Very low-protein diet plus ketoacids in chronic kidney disease and risk of death during end-stage renal disease: a historical cohort controlled study.

BACKGROUND: Very low-protein intake during chronic kidney disease (CKD) improves metabolic disorders and may delay dialysis start without compromising nutritional status, but concerns have been raised on a possible negative effect on survival during dialysis. This study aimed at evaluating whether a very low-protein diet during CKD is associated with a greater risk of death while on dialysis treatment. METHODS: This is an historical, cohort, controlled study, enrolling patients at dialysis start previously treated in a tertiary nephrology clinic with a very low-protein diet supplemented with amino acids and ketoacids (s-VLPD group, n = 184) or without s-VLPD [tertiary nephrology care (TNC) group, n = 334] and unselected patients [control (CON) group, n = 9.092]. The major outcome was survival rate during end-stage renal disease associated to s-VLPD treatment during CKD. The propensity score methods and Cox regression model were used to match groups at the start of dialysis to perform survival analysis and estimate adjusted hazard ratio (HR). RESULTS: In s-VLPD, TNC and CON groups, average age was 67.5, 66.0 and 66.3 years, respectively (P = 0.521) and male prevalence was 55, 55 and 62%, respectively (P = 0.004). Diabetes prevalence differed in the three groups (P < 0.001), being 18, 17 and 31% in s-VLPD, CON and TNC, respectively. A different prevalence of cardiovascular (CV) disease was found (P < 0.001), being similar in TNC and CON (31 and 25%) and higher in s-VLPD (41%). Median follow-up during renal replacement therapy (RRT) was 36, 32 and 36 months in the three groups. Adjusted HR estimated on matched propensity patients was 0.59 (0.45-0.78) for s-VLPD versus CON. Subgroup analysis showed a lower mortality risk in s-VLPD versus matched-CON in younger patients (<70 years) and those without CV disease. No significant difference in HRs was found between s-VLPD and TNC. CONCLUSION: s-VLPD during CKD does not increase mortality in the subsequent RRT period.

Creatinine clearance, cystatin C, beta2-microglobulin and TATI as markers of renal function in patients with proteinuria.

BACKGROUND: Proteinuria is a risk factor for end-stage renal disease (ESRD). Creatinine clearance (CrCl) is usually used as a marker to monitor the progression of ESRD, while cystatin C (CYST) has also been considered as a marker of renal function. Tumor-associated trypsin inhibitor (TATI) has been shown to be a promising marker of renal function. The aim of this study was to examine the relationship between CrCl, CYST, ß(2)-microglobulin (B2M) and TATI, with glomerular filtration rate (GFR) in patients with different levels of proteinuria. METHODS: Seventy-one patients (37 males, 34 females, mean age 53 ± 15 years) were included in the study. GFR was measured by the bladder cumulative method using (99m)Tc-DTPA. Blood levels of CYST, B2M and TATI were also measured. CrCl and proteinuria were determined by 24-hour urine collection. Statistical analysis was performed with multivariate analysis. RESULTS: The results are expressed as the ratio to GFR of CrCl and reciprocals of CYST (100/CYST), B2M (100/B2M) and TATI (100/TATI). The ratio CrCl/GFR increased from 1.41 in patients with proteinuria <1 g/day, to 1.66 (p<0.05) in those with proteinuria >3 g/day. The ratio 100/CYST/GFR was 1.67 and 2.28 (p<0.05), 100/B2M/GFR 0.90 and 0.69 and 100/TATI/GFR 0.14 and 0.19, respectively. Multivariate analysis demonstrated that ClCr/GFR as well as 100/CYST/GFR was independently related to the degree of proteinuria. CONCLUSIONS: CrCl and CYST overestimate GFR in patients with heavy proteinuria, while the ratios 100/TATI and 100/B2M with GFR do not significantly change. The direct measurement of GFR still remains the best method to assess the progression of renal damage in patients with heavy proteinuria.

Use of ultrasound to assess the response to therapy for secondary hyperparathyroidism.

