Plasma adiponectin levels in chronic kidney disease patients: relation with molecular inflammatory profile and metabolic status.

BACKGROUND AND AIM: Adiponectin (ADPN) exerts anti-inflammatory and cardio protective effects and is associated with decreased cardiovascular risk, however its role in patients with chronic kidney disease is unclear. METHODS AND RESULTS: We investigated the correlation between plasma ADPN levels, the progression of CVD and CKD and the inflammatory gene expression profile of peripheral blood mononuclear cells in patients from the NephroPLIC study (a prospective study aimed at addressing the progression of cardiovascular damage in relation to kidney dysfunction). Plasma ADPN levels were directly correlated with age, HDL-C and creatinine, and inversely with BMI, triglycerides and glomerular filtration rate (GFR). Multiple regression analysis identified plasma creatinine and HDL as the independent factors associated with ADPN plasma levels. In peripheral blood mononuclear cells (PBMC), the mRNA expression of MCP-1, CD40, Cox-2, TLR4, PAI-1, TNF alpha, resistin and RAGE was up-regulated in the group with higher GFR and higher ADPN plasma levels compared to that with low GFR and ADPN plasma levels. Patients with similar GFR values showed no differences in the gene expression profile of PBMC although ADPN levels were associated with decreased CRP and IL-6 plasma levels and decreased IMT and heart left ventricular mass. CONCLUSION: In CKD patients who are not in dialysis ADPN plasma levels are associated with a reduced renal excretory function, but correlate inversely with the determinants of the metabolic syndrome such as glucose, triglycerides and BMI, and directly with HDL. Furthermore, in patients with a similar degree of renal impairment, ADPN plasma levels are associated with a better cardiometabolic profile, despite no significant difference being observed in the gene expression pattern of PBMC.

Effect of the -420C/G variant of the resistin gene promoter on metabolic syndrome, obesity, myocardial infarction and kidney dysfunction.

OBJECTIVE: Resistin is an adipokine that has been suggested to be correlated with markers of inflammation and to be predictive of coronary atherosclerosis and type II diabetes in humans. A common single nucleotide polymorphism (SNP) (-420C/G) in the promoter of resistin is associated with increased resistin plasma levels and susceptibility to type II diabetes. The aim of this study was to investigate the association of the -420C/G polymorphism with metabolic syndrome, obesity, myocardial infarction and kidney disease. DESIGN AND RESULTS: First we studied 1542 subjects from the PLIC study (a population based cohort). GG carriers showed an higher prevalence of obesity and metabolic syndrome as well as increased plasma triglycerides levels, BMI, systolic and diastolic blood pressure and cardiovascular risk according to Framingham algorithm (P < 0.05 for all). Next we investigated the presence of the -420C/G resistin polymorphism in a case-control study that included 300 subject with myocardial infarction and 300 age and sex matched controls and then we studied the role of the -420C/G SNP in 88 patients with mild to moderate renal dysfunction. No statistically significant differences in allele frequencies between the PLIC study, the myocardial infarction (MI) cases and the subjects with renal dysfunction were observed. Pro-inflammatory gene expression profiling of peripheral blood mononuclear cells failed to detect any difference between wild type subjects and carriers of the rare allele. CONCLUSION: Our data suggest that the presence of the -420C/G SNP of the resistin gene is associated with increased obesity and metabolic syndrome, although it is not different in subjects at high cardiovascular risk such as patients with myocardial infarction or patients with renal dysfunction compared with controls.

Role of vitamin E-coated membrane in reducing advanced glycation end products in hemodialysis patients: a pilot study.

