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Survival is not enough is a yearly international event started in 2007 in Naples, Italy, in the week of the World Kidney Day to discuss the needs of renal patients and the quality of life of a category of patients living a machine-dependent life. Renal patients and their associations, philosophers, economists, nephrologists, and health care managers are enrolled to discuss about the possibility to grant the best cures and care without reducing the quality and the quantity of the services the patients need. Various quests have arisen for (1) a new cadre of managers capable of keeping health accounts in balance without cutting expenditure but by reducing waste of resources, (2) the promotion of prevention as the only measure capable of reducing costs in the long run, and (3) the promotion of clinical and translational research. The changes occurring in the health system should be viewed as a window of opportunity, including the advent of the medical-industrial complex firstly described in 1980, an event originating in the United States of America and now spreading worldwide., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Chronic renal failure and uremia represent states wherein high blood levels of homocysteine, a cardiovascular risk factor, are largely resistant to folate therapy. Indeed, normalization of homocysteine levels through vitamin administration is rarely achieved in this population, and this fact could explain, among other causes, the negative results of intervention trials designed to lower cardiovascular risk. Dialysis itself lowers homocysteine levels, albeit transitorily. N-acetylcysteine therapy could induce an additional decrease in homocysteine removal during dialysis, thus representing an alternative approach in the attempt to lower cardiovascular risk in these patients., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Low protein diets, made either of natural foods or of L-essential amino acids and/or their nitrogen-free ketoanalogues, are feasible, safe, and efficient means to reduce disease progression in patients with chronic kidney disease and do not prejudice patient outcomes once they get into Renal Replacement Therapy. They ameliorate symptomatology, grant a positive nitrogen balance, reduce proteinuria, improve osteodystrophy and lipid profile, reduce serum concentrations of uric acid, phosphate, and maintain plasma bicarbonate within normal limits thus preventing metabolic acidosis. They also reduce the number of hypotensive drugs and the quantity of erythropoietin to be administered to achieve target hemoglobin concentrations, and do not deteriorate quality of life. On the contrary, they retard progression of chronic kidney disease. There is a need to motivate patients to increase adherence to.

Hydrogen sulfide, H(2)S, is the third endogenous gas with cardiovascular properties, after nitric oxide and carbon monoxide. H(2)S is a potent vasorelaxant, and its deficiency is implicated in the pathogenesis of hypertension and atherosclerosis. Cystathionine beta-synthase, cystathionine gamma-lyase, and 3-mercaptopyruvate sulfurtransferase catalyze H(2)S formation. Chronic kidney disease is characterized by high prevalence of hyperhomocysteinemia, hypertension, and high cardiovascular mortality, especially in hemodialysis patients. H(2)S levels are decreased in hemodialysis patients through transcriptional deregulation of genes encoding for the H(2)S-producing enzymes. Potential implications relate to the pathogenesis of the manifestations of the uremic syndrome, such as hypertension and atherosclerosis., (Copyright 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

There are scanty data available on alexithymia in patients with end-stage renal disease, which point to an independent association with depression and social support. This study was devised to investigate the prevalence of alexithymia and sleep disorders in patients maintenance hemodialysis with insuppressible secondary hyperparathyroidism, who need parathyroidectomy (PTX), because previous data from our laboratories as well as those of others showed that this patient-group are the worst sleepers among hemodialysis patients with end-stage renal disease. A total of 40 patients needing PTX were enrolled and studied before the surgery. As for the control group, 80 patients on maintenance hemodialysis not needing PTX were enrolled. We measured alexithymia with the Toronto Alexithymia Score (TAS-20), sleep disorders with the Pittsburgh Sleep Quality Index (PSQI), and depression with Beck Depression Inventory (BDI), intact parathyroid hormone (iPTH), calcium, phosphate, use of antihypertensives, systolic and diastolic blood pressure, hemoglobin concentration, and albumin concentration. Patients needing PTX in comparison with those not needing PTX had significantly higher iPTH, calcium, and phosphate; they also had significantly higher systolic and diastolic blood pressure. They were more significantly alexithymic (P < .001), had more severe sleep disorders (P < .001), and were more depressed (P < .043). In multivariate analysis, BDI correlated significantly with iPTH concentration (r = 0.505, P < .001). A reduction of TAS-20 occurred after PTX which correlated with the number of patients on antihypertensive drugs, PSQI, BDI, hemoglobin concentration in the univariate and multivariate analysis. When TAS-20 and PSQI were adjusted for BDI (using analysis of variance) there was still a significant difference of TAS-20 and PSQI between patients needing PTX and not needing PTX (P < .001). This study confirms the high prevalence of sleep disorders in patients with unsuppressed secondary hyperparathyroidism and discloses a high prevalence of Alexithymia which is ameliorated by PTX. However, the correlation of Alexithymia with sleep disorders does not depend on depression., (Copyright 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Hydrogen sulphide, H(2)S, is the third endogenous gas with putative cardiovascular properties, after nitric oxide and carbon monoxide. H(2)S is a vasorelaxant, while H(2)S deficiency is implicated in the pathogenesis of hypertension and atherosclerosis. Cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (MPS) catalyze H(2)S formation, with different relative efficiencies. Chronic kidney disease (CKD) is characterized by elevation of both plasma homocysteine and cysteine, which are substrates of these enzymes, and by a high prevalence of hypertension and cardiovascular mortality, particularly in the haemodialysis stage. It is possible that the H(2)S-generating pathways are altered as well in this patient population., Methods: Plasma H(2)S levels were measured with a common spectrophotometric method. This method detects various forms of H(2)S, protein-bound and non-protein-bound. Blood sulphaemoglobin, a marker of chronic exposure to H(2)S, was also measured, as well as related sulphur amino acids, vitamins and transcriptional levels of relevant genes, in haemodialysis patients and compared to healthy controls., Results: Applying the above-mentioned methodology, H(2)S levels were found to be decreased in patients. Sulphaemoglobin levels were significantly lower as well. Plasma homocysteine and cysteine were significantly higher; vitamin B(6), a cofactor in H(2)S biosynthesis, was not different. H(2)S correlated negatively with cysteine levels. CSE expression was significantly downregulated in haemodialysis patients., Conclusions: Transcriptional deregulation of genes encoding for H(2)S-producing enzymes is present in uraemia. Although the specificity of the method employed for H(2)S detection is low, the finding that H(2)S is decreased is complemented by the lower sulphhaemoglobin levels. Potential implications of this study relate to the pathogenesis of the uraemic syndrome manifestations, such as hypertension and atherosclerosis.

