L-carnitine infusions may suppress serum C-reactive protein and improve nutritional status in maintenance hemodialysis patients.

Scattered reports indicate that L-carnitine may suppress proinflammatory cytokines in sick individuals without renal disease and may improve protein synthesis or nitrogen balance either in patients without renal disease or in maintenance hemodialysis (MHD) or chronic peritoneal dialysis patients. We conducted an experimental study in MHD patients to evaluate the effects of L-carnitine treatment on inflammatory and protein-energy nutritional status. MHD patients were assigned to receive intravenous injections of L-carnitine 20 mg/kg (n = 48) or placebo (n = 65) thrice weekly at the end of each hemodialysis treatment for 6 months. The carnitine-treated group showed a statistically significant decrease in serum C-reactive protein and increase in serum albumin and transferrin, blood hemoglobin, and body mass index. Conversely, in the placebo-treated group, a significant decrease was reported for serum albumin, serum transferrin, and body mass index, whereas the other considered measures did not change significantly. These preliminary findings suggest that in MHD patients, L-carnitine therapy may suppress inflammation, particularly among those patients with C-reactive protein > or =3 mg/dL, and may improve protein-energy nutritional status.     

Serum matrix metalloproteinases MMP-2 and MMP-3 levels in dialysis patients vary independently of CRP and IL-6 levels

BACKGROUND: Patients on chronic hemodialysis or peritoneal dialysis often develop an inflammatory state that causes morbidity and mortality. Cross-sectional studies of dialysis patients have determined that C-reactive protein (CRP) is a predictor of morbidity. Little is known as to whether CRP, cytokines, such as IL-6 and IL-1beta that stimulate the synthesis of CRP, or matrix metalloproteinases (MMPs) are markers of inflammation in patients on dialysis. METHODS: We assayed by ELISA serum levels of MMP-2, MMP-3, IL-6 and CRP in healthy individuals and in patients with pre-end-stage renal disease (pESRD, n = 10), peritoneal dialysis (PD, n = 11), hemodialysis (HD, n = 17) and renal transplant (TX, n = 10). RESULTS: MMP-2 was significantly elevated before dialysis, perhaps indicative of progressive chronic renal sclerosis. MMP-3 was markedly elevated in hemodialysis patients but not in pESRD or PD patients, and may be related to the hemodialysis process and/or accelerated atherogenesis in these patients. IL-6 was significantly elevated in all patient groups, including pESRD patients. There were no statistically significant differences in CRP levels among the study groups. CRP correlated with IL-6, but not with MMP-2 or MMP-3. CONCLUSIONS: The data indicate that there are measurable differences in the expression of MMPs within the dialysis patient population. Because dialysis can be associated with local and systemic inflammation, increased levels of MMP-3 in the hemodialysis group may be a reflection of gene stimulation induced by inflammatory cytokines and should be considered as a marker of chronic, local inflammation.     

血液透析患者心脏瓣膜钙化及其危险因素

目的观察尿毒症血液透析患者心脏瓣膜钙化(VC)情况并分析其危险因素。方法使用HDI-5000彩色超声诊断仪检测222例尿毒症维持性血液透析(HD)患者心脏VC情况,将患者分为VC组与无VC组,比较两组患者SGA评分、血压、透析前血红蛋白(Hb)、血清白蛋白(Alb)、前白蛋白(pAlb)、血钙、血磷、全段甲状旁腺激素(iPTH)、血脂及C反应蛋白(CRP)等指标。结果VC组76例(34.2%),无VC组146例(65.8%)例。VC组年龄显著大于无VC组,肾衰竭病程显著长于无VC组,高血压持续时间、吸烟年支数、中～重度营养不良者比例、CRP、血钙、血磷及iPTH等都显著高于无VC组,Alb及pAlb显著低于无VC组。多因素分析显示Alb<30g/L、pAlb<200mg/L、SGA评分中～重度及CRP>5mg/L均与VC显著相关。结论VC发生不仅与年龄、肾衰竭病程、高血压持续时间、吸烟年支数、钙磷代谢紊乱及继发性甲状旁腺功能亢进有密切联系,而且与炎症和营养不良显著相关,患者心脏的发生是多种因素综合作用的结果。     