INTRODUCTION: Advanced glycation end products (AGEs) are markers of oxidative stress. AIMS: To assess if a vitamin-E-coated dialyzer affects plasma AGE levels and endothelial function in hemodialysis patients. METHODS: 16 patients were dialyzed with a synthetic modified cellulose membrane (SMC, n = 8) or a vitamin E-coated dialyzer (n = 8), respectively. At week 32 endothelial function was determined as brachial artery flow-mediated dilatation (FMD). Total AGEs, free pentosidine (FP), protein-bound pentosidine (BP) and autoantibodies against oxidized LDL (ox-LDL-autoantibodies) were assessed at baseline (T0) and at 16, 32, 40 and 42 weeks (T16, T32, T40 and T42). RESULTS: At T16 and T32 FP and BP were lower in vitamin E than in SMC (T 16: 88.7 +/- 8.96 vs. 124.2 +/- 11.90 pmol/ml plasma; p = 0.04, and 22.9 +/- 2.99 vs. 32.8 +/- 2.98 pmol/mg proteins; p = 0.04. T32: 78.7 +/- 8.54 vs. 123.7 +/- 10.15 pmol/ml plasma; p = 0.007, and 19.9 +/- 2.0 vs. 33.67 +/- 2.41 pmol/mg proteins; p = 0.001). In vitamin E, AGEs were lower at T32, T40 and T42 (946.7 +/- 80.91 vs. 1,351.2 +/- 179.33 AU/ml, p = 0.05; 986.9 +/- 59.63 vs. 1,509.9 +/- 154.17 AU/ml, p = 0.013; 890.3 +/- 73.70 vs. 1,453.9 +/- 153.16 AU/ml, p = 0.009). At T32 AGEs, ox-LDL autoantibodies and FMD were inversely correlated (R = -0.70 p = 0.007 and R = -0.59, p = 0.04, respectively). CONCLUSIONS: Vit E-coated membrane reduces plasma AGEs levels and AGEs values are negatively correlated with FMD.

[Census of the Italian Nephrology and Dialysis Units. Comparison between Lombardy and Piedmont]. / Censimento 2004 Centri di Nefrologia e Dialisi. Confronto tra Piemonte e Lombardia.

The Italian Society of Nephrology promoted a national survey to obtain detailed information from all the Renal and/or Dialysis Units through an on-line questionnaire concerning structural, technological and human resources, as well as organisation characteristics and activities. The purpose of this initiative was to obtain regional reference benchmarks for each Nephrology Unit. In this paper we compare two northwestern Italian Regions: Lombardy and Piedmont. As far as epidemiology is concerned, the prevalence of dialysis patients is quite similar in the two Regions: for haemodialysis 616 pmp (patients per million population) in Lombardy and 595 in Piedmont, for peritoneal dialysis 104 pmp vs. 114 pmp, while the incidence of dialysis patients is 169 vs. 166 pmp. The gross mortality for dialysis patients is 12.4% vs. 13.7% and 0.9% vs. 2.0% in transplanted patients. The distribution of vascular access is also quite similar in the two Regions: prevalent arteriovenous fistula 83% vs. 74%, central venous catheter 11% vs. 18%, vascular grafts 7% vs. 8%. Structural resources: the hospital beds (49 pmp in the two Regions) and the dialysis places (161 vs. 166 pmp) do not differ between the two Regions. Personnel resources: physicians 37 pmp in Lombardy and 44 pmp in Piedmont, renal nurses 167 pmp vs. 186, respectively. Activity: hospital admission 1722 pmp vs. 1507 pmp, renal biopsies 131 pmp vs. 109 pmp. Although the two regions examined are numerically different, both have a high standard of quality, making Italy a model of nephrology organisation. This initiative to take a census of the Italian Nephrology and Dialysis Units provides an interesting tool to describe the present status of the operational structures, to identify precise benchmarking values, at both the regional and national level, and to act as a prelude for further rationalization and growth of the nephrology network in Italy.

[Census 2004 of the Italian Renal and Dialysis Units--Piemonte, Liguria and Valle d'Aosta]. / Censimento 2004 dei Centri di Nefrologia e Dialisi italiani. Piemonte--Liguria--Valle d'Aosta.

The Italian Society of Nephrology (SIN) promoted a national survey in order to obtain detailed information from all Renal and/or Dialysis Units using the on-line questionnaire (158 items) regarding structural and technological resources, medical workforce organisation and activity features. The purposes of this initiative were to obtain regional benchmarks as references for renal units and to describe the current Italian renal network in order to plan further interventions for the next 5 years. In this paper data of the first three Italian Regions (Piemonte, Liguria and Valle d'Aosta) which completed the survey (100% of the units) are reported. Main findings in the 3 Regions. A) Epidemiology: prevalence of dialysis patients = 709, 720, 787 pmp (per million population); prevalence of transplanted patients = 325, 387, 279 pmp; incidence of dialysis patients = 166, 191, 156 pmp; gross mortality of dialysis patients = 13.7, 15.0, 13.0%; distribution of vascular access in prevalent dialysis patients: arteriovenous fistula = 74, 83, 76%, central venous catheter = 18, 12, 15%, vascular graft = 8, 5, 9%. B) Structural resources: hospital's number of beds = 49, 72, 49 pmp, dialysis places = 166, 158, 164 pmp. C) Personnel resources: renal physicians = 44, 47, 41 pmp, renal nurses = 186, 194, 205 pmp; each renal physician takes care of 16, 15, 19 dialysis patients and each renal nurse cares for 3.8, 3.7, 3.8 dialysis patients. D) Activity: admission to hospital = 1507, 2392, 1606 pmp, renal biopsies = 109, 133, 57 pmp. Despite discrepancies in population density in the three Regions, most indexes are surprisingly similar and show the satisfactory level of renal care attained in the Northwestern Italian area. Further improvements in health care management can be predicted as a consequence of a direct comparison between needs and results in the various Regions of the Country.