CKD is utilized as a paradigm, a chronic disease which allows decades of life conquered with great effort through a machine, a life with many losses and many dependencies. We must understand the patient's needs, which are not related to availability of drugs and machines and hospitals. We cannot provide good medical care with the limited amount of national product devoted to health care. Society is much older than ever before. We need a new cadre of economists working on health care with vision and ability, keeping in mind that there are no resources and there are no expenses which can be cut in medical care nowadays. We have to switch from curative medicine towards prevention, by implementing clinical research, bearing in mind that in the Western world, democracy was granted through the correct allocation of resources. The search for happiness and good quality of life are old concepts born in the Mediterranean area over the centuries, starting with Hesiod and Homer, and sleep and dreams were being investigated centuries before Freud was born.

Dialysis for octogenarian and nonagenarian patients has increased dramatically in recent decades. Worldwide Registries of dialysis and transplantations show how the incidence rate of patients older than 80 years of age is almost doubled. This increase is probably due to liberalisation of acceptance criteria for dialysis, together with the ageing population. In recent years, the Sicilian and Campanian Registries of dialysis and transplantations have also observed a progressive increase in the elderly population. In order to study survival in this class of patients, we performed a study on a sample of Sicilian and Campanian patients. Regarding Sicilian patients, we considered a sample of 497 patients and grouped them into 3 categories of risk: in the first group (low risk) patients included were <70 years old without any co-morbidities; in the second group (average risk), we selected patients between 70 and 80 years old with one or more co-morbidities: in the third group (high risk patients), we included patients aged more than 80 years or with a high number of co-morbidities. The probabilities of survival in the low risk patients after 48 months of treatment was 96.1%; this probability fell to 82.9% for patients included in the high risk group; while the probability of survival for average risk patients was 91.7%. Given the high risk presented by older patients, we focused the second part of our analysis only on octogenarians, studying both Sicilian and Campanian patients. 64 Sicilian patients (33 males and 31 females--51.56% and 48.43% respectively) were observed: and their survival was 81.25% after 48 months. The sample of Campanian octogenarian patients considered for this study included 26 patients (12 males--53.85%--and 14 females--46.15%), observed for a shorter period (36 months). The probabilities of survival after 36 months was 84.61%. To sum up, elderly patients represent a growing reality on dialysis registries in Sicily and Campania. Future research concerning this class of patients should be developed in order to individualize suitable stratification risk indices; knowing patterns and probability of survival might help physicians in the dialysis decision-making process.

High levels of homocysteine have been implicated as a cardiovascular risk factor in the general population and in patients with chronic renal failure, and particularly patients on hemodialysis. To classify a risk factor as causally related to a certain disease, both strong epidemiologic data and sound basic-science studies establishing a mechanism are needed. Among the latter, the hypomethylation of proteins and DNA, and protein homocysteinylation, have been investigated in uremia, providing for an array of toxic effects in this disease.

