High density lipoprotein cholesterol levels are an independent predictor of the progression of chronic kidney disease.

OBJECTIVES: Patients with chronic kidney disease (CKD) often present with reduced plasma HDL cholesterol (HDL-C) levels. Whether this reduction in an epiphenomenon or is involved in disease progression is unclear. The aim of this study was to investigate the relation between HDL-C levels/function and CKD progression in patients with different degrees of disease. DESIGN: A total of 176 patients with CKD [glomerular filtration rate (GFR) 50.3 ± 29.1 mL min⁻¹] were recruited and followed for up to 84 months. Lipid profile, metabolic status and kidney function were evaluated at predetermined times. Age-matched control subjects were selected from the PLIC study (n = 453). Scavenger receptor class B member 1 (SR-BI) and ATP-binding cassette transporter A1 (ABCA-1)-dependent efflux of cholesterol were measured in CKD patients and in age-matched control subjects. RESULTS: Low HDL-C levels, diabetes and hypertension were associated with reduced GFR. At follow-up, low HDL-C levels were associated with earlier entry in dialysis or doubling of the plasma creatinine level (P = 0.017); HDL-C levels were the only lipid parameter that affected the progression of CKD (hazard ratio 0.951, 95% confidence interval 0.917-0.986, P = 0.007), independently of the presence of diabetes. Only SR-BI-mediated serum cholesterol efflux was significantly reduced in the group of CKD patients with low HDL-C levels compared to the control group. CONCLUSIONS: CKD patients with low levels of plasma HDL-C have a poor prognosis. HDL functionality is also impaired in renal dysfunction. These data support the relevance of HDL in influencing CKD progression.

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.

Reduction in urea distribution volume over time in clinically stable dialysis patients.

We have previously shown that, assuming urea distribution volume (V) remains constant for 1 month, ionic dialysance (ID) allows the dialysis dose to be calculated without the need for blood sampling. The aim of this multicenter study was to verify whether the assumption of a constant V can be extended to 1 year. In clinically stable patients receiving thrice-weekly hemodialysis at 13 dialysis centers, V and Kt/V were assessed during three dialysis sessions at baseline and 1 year later using ID as dialyzer urea clearance and the single-pool urea kinetic model. Baseline albumin, hemoglobin, and C reactive protein were prespecified covariates for predicting the change in V over time. Of the 52 enrolled patients, 40 (25 males; age 63.0+/-13.5 years) completed the study. Baseline end-dialysis body weight (62.4+/-13.7 kg) showed a non-significant 1% reduction during follow-up (-0.6+/-2.8 kg; P=0.175), whereas V significantly decreased from 29.0+/-6.8 to 27.4+/-6.0 l (-1.6+/-3.0 l or 4.5%; P=0.002). The reduction in V was greater when baseline albumin was lower (P=0.001) and baseline V was higher (P=0.005). The single-pool K(t)/V calculated using baseline V underestimated the actual value by 0.07+/-0.16 (P=0.008). The slight underestimate of Kt/V during follow-up suggests that annual V evaluations may be sufficient for dialysis dose quantification as the only risk is underestimating the actually delivered dialysis dose. However, the relationship between baseline albumin and the reduction in V over time may have nutritional value, and suggests more frequent V evaluations.

[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.

Study of calcium metabolism in idiopathic hypercalciuria by strontium oral load test.

Calcium excretion and absorption were evaluated in hypercalciuric calcium stone formers by the study of Sr2+ excretion and absorption after an oral load. Ca2+ stone formers (n = 140) were studied, and the results were compared in the 83 of them who had idiopathic hypercalciuria and in the 57 who had Ca2+ excretion within reference values. Hypercalciuric patients showed increased renal Sr2+ clearance (CRE; 5.26 +/- 0.358 vs 3.29 +/- 0.277 mL/min; P <0.001), whereas Sr2+ absorption [assessed as the area under the serum concentration-time curve (AUC)] was increased at 30 and 60 min (1.53 +/- 0.087 vs 1.21 +/- 0.071 mmol. L-1. min; P <0.05), but not at 240 min after the load. In hypercalciuric patients, the AUCs were positively correlated with urinary Sr2+ fractional excretion (P <0. 001). Conversely, in normocalciuric patients plasma parathyroid hormone (PTH) was negatively correlated with the AUCs (P <0.01) and CRE (P <0.05), whereas 1,25-dihydroxyvitamin D plasma concentrations normalized to PTH were positively correlated with the AUCs (P <0.05). The results of Sr2+ load tests suggest that in the hypercalciuric population, Ca2+ absorption is altered predominantly in the duodenum and that the normal regulation exerted by calciotropic hormones on tubular and enteral Ca2+ handling is lost.