左卡尼汀对血液透析患者微炎症及营养状况的影响

目的探讨左卡尼汀对维持性血液透析患者微炎症及营养状况的影响。方法选择62例维持性血液透析患者，随机分为左卡尼汀组和对照组，检测二组患者治疗前、治疗后血C反应蛋白（CRP）、血红蛋白（Hb）、白蛋白（Alb）和血肌酐（SCr）值，计算Kt／V值。结果与治疗前及对照组治疗后比较，左卡尼汀组患者治疗后CRP水平下降，Alb、Hb升高，差异有统计学意义（P〈0．05）；对照组患者治疗前后CRP、Alb、Hb无统计学差异（P〉0.05）；二组患者治疗前后SCr、Kt/V值均无统计学差异（P〉0．05）。结论左卡尼汀可减轻维持性血液透析患者微炎症反应，改善患者营养状态。     

Hemodialysis central venous catheters as a source of inflammation and its implications

The mortality rate for end-stage renal disease patients is six times higher than in the general population. Hemodialysis central venous catheter (CVC) utilization has increased by 50% between 1998 and 2004 and data from the United States Renal Data System suggest that 81% of the patients initiate hemodialysis through a CVC. There is evidence that the two observations are linked in both an obvious way (catheter-related sepsis) as well as in a less obvious manner-chronic inflammation. Inflammation is highly prevalent in chronic hemodialysis (CHD) patients and is consistently associated with poor outcomes. Some of the most important consequences of inflammation in CHD include, but are not limited to, cardiovascular disease, uremic protein-energy wasting, erythropoietin hyporesponsiveness, and increased hospitalization and death rates. Use of CVC has been long suspected to play a role in the inflammatory response in CHD patients. Recent studies have shown that the presence of CVCs is associated with higher levels of C-reactive protein (CRP), lower serum albumin values, and lower hemoglobin values. Furthermore, there are data showing that CRP levels decrease following CVC removal. Accordingly, avoidance of CVC represents an effective strategy to limit the inflammatory response in CHD patients and potentially prevent its devastating consequences.     

Nutritional status in hemodialysis patients: options for on-line convective treatment.

Although hemodialysis (HD) has improved the life expectancy of patients with end-stage renal disease (ESRD), uremic patients continue to experience high morbidity and mortality. Two of the most important risk factors for morbidity and mortality are protein-energy malnutrition (PEM) and inflammation. The causes for PEM in ESRD are numerous. The use of materials for dialysis, especially of the dialyzer membrane, is reported as one of the recognized causes for chronic inflammation in hemodialysis. We performed a 6-month prospective study examining the influence of on-line predilution hemodiafiltration on the inflammatory and nutritional status in a population of male hemodialysis patients using ultrapure dialysis fluid and polyamide dialyzers. We evaluated serum C-reactive protein, albumin, and transferrin and some nutritional parameters such as body mass index (BMI), phase angle (phi), fatty mass (FM), and free fatty mass (FFM) using bioelectrical impedance (BIA). Results showed significant amelioration of BMI and the re-equilibrium of the acute phase protein after on-line predilution hemodiafiltration. These results support the hypothesis that on-line predilution hemodiafiltration, as convective extracorporeal treatment, may be used to treat malnourished hemodialysis patients and to prevent malnutrition in the ESRD patient at risk for malnutrition.     