Background: L-Carnitine, the acyl carrier into mitochondria, is derived from trimethyllysine. The formation of the latter compound is catalyzed by an S-adenosylmethionine methyltransferase, yielding S-adenosylhomocysteine (AdoHcy), the homocysteine direct precursor, as a product. Aim of this work was to determine if exogenously administered L-propionyl carnitine affects plasma levels of homocysteine, a cardiovascular risk factor, and its active metabolite AdoHcy, in chronic renal failure patients on hemodialysis., Methods: Plasma homocysteine and AdoHcy were determined by means of HPLC separation and detection in 14 hemodialysis patients before and after two months of i.v. L-propionyl carnitine treatment., Results: No significant differences were observed in plasma concentrations of homocysteine or AdoHcy after therapy., Conclusions: Treatment with a carnitine derivative does not significantly influence the plasma concentrations of homocysteine or of its active metabolite, AdoHcy, which are involved as risk factors for cardiovascular disease in chronic hemodialysis patients.

Chronic renal failure (CRF) is frequently associated with increased plasma levels of homocysteine (Hcy), an amino acid that can be considered a new uremic toxin according to recent evidence. Studies on Hcy described first homocystinuria, an inherited disease characterized by high plasma Hcy levels and premature cardiovascular disease, resulting in high mortal-ity rates. Hyperhomocysteinemia was then shown to be associated with cardiovascular events both in the general population and in CRF patients. Hcy is a sulfur amino acid derived from dietary methionine, an essential amino acid. Methionine is condensed with ATP to form S-adenosylmethionine (AdoMet), the universal methyl donor in transmethylation reactions. The AdoMet demethylated product is S-adenosylhomocysteine (AdoHcy), which is the direct precursor of Hcy in vivo. Hcy is toxic for the endothelium, it enhances vascular smooth muscle cell proliferation, increases platelet aggregation, and acts on the coagulation cascade and fibrinolysis. Several mechanisms have been discussed to explain Hcy toxicity. Hcy levels increase as renal function declines and progresses to ESRD; the causes of hyperhomocysteinemia are still unclear. Studies in humans show that renal metabolic extraction depends on renal plasma flow; in addition, an alteration of the extrarenal metabolic clearance, depending on uremic toxins, may occur. Among the consequences of hyperhomocysteinemia in renal failure are: impaired protein methylation, with altered protein repair processes; DNA hypomethylation, with an alteration in the allelic expression of genes regulated through methylation; and protein homocysteinylation. Further, this review is dealing with the 'reverse epidemiology' issue, outlining also the main Hcy-lowering strategies.

About 85% of patients on maintenance hemodialysis have sleep disorders that depend on comorbidities, age, morning dialytic shift, and blood pressure. They are ameliorated by erythropoietin, by transplantation, and by daily and nocturnal dialysis. Some data exist on sleep disorders in CKD patients, and show that lack of a refreshing sleep is present even at early stages of the disease and may affect 82.2% of patients without any relationship to comorbidities.

Cardiovascular disease is a major cause of morbidity and mortality in chronic kidney disease. Radionuclide-based methods can be used for analyses on the perfusion of coronary arteries and ventricular function. The present study reports the use of a new procedure for continuous measurements of left ventricle function during a dialytic session with the use of a recently developed portable gamma radiation detector (ventricular function study system). On average, left ventricle ejection fraction and stroke volume progressively and continuously decreased throughout the session (end session versus baseline: -13.8% for ejection fraction, -25.9% for stroke volume, P<.02). A biphasic response was found for heart rate: a transient modest decrease (at session midpoint, -4.2%) followed by an increase up to values higher than baseline (end session, +4.7%). Cardiac output decreased by 10.4% at session midpoint (P=.023 versus baseline) without further reduction in the following hours. Mean changes in systolic pressure paralleled data for cardiac output. Individual changes in indices of left ventricle function were scattered and strongly were correlated with thickness of interventricular septum and telediastolic left ventricular volume measured by standard echocardiogram in the interdialytic period (R>.75, P<.05). Data indicate that the ventricular function study system could be a powerful tool for characterization of the profile of left ventricular function in hemodialyzed patients.

Hyperhomocysteinemia, highly prevalent in well-nourished patients with chronic renal failure and in uremia, causes toxic effects that can be envisioned in terms of cardiovascular risk increase. However, its effects on cellular metabolism and on gene expression, not to mention receptor regulation, only recently are being evaluated. For example, it has been shown that hypomethylation induced by hyperhomocysteinemia can alter erythrocyte membrane protein repair and gene expression. In addition, increased plasma protein L-isoaspartyl content, related to hyperhomocysteinemia and uremic toxicity, determines specific effects on protein function, with a reduced binding of homocysteine to albumin. We propose that uremia is a state in which proteins present a widespread derangement of structure-function relationships.

