Role of components of frailty on quality of life in dialysis patients: a cross-sectional study.

BACKGROUND: Many people on dialysis suffer a variety of conditions that can affect frailty (the condition or quality of being frail), such as comorbidities, disabilities, dependence, malnutrition, cognitive impairment and poor social conditions. Frailty is suspected to affect quality of life (QoL). OBJECTIVES: The study aimed to evaluate the effect of the different components of frailty on the QoL of people on dialysis. METHODS: We enrolled 203 out of 233 prevalent patients on dialysis in the Trieste area of Italy. We applied the Short-Form 36 (SF-36) questionnaire, Activities of Daily Living, Instrumental Activities of Daily Living, Subjective Global Assessment scales and Karnofsky Index. In addition we analysed their social conditions. RESULTS: Dependence, malnutrition and disability had a negative role on QoL. Living with family and good social-economic conditions were significantly related to a better QoL. CONCLUSIONS: Dependence, malnutrition, disability, poor social and economic conditions have a significant effect on life quality. The role of comorbidities appears to be less important. Screening of patients, nutritional and functional rehabilitation and prevention of social isolation appear to be indispensable in guaranteeing a satisfactory life quality.

Acetate-free biofiltration reduces intradialytic hypotension: a European multicenter randomized controlled trial.

BACKGROUND: Intradialytic hypotension (IH) is a common complication of bicarbonate hemodialysis (BD) and contributes to the intolerance of dialysis and the high cardiovascular morbidity and mortality among dialysis patients, the risk of which can be contained by convective therapies. AIMS/METHODS: To assess whether acetate-free biofiltration (AFB), a hemodiafiltration technique found to improve intradialytic cardiovascular stability in short-term studies, can influence long-term IH rates, predialysis systolic blood pressure (SBP), cardiovascular morbidity and mortality by comparison with BD, we analyzed data from a randomized controlled trial enrolling 371 new-to-dialysis patients, 194 on BD and 177 on AFB. RESULTS: During a 3-year follow-up, AFB carried a significantly lower risk of IH (incidence rate ratio 0.60 (95% CI 0.53-0.68), p < 0.0001). SBP dropped on AFB (p = 0.01), while it did not change on BD. Cardiovascular morbidity and mortality were similar between AFB and BD. CONCLUSION: AFB carries a lower long-term IH rate and reduces SBP by comparison with BD.

High plasma retinol binding protein 4 (RBP4) is associated with systemic inflammation independently of low RBP4 adipose expression and is normalized by transplantation in nonobese, nondiabetic patients with chronic kidney disease.

OBJECTIVE: Adipose-secreted retinol binding protein 4 (RBP4) circulates in free (active) and transthyretin (TTR)-bound forms and may be associated with obesity-related inflammation. Potential involvement of plasma and adipose RBP4 in systemic inflammation in the absence of obesity and diabetes is unknown. Inflammation reduces survival in chronic kidney disease (CKD) [particularly in maintenance haemodialysis (MHD)], and plasma RBP4 may increase with renal dysfunction. We investigated (i) potential associations between RBP4 and inflammation in CKD and (ii) the role of adipose tissue in this putative interaction. DESIGN: Cross-sectional. PATIENTS: Nonobese, nondiabetic patients with CKD undergoing conservative (CT: n = 10) or MHD treatment (n = 25) and healthy control subjects (C: n = 11). Renal transplant recipients (n = 5) were studied to further assess the impact of restored near-normal renal function. MEASUREMENTS: Plasma RBP4, TTR and C-reactive protein (CRP), adipose RBP4 expression. RESULTS: Plasma RBP4, TTR and CRP were highest in MHD (P < 0·05). Adipose RBP4 mRNA was, however, comparably low in CT and MHD (P < 0·05 vs C), and all parameters were normalized in transplant recipients (P < 0·05 vs MHD). In all subjects (n = 51), creatinine and TTR (P < 0·05) but not adipose RBP4 mRNA were associated with plasma RBP4. Plasma RBP4 but not its adipose expression was in turn associated positively (P < 0·05) with CRP independently of creatinine-TTR. CONCLUSIONS: High plasma RBP4 and inflammation are clustered in CKD in the absence of obesity and diabetes and are normalized by transplantation. Adipose RBP4 expression is not involved in plasma RBP4 elevation, which appears to be mainly because of passive accumulation, or in CKD-associated inflammation.

Hemodialysis induces p66(shc) gene expression in nondiabetic humans: correlations with oxidative stress and systemic inflammation.