Soluble Fas: a novel marker of inflammation in uremia

BACKGROUND: Inflammation has been associated with atherosclerotic cardiovascular disease (CVD) and anemia in patients with end-stage renal disease (ESRD). Recent studies have shown that serum levels of soluble Fas (sFas), an antiapoptotic and proinflammatory molecule, are elevated in patients with cardiac disease and patients with ESRD. We therefore sought to investigate serum levels of sFas in uremic patients and its correlation with known markers of inflammation, anemia and CVD. METHODS: The study included 25 ESRD patients (14 on hemodialysis, 11 on CAPD), 27 patients with chronic kidney disease (CKD; creatinine clearance <50 ml/min/1.73 m2), and 14 normal control subjects. We measured serum levels of sFas, C-reactive protein (CRP), and albumin. We also investigated the association of serum sFas levels with the presence of CVD and with erythropoietin (EPO) dosage. RESULTS: Levels of sFas were elevated in CKD and ESRD patients compared to controls. sFas levels correlated negatively with creatinine clearance. In the dialysis patients, we observed that sFas levels were higher among those with CVD. Serum levels of sFas correlated with serum levels of CRP (r=0.31; P=0.03), serum levels of albumin (r=-0.35, P=0.02), and EPO dosage (r=0.51; P=0.009). CONCLUSION: These results suggest that sFas may be a marker of inflammation in CKD and ESRD patients.     

Effect of treatment with omega-3 fatty acids on C-reactive protein and tumor necrosis factor-alfa in hemodialysis patients

C-reactive protein (CRP), a strong independent risk marker of cardiovascular disease (CVD), and tumor necrosis factor-alfa (TNF-α), a known pro-inflammatory cytokine, are elevated and have damaging effects in patients with chronic renal failure (CRF). Omega-3 fatty acids play an important modulatory role in inflammatory responses. The aim of this study is to review the alterations in serum levels of TNF-α, CRP and other parameters caused by omega-3 supplementation in dialysis patients. The clinical trial was performed in 37 patients with end-stage renal disease undergoing dialysis in hemodialysis centers of three university hospitals in Tabriz. Blood samples were obtained from the study patients for hemoglobin, albumin, ferritin, triglyceride, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL)-cholesterol, TNF-α and high specific-CRP (hs-CRP) measurement. The patients received 3 g omega-3 per day for 2 months. The side-effects noticed were nausea, diarrhea and dyspepsia and undesired drug smell. The difference noted in hemoglobin, albumin, ferritin, CRP, triglyceride, total, LDL and HDL-cholesterol before and after supplementation with omega-3 fatty acid was not statistically significant (P > 0.05). However, the use of omega-3 decreased the serum levels of TNF-α significantly. We conclude that the use of 3 g of omega-3 per day caused significant decrease in serum levels of TNF-α in the dialysis population, and its use is recommended in such patients.     

Uremia alters HDL composition and function

Functional impairment of HDL may contribute to the excess cardiovascular mortality experienced by patients with renal disease, but the effect of advanced renal disease on the composition and function of HDL is not well understood. Here, we used mass spectrometry and biochemical analyses to study alterations in the proteome and lipid composition of HDL isolated from patients on maintenance hemodialysis. We identified a significant increase in the amount of acute phase protein serum amyloid A1, albumin, lipoprotein-associated phospholipase A2, and apoC-III composing uremic HDL. Furthermore, uremic HDL contained reduced phospholipid and increased triglyceride and lysophospholipid. With regard to function, these changes impaired the ability of uremic HDL to promote cholesterol efflux from macrophages. In summary, the altered composition of HDL in renal disease seems to inhibit its cardioprotective properties. Assessing HDL composition and function in renal disease may help identify patients at increased risk for cardiovascular disease.     

Protein and energy: recommended intake and nutrient supplementation in chronic dialysis patients

Nutritional status is an important predictor of clinical outcome in end-stage renal disease (ESRD) patients, especially in patients on chronic hemodialysis. Uremic malnutrition is strongly associated with increased risk of death and hospitalization events in this patient population, and decreased muscle mass is the most significant predictor of these outcomes. Several factors that influence protein metabolism predispose chronic hemodialysis patients to increased catabolism and loss of lean body mass. The available evidence suggests that low protein and energy intake associated with advanced uremia along with catabolic consequences of dialytic therapies can lead to the development of uremic malnutrition. Recent studies show that the hemodialysis procedure induces a net protein catabolic state at the whole-body level as well as skeletal muscle. There is evidence to suggest that these undesirable effects are due to decreased protein synthesis and increased proteolysis. Provision of nutrients, either in the form of intradialytic parenteral nutrition or oral feeding during hemodialysis, can adequately compensate for the catabolic effects of the hemodialysis procedure. While the mechanisms of these effects are not studied in detail, changes in extracellular amino acid concentrations, along with certain anabolic hormones such as insulin, are important mediators of these actions.     