Plasma proteins in hemodialysis patients display a significant increase in deamidated/isomerized Asx (asparagine and aspartic acid) content, a marker of protein fatigue damage. This has been linked to the toxic effects of hyperhomocysteinemia in uremic erythrocytes; however, treatment aimed at abating homocysteine levels did not lead to significant reductions in plasma protein damage. The hypothesis that lack of reduction in protein damage could be due to protein increased intrinsic instability, as result of interference with the uremic milieu rather than to hyperhomocysteinemia, was put forward. The deamidated/isomerized Asx content of normal plasma incubated with several uremic toxins for 24 h, 72 h, and 7 d was measured, identifying a group of toxins that were able to elicit this kind of damage. Uremic toxins were also incubated with purified human albumin, and dose-response experiments with the two most toxic agents in terms of protein damage (guanidine and guanidinopropionic acid) were carried out. The effect of the hemodialysis procedure on protein damage was evaluated. For investigating also the consequences of these alterations, human albumin was treated in vitro to produce an increase in deamidated/isomerized Asx residues, and the effects of albumin deamidation on protein binding were evaluated. Among the uremic toxins that are able to elicit protein damage, guanidine produced a dose-dependent increase in protein damage. No difference was found after a hemodialysis session. Deamidated albumin shows normal binding capacity to warfarin, salicylic acid, or diazepam but reduced binding to homocysteine. In conclusion, uremic toxins, especially guanidine, display an ability to induce significant protein damage, which can in turn have functional consequences.

In the general population, hyperhomocysteinemia is an independent risk factor for cardiovascular disease (ischemic disease, such as stroke and myocardial infarction, and arterial and venous thrombosis). We can presume that the association is causal, based on the example of homocystinuria, and on the evidence put forward by several basic science and epidemiologic studies. However, the results of large intervention trials, which may grant further support to this hypothesis, are not yet available. In chronic renal failure and in uremia, the evidence that is offered by carefully performed prospective studies also indicate the presence of an association, although some studies suggest reverse epidemiology. The mechanisms underlying the association, and able to explain the several toxic effects of homocysteine, related or not to cardiovascular disease, are unclear. Oxidation, nitrosylation, and hypomethylation are among the postulated mechanisms. In uremia, protein hypomethylation interferes with protein repair; DNA hypomethylation impairs regulation of gene expression, whereas folate treatment reverts such alterations. Acylation, another structural modification able to impair protein function, is a possible mediator of homocysteine toxicity.

Background: Previous studies report that urinary albumin excretion is associated with coronary heart disease (CHD). The present epidemiologic study investigated if (1) blood pressure status affects the association of urinary albumin excretion with CHD; and (2) urinary albumin excretion is associated with low renal function also., Methods: The cross-sectional association was analyzed of overnight urinary albumin excretion with prevalence of CHD (myocardial infarction and/or ischemia as defined by standard electrocardiogram) and low renal function (overnight creatinine clearance <60 mL/min) in a population sample of 1632 men and women with ages 45 to 64 years. Hypertension, hypercholesterolemia, smoking habit, and diabetes mellitus were included in analyses., Results: CHD prevalence was in the whole sample 8.2% (N= 134), in the hypertensive subgroup 11.9% (N= 79), and in the nonhypertensive subgroup 5.7% (N= 55). For the association between urinary albumin excretion (logarithm-transformed due to skewed distribution) and CHD, the multivariate logistic coefficient with 95% CI was significant in the whole sample (+0.79, 95% CI =+0.32/+1.26, P < 0.001) and in the hypertensive subgroup (+0.97, 95% CI =+0.70/+1.24, P < 0.001), not in the nonhypertensive subgroup (-0.06, 95% CI =-0.80/+0.68, P= 0.997). Prevalence of low creatinine clearance was in the whole sample 4.0% (N= 66), in the hypertensive subgroup 4.8% (N= 32), and in the nonhypertensive subgroup 3.5% (N= 34). The logistic coefficient between urinary albumin excretion and low creatinine clearance was borderline significant in the whole sample (+0.56, 95% CI =-0.02/+1.14, P= 0.090), significant in the hypertensive subgroup (+0.73, 95% CI =+0.04/+1.42, P= 0.044), not significant in the nonhypertensive subgroup (-0.07, 95% CI =-1.25/+1.10, P= 0.913)., Conclusion: Results support the use of urinary albumin excretion as marker of CHD and slightly reduced renal function in hypertensives.