OBJECTIVE: Oxidative stress and inflammation characterize hemodialysis (HD) and are associated with malnutrition, cardiovascular disease, and poor clinical outcome. p66(shc) stimulates oxidative stress and atherogenesis. The objective of the present study was to assess p66(shc) expression levels in HD and their associations with inflammatory and oxidative stress markers. DESIGN: p66(shc) messenger ribonucleic acid (mRNA) was compared with systemic oxidative stress and inflammation markers in control subjects and patients on HD before and after a single HD session in a cross-sectional analysis. SETTING: Outpatient hemodialysis unit. PATIENTS: The study included stable HD patients (n = 21, men/women: 18/3) who were on HD 3 times per week for a minimum of 8 weeks; age-matched control subjects (n = 22, men/women:17/5). MAIN OUTCOME MEASURE: mRNA levels of p66(shc), tumor necrosis factor α (TNF-α), and pentraxin 3 (PTX3), p66(shc) protein levels in white blood cells, lipid peroxidation (in the form of plasma thiobarbituric acid-reactive substance [TBARS]) and serum C-reactive protein. RESULTS: In patients on dialysis, of the p66(shc), TNF-α, and PTX3 mRNAs, p66(shc) protein levels were higher (P < .05) than in control subjects, as well as plasma TBARS and C-reactive protein (P < .05). p66(shc) mRNA directly correlated with TBARS (r = 0.69, P = .0005) and with TNF-α mRNA (r = 0.63, P = .003). These associations were confirmed in the whole study population (TBARS: r = 0.541, P = .0003; TNF-α: r = 0.581, P < .0001), whereas in the control group only the positive association between p66(shc) and TNF-α was detected. TNF-α was directly correlated with PTX3 both in HD patients (r = 0.72, P = .0005) and in the whole study group (r = 0.678, P < .0001). The dialysis session affected neither p66(shc) and TNF-α mRNA nor p66(shc) protein expression, whereas it further increased (P = .002) PTX3 mRNA. As compared with predialysis levels, TBARS were reduced (P < .05) after dialysis. In these conditions, p66(shc) remained directly correlated with TNF-α (r = 0.901, P < .0001). CONCLUSIONS: Increased p66(shc) gene expression correlates with TNF-α mRNA and with levels of markers of oxidative stress in HD. We suggest a novel link between HD-associated inflammation and p66(shc) gene expression contributing to systemic oxidative stress.

Complete correction of anemia by erythropoiesis-stimulating agents is associated with insulin resistance in hemodialysis patients.

Insulin resistance and anemia secondary to erythropoietin deficiency characterize patients with end-stage kidney disease. In a cross-sectional analysis, we examined the relationship between erythropoietin-mediated correction of anemia and insulin sensitivity in nondiabetic hemodialysis patients. Insulin sensitivity (euglycemic-hyperinsulinemic clamp) and endogenous glucose production (primed-continuous infusion of [6,6-(2)H(2)]glucose) were determined in two groups of patients with normal hemoglobin (n:8; mean hemoglobin: 14.0 ± 0.3 g/dl) or with mild anemia (n:10; mean hemoglobin: 12.1 ± 0.9 g/dl). The patients with normal hemoglobin were receiving higher (P < 0.05) erythropoietin doses than those with mild anemia (171 ± 73 and 91 ± 39 U kg(-1) wk(-1), respectively). The two groups were matched for all other potential determinants of insulin resistance. Endogenous glucose production was similar in the two groups of patients in the postabsorptive state and was completely suppressed by insulin infusion. During the hyperinsulinemic clamp, the rate of glucose infusion to maintain euglycemia was significantly lower (P < 0.01) in the patients with normal hemoglobin levels [166 ± 31 mg (m(2))(-1) min(-1)] than in those with mild anemia [251 ± 49 mg (m(2))(-1) min(-1)] and in a group of matched controls [275 ± 68 mg (m(2))(-1) min(-1)]. In pooled patients, individual values of hemoglobin concentrations inversely correlated with the rates of insulin-mediated glucose infusion, both as absolute values (r = -0.58; P < 0.05) and as values normalized by steady-state plasma insulin concentration (r = -0.74; P < 0.001). In conclusion, this exploratory study indicates that complete correction of anemia by erythropoietin treatment in patients with end-stage kidney disease on hemodialysis is associated with impaired insulin sensitivity.

