、血压及代谢的影响.方法 选择西安交通大学医学院第一附属医院血液净化科MHD患者50例,采用数字表法随机分为无糖透析液组、含糖透析液组,血液透析(hemodialysis,HD)时分别使用无糖透析液和葡萄糖浓度为5.5 mmol/L的含糖透析液,持续观察3个月,并检测患者每次透析开始、透析2h、透析结束时血糖和血压,及观察期前后的血清白蛋白、糖化血红蛋白、血脂等指标.结果 无糖透析液组低血糖和低血压的发生率均高于含糖透析液组(P＜0.05),两组患者透析各时间点血糖水平差异无统计学意义(P＞0.05).两组患者在观察期前与观察期结束后血清白蛋白水平、糖化血红蛋白、血脂等差异无统计学意义(P＞0.05).结论 维持性血液透析患者应用葡萄糖浓度为5.5 mmol/L的含糖透析液能降低透析过程中低血糖和低血压的发生率,且不影响血清白蛋白、糖化血红蛋白、血脂等指标,具有安全性、可靠性.     

Autoantibody against N(epsilon)-(carboxymethyl)lysine: an advanced glycation end product of the Maillard reaction.

Prolonged incubation of proteins with reducing sugar produces advanced glycation end products (AGEs), which are implicated as factors for aging and diabetic complications. We previously demonstrated the presence of N(epsilon)-(carboxymethyl)lysine (CML), one of the main AGE structures, in human and animal tissues using a monoclonal anti-CML antibody (6D12). These findings suggest that CML structures present in vivo could serve as immunogens to generate autoantibodies. This suggestion was tested in the present study. First, plasma samples from diabetic rats reacted positively with AGE bovine serum albumin (BSA). These reactivities increased with the duration of diabetic states and were inhibited specifically by CML-BSA. Second, a fraction purified from plasma of diabetic patients, which bound to AGE-BSA, showed a positive reaction to CML-BSA and furthermore also to human lens proteins, which are known to undergo CML modification in vivo. Finally, patients with renal failure caused by diabetes or nondiabetic pathologies had a higher autoantibody activity against CML structure than that in normal subjects or diabetic patients without renal failure. These results indicate that CML accumulated in vivo serves as an immunological epitope to generate an autoantibody specific for CML that might be used as a potential marker for diabetic nephropathy or chronic renal failure.     

Changes in quality of life after renal transplantation

Studies were performed to investigate the relationship between serum interleukin-6 (IL-6) and the nutritional status in chronic hemodialysis patients. Serum IL-6 in 45 patients (21 men and 24 women), each with chronic renal failure and having undergone hemodialysis for more than 3 years, was measured before and after a dialysis session. The nutritional status of each patient was evaluated by measuring body mass index (BMI), body weight loss for 3 years, midarm muscle area (MAMA), serum albumin, prealbumin, and insulin-like growth factor-1. Serum IL-6 was significantly higher in the patients undergoing hemodialysis (11.7 +/- 2.8 pg/mL) than in healthy volunteers (< 0.6 pg/mL). There was no further increase in serum IL-6 after a dialysis session when the extracellular water volume was corrected by the ultrafiltrate volume. Predialytic serum IL-6 was significantly correlated with serum albumin (r = -0.4, P = 0.006), cholinesterase (r = -0.51, P = 0.001), body weight change for 3 years (r = -0.48, P = 0.001) and MAMA r = -0.39, P = 0.05). With the patients divided into two groups, a high serum IL-6 (>10 pg/mL) group and low serum IL-6 (<10 pg/mL) group, the body weight loss for 3 years (-4.60% +/- 1.39% v 0.76 +/- 0.75%, P < 0.01) was significantly higher, and the serum albumin level (3.66 +/- 0.10 g/dL v 3.96 +/- 0.05 g/dL, P < 0.05) was significantly lower in those patients with high serum IL-6 than in those with low serum IL-6. The results of a multiple regression analysis indicated that the serum IL-6 level was dependent on the duration of hemodialysis, age, and the dialysis membrane properties. These results suggest that the nutritional status in chronic hemodialysis patients was affected, at least in part, by the circulating IL-6 level. Multiple factors, such as long-term hemodialysis, aging, and the use of a regenerated cellulose membrane dialyzer, were associated with this increased level of IL-6.     