Background: The adjustment of comorbidity is important in international hemodialysis comparisons. The aim of this study is to verify if it is possible to use the Charlson Comorbidity Index (CCI), in an Italian population of incident hemodialysis patients from the Campania region as outcome predictors. A similar proposal has already been made for an American population of incident patients in peritoneal dialysis., Methods: The data for this study come from the Uremic Registry of Campania taken in the year 2001. This is an observational study in which demographic, comorbid, laboratory, treatment and insurance data were collected in 111 dialysis units (70%) in Campania. We evaluated 515 hemodialysis incident patients who were hemodialyzed in Campania between January 1 and December 31, 2001. The study was restricted to patients who had already undergone 90 days of hemodialysis. The duration of this study was 15 months. Charlson Comorbidity Index was performed. In 128 patients (24.8%) BIA measurements were performed after dialysis., Statistics: We used Student's t test for unpaired data and Cox proportional model to analyze predictors of mortality. The variables analyzed were age at start of hemodialysis, sex, CCI, hemoglobin, diabetes, hypertension, albumin, days of hospitalization. The statistically significant variables, analyzed initially by univariate analysis, were chosen for multivariate analysis. We considered p < 0.05 statistically significant., Results: A total of 515 patients (M = 316, F = 199) (age: 63.62 +/- 15.35 years) presented with the following diseases: NO diagnosed in 93 patients (19%), GN in 64 (13%) IN in 42 (99%), Hereditary in 55 (11%), Vascular in 66 (14%), Diabetes in 135 (28%), others in 30 (6%). Hemoglobin levels were 10.71 +/- 1.51 g/dL and albumin was 3.79 +/- 0.54 g/dL. The days of hospitalization for the population studied were 3364/year. After the study, 75 patients died and the overall mortality rate was 11.65/100 patient/years. Univariate analysis shows that there are significant differences calculated for age (median value 73 and 65 years, respectively for non-survivers and survivers), BMI (median value and 22 and 24 kg/m2, respectively), Hb (median value 9.5 and 11 g/dL, respectively), Albumin (median value 3.5 and 3.8 g/dL, respectively), days of hospitalization (median value 8 and zero days, respectively), CCI (median value 6 and 4 score, respectively, phase angle (median value 3.3 and 4 degree, respectively). The mortality rates (100 dialysis years) by the CCI score: the mortality rate was zero for patients with a CCI of 3; and it increased to approximately 60% of patient years with a CCI score of 6 or greater. The linear correlation between CCI and phase angle in living (y = 18.90 x -3.83; R2 = 0.56) and in the dead (y = 13.01 x -1.87; R2 = 0.29)., Discussion: We found that CCI is a strong predictor of mortality in incident HD patients as has also been indicated in PD patients; CCI correlates with phase angle calculated from Bioelectrical Impedance Analysis and this last factor can be used in the following examinations; several days of hospitalization are a very important determinant in the survival in hemodialysis patients.

Background: Female gender is associated with high erythropoietin (EPO) resistance in end-stage renal disease. The aim of our study was to investigate the roles of age and menstrual status in this relationship., Methods: Cross-sectional analysis of registry data for 3,224 hemodialysis adults treated with EPO. Data collection included gender, age, weight, height, dialytic age, hemoglobin, EPO dose, and, for women with ages 25-44 only, also information on menstrual status and iron homeostasis. EPO resistance index (ERI) was calculated as EPO dose per kilogram BW/hemoglobin., Results: Men and women had not significantly different hemoglobin and significantly different EPO dose per kilogram weight (women vs. men, +18.2%, p < 0.001). Thus, ERI was higher in women than in men (+19.5%, p < 0.001). The gender-associated difference in ERI linearly decreased along age groups: +30.9% for ages 25-44, +23.2% for ages 45-64, and +14.2% for ages 65-84 (p < 0.05 for interaction between age and gender-associated difference in ERI). Within the subgroup of women with ages 25-44, women with menses in comparison to women without had 44.6% higher ERI (p < 0.01) due to combination of lower hemoglobin (p < 0.05) with higher EPO dose (p < 0.001). Women with menses had also lower serum iron, transferrin saturation, and serum ferritin (p < 0.001)., Conclusion: The gender-associated difference in ERI is lower with increasing patients' age. The large difference between young men and women is due to women with menses who have iron deficiency more frequently than women without periods.

Background: Plasma homocysteine, a new cardiovascular risk factor in both children and adults, is higher in chronic renal failure or kidney transplant patients. This alteration has been linked, in chronic renal failure, to plasma protein damage, represented by increased L-isoaspartyl residues. We measured plasma homocysteine levels and plasma protein damage in pediatric patients from four different Italian regions with conservatively treated renal failure; hemodialysis, continuous ambulatory peritoneal dialysis (CAPD), or transplants, to establish the presence of protein damage and the relative role of hyperhomocysteinemia., Methods: High performance liquid chromatography (HPLC) separation measured total plasma homocysteine levels, using precolumn derivatization with ammonium 7-fluorobenzo-2-oxa-1, 3-diazole-4-sulphonate (SBD-F). Plasma protein L-isoaspartyl residues were quantitated using human recombinant protein carboxyl methyl transferase (PCMT)., Results: In all patient groups, homocysteine levels were significantly higher with respect to the control (Control: 6.87 +/- 0.73 microM) conservatively treated, 14.19 +/- 1.73 microM; hemodialysis, 27.03 +/- 4.32 microM; CAPD, 22.38 +/- 3.73 microM; transplanted, 20.22 +/- 2.27 microM, p < 0.001 vs. control]. Plasma protein damage was significantly higher in conservatively treated, hemodialysis (HD) and CAPD patients, while in transplant patients it was no different from the control., Conclusions: We concluded that in pediatric patients of different Italian geographical origin, plasma homocysteine levels were significantly higher in all groups with respect to healthy children; therefore contributing to the elevated cardiovascular risk present in these patients. Plasma protein L-isoaspartyl content was higher in renal failure patients, but kidney transplant patients had normal levels, indicating that this kind of protein damage relates more to the toxic action of uremic retention solutes, than to plasma homocysteine levels.