Impact of hemodialysis on endogenous plasma and muscle carnitine levels in patients with end-stage renal disease

BACKGROUND: End-stage renal disease (ESRD) patients undergoing hemodialysis treatment have reduced plasma L-carnitine levels; however, the relationship between dialysis age and carnitine status is poorly understood. This study examined the relationship between duration of dialysis and plasma and skeletal muscle concentrations of L-carnitine and its esters in ESRD patients. METHODS: Blood samples were collected from 21 patients at baseline and throughout the first 12 months of hemodialysis. In 5 patients, muscle samples were obtained after 0, 6, and 12 months of hemodialysis. Blood and muscle samples were collected from an additional 20 patients with a mean dialysis age of 5.10 years. L-carnitine, acetyl-L-carnitine, and total L-carnitine were measured by high-performance liquid chromatography (HPLC). RESULTS: The mean +/- SD plasma L-carnitine concentration in ESRD patients who had not yet started hemodialysis was 50.6 +/- 20.0 micromol/L. Significantly lower concentrations were observed after 12 months (29.7 +/- 10.5 micromol/L) and >12 months (22.0 +/- 5.4 micromol/L) of hemodialysis treatment. Acetyl-L-carnitine also declined with dialysis age, while plasma nonacetylated acylcarnitines continued to increase with the progression of hemodialysis therapy. An inverse relationship between dialysis age and muscle L-carnitine concentrations was observed. CONCLUSION: Long-term hemodialysis treatment is associated with a significant reduction in endogenous plasma and muscle L-carnitine levels and a significant increase in plasma acylcarnitines. The majority of the change in plasma L-carnitine concentrations occurs within the first few months of hemodialysis, while muscle levels continue to decline after 12 months of treatment.     

Comparison of glycated albumin and hemoglobin A(1c) levels in diabetic subjects on hemodialysis

Glycated albumin is thought to more accurately reflect glycemic control in diabetic hemodialysis patients than hemoglobin A(1c) because of shortened red cell survival. To test this, glycated hemoglobin and albumin levels were measured in blood samples collected from 307 diabetic subjects of whom 258 were on hemodialysis and 49 were without overt renal disease. In diabetic subjects with renal disease, relative to those without, the mean serum glucose and glycated albumin concentrations were significantly higher while hemoglobin A(1c) tended to be lower. The glycated albumin to hemoglobin A(1c) ratio was significantly increased in dialysis patients compared with the controls. Hemoglobin A(1c) was positively associated with hemoglobin and negatively associated with the erythropoietin dose in hemodialysis patients, whereas these factors and serum albumin did not significantly impact glycated albumin levels. Using best-fit multivariate models, dialysis status significantly impacted hemoglobin A(1c) levels without a significant effect on glycated albumin. Our results show that in diabetic hemodialysis patients, hemoglobin A(1c) levels significantly underestimate glycemic control while those of glycated albumin more accurately reflect this control.     

Hyperlipidemia in uremic children: response to peritoneal dialysis and hemodialysis.

Hemodialysis and hyperlipidemia have been associated in both adults and children. The present study indicates hyperlipidemia in uremic children treated with peritoneal dialysis and implies that the cardiovascular risk felt to exist with hemodialysis also exists in peritoneal dialysis. Thirty-eight children with chronic renal insufficiency or end-stage renal disease were followed serially under varying conditions of medical management, hemodialysis, peritoneal dialysis, and transplantation. Serum triglyceride concentrations in patients on peritoneal dialysis were not significantly different from those in patients on hemodialysis, but both were significantly higher (P less than 0.01) than concentrations in patients on medical management and transplantation.     