Secondary hyperparathyroidism (SHPT) is a common complication in patients with chronic kidney disease. In SHPT, the biology of parathyroid cells changes significantly toward diffuse nodular hyperplasia. Currently, diagnosis of SHPT is based on intact parathyroid hormone serum levels and parameters of mineral metabolism. The morphologic diagnosis of SHPT relies on high-resolution ultrasonography with color Doppler imaging. This report describes a maintenance hemodialysis patient with severe SHPT treated using conventional therapy (phosphate binders and oral/intravenous vitamin D or analogues) and the subsequent addition of a calcimimetic. The role of color Doppler ultrasonography in the diagnosis, clinical follow-up, and assessment of therapeutic response of SHPT is discussed. This case suggests that the availability of calcimimetics has changed the natural history of clinical SHPT and may change the therapeutic utility of parathyroidectomy. Use of color Doppler ultrasonography further supports these therapeutic advances, allowing evaluation of the morphologic and vascular changes in hyperplastic parathyroid glands and aiding clinical, pharmacologic, and surgical strategies.

Lipoprotein glomerulopathy: first report of 2 not consanguineous Italian men from the same town.

It is well known that the abnormal accumulation of lipids can occur in kidneys of patients affected by some metabolic disorders due either to inherited enzymatic deficiency or to an acquired lipid alteration as in nephrotic syndrome. Lipoprotein glomerulopathy (LG), briefly described in a patient of Koitabashi in 1987 in a review on renal lipidoses authored by Faraggiana and Churg, represents an emerging novel storage renal disease. This rare and unique nephropathy is characterized by the presence of lipoprotein thrombi in dilated glomerular capillary lumina associated with type III hyperlipoproteinemia, and high serum levels of apolipoprotein E (apo E). Several specific studies conducted by Saito et al on his patients from 1989, revealed that it was an hereditary disease with an autosomal recessive pattern that predominantly affects patients of Asian ancestry, mainly the Japanese population, but which very seldom, can also occur in white subjects. The disorder is probably due to an inherited altered lipid metabolism due to a mutation of the apo E genetic code. Clinically, LG is characterized by proteinuria generally associated with nephrotic syndrome and progressive renal insufficiency. We describe the cases of 2 Italian adult white male patients affected by LG, admitted in our nephrology unit in 2004 and in 2009, respectively.

Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: results from the RISCAVID study.

BACKGROUND: Resistance to erythropoiesis-stimulating agents (ESAs) is often associated with chronic inflammation. Here, we investigated how anaemia, ESA resistance and the plasma levels of biological markers of inflammation could influence all-cause and cardiovascular disease morbidity and mortality. METHODS: Seven hundred and fifty-three haemodialysis (HD) patients (mean age 66 ± 14.2 years, mean dialytic age 70 ± 77 months and diabetes 18.8%) were enrolled and followed-up for 36 months. Demographic, clinical and laboratory data, co-morbidity conditions, administered drugs, all-cause mortality and fatal/non-fatal cardiovascular (CV) events were recorded. We measured ESA resistance index, C-reactive protein (CRP) and interleukin-6 (IL-6). RESULTS: Six hundred and fifty-one patients (86.4%) received ESAs. Patients with haemoglobin level <11 g/dL (n = 225) showed increased risk of CV [relative risk (RR) 1.415, 95% confidence interval (CI) 1.046-1.914] and overall mortality (RR 1.897, 95% CI 1.423-2.530) versus patients with haemoglobin levels >11 g/dL. ESA resistance values categorized into quartiles (Quartile I <5.6, Quartile II 5.7-9.6, Quartile III 9.7-15.4 and Quartile IV >15.4) correlated with all-cause mortality and fatal/non-fatal CV events (RR 1.97, 95% CI 1.392-2.786; RR 1.619, 95% CI 1.123-2.332, respectively). Furthermore, albumin was significantly reduced versus reference patients and correlated with all-cause mortality and CV events; CRP levels were higher in hyporesponders (Quartile IV) (P < 0.001) and predicted all-cause mortality and CV events. IL-6 but not CRP was a strong predictor of ESA resistance. CONCLUSIONS: ESA responsiveness can be considered a strong prognostic factor in HD patients and seems to be tightly related to protein-energy wasting and inflammation.

A case of pheochromocytoma presenting as secondary hyperaldosteronism, hyperparathyroidism, diabetes and proteinuric renal disease.

A 35-year-old woman was admitted to the Nephrology and Dialysis Unit of Pisa University for hypertension, hypokalaemia, renal impairment, proteinuria and hyperglycaemia. plasma renin activity (PRA) and plasma aldosterone were elevated, but Doppler ultrasound and angio-computed tomography (CT) of renal arteries were normal. Abdomen CT revealed only a left adrenal mass, and measurement of catecholamines suggested the diagnosis of pheochromocytoma. Biochemical findings suggestive of hyperparathyroidism were also detected, but a multiple endocrine disorder was excluded by genetic analysis. Pathology examination confirmed the pheochromocytoma and immunohistochemistry also showed positivity for parathyroid hormone. After surgery, disappearance of the symptoms and normalization of all haemodynamic and humoral parameters was observed. This is a rare case of pheochromocytoma responsible for secondary hyperaldosteronism, hyperparathyroidism, proteinuric renal disease and diabetes mellitus.