An elevated blood level of homocysteine (Hcy), a sulfur amino acid, is associated with increased cardiovascular risk. Hcy is generated from S-adenosylhomocysteine (AdoHcy), the demethylated product of S-adenosylmethionine (AdoMet) in transmethylation reactions. AdoHcy is a competitive inhibitor of AdoMet-dependent methyltransferases. AdoHcy accumulation is prevented by rapid metabolism of its products. Chronic renal failure (CRF) is almost constantly associated with hyperhomocysteinemia. It has been shown that: (1) AdoHcy concentration is significantly increased and the AdoMet-AdoHcy ratio is reduced in erythrocytes of patients with CRF; (2) erythrocyte membrane protein methyl esterification, catalyzed by the enzyme protein L-isoaspartyl O-methyltransferase (PCMT; EC 2.1.1.77), is reduced in CRF; PCMT catalyzes a repair reaction involved in the conversion of an isopeptide bond (detrimental to protein structure and function) into a normal peptide bond; (3) D-aspartate residues, a side product of protein methylation and repair, are significantly reduced in erythrocyte membrane proteins of patients with CRF; and (4) folate treatment significantly reduces plasma Hcy levels and improves AdoMet-AdoHcy ratios. Stable isotope studies recently confirmed that the rate of methyl transfer reactions is significantly reduced in uremia. Additional evidence, obtained by independent groups, is consistent with this interpretation. We recently found increased isoaspartyl content of circulating plasma protein levels, particularly albumin, which was only partially reduced after folate treatment, in uremia. This kind of molecular damage possibly is caused by protein increased intrinsic instability as a result of interference with the uremic milieu. In conclusion, Hcy is an uremic toxin involved in protein molecular damage through the inhibition of methylation reactions and protein PCMT-mediated repair.

Homocystinuria, an inherited disease in which plasma levels of homocysteine are high, was discovered in the sixties and it soon became clear that the affected patients had striking features of generalized atherosclerosis. The most common causes of death were arterial and venous thrombosis, stroke, or myocardial infarction. Observations in this human model of hyperhomocysteinemia led to studies in the general population whose findings suggest - though not conclusively- that homocysteine is a cardiovascular risk factor. The same is true for patients with chronic renal failure who almost always have moderate to severe high blood homocysteine levels. Homocysteine accumulates in relation to the concentration of its precursor, S-adenosylhomocysteine, a powerful competitive transmethylation inhibitor. Inhibition of a methyltransferase required to repair damaged proteins has actually been detected in uremic patients' red blood cells. However, in view of the multiple, widespread metabolic roles of S-adenosylmethionine-dependent methyltransferases, in many organs and tissues including the vascular endothelium, hypomethylation is currently interpreted as one of homocysteine's most important mechanisms of action. Various biological compounds, including small molecules and nucleic acids, as well as proteins, which are involved in the pathophysiology of thrombosis and atherosclerosis, are all potential targets of hypomethylation. Epidemiological studies and experimental models tend to confirm that homocysteine is both a cardiovascular risk factor and a uremic toxin, acting through different mechanisms.

Homocysteine, a sulfur amino acid, is an important methionine derivative, which has been implicated in the pathogenesis of atherothrombosis. Although only observational, epidemiological studies are available at present, the evidence of an association between hyperhomocysteinemia and increased cardiovascular risk is quite strong and this is confirmed also in a population of chronic renal failure patients. From a biochemical standpoint at least three mechanisms have been summoned so far in order to explain homocysteine toxicity including: oxidation, hypomethylation, and acylation. Proteins are believed to play a crucial role as homocysteine molecular targets. Interference with the functions of several of such macromolecules has been so far described being mediated by any of the above mechanisms. Vitamins may positively influence homocysteine metabolism, thus facilitating the metabolic clearance of this compound. Therefore they are presently considered as potential means for reducing plasma levels of this amino acid and preventing vascular occlusions in hyperhomocysteinemic patients. These compounds, with special regard to folate, are eligible for interventional clinical trials, from which the definitive answer on the role of homocysteine in atherothrombosis is expected.