[Obesity in dialysis and reverse epidemiology: true or false?]. / L'obesita' in dialisi e l'epidemiologia inversa: vero o falso?

About 50% of patients who undergo dialysis are overweight or obese. Rather than being a disadvantage, the extra weight is associated with improved survival in this patient group. However, the relationship between weight and outcome is complex among dialysis patients. In the general population obesity constitutes a clear cardiovascular risk factor. By contrast, in obese dialysis patients the nutritional status may be better, and obesity thus provides, at least in the short term, some protection against malnutrition and the associated morbidity. On the other hand, some studies suggest that mortality in the long term is directly correlated with excess weight and obesity, which indicates that fat represents a risk factor also in uremia. In the elderly, particularly those affected by end-stage renal disease, endocrine and metabolic effects on the nitrogen balance cause the loss of muscle mass despite an excess of adipose tissue, which is a condition known as sarcopenic obesity. While a good nutritional state is found in some obese dialysis patients, which probably accounts for the improved survival of the obese group as a whole, there is a sizable proportion of sarcopenic obese, which is probably increasing. Sarcopenic obesity is not only characterized by the reduction of muscle mass but also by the accumulation of fat surrounding the abdominal viscera (visceral fat syndrome), which may be associated with a greater degree of metabolic and atherosclerotic disease. Several studies have shown that malnutrition associated with obesity, including sarcopenic obesity, is the risk factor most closely correlated with morbidity and mortality both in dialysis patients and the general population. The timely identification of this condition has therefore become necessary in the dialysis population now dominated by the elderly and very elderly. Body mass index is inadequate as a measure of sarcopenic obesity since it cannot define muscle mass nor indicate the localization of the fat in the visceral compartment. Other indices must be developed and validated in well performed clinical trials to identify fat localization and the presence of sarcopenia.

Diabetics on dialysis in Italy: a nationwide epidemiological study.

BACKGROUND: Diabetes mellitus is a common disease, comprising 4-8% of the general population and up to 45% of new dialysis patients in industrialized countries. METHODS: We performed a nationwide study with the aim of analysing the approach of various centres to diabetic patients and to gather data on the epidemiology, clinical characteristics and complications of type 1 and type 2 diabetics. RESULTS: We acquired the data from 513 dialysis centres, 3665 prevalent diabetic patients and 4337 diabetic patients who started dialysis in the previous 10 years. Patient education and dialysis initiation: Sixty percent of the centres educate the patient regarding diet, pharmacological therapy and prevention of diabetic complications; in 245 centres (48%), this task belonged exclusively to the nephrologist and not to a multidisciplinary team. Seventy percent of the centres reported planning the initiation of dialysis and preparing the fistula between 1 and 3 months (78.5%) before the initiation of dialysis. Epidemiological and clinical data: Diabetic patients (56.9% males) represented 12.5% of the total dialysis population in Italy. The ratio between diabetes type 2 and type 1 was 5.3. The initial treatment was haemodialysis (HD) in 2533 patients (bicarbonate HD 88.8%) and peritoneal dialysis (PD) in 405 patients (CAPD 82.2%). During their dialytic life, 383 patients (226 from HD and 157 from PD) changed treatment modality, mainly because of cardiocirculatory instability (158 cases) or infection of the catheter tunnel/peritoneum (89 cases). The changes were mainly directed from bicarbonate HD and CAPD towards diffusive-convective extracorporeal techniques. Blood glucose (mean 154 +/- 56.8 mg/dl) exceeded 200 mg/dl in 15.2% of patients; serum cholesterol was >200 mg/dl in 39.3% of patients; serum triglycerides exceeded 200 mg/dl in 39.2% of patients and mean values for glycosylated haemoglobin was 7.2 +/- 1.8%. The nutritional state was judged to be normal in 59.6% of patients, 16.2% appeared to be mildly malnourished and 3% severely malnourished; 21.1% of subjects were obese. Echocardiography showed left ventricular hypertrophy in 90% of patients and echocolordoppler examination of the great vessels showed pathological findings (plaques and stenoses) in 73%. Pharmacological therapy. Sixty-nine percent of patients were treated with antihypertensive drugs, mainly calcium antagonists (50%) and ACE inhibitors (27%). Nitrates were prescribed for 33% of patients; antiplatelet or anticoagulant drugs were prescribed for 37% of patients. CONCLUSIONS: The present study demonstrates that the prevalence of diabetics in dialysis continues to increase in Italy, but remains less than that in Northern European countries. Type 2 diabetes is as dangerous as type 1 in terms of serious complications. There appears to be a greater awareness on the part of nephrologists of the serious problems associated with the care of diabetic patients in dialysis. The ideal dialytic modality has not been determined, dialysis is often not initiated in a timely manner and optimal drug therapy is not always prescribed. The aspirations to treat the diabetic dialysis patient according to currently accepted best practice guidelines still need to be fully realized.