A vitamin E-coated polysulfone membrane reduces serum levels of inflammatory markers and resistance to erythropoietin-stimulating agents in hemodialysis patients: results of a randomized cross-over multicenter trial.

BACKGROUND: Oxidative stress is prevalent in dialysis patients and has been implicated in the pathogenesis of cardiovascular disease and anemia. Vitamin E is a fat-soluble antioxidant that plays a central role in reducing lipid peroxidation and inhibiting the generation of reactive oxygen species. The aim of this cross-over randomized study was to compare the effects of a vitamin E-coated polysulfone (Vit E PS) membrane and a non-vitamin E-coated polysulfone (PS) membrane on inflammatory markers and resistance to erythropoietin-stimulating agents (ESAs). METHODS: After a 1-month run-in period of standard bicarbonate dialysis with a synthetic membrane, 62 patients of both genders, and older than 18 years, dialysis vintage 48 ± 27 months, BMI 22 ± 3 (from 13 different dialysis units) were randomized (A-B or B-A) in a cross-over design to Vit E PS (treatment A) and to PS (treatment B) both for 6 months. C-reactive protein (CRP) and interleukin-6 (IL-6) concentrations were determined by a sandwich enzyme immunoassay at baseline and every 2 months; red blood cell count, ESA dose and ESA resistance index (ERI) were assessed monthly. RESULTS: Hemoglobin (Hb) levels significantly increased in the Vit E PS group from 11.1 ± 0.6 g/dl at baseline to 11.5 ± 0.7 at 6 months (p < 0.001) and remained unchanged in the PS group. Although ESA dosage remained stable during the observation periods in both groups, ERI was significantly reduced in the Vit E PS group from 10.3 ± 2.2 IU-dl/kg/g Hb week at baseline to 9.2 ± 1.7 at 6 months (p < 0.001). No significant variation of ERI was observed in the PS group. A significant reduction in plasma CRP and IL-6 levels was observed in the Vit E PS group: CRP from 6.7 ± 4.8 to 4.8 ± 2.2 mg/l (p < 0.001) and IL-6 from 12.1 ± 1.4 to 7.5 ± 0.4 pg/ml (p < 0.05). In the PS group, CRP varied from 6.2 ± 4.0 to 6.4 ± 3.7, and IL-6 from 10.6 ± 2.1 to 9.6 ± 3.5 (p = n.s.). CONCLUSIONS: Treatment with Vit E PS membranes seems to lead to a reduction in ESA dosage in HD patients; in addition, a low chronic inflammatory response may contribute to a sparing effect on exogenous ESA requirements.

Impact of calcium, phosphate, PTH abnormalities and management on mortality in hemodialysis: results from the RISCAVID study.

BACKGROUND: Despite substantial progress in medical care, the mortality rate remains unacceptably high in dialysis patients. Evidence suggests that bone mineral dismetabolism (CKD-MBD) might contribute to this burden of death. However, to date only a few papers have investigated the clinical relevance of serum mineral derangements and the impact of different therapeutic strategies on mortality in a homogeneous cohort of south European dialysis patients. METHODS: The RISCAVID study was a prospective, observational study in which all patients receiving hemodialysis (HD) in the north-western region of Toscany in June 2004 were enrolled (N=757) and followed up for 24 months. RESULTS: At study entry, only 71 (9%) patients of the entire study cohort exhibited an optimal control of serum phosphorous (Pi), calcium (Ca), calciumX-phosphorous product (CAXPi) and intact parathyroidhormone (iPTH) according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) clinical guidelines. Despite a similar prevalence, the severity of CKD-MBD appeared different to the results reported in the USA. Interestingly, none of the serum biomarkers or number of serum biomarkers within KDOQI targets was independently associated with all-cause and cardiovascular (CV) mortality. Among treatments, Sevelamer was the only drug independently associated with lower all-cause and cardiovascular mortality (p<0.001). CONCLUSION: The RISCAVID study highlights the difficulty of controlling bone mineral metabolism in HD patients and lends support to the hypothesis that a carefully chosen phosphate binder might impact survival in HD patients.