Strontium absorption and excretion in normocalciuric subjects: relation to calcium metabolism.

The relationships of Sr intestinal absorption and renal excretion with biohumoral factors regulating Ca metabolism were studied in 47 normocalciuric subjects with Ca kidney stones. Sr concentrations were measured in serum and urine after an oral load of stable Sr (30.2 mumol/kg body wt). Enteral absorption of the ion (9.77 +/- 0.438 mmol.L-1.min, 240 min after Sr administration), expressed as the area under the plasma concentration-time curve (AUC), and renal clearance (CRE) in these subjects during the test (2.80 +/- 0.336 mL/min) were not different from values for 27 controls. CRE was not correlated with AUCs. Plasma concentrations of parathyroid hormone (PTH) negatively correlated with AUCs (P < 0.01) and correlated with CRE after one outlier was excluded (P < 0.05). Plasma concentrations of 1,25-dihydroxyvitamin D correlated positively with AUCs (P < 0.01) when normalized to the plasma concentration of PTH. Multiple stepwise regression showed that PTH and phosphatemia were significantly related to AUC values at 240 min (P < 0.01). These findings suggest that Sr absorption and excretion reflect the regulation of Ca metabolism, but some differences in renal handling of the two ions may exist.

Nonacidotic proximal tubulopathy transmitted as autosomal dominant trait.

The family of a patient with a nonacidotic and hypercalciuric proximal tubulopathy was studied. The proband showed glycosuria, aminoaciduria, tubular proteinuria, renal hypophosphatemia, and urate tubular hyporeabsorption without bicarbonate loss. He also presented increased urine calcium excretion, plasma 1,25-dihydroxyvitamin D, and enteral calcium absorption. Clinical consequences of the tubulopathy were osteopenia and calcium kidney stones. Fifteen of the proband's relatives were studied; six of them had renal hypophosphatemia, 10 presented hypercalciuria, and three showed both hypercalciuria and hypophosphatemia. No other reabsorption defects were observed. High plasma levels of 1,25-dihydroxyvitamin D were found in 13 family members; their values correlated positively with calcium excretion and negatively with tubular phosphate reabsorption. None produced stones or had reduced mineral bone density. Hypophosphatemia and hypercalciuria occurred in the two generations studied; their transmission was independent of gender, and male-to-male transmission occurred for both defects. Our findings suggest that a genetic alteration of proximal tubular function could cause multiple reabsorption defects in the proband or renal phosphate leakage in the proband's relatives. The genotypic alteration causing the proximal dysfunctions may be monogenic, with an autosomal dominant pattern of inheritance and variable expressivity. Increased calcium excretion may be due to the proximal tubular alteration; alternatively, it may be the result of a genetic background predisposing to idiopathic hypercalciuria. Phosphate and calcium loss could stimulate 1,25-dihydroxyvitamin D synthesis in proximal tubular cells.

L-asparaginase in acute lymphoblastic leukemia treatment: the role of human antithrombin III concentrates in regulating the prothrombotic state induced by therapy.

It is well known that L-asparaginase (L-Ase) treatment may cause thrombotic events in patients with acute lymphoblastic leukemia (ALL). The mechanism of this effect is not well understood although a reduction in plasma antithrombin III (AT III) levels is observed. In our study, a group of patients treated with L-Ase received AT III concentrates as adjuvant treatment. This adjuvant treatment reduced the levels of plasma D-dimer and thrombin-antithrombin complex, which are considered as early markers of a hypercoagulability state. These preliminary data suggest that large randomized trials will have to be conducted to improve our understanding of the role of AT III concentrates in ALL therapy.