[Early therapeutic education in chronic renal disease: a new approach]. / La presa in carico precoce nell'insufficienza renale cronica: un nuovo approccio.

Chronic renal failure (CRF) remains a significant problem. Early referral of patients reduces cardiovascular risk and allows better quality of life and life expectancy. Uremic patients represent a typical example of chronic disease, which requires multidisciplinary team involvement and stratification of treatment processes. During the evolution of the disease to chronicity, the patient requires different clinical approaches that form part of a unique treatment process, involving day-to-day management, carried out by the general practitioner, as well as the handling of acute events requiring specialized clinical management. Early referral essentially requires three steps. The first step is therapeutic education, which includes information, sensitiveness, training and acceptance of the disease. The second step is the assembling of a multidisciplinary team in which the members are able to work together, coordinating and managing treatment protocols. These two steps allow the design of the third step, disease management, which consists of a methodology based on an integrated approach to the dis-ease allowing continuous improvement in medical care, in the patient's quality of life and a better use of economic resources.

[Intravenous folinic acid and vitamin B12 supplementation and homocysteine concentration in hemodialysis patients]. / Supplementazione e.v. di acido folinico e vitamina B12 e concentrazioni di omocisteina nei pazienti emodializzati.

INTRODUCTION: Hyperhomocysteinemia is one of the causes of the increased incidence of cardiovascular disease in uremia. Since homocysteine (Hcy) metabolism depends on the availability of folate and vitamin B12, we have measured the effects of chronic i.v. supplementation of folinic acid and vitamin B12 in a group of patients on maintenance hemodialysis. METHODS: We compared the blood concentration of total Hcy (tHcy), vitamin B12 and folate and the intraerythrocyte concentration of folate in a group of 27 hemodialysis patients (Treated group), given an i.v supplementation with folinic acid (0.9 mg) and Vitamin B12 (cyanocobalamine 1.5 mg and hydroxycobalamine 1.5 mg) three times per week at the end of each dialysis session with those measured in a similar group of 28 hemodialysis patients without supplementation (No Treatment group). The patients were also characterized for the thermolabile variant (mutation C667-->T) of the enzyme methylene-tetrahydrofolate reductase (tMTHFR). RESULTS: High plasma levels (< 11.7 micromol/L) of tHcy were observed in 54/55 patients. T patients had Hcy values significantly lower than NT ones (31.7+/-3.6 vs. 1.1+/-8.3micromol/L, p < 0.05). Serum vitamin B12 (1200 73.6 vs. 762+/-72.2 pmol/L, p < 0.001) and intraerythrocyte folate levels were also significantly higher in the T group (2176+/-127 vs. 1511+/-156, p < 0.005), while no significant difference was observed for serum folate. The distribution of tMTHFR genotypes was similar in the two groups. Homozygous patients showed higher levels of Hcy in comparison with wild type patients both in the whole population (62.32+/-15.9 vs.30.43+/-3.2, p < 0.05) and in the NT group (87.8+/-25.3 vs.36.8+/-13.1., p < 0.05), while no significant difference was observed among genotypes in the T group. CONCLUSIONS: Uremic patients on hemodialysis, when supplemented with even low i.v. dose of folinic acid and vitamin B12, show significantly lower plasma levels of tHcy than non-supplemented patients.

Reduction of the homocysteine plasma concentration by intravenously administered folinic acid and vitamin B(12) in uraemic patients on maintenance haemodialysis.