Dimethylarginine levels and nutritional status in hemodialysis patients.

BACKGROUND: Asymmetric dimethylarginine (ADMA)and symmetric dimethylarginine (SDMA) originate from hydrolysis of methylated proteins, including dietary proteins, and are retained in end-stage renal disease(ESRD). This study aimed to detect the correlation of ADMA and SDMA to nutritional parameters in dialysis patients. METHODS: Before and after a single dialysis session, larginine, ADMA and SDMA plasma levels were measured in 38 hemodialysis patients by HPLC-tandem mass spectrometry. Biochemistry, protein intake, anthropometry and bioelectric impedance analysis were evaluated. RESULTS: Predialysis plasma levels of ADMA were higher than in normal controls (n=20) (1.14 +/- 0.27 mumol/Lvs. 0.56 +/- 0.09 mumol/L, p<0.001), as were SDMA levels(3.49 +/- 1.00 mumol/L vs. 0.44 +/- 0.13 mumol/L, p<0.001).On univariate analysis, predialysis ADMA levels were inversely related to BMI and albumin levels, whereas SDMA was directly related to nPNA, phase angle, prealbumin and creatinine serum levels. ADMA/SDMA ratio was inversely related to prealbumin and albumin, creatinine, urea and phosphorus serum levels, as wellas nPNA, but positively to C-reactive protein. On multiple regression analysis, serum albumin and BMI were the stronger predictors of ADMA, whereas prealbumin serum levels followed by dietary protein intake were the stronger predictors of SDMA. Prealbumin followed by C-reactive protein was predictive of the ADMA/SDMA molar ratio. CONCLUSIONS: Our results confirm that ADMA and SDMA levels are increased in ESRD patients and suggest that a link may exist with inflammation and nutritional status. High ADMA levels associated with reduced SDMA may be a predictive marker of malnutrition-inflammation-atherosclerosis syndrome.

Long-term treatment with cinacalcet and conventional therapy reduces parathyroid hyperplasia in severe secondary hyperparathyroidism.

BACKGROUND: The effect of cinacalcet on the structural pattern of hyperplastic parathyroid glands was evaluated, using high-resolution colour Doppler (CD) sonography, in haemodialysis patients with severe, inadequately controlled, secondary hyperparathyroidism (sHPT). METHODS: Nine patients (6 males, 3 females; mean age +/- SD, 55.5 +/- 12.6 years) received cinacalcet, with adaptation of existing concomitant therapies. Biochemical parameters and the morphology and vascular pattern of hyperplastic parathyroid glands were measured at baseline and every 6 months thereafter, for a follow-up period of 24-30 months. RESULTS: At baseline, 28 hyperplastic glands were identified. Cinacalcet led to a reduction in glandular volume during the course of the study: 68% in glands with a baseline volume <500 mm(3) and 54% in glands with a baseline volume >or=500 mm(3). The mean volume +/- SD of glands <500 mm(3) changed significantly from the baseline (233 +/- 115 mm(3)) to the end of follow-up (102 +/- 132 mm(3), P = 0.007). Levels of mean serum phosphorus, calcium and calcium-phosphorus product decreased, but not significantly, whereas there were significant decreases in mean parathyroid hormone +/- SD levels (1196 +/- 381 pg/ml versus 256 +/- 160 pg/ml; P < 0.0001) and alkaline phosphatase +/- SD levels (428 +/- 294 versus 223 +/- 88 IU/l; P = 0.04), accompanied by an improvement in a subjective clinical score. CONCLUSIONS: Cinacalcet, in combination with conventional treatments, led to an improvement in biochemical and clinical parameters of sHPT and reduced glandular volume in patients with severe sHPT. Volume reduction was more evident in smaller glands. Longer term, larger, randomized clinical trials are needed to confirm these preliminary findings and to further define a more systematic approach in the treatment of sHPT.

Chronic inflammation and mortality in haemodialysis: effect of different renal replacement therapies. Results from the RISCAVID study.