Independent effects of residual renal function and dialysis adequacy on actual dietary protein, calorie, and other nutrient intake in patients on continuous ambulatory peritoneal dialysis.

Previous studies have suggested that the cross-sectional relationship observed between total solute clearance (Kt/V) and dietary protein intake (DPI) in patients undergoing dialysis is possibly mathematical in origin. A cross-sectional study on 242 patients undergoing continuous ambulatory peritoneal dialysis (CAPD) was performed to determine the differential effects of dialysis adequacy and residual renal function (RRF) on actual dietary intake. All patients underwent a 7-d food frequency questionnaire to quantify daily dietary protein, calorie (DCI), and other nutrient intake, subjective global assessment (SGA), and collection of 24-h dialysate and urine for total (PD and renal) Kt/V and RRF. Patients were categorized into three groups: I (n = 94), total Kt/V >/=1.7 and GFR >0.5 ml/min per 1.73 m(2); II (n = 58), total Kt/V >/=1.7 but GFR <0.5 ml/min per 1.73 m(2); and III (n = 90), total Kt/V <1.7. Sixty-nine percent versus 62% versus 42% of group I versus II versus III patients were well nourished according to SGA (P = 0.004). DPI (1.23 [0.47] versus 1.12 [0.49] versus 0.99 [0.40] g/kg per d; P = 0.002) and DCI (27.3 [8.9] versus 23.8 [8.6] versus 23.0 [8.2] kcal/kg per d; P = 0.002) showed significant decline across the three groups. Intake of other nutrients, including carbohydrate, fat, fatty acids, and cholesterol was higher for group I compared with groups II and III. Adjusting for age, gender, weight, and diabetes, every 1 ml/min per 1.73 m(2) increase in GFR was associated with a 0.838-fold increase in DCI (95% confidence interval to interval, 0.279 to 1.397; P = 0.003) and a 0.041-fold increase in DPI (95% confidence interval, 0.009 to 0.072; P = 0.012), whereas every 0.25-unit increase in total (PD and renal) Kt/V was associated with a 0.570-fold increase in DCI (95% confidence interval, 0.049 to 1.092; P = 0.032) and a 0.052-fold increase in DPI (95% confidence interval, 0.023 to 0.081; P = 0.001). Greater small-solute clearances are associated with better dietary intake and better nutrition. The study confirmed significant and independent effect of RRF, but not PD solute clearance, on actual DPI, DCI, and other nutrient intake in patients on CAPD.     

Association between blood indoxyl sulfate and carbonyl stress marker in hemodialysis patients

BACKGROUND: Indoxyl sulfate (IS) is a protein-bound solute, which is progressively retained in blood according to the decline of renal function. However, clinical relevance of excess IS in hemodialysis (HD) patients remains unknown. PATIENTS AND METHODS: We measured serum IS and clinical parameters including pentosidine, carboxymethyllysine (CML) and homocysteine levels in 55 HD patients (age: 67 +/- 2 years, time on HD: 67 +/- 11 months, male/female = 30/25), and examined the relationship between IS and these data. RESULTS: Serum IS was markedly increased in HD patients (80.49 +/- 6.17 microg/ml) compared to normal range (< 1.9 microg/ml). IS was significantly and positively correlated with time on HD (p < 0.01), blood urea nitrogen (p < 0.01), beta2-microglobulin (p < 0.03), and protein catabolic rate (PCR) (p < 0.01). The patients with increased IS needed a higher erythropoietin dosage. Blood IS was positively correlated with pentosidine (r = 0.505, p < 0.01) and CML (r = 0.275, p < 0.05). In contrast, blood IS was not associated with nutritional and inflammatory parameters. A stepwise multiple regression analysis revealed that time on HD, PCR and pentosidine were significant determinants of IS. CONCLUSIONS: Serum IS was related to time on HD and dietary protein intake. Accumulated IS may be associated with enhanced carbonyl stress in chronic HD patients.     