Antithrombin III in uremia

Antithrombin III (AT-III) was measured immunologically in 20 uremic patients on maintenance hemodialysis and in 10 non-dialysed uremic patients. The dialysed patients had slightly elevated AT-III levels. The non-dialysed patients had significantly elevated AT-III levels. A negative correlation was found between AT-III and serum creatinine and between AT-III and serum albumin. AT-III did not correlate to the heparin amount required for hemodialysis. A negative correlation was found between the heparin requirement and serum albumin. It is suggested, that serum albumin might facilitate the action of AT-III and heparin. It is also suggested, that AT-III levels may be high in active renal disease, decreasing as uremia advances.     

Uremic malnutrition is a predictor of death independent of inflammatory status

BACKGROUND: Several studies have pointed out the influence of nutritional parameters and/or indices of inflammation on morbidity and mortality. Often, these conditions coexist, and the relative importance of poor nutritional status and chronic inflammation in terms of predicting clinical outcomes in chronic hemodialysis (CHD) patients has not been clarified. METHODS: We undertook a prospective cohort study analyzing time-dependent changes in several established nutritional and inflammatory markers, and their influence on mortality in 194 CHD patients (53% male, 36% white, 30% with diabetes mellitus, mean age 55.7 +/- 15.4 years) throughout a 57-month period. Serial measurements of serum concentrations of albumin, prealbumin, creatinine, transferrin, cholesterol, and C-reactive protein (CRP), as well as normalized protein catabolic rate, postdialysis weight, and phase angle and reactance by bioelectrical impedance analysis were performed every 3 months. Clinical outcomes were simultaneously assessed using indicators of mortality. RESULTS: Serum albumin, serum prealbumin, serum creatinine, and phase angle were significant predictors of all-cause mortality, even after adjustment for serum CRP concentrations. Serum CRP concentrations were not significantly associated with mortality. Serum albumin concentrations and phase angle were also independent predictors of cardiovascular deaths in the multivariate model. CONCLUSION: The nutritional status of CHD patients predicts mortality independent of concomitant presence or absence of inflammatory response. Prevention of, and timely intervention to treat uremic malnutrition by suitable means are necessary independent of the presence and/or therapy of inflammation in terms of improving clinical outcomes in CHD patients.     

Impact of albumin synthesis rate and the acute phase response in the dual regulation of fibrinogen levels in hemodialysis patients

BACKGROUND: Fibrinogen is a risk factor for cardiovascular disease. It also is an acute phase protein (APP) and its plasma concentration increases with inflammation. Fibrinogen synthesis correlates with albumin synthesis in nephrotic patients and in patients with an expanded plasma volume even when serum albumin is normal and there is no inflammatory disease. The relationships among albumin synthesis, the acute phase response and plasma fibrinogen levels in hemodialysis patients are unknown. METHODS: In 74 hemodialysis patients, albumin synthesis, plasma volume (PV) and acute phase proteins (APPs) C-reactive protein (CRP), alpha1 acid glycoprotein (alpha1 AG), ceruloplasmin (Cer), and interleukin 6 (IL-6) were measured in serum and fibrinogen in plasma, and the results analyzed by multiple regression analysis. CRP, IL-6, alpha1 AG, Cer and fibrinogen were measured monthly, which enabled us to determine whether changes in these APPs correlated with the levels of and variability in plasma fibrinogen over time using a longitudinal modeling approach. Length of follow-up for the 74 patients ranged from 3.25 to 67.5 months. RESULTS: Baseline fibrinogen (548.6 +/- 106. 4 mg/dL) was significantly greater than levels reported for normal adults and correlated positively with albumin synthesis (P < 0.001), age (P < 0.001) and log CRP (P = 0.002) and negatively with PV (P < 0.001). Longitudinally, fibrinogen varied positively with long-lived APPs, Cer and alpha1 AG, as well as the short-lived APP, CRP. CONCLUSION: Plasma fibrinogen concentration is high in HD patients and directly correlates with increased albumin synthesis rates and the serum levels of APPs. Fibrinogen levels also correlate negatively with PV. Fibrinogen levels vary over time in synchrony with levels of other long-lived APPs, supporting the hypothesis that fibrinogen is regulated in part as a component of the acute phase response and in part by factors that increase albumin synthesis.     