BACKGROUND: The 'RISchio CArdiovascolare nei pazienti afferenti all' Area Vasta In Dialisi' (RISCAVID) study is an observational and prospective trial including the whole chronic haemodialysis (HD) population in the northwest part of Tuscany (1.235 million people). The aim of the study was to elucidate the relevance of traditional and non-traditional risk factors of mortality and morbidity in HD patients as well as the impact of different HD modalities. METHODS: A total of 757 HD patients (mean age 66 +/- 14 years, mean dialytic age 70 +/- 76 months, diabetes 19%) were prospectively followed up for 30 months and all-cause mortality, cardiovascular (CV) mortality and non-fatal CV events (acute myocardial infarction and stroke) were registered. At the time of the enrolment, demographic, clinical and laboratory data of the whole population were entered into a centralized database. Serum albumin, high-sensitive C-reactive protein (CRP), interleukin-6 (IL-6) and interleukin-8 (IL-8) were centrally determined at the start of the study. Patients were stratified into three groups according to the HD modality: standard bicarbonate HD (BHD) (n = 424), haemodiafiltration (HDF) with sterile bags (n = 204) and online HDF (n = 129). The Cox proportional hazards regression assessed adjusted differences in CV morbidity and mortality risk; a multivariate analysis was also performed. RESULTS: All-cause and CV mortality was 12.9%/year and 5.9%/year, respectively. Patients with combined high levels of CRP and pro-inflammatory cytokines showed an increased risk for CV (RR 1.9, P < 0.001) and all-cause mortality (RR 2.57, P < 0.001). Multivariate analysis adjusted for comorbidity and demographic showed CRP as the most powerful mortality predictor (P < 0.001) followed by IL-6. The Cox proportional hazards regression assessed that online HDF and HDF patients had a significantly increased adjusted cumulative survival than BHD (P < 0.01). CONCLUSIONS: Data at 30 months from this study showed the synergic effect of CRP and pro-inflammatory cytokines as the strong predictors of all-cause and CV mortality. HDF was associated with an improved cumulative survival independent of the dialysis dose.

Blunted post-ischemic increase of the endothelial skin blood flowmotion component as early sign of endothelial dysfunction in chronic kidney disease patients.

With the aim to investigate microvascular endothelial function in chronic kidney disease (CKD) patients on conservative treatment, skin blood flowmotion (SBF) was explored by spectral Fourier analysis of skin forearm laser Doppler tracing, registered before and following forearm ischemia in 32 III to V stage CKD patients (23 males, mean age: 52+/-12 years), without diabetes or cardiovascular disease, and in 32 age and sex matched healthy subjects. The power spectral density (PSD) of the 0.009-1.6 Hz total spectrum SBF, as well as of five sub-intervals, each of them related to endothelial (0.009-0.02 Hz), sympathetic (0.02-0.06 Hz), myogenic (0.06-0.2 Hz), respiratory (0.2-0.6 Hz) or cardiac (0.6-1.6 Hz) activity, was measured in PU(2)/Hz (PU=perfusion unit; 1 PU=10 mV). Under basal conditions CKD patients and controls did not differ in skin perfusion or in PSD of total spectrum SBF, as well as of each of the five subintervals considered. No substantial difference was also observed in skin post-ischemic hyperemia between patients and controls. A significant post-ischemic increase in the normalized value of endothelial sub-interval was observed in controls (p<0.05, GLM ANOVA analysis of variance), but not in CKD patients. A lower per cent increase in absolute PSD value of endothelial sub-interval was also observed in CKD patients compared to controls (185+/-98 % vs 279+/-243 %, p<0.05). The post-ischemic per cent increase in absolute PSD of endothelial sub-interval was negatively related to the systolic blood pressure (r=-0.45, p<0.01), to the mean arterial blood pressure (r=-0.40, p<0.05) and to the PTH serum levels (r=-0.38, p<0.05) in CKD patients. The blunted post-ischemic increase of the endothelial SBF sub-interval can be considered an early sign of microvascular endothelial dysfunction in the CKD studied patients. Arterial hypertension seems to be the main factor related to this SBF abnormality, together with the hormonal CKD related abnormalities.

Potential benefits of renal diets on cardiovascular risk factors in chronic kidney disease patients.