Insulin action on glucose and protein metabolism during L-carnitine supplementation in maintenance haemodialysis patients.

BACKGROUND: Impaired protein anabolism and insulin resistance are characteristic features of maintenance haemodialysis patients. We have used a randomised, matched-paired, double-blind, placebo-controlled experimental design to determine the capability of intravenous L-carnitine supplementation to modify insulin resistance and protein catabolism in non-diabetic patients with end-stage renal disease (ESRD) undergoing chronic haemodialysis treatment. METHODS: L-carnitine (20 mg x kg(-1)) (n = 9) or placebo (n = 10) were given intravenously at the end of seven consecutive dialysis sessions. Whole-body protein and glucose metabolism were assessed on interdialytic days by the L[1-(13)C]leucine and the [2,2-(2)H(2)]glucose kinetic models in the postabsorptive state and during euglicemic hyperinsulinemic clamp studies at baseline and at the end of the treatment period. RESULTS: L-carnitine supplementation was associated with lower (P < 0.05) rates of leucine oxidation (-11 +/- 12%) and appearance from proteolysis (-6 +/- 2%) during the clamp studies than after placebo supplementation. The rates of glucose appearance in the postabsorptive state did not change significantly in the patients receiving L-carnitine treatment. Insulin-mediated glucose disappearance was improved by L-carnitine only in those patients (n = 5) (+18 +/- 3%, P < 0.05 vs placebo group, n = 5) with greater baseline insulin resistance, selected according to the median value of insulin sensitivity before treatment. CONCLUSIONS: L-carnitine supplementation was associated with protein-sparing effects in maintenance haemodialysis patients during hyperinsulinemia.

Higher total ghrelin levels are associated with higher insulin-mediated glucose disposal in non-diabetic maintenance hemodialysis patients.

BACKGROUND & AIMS: Insulin resistance is common in maintenance hemodialysis (MHD) and it can contribute to exceedingly high mortality in MHD patients. Ghrelin is a gastric hormone whose total plasma concentration is increased in MHD. Emerging data suggest a potential role of ghrelin to modulate intermediate metabolism but the metabolic impact of ghrelin in chronic kidney disease is unknown. The current study aimed at assessing the potential relationships between ghrelin and insulin sensitivity in MHD. METHODS: Total (T-Ghr) and acylated (A-Ghr) ghrelin as well as insulin-mediated glucose disposal [(M): hyperinsulinemic-euglycemic clamp] were measured in non-diabetic non-obese ambulatory MHD patients (n=19, 16 Males). C-reactive protein (CRP) was also measured since systemic inflammation is associated with insulin resistance in non-renal patients and inflammation is negatively modulated by ghrelin in experimental models. RESULTS: Compared to control subjects (C: n=9, 7 Males), MHD had similar body fat and resting energy expenditure but reduced M and increased CRP (P<0.05). MHD also had higher T-(P<0.05) but not A-Ghr. M was associated positively with T-Ghr and negatively with CRP in linear regression analysis in MHD. In stepwise multiple regression analysis only T-Ghr remained associated with M (P<0.05) in a model including A-Ghr and CRP. CONCLUSIONS: Insulin sensitivity is associated negatively with systemic inflammation and positively with total plasma ghrelin in non-diabetic MHD patients. Based on available knowledge these results suggest a potential novel role of ghrelin in preserving insulin sensitivity in MHD.

Association of interferon-gamma +874A polymorphism with reduced long-term inflammatory response in haemodialysis patients.