Inflammation and dietary protein intake exert competing effects on serum albumin and creatinine in hemodialysis patients.

BACKGROUND: Cross-sectional studies have shown an inverse correlation between serum C-reactive protein (CRP) and serum albumin concentration in hemodialysis patients. The net effects of inflammation and dietary protein intake on nutritional markers over time are unknown. METHODS: To explore the effects of CRP and normalized protein catabolic rate (nPCR) on serum albumin and creatinine, we analyzed six consecutive months of laboratory data from 364 hemodialysis patients, using a multivariable Mixed model with conservative biases. RESULTS: The overall trend over time in serum albumin was slightly positive (0.039 g/dL/month) and in serum creatinine slightly negative (-0.052 mg/dL/month). With increasing CRP, serum albumin declined significantly (-0.124 g/dL/month per unit increase in log CRP, adjusted for age, gender, race, diabetes, and nPCR, P < 0.0001). Serum albumin increased with increasing nPCR (0.021 g/dL/month per 0.1 g/kg/day, P < 0.0001). The effect of CRP on albumin was attenuated in African Americans and at a higher nPCR. Corresponding values for creatinine mirrored those for albumin. With increasing CRP, creatinine declined significantly [-0.142 mg/dL/month per unit increase in log CRP, adjusted for age, gender, race, diabetes (time since initiation of dialysis; vintage), Kt/V, and nPCR, P = 0.002]. Serum creatinine increased with increasing nPCR (0.183 mg/dL/month per g/kg/day, P < 0.0001). CONCLUSIONS: Proxies of inflammation and dietary protein intake exert competing effects on serum albumin and creatinine in hemodialysis patients. These data provide a rationale for prospective testing of dietary protein supplementation in hemodialysis patients with biochemical evidence of ongoing inflammation and "malnutrition."     

Plasma fibronectin levels in patients with chronic uremia

Plasma fibronectin (FN) concentration was measured in patients with idiopathic glomerulonephritis (GN) with or without impaired renal function, in uremic patients undergoing periodic hemodialysis and in renal transplant patients before and after an acute rejection crisis. Results show normal FN levels in idiopathic GN and in renal transplant patients with normal renal function, while significantly lower levels were found in GN with severe renal damage, in uremia before and after dialysis, and in renal transplant patients during acute and chronic graft rejection. Significant correlations between high serum creatinine values and low plasma FN levels were found in renal transplant patients. These findings suggest that the kidney may influence FN levels in the blood since acute (rejection crisis) and chronic renal failure (uremia) cause low concentrations of this protein, while levels tend to return to normal values in patients with uremia after renal transplantation. We hypothesize that the normal kidney removes or perhaps degrades some substances or hormones that may control the release or synthesis of FN. These substances are not dialyzed by cellophane membranes since low plasma FN levels persist after periodic hemodialysis. Only the renal graft provokes an increase of FN in the blood stream.     

Protein-bound uremic retention solutes

Protein-bound uremic retention solutes are molecules with low molecular weight (MW) but should be considered middle or high MW substances. This article describes the best known substances of this group, which include p-cresol, indoxyl sulfate, hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furan-propionic acid (CMPF), and homocysteine. At concentrations encountered during uremia, p-cresol inhibits phagocyte function and decreases leukocyte adhesion to cytokine-stimulated endothelial cells. CMPF has been implicated in anemia and neurologic abnormalities of uremia. CMPF could alter the metabolism of drugs of inhibiting their binding to albumin and their tubular excretion. Indoxyl sulfate administrated to uremic rats increases the rate of progression of renal failure. Hippuric acid inhibits glucose utilization in the muscle, and its serum concentration is correlated with neurologic symptoms of uremia. Homocysteine predisposes uremic patients to cardiovascular disease through impairment of endothelial and smooth muscle cell functions. The removal of protein-bound compounds by conventional hemodialysis is low. Other strategies to decrease their concentrations include increase in dialyze pore size, daily hemodialysis, peritoneal dialysis, reduction of production or acceleration of degradation, and preservation of residual renal function.