Dietary manipulation, including protein, phosphorus, and sodium restriction, when coupled with the vegetarian nature of the renal diet and ketoacid supplementation can potentially exert a cardiovascular protective effect in chronic renal failure patients by acting on both traditional and nontraditional cardiovascular risk factors. Blood pressure control may be favored by the reduction of sodium intake and by the vegetarian nature of the diet, which is very important also for lowering serum cholesterol and improving plasma lipid profile. The low protein and phosphorus intake has a crucial role for reducing proteinuria and preventing and reversing hyperphosphatemia and secondary hyperparathyroidism, which are major causes of the vascular calcifications, cardiac damage, and mortality risk of uremic patients. The reduction of nitrogenous waste products and lowering of serum PTH levels may also help ameliorate insulin sensitivity and metabolic control in diabetic patients, as well as increase the responsiveness to erythropoietin therapy, thus allowing greater control of anemia. Protein-restricted diets may have also anti-inflammatory and anti-oxidant properties. Thus, putting aside the still debatable effects on the progression of renal disease and the more admitted effects on uremic signs and symptoms, it is possible that a proper nutritional treatment early in the course of renal disease may be useful also to reduce the cardiovascular risk in the renal patient. However, conclusive data cannot yet be drawn because quality studies are lacking in this field; future studies should be planned to assess the effect of renal diets on hard outcomes, as cardiovascular events or mortality.

The Pisa experience of renal biopsies, 1977-2005.

INTRODUCTION: Although several registries collecting data of patients with kidney diseases exist, only a few specifically collect data relating to renal biopsy. Kidney biopsy has been performed routinely in Pisa since 1977; the aim of this study was to report the relative frequency of nephropathies according to gender, age at time of biopsy, clinical presentation and renal function, based on histological diagnoses during the years 1977 through 2005. During this time, 3,810 kidney biopsies were performed, of which 89.3% were from native (n=3,446) and 10.7% from transplant kidneys. Throughout this period, 5% of renal biopsies were not diagnostic, so in this paper we report data regarding 3,269 native kidney nephropathies. METHODS: During the years 1977 through 2005, data for renal biopsies were collected on specific registers filled out by clinicians. Information collected in the database included a variety of indicators, such as clinical anamnesis, creatinine clearance, daily proteinuria, hemoglobin levels, blood pressure, height and weight, clinical presentation, and current medications. Clinical presentation was defined as urinary abnormalities (UA), nephrotic syndrome (NS) and acute nephritic syndrome (ANS). Renal diseases were divided into 4 major categories: primary glomerulonephritis (GN), secondary GN, tubulointerstitial nephropathies (TIN) and vascular nephropathies (VN). RESULTS: From 1977 up to 1987, a mean of 95 +/- 18 renal biopsies/year were performed; this number significantly increased to 185 +/- 22 renal biopsies/year (range 138-200) (p<0.001) in the following period (1988-2005). Renal biopsy was more frequently performed in males (59%) compared with females (41%). Of all diseases of the native kidney, primary GN was the most frequent (66%), followed by secondary GN (25.6%), TIN (4.2%) and VN (4.2%). The type of primary GN with the highest frequency was mesangial GN (both IgA and non-IgA) (45.7%), followed by membranous GN (23%), focal segmental glomerulosclerosis (19.8%), minimal change disease (5.3%), crescentic GN (4.2%) and postinfectious GN (2%). In terms of age, renal biopsy was more frequently performed in patients aged 20 to 60 years, and nearly 60% of patients presented a glomerular filtration rate (GFR) >60 ml/min at the time of biopsy. The main clinical reason for performing renal biopsy was UA, in all the types of nephropathies. CONCLUSIONS: We confirm data that renal diseases are more frequent in men, with the exception of secondary GN. The mean age at diagnosis was 42 years resulting from the tendency not to perform renal biopsies in children and in elderly patients. Renal biopsy was mainly performed in patients with GFR >60 ml/min and asymptomatic urinary abnormalities suggesting concern on the part of clinicians regarding glomerular diseases. The tendency to perform renal biopsies has been significantly increasing throughout our follow-up period.

Erythrocyte transmembrane electron transfer in haemodialysis patients.