BACKGROUND: Hyperhomocysteinaemia is an independent cardiovascular risk factor which can induce vascular lesions, thus contributing to the early development of atherosclerosis. Low-dose folic acid supplementation reduces the pretreatment homocysteine plasma levels by 25-35%. Recent studies report that higher intravenous or oral administration of the active form of folic acid reduces the homocysteine plasma concentration by nearly 70%. The reduction could also be influenced by the thermolabile variant of methylenetetrahydrofolate reductase (tMTHFR) and by the dialysis modality. METHODS: A cross-sectional clinical study was performed to evaluate the effect of a drug containing folinic acid and vitamin B(12) on the plasma homocysteine concentration and whether this variable could also be influenced by the presence of a genetic variant of the methionine pathway and the use of different dialysis modalities. The plasma homocysteine concentration was measured in 55 patients undergoing haemodialysis, 27 of whom have been treated intravenously for megaloblastic anaemia using a drug containing low concentrations of folinic acid and vitamin B(12) at the end of each dialysis session for 6 months. The presence of tMTHFR was sought by molecular analysis, and the role of the dialysis modality was also investigated. RESULTS: The patients given the folic acid treatment had lower homocysteine plasma levels than those not so treated. The plasma homocysteine concentration was significantly higher in the tMRHFR homozygotes than in the patients with a normal genotype, significantly lower in the treated than in the untreated homozygotes, and significantly higher in the untreated homozygotes than in the untreated subgroup with a normal genotype. The homocysteine level was also significantly lower in the patients who underwent convective haemodialysis than in those who received standard bicarbonate dialysis. CONCLUSIONS: A drug containing low concentrations of folinic acid combined with vitamin B(12) using an intermittent intravenous regimen is effective in reducing the homocysteine plasma concentration in uraemic patients. The homocysteine levels seem also to depend on genotype and dialysis modality.

Kaposi's sarcoma in a patient with focal glomerulosclerosis.

We report the clinical features and outcome af a patient who presented Kaposi's sarcoma following immunosuppressive therapy for FGS; Cyclophosphamide and steroids were administered; the patient recovered after three months treatment with i.v. vinblastine.

Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: results from an international comparative study.

This report notes the differences in the classification of the primary renal disease (PRD) used in different renal dialysis and transplant registries worldwide. The heterogeneity of coding systems complicates the comparative analysis of end-stage renal disease from different regions. Using data collected over two decades in the United States, Europe, and Australia/New Zealand, we present a method for reorganization of the classes of PRD that allows a straightforward comparison of retrospective data from these registries.

Cancer in patients on dialysis for end-stage renal disease: an international collaborative study.

BACKGROUND: Previous studies have suggested that the frequency of cancer is higher in patients with end-stage renal disease (ESRD) than in the general population, but have not established whether this increase is confined to certain cancers or to certain categories of ESRD patients. The aim of this study was to examine the risk of cancer in a large cohort of patients treated by dialysis but not transplantation. METHODS: We assembled a cohort of 831,804 patients who received dialysis during the period 1980-94 for ESRD in the USA, Europe, Australia, or New Zealand. We compared the observed frequency of cancer among these patients during 2,045,035 person-years of follow-up with the frequency of cancer in the respective background populations. FINDINGS: During average follow-up of 2.5 years, 25,044 (3%) of 831,804 patients developed cancer compared with an expected number of 21,185 (standardised incidence ratio 1.18 [95% CI 1.17-1.20]). We observed a higher risk of cancer in patients younger than 35 years (3.68 [3.39-3.99]), and the risk gradually decreased with increasing age. High risks were observed for cancer of the kidney (3.60 [3.45-3.76]), bladder (1.50 [1.42-1.57]), and thyroid and other endocrine organs (2.28 [2.03-2.54]). Excess cancers appeared in several organs for which viruses have been suspected as causative agents, whereas cancers of the lung, colorectum, prostate, breast, and stomach were not consistently increased. INTERPRETATION: The overall risk of cancer is increased in patients with ESRD, and the distribution of tumour types resembles the pattern seen after transplantation (although we have no data to make the comparison with skin cancer). The excess risk can largely be ascribed to effects of underlying renal or urinary-tract disease, or of loss of renal function, on the kidney and bladder, and to increased susceptibility to viral carcinogenesis. The relative risk, which is especially high in younger patients, gradually diminishes with age.

Folate measurements in patients on regular hemodialysis treatment.

Patients on regular hemodialysis treatment may develop megaloblastic anemia caused by folate deficiency, but whether folate supplementation is required is still controversial, particularly during erythropoietin administration. Erythrocyte folate concentration is a better indicator of folate status than serum folate, although the latter is the variable generally measured. We measured serum and erythrocyte folate in blood samples from 112 regular hemodialysis patients (57 men, 55 women, 50 treated with erythropoietin, and 62 not) by Stratus Folate immunoenzymatic assay (Dade). Patients with very low serum (<2.87 ng/mL) but normal erythrocyte folate were reinvestigated 4 months later without receiving folate supplementation meanwhile. Serum folate concentrations were 0.48 to 12.76 ng/mL (median, 3.40) and erythrocyte folate 0.19 to 1.85 microg/mL (median, 0.42). Only 37% serum folate values were in the relevant reference interval compared with 80.2% erythrocyte folate values (3.08 to 17.65 ng/mL and 0.24 to 0.64 microg/mL, respectively). A significant correlation was found between serum and erythrocyte folate concentrations, without clinical relevance caused by the wide scatter around the regression line. Serum and erythrocyte folate did not vary significantly between patients given erythropoietin and those not so treated. The folate status of the 24 patients with very low serum folate was almost unchanged 4 months later. According to the serum folate test, 63% of patients needed folate supplementation, whereas the erythrocyte folate test, a better indicator of folate status, suggested that only 1.8% of patients needed folate supplementation. Erythropoietin therapy appears not to be an indication for standard folate supplementation in hemodialysis patients.