Plasma levels of advanced glycation end products in children with renal disease

In adults, advanced glycation end products (AGEs) rise slowly in tissues and circulation during aging, and accumulate at an accelerated rate both in diabetes and chronic renal insufficiency (CRI). We aimed to investigate the pattern of AGE accumulation in children/adolescents with CRI and on renal replacement therapy by dialysis and transplantation. Concentrations of fluorescent AGEs, carboxymethyllysine (CML) and lipofuscin-like substance (LFLS, a marker of lipid peroxidation) were followed. Data were obtained from 11 CRI patients on conservative treatment (age 12.6±1.7 years, serum creatinine: 205.7±17.5 μmol/l), ten patients on renal replacement therapy with dialysis (13.6±1.7 years, 698.2±48.9 μmol/l) and nine patients after kidney transplantation (15.9±1.1 years, 115.9±12.0 μmol/l) and comparison made with the data from 28 healthy controls (11.8±8.2 years, 44.1±8.2 μmol/l). In controls, an age-dependent rise of fluorescent AGE and CML levels was observed. In the CRI group, fluorescent AGEs [0.38±0.03×10⁵ arbitrary units (AU)] and CML (369±26 ng/ml) concentrations were doubled compared with controls (0.16±0.03×10⁵ AU and 189±42 ng/ml, respectively) and even higher levels were revealed in dialyzed patients (0.80±0.05×10⁵ AU; 650±94 ng/ml). Successful kidney transplantation significantly reduced but did not normalize fluorescent AGE levels (0.39±0.03 ×10⁵ AU), while the decline in CML levels (550±47 ng/ml) was insignificant. Plasma LFLS was elevated in CRI (19.6± 1.7 AU) and was even higher in dialyzed children (32.0±5.3 AU) compared with healthy controls (7.1± 1.4 AU). Kidney transplantation did not normalize LFLS levels (20.3±5.3 AU), pointing to persistently enhanced lipid peroxidation. Our study provides the first data on enhanced fluorescent AGEs and CML levels in children/adolescents with CRI and on dialysis. Successful renal transplantation decreased but did not normalize AGE levels, probably because of still-impaired renal function with enhanced oxidative stress, as well as the influence of immunosuppressive therapy. Received: 13 July 2000 / Revised: 8 June 2001 / Accepted: 12 July 2001     

Renal insulin resistance syndrome, adiponectin and cardiovascular events in patients with kidney disease: the mild and moderate kidney disease study

The relationship among insulin resistance, adiponectin, and cardiovascular (CV) morbidity in patients with mild and moderate kidney disease was investigated. Insulin sensitivity (Homeostasis Model Assessment of Insulin Resistance [HOMA-IR]) and adiponectin plasma levels were assessed in 227 nondiabetic renal patients at different degrees of renal dysfunction and in 76 healthy subjects of similar age and gender distribution and body mass index. In renal patients, association with prevalent CV events was evaluated, and incident CV events were evaluated in a prospective study. HOMA-IR was markedly higher in patients than in healthy subjects (3.59 +/- 3.55 versus 1.39 +/- 0.51; P < 0.01). In renal patients, HOMA-IR was significantly correlated with body mass index (r = 0.477; P < 0.01), triglycerides (r = 0.384; P < 0.01), adiponectin plasma levels (r = -0.253; P < 0.01), and age (r = 0.164; P < 0.05), but not with renal function (GFR by iod-thalamate clearance). Patients with previous CV events were significantly older, had higher HOMA-IR and serum triglycerides, and had lower adiponectin plasma levels (all P < 0.05). Logistic regression analysis revealed age (P < 0.001) and adiponectin (P < 0.002) as independent variables related to prevalent CV events. In the prospective study, median follow-up was 54 mo. Patients who experienced CV events had significantly higher serum glucose and lower adiponectin plasma levels (both P < 0.05). In patients with chronic kidney diseases, a syndrome of insulin resistance is present even in the earliest stage of renal dysfunction, and several components of this syndrome are associated with CV events. Moreover, hypoadiponectinemia is a novel putative CV risk factor in patients with mild and moderate renal failure.