The effect of a meat load on the renal handling of acid-base balance was studied in ten healthy subjects (GFR by inulin clearance = 98.5 +/- 8.14 ml.min-1.1.73 m-2) and in ten patients affected by chronic renal failure (CRF) (GFR = 39.9 +/- 5.3 ml.min-1.1.73 m-2). After the meat load (2 g.kg-1 body weight of cooked unsalted red meat), GFR increased by 26.9% (peak value) over baseline in healthy subjects and by 32% in CRF patients. The acid-base status of the healthy subjects was in the normal range, whereas the CRF patients disclosed a slight metabolic acidosis. After a meat load, there was, in the healthy subjects, an increase in the filtered load of bicarbonate coupled to an enhanced tubular reabsorption and urinary excretion. The time course between bicarbonate load and urinary excretion was coincident. In CRF patients, the increase of bicarbonate tubular load after the meal was associated with an increase in tubular reabsorption but not in urinary excretion of this anion. The relationship between bicarbonate load and reabsorption was linear in both groups up to the highest filtered loads. Baseline titratable acidity (TA) and ammonium (NH4+) excretion (expressed per ml GFR) were increased in CRF patients as compared with control subjects, but no changes were found after the meat load in both groups in these experimental conditions. The data indicate that the renal tubules contribute to the maintenance of acid-base balance both in healthy subjects and in CRF patients by reabsorbing most of the additional bicarbonate load. The transient, but significant, increase in bicarbonate excretion observed in healthy subjects could be related to the increased tubular load of bicarbonate. In CRF patients, tubular bicarbonate reabsorption was more complete, possibly because of the stimulation of H+ secretion by the mild metabolic acidosis. TA and NH4+ did not participate in tubular compensation of the increased buffer load.

The enzyme protein carboxyl methyltransferase type II has been recently shown to play a crucial role in the repair of damaged proteins. S-adenosylmethionine (AdoMet) is the methyl donor of the reaction, and its demethylated product, S-adenosylhomocysteine (AdoHcy), is the natural inhibitor of this reaction, as well as of most AdoMet-dependent methylations. We examined erythrocyte membrane protein methyl esterification in chronic renal failure (CRF) patients on conservative treatment or hemodialyzed to detect possible alterations of the methylation pattern, in a condition where a state of disrupted red blood cell function is present. We observed a significant reduction in membrane protein methyl esterification in both groups, compared to control. The decrease was particularly evident for cytoskeletal component ankyrin, which is known to be involved in membrane stability and integrity. Moreover, we observed a severalfold rise in AdoHcy levels, while AdoMet concentration was comparable to that detected in the control, resulting in a lower [AdoMet]/[AdoHcy] ratio (P < 0.001). Our findings show an impairment of this posttranslational modification of proteins, associated with high AdoHcy intracellular concentration in CRF. The data are consistent with the notion that, in CRF, structural damages accumulate in erythrocyte membrane proteins, and are not adequately repaired.

Chronic renal failure affects the secretion of pituitary glycoprotein hormones by mechanism(s) that are still unknown. In this study, we evaluated serum concentrations of TSH, free thyroid hormones (FT4, FT3), LH, FSH, testosterone (T), and alpha-subunit (alpha-SU) in 25 uremic patients (19 males and 6 females), both in basal conditions and after stimulatory and inhibitory tests. Basal TSH levels were in the normal range, while FT4 and FT3 were significantly lower than in controls. Basal LH and FSH levels were clearly elevated. The LH levels measured by RIA were significantly higher than those measured by a "two-site" IRMA (48.9 +/- 16.5 vs 18.0 +/- 8.6 U/L) due to alpha-SU cross-reactivity in RIA. FSH bioactivity was normal in all patients. Serum T was normal in all but 3 males, without any correlation with LH and FSH levels. Serum alpha-SU concentrations were significantly elevated (5.5 +/- 3.0 vs 0.4 +/- 0.2 microgram/L). Of 17 patients, the TSH response to TRH was normal in 9 and impaired in 8, whereas alpha-SU response was normal in 5 and impaired in 12. In 8 male patients, TRH plus GnRH caused a normal LH and FSH response in 4 patients, while the increase of alpha-SU was normal in only one patient and significantly lower than expected in subjects with comparable basal alpha-SU levels in the remaining 7. In 2 patients, the combined suppression test with T undecanoate and T3 completely blocked TSH secretion and reduced both LH and FSH release by 30%, while serum alpha-SU levels did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Ten patients with chronic renal failure (GFR 29-97 ml/min), on free diets providing 1 g/kg B.W. of proteins, ingested an oral protein load (meat meal, 2 g/kg B.W.). GFR and RPF increased significantly over baseline with no change in filtration fraction. Within 30 min of the meal and for the next 3 h a statistically significant increase was observed in the plasma concentrations of the following amino acid groups: essential, non-essential, total, branched-chain, ketogenic, glycogenic, glycogenic and ketogenic, basic, acid, polar and non-polar. At 30 min the smallest increase was seen in acid and polar amino acids (6.7% and 7.6%, respectively). At 180 min the largest increase (78.8%) was seen for glycogenic and ketogenic amino acids and total plasma amino acids were 1.58 times baseline. After the meat meal plasma glucagon and insulin rose significantly, while growth hormone, plasma renin activity and aldosterone did not vary.