BACKGROUND: We have studied the effects of interferon (IFN)-gamma allelic variations on expression levels of pro- and anti-inflammatory cytokines and on long-term inflammatory status in haemodialysis patients. METHODS: Genotyping was performed in 123 patients for single nucleotide polymorphisms in the first intron of the IFN-gamma gene (+874 T/A). They were prospectively followed for 2 years. Cytokine mRNA levels in whole blood cells (detected by real time (RT)-PCR technique) and serum C-reactive protein (CRP) concentrations were compared in patient groups with different IFN-gamma genotypes. Serum CRP was evaluated every month and inflammatory state was defined as percent of abnormal values (above 5 mg/l) over total determinations. Of the total, 102 patients survived and completed 24+/-1 monthly CRP determinations. The IFN-gamma +/-874 A/A, 'low-producer' genotype was associated with decreased (P<0.05) mRNA levels of IFN-gamma and of interleukin-6 and with a lower (P<0.05) frequency of CRP elevation (37+/-6%) than the +/-874 A/T and T/T, 'intermediate and high-producer' genotypes (59+/-6%, and 60+/-5%, respectively). The mRNA levels of tumor necrosis factor-alpha, IL-10 and of transforming growth factor-beta1 were not different in the three groups of patients. Pooled analysis in deceased (10+/-3 monthly CRP determinations) and survived patients confirmed the results obtained in the patients who completed the follow-up period. CONCLUSIONS: The 'low-producer' IFN-gamma +874 A/A genotype was associated with a preventive effect on long-term CRP elevation in haemodialysis patients possibly mediated by decreased gene expression of IFN-gamma and IL-6.

Blood volume controlled hemodialysis in hypotension-prone patients: a randomized, multicenter controlled trial.

BACKGROUND: Recently we have devised and tested a biofeedback system for controlling blood volume (BV) changes during hemodialysis (HD) along an ideal trajectory (blood volume tracking, BVT), continuously modifying the weight loss rate and dialysate conductivity. This multicenter, prospective, randomized, crossover study aimed to clarify whether BVT (treatment B) can improve hypotension-prone patients' treatment tolerance, compared with conventional hemodialysis (treatment A). METHODS: Thirty-six hypotension-prone patients enrolled from 10 hemodialysis (HD) centers were randomly assigned to either of the study sequences ABAB or BABA, each lasting four months. RESULTS: A 30% reduction in intradialytic hypotension (IDH) events was observed in treatment B as compared with A (23.5% vs. 33.5%, P = 0.004). The reduction was related to the number of IDH in treatment A (y = 0.54x + 5; r = 0.4; P < 0.001): the more IDH episodes in treatment A, the better the response in treatment B. The best responders to treatment B showed pre-dialysis systolic blood pressure values higher than the poor responders (P = 0.04). A 10% overall reduction in inter-dialysis symptoms was obtained also in treatment B compared to A (P < 0.001). Body weight gain, pre-dialysis blood pressure, intradialytic weight loss as well as Kt/V did not differ between the two treatments. CONCLUSIONS: An overall improvement in the treatment tolerance was observed with BVT, particularly intradialytic cardiovascular stability. Patients with the highest incidence of IDH during conventional HD and free from chronic pre-dialysis hypotension seem to respond better. Inter-dialysis symptoms also seem to improve with control of BV.

The effects of control of thermal balance on vascular stability in hemodialysis patients: results of the European randomized clinical trial.

BACKGROUND: Many reports note that the use of cool dialysate has a protective effect on blood pressure during hemodialysis (HD) treatments. However, formal clinical trials in which dialysate temperature is tailored to the body temperature of appropriately selected hypotension-prone patients are lacking. METHODS: We investigated the effect of thermal control of dialysate on hemodynamic stability in hypotension-prone patients selected from 27 centers in nine European countries. Patients were eligible for the study if they had symptomatic hypotensive episodes in 25% or more of their HD sessions, assessed during a prospective screening phase over 1 month. The study is designed as a randomized crossover trial with two phases and two treatment arms, each phase lasting 4 weeks. We used a device allowing the regulation of thermal balance (Blood Temperature Monitor; Fresenius Medical Care, Bad Homberg, Germany), by which we compared a procedure aimed at preventing any transfer of thermal energy between dialysate and extracorporeal blood (thermoneutral dialysis) with a procedure aimed at keeping body temperature unchanged (isothermic dialysis). RESULTS: One hundred sixteen HD patients were enrolled, and 95 patients completed the study. During thermoneutral dialysis (energy flow rate: DeltaE = -0.22 +/- 0.29 kJ/kg x h), 6 of 12 treatments (median) were complicated by hypotension, whereas during isothermic dialysis (energy flow rate: DeltaE = -0.90 +/- 0.35 kJ/kg x h), the median decreased to 3 of 12 treatments (P < 0.001). Systolic and diastolic blood pressures and heart rate were more stable during the latter procedure. Isothermic dialysis was well tolerated by patients. CONCLUSION: Results show that active control of body temperature can significantly improve intradialytic tolerance in hypotension-prone patients.