Effects of erythropoietin administration on blood pressure and urinary albumin excretion in rats.

The effects of recombinant human erythropoietin (rHuEPO) administration on blood pressure and urinary albumin excretion were studied in normotensive Wistar-Kyoto rats (WKY), in spontaneously hypertensive rats (SHR), and in SHR rats treated with an angiotensin converting enzyme inhibitor (SHR-ACEi). Rats were housed in metabolic cages and treated with rHuEPO (150 U/kg body weight [bw] three times a week) for 6 weeks. Control animals received the vehicle only (0.25 mL of physiological saline). An angiotensin converting enzyme inhibitor was administered in the drinking water for 6 weeks (spirapril 5 mg/kg bw). Systolic blood pressure (SBP), and 24 h urinary albumin excretion (UAE) were measured once a week. No significant differences in SBP were observed between rHuEPO and vehicle-treated normotensive animals at the end of the treatment (171.9 +/- 4.9 v 172.1 +/- 5.6 mm Hg, respectively). After 6 weeks, SBP was significantly higher in SHR and SHR-ACEi groups treated with rHuEPO than in control groups (239.8 +/- 7.3 and 243.0 +/- 7.3 mm Hg v 218.1 +/- 6.0 and 187.9 +/- 4.6 mm Hg, respectively); UAE was significantly higher in groups treated with rHuEPO than in control groups (WKY: 265.9 +/- 19.5 v 127.0 +/- 12.3 microg/100 g bw, SHR: 1668.4 +/- 564.6 v 234.8 +/- 22.9 microg/100 g bw, and SHR-ACEi: 1522.7 +/- 448.3 v 143.0 +/- 18.9 microg/100 g bw, respectively). We concluded that erythropoietin treatment causes an increase in arterial pressure in SHR only, and an increase in UAE in both normotensive and hypertensive rats. The albuminuric effect was not entirely dependent on increased blood pressure. The treatment with an angiotensin converting enzyme inhibitor did not modify either the proteinuric or the pressor effects.

Hepatitis G virus infection in hemodialysis patients.

The increased risk of hemodialysis patients for infections sustained by hepatitis viruses is likely to extend to a newly discovered parenterally transmitted virus, HGBV-C/HGV, able to cause acute and chronic hepatitis. The aim of this study was to assess the prevalence and clinical relevance of this infection in Italian hemodialysis patients. Nineteen of 100 patients (19%) on maintenance hemodialysis were viremic for HGBV-C/HGV, and all of them were infected with a HGV-like genotype. Eight of these patients were coinfected by hepatitis B or hepatitis C viruses. A clinical picture of chronic hepatitis was not appreciable in patients with isolated HGV infection and the presence of HGV did not appear to modify the clinical course of hepatitis B and hepatitis C infections.

Cancer among patients on renal replacement therapy: a population-based survey in Lombardy, Italy.

Longer and better survival of End-Stage Renal Disease (ESRD) patients undergoing renal replacement therapy (RRT) is now associated with a higher prevalence of new elderly patients receiving renal replacement therapy (dialysis). In order to help clarify the association of cancer risk with RRT, the incidence of cancer in a population-based cohort of uraemic patients in the Region of Lombardy, northern Italy, was undertaken using data from the Lombardy Regional Dialysis and Renal Transplant Registry. A total of 479 cases of cancer of all sites was recorded in this population. There were statistically significantly elevated risks of primary liver cancer, kidney cancer, thyroid cancer, lymphoma and multiple myeloma. When the data were examined according to primary renal diseases, there did not appear to be any particular association between excess cancer risk and the underlying pathology. While some caution must be expressed in interpreting these data, due to the relatively small numbers of cases expected in many of the disease entities, the results indicate an excess of renal-cell and liver carcinomas and lymphomas in patients receiving RRT and highlight the necessity of careful follow-up and awareness of these associations, together with the need for early detection of such tumours.