BACKGROUND AND AIMS: Patients with chronic renal failure, especially those treated with haemodialysis, have an increased risk of developing atherosclerotic vascular disease probably as a result of enhanced oxidative stress. The human cell membrane possesses electron transfer systems which protect against extracellular pro-oxidant challenge. We evaluated (1) the erythrocyte velocity of ferricyanide reduction (RBC vfcy) in 25 uraemic patients (aged 25-71 years; 14 males), (2) the changes induced by a single haemodialysis session and (3) biomarkers of oxidative stress. METHODS AND RESULTS: Before and after a mid-week dialysis session, we measured RBC vfcy, erythrocyte glutathione (RBC GSH), plasma and red cell membrane malondialdehyde (P and RBC MDA), plasma sulphydryl groups (P SH), plasma vitamin C levels and haemolysis percentage. Pre-dialysis RBC GSH (0.68+/-0.13 vs 0.80+/-0.13 mg/mL, p<0.01), P SH (266+/-74 vs 406+/-78 micromol/L, p<0.01) and plasma vitamin C (7.0+/-5.1 vs 21.5+/-8.5mg/L, p<0.001) were lower than in 25 age-sex-matched healthy controls; P MDA (1.57+/-0.52 vs 0.54+/-0.29 nmol/mL, p<0.001), RBC MDA (0.42+/-0.13 vs 0.34+/-0.16 nmol/mL, p<0.05) and haemolysis (1.2+/-0.3 vs 0.7+/-0.3%, p<0.001) were increased. Baseline RBC vfcy did not differ from normals (13.1+/-5.2 vs 12.9+/-3.2 mmol/mL/h). Following dialysis, RBC vfcy (to 8.9+/-4.5 mmol/mL/h, p<0.001) decreased, as well as P MDA, RBC MDA and plasma vitamin C (to 2.5+/-1.4 mg/L, p<0.001), whereas P SH groups increased (to 413+/-99 micromol/L, p<0.001); haemolysis percentage remained high. RBC vfcy values were correlated to RBC GSH and vitamin C levels. CONCLUSIONS: Uraemic patients showed signs of oxidative stress. Pre-dialysis RBC vfcy is maintained in the normal range on account of a reduced intracellular content of GSH and in spite of low plasma ascorbate. A single haemodialysis treatment reduced biomarkers of protein and lipid oxidation but markedly impaired transmembrane electron transfer, which could be explained by acute depletion of electron donors.

Soy protein diet improves endothelial dysfunction in renal transplant patients.

BACKGROUND: Since it has been demonstrated that soy diet can improve endothelial function, in the present study we evaluated the effect of dietary substitution of 25 g of animal proteins with soy proteins on endothelial dysfunction in renal transplant patients. METHODS: In 20 renal transplant patients (55 +/- 11 years, serum creatinine 1.7 +/- 0.6 mg/dl), brachial artery flow mediated dilation (FMD) and endothelium-independent vasodilation (sublingual nitroglycerine, 25 microg) were measured at baseline, after 5 weeks of a soy diet and finally after 5 weeks of soy wash-out. Changes in plasma lipids, markers of oxidative stress (lipid peroxides, LOOH) and inflammation (C-reactive protein), isoflavones (genistein and daidzein), asymmetric dimethyl arginine (ADMA) and L-arginine were also evaluated. RESULTS: At baseline, patients showed a significantly lower FMD as compared with age-matched healthy subjects (3.2 +/- 1.8 vs 6.3 +/- 1.9, respectively; P < 0.001), while response to nitroglycerine was similar. After soy diet, actual protein intake was not changed, cholesterol and lipid peroxides were significantly reduced, and isoflavones were detectable in plasma. Soy diet was associated with a significant improvement in FMD (4.4 +/- 2.0; P = 0.003 vs baseline), while response to nitroglycerine was unchanged. Improvement in FMD was related to L-arginine/ADMA ratio changes, but no significant relation was found to changes in cholesterol, lipid peroxides or genistein and daidzein plasma concentrations. After 5 weeks of soy diet discontinuation, FMD (3.3 +/- 1.7%) returned to baseline values and isoflavones were no longer detectable in plasma. CONCLUSIONS: A soy protein diet for 5 weeks improves endothelial function in renal transplant patients. This effect seems to be strictly dependent on soy intake as it disappears after soy withdrawal and is mediated by an increase in the L-arginine/ADMA ratio, independently of change in lipid profile, oxidative stress or isoflavones.

Acute effects of hemodialysis on left ventricular function evaluated by tissue Doppler imaging.