The renal hemodynamic response to a meat meal (2 g/kg BW) was studied in 11 healthy children and in 10 children with a mean plasma creatinine concentration of 2.6 +/- 0.1 mg/dl due to chronic renal failure (CRF) of various etiologies. In the healthy status, after a meat meal, the glomerular filtration rate (GFR) increased significantly from a baseline value of 119.0 +/- 5.0 to a peak of 159 +/- 5.8 ml/min x 1.73 m2; in CRF baseline GFR averaged 49 +/- 4.0 and at peak 76.6 +/- 7.2 ml/min x 1.73 m2 (p less than 0.005). The peak GFR response was reached earlier in healthy subjects than in CRF (p less than 0.05) and did not correlate with age or with baseline GFR. Renal plasma flow (RPF) in healthy controls increased from 532 +/- 32 at baseline to 646 +/- 42.9 ml/min x 1.73 m2 after the meal (p less than 0.005). Also in CRF after a meat meal there was a significant increase in RPF from 278 +/- 51 to 65 +/- 66 ml/min x 1.73 m2 (p less than 0.005). The filtration fraction was not affected. The percent increase over baseline values of GFR and RPF at the peak was significantly higher in diseased children. Renal reserve averaged 28.1 +/- 5.3 ml/min in diseased children and 39.7 +/- 5.2 ml/min (p less than 0.01). The data indicate that (1) a meat meal is a suitable method to recruit renal reserve in normal children and in children with chronic renal failure, and (2) the renal reserve is normal in chronic renal failure.

With hemoperfusion there is a sharp decline in the solute concentration of the blood compartment, but immediately after HP the concentration of these substances rises to the original level (post-Hp rebound). It may be inferred that the result would be better and the rebound phenomenon less marked if hemoperfusion could be combined with a continuous dialysis system such as CAPD. The study was performed in 3 children of our CAPD program. All patients were dialysed with 5 daily exchange each of one liter. The patients underwent at 2-hours hemoperfusion with a charcoal column (Gambro Adsorba 150 c) once a week. The data obtained with this form of treatment are indicative for a: significant increase of weekly clearance for uric acid and creatinine. low urea generation rate far 1-3 days after HP. low post-Hp rebound and reduced platelet count but not platelet activation.

The degree of catabolism was studied in a group of seven patients with postsurgical acute renal failure, and net protein catabolism of 43.1 to 927 g/day. In 70% of a group of 30 patients with stable chronic renal failure receiving and 18 g high biological value protein diet, urea synthesis was equivalent to what could be accounted for by the protein content of the food. This equivalence was not found in studies in both adults and children who were treated for catabolic chronic renal failure. Data obtained show the superiority of feeding essential amino acids with an adequated caloric supply. The need for studies aimed at adapting the uremic patient to protein depletive mechanisms is strongly stressed.

Thyroid function was measured in 30 healthy subjects and 84 patients with various degrees of nephron loss (GRF: 70 +/- 15 m/min, 30 +/- 16 ml/min, 10 +/- 7 ml/min and 2.1 +/- 1.3 ml/min). A low T3 and T4 syndrome is evident when GRF is reduced to 30 +/- 16 ml/min while a blunted TSH response is detected earlier in the course of nephron loss. T3 response to TRH was normal and FT4 was not affected by renal dysfunction. The data indicate that in nephron loss hypothalamic-pituitary abnormalities occur.

Vascular tissues from uremic patients show increased prostaglandin synthesizing capacity while uremic platelets have decreased thromboxane synthesis. It has been suggested that the platelet defects in uremia are partially corrected by hemodialysis and a correlation with the levels of guanidinsuccinic acid, phenolic acid, creatinine or urea has been demonstrated. In our study 6 patients with end-stage renal disease on RHT, underwent, daily and for ten days, two-hours hemoperfusion, in order to obtain lower levels of toxic metabolites such as creatinine (less than 6 mg/dl.). Before and after this intensive treatment we have evaluated BTG plasmatic levels and thromboxane formation by platelets after thrombin and arachidonic acid stimulation. The thromboxane formation was not increased following this treatment, whereas BTG plasmatic levels were significantly diminished.

Glucose utilization from the dialysate of up to 140 g/day was found during CAPD therapy in 5 children on short and long term studies. The energy input via the dialysate was associated with increased insulin secretion as indicated by the daily insulin response calculated from analyzing the area under the insulin curve during 5 daily exchanges of dialysate. After 6 months glucose tolerance was normal with normal values for early and late insulin response as well as for glucose disappearance rate during an intravenous glucose tolerance test. Nitrogen balance on free diets (energy input 100% RDA and protein input 133% RDA) showed that CAPD is an anabolic technique since the balance was positive when measured during 42 days out of 12 months in each child. Growth was normal in one boy and in addition a girl reached her final height; it was unsatisfactory in the other children. It is concluded that CAPD is an anabolic technique which favourably affects many factors associated with growth retardation in children with end stage renal failure and therefore it represents an interesting tool for defining a more rationale approach for research in this field.