Evidence exists that left ventricular function is impaired in chronic uremic patients. During hemodialysis (HD) treatment, myocardium undergoes electrolyte, hemodynamic and neuro-humoral stress; however, data about the acute changes on ventricular function are controversial. Aim of the present study was to evaluate the effect of a single hemodialysis session on left ventricular (LV) systolic and diastolic function using pulsed tissue Doppler imaging (TDI) sampled by echocardiography. The study group included 20 uremic patients (17 males, aged 51+/-13 yrs) on maintenance HD, free from clinically overt cardiac dysfunction who underwent echocardiography with pulsed TDI 30 min prior and 30 min after a HD session. TDI was performed by placing the sample volume in the center of the basal lateral segment and the basal interventricular septum in the apical four-chamber view. Myocardial systolic wave (S(m)) and early (E(m)) and atrial (A(m)) diastolic waves were measured. On standard sonography examination, no significant changes in LV systolic function parameters were observed after HD, but the indices for LV diastolic function deteriorated significantly (peak E, 75.4+/-11.2 vs. 58.8+/-12.5 cm/s, P<0.01; E/A ratio, 1.0+/-0.3 vs. 0.8+/-0.2, P<0.01). However, regarding TDI measures following HD, the patients exhibited a lower S(m) peak (septum: 7.6+/-1.1 vs. 5.9+/-0.8 cm/s; lateral wall: 7.7+/-1.7 vs. 6.8+/-1.2 cm/s, P<0.001), a lower E(m) peak (septum: 8.3+/-1.6 vs. 6.3+/-1.7 cm/s; lateral wall: 10.2+/-2.4 vs. 7.1+/-1.9 cm/s, P<0.001), and a reduced E(m)/A(m) ratio (septum: 1.0+/-0.4 vs. 0.7+/-0.2; lateral wall: 1.2+/-0.5 vs. 0.7+/-0.2, P<0.001, respectively), as compared to pre-HD parameters. Of interest, peak E(m), and E(m)/A(m) ratio of the lateral wall were negatively related to ultrafiltration rate (r = -0.60, P<0.05 and -0.69, P<0.01, respectively). Our data indicate that a single hemodialysis session is associated with acute deterioration of diastolic and systolic parameters of myocardial function, as assessed by TDI. These reversible changes could be considered as a cardiac stunning that seems to be related to the ultrafiltration rate and then to the interdialysis weight gain. These findings suggest that low ultrafiltration volume and/or limited interdialytic weight gain are cardioprotective measures in hemodialysis patients.

Effect of boiling on dietary phosphate and nitrogen intake.

OBJECTIVE: Dietary phosphate restriction is one of the means of phosphatemia control in dialysis patients. To limit dietary phosphate intake, appropriate food choices are recommended, but this often creates a conflict with the high-normal protein requirement of dialysis patients. Although food processing by boiling may be a safe tool for eliminating many minerals, this method poses a risk for loss of important nutrients, including proteins. The goal of this study was to assess the effect of boiling on phosphate and protein nitrogen changes in commonly used foods that contain proteins of high biological value. METHODS: We evaluated the true retention values of dry matter, crude protein, and total phosphorus in fresh beef and chicken breast before and after 10, 20, and 30 minutes of boiling; the reported values represent the average of five determinations. RESULTS: Compared with crude raw samples, dry matter retention in cooked beef was reduced up to 92% +/- 6%, crude protein retention was reduced up to 87% +/- 10%, and phosphorous retention was reduced up to 42% +/- 13%; similar data were obtained when boiling the chicken breast, 93% +/- 3%, 81% +/- 4%, and 63% +/- 6%, respectively. CONCLUSIONS: Our results show that consuming boiled foods can significantly reduce dietary phosphate while preserving protein intake, namely reducing the effective phosphate intake per gram of dietary protein. This can represent additional advice to the patient for limiting the dietary phosphorus load at the same protein intake, leading to a better control of phosphate balance together with a lower risk of protein malnutrition.

Interleukin-8 is a powerful prognostic predictor of all-cause and cardiovascular mortality in dialytic patients.

BACKGROUND: Cohort studies have demonstrated an association between C-reactive protein (CRP) and interleukin-6 (IL-6) and all-cause and cardiovascular mortality in end-stage renal disease (ESRD) patients. Interleukin-8 (IL-8) appears to be not only the plasma expression of the acute-phase response but also a direct pathogenetic mediator of the atherosclerotic process. METHODS: To evaluate the role of IL-8 in predicting outcome, 76 chronic dialytic patients were prospectively followed for 18 months. At baseline, blood samples were taken for analysis of high-sensitivity CRP, IL-6, IL-8 and other standard laboratory analyses. RESULTS: Median IL-8 was 5.2 mg/l, therefore near half of the patients had IL-8 values within the range of 'normal limits'. IL-6 and CRP were significantly correlated (r = 0.45, p < 0.001) and a positive correlation was also found between IL-6 and IL-8 (r = 0.39, p < 0.001). The correlation coefficient between IL-6 and CRP was 0.43 (p < 0.001) and 0.50 (p < 0.001) in patients without and with history and/or clinical signs of cardiovascular disease, respectively. After a follow-up of 1.5 years, 8 patients had died from cardiovascular causes and another 7 patients for other reasons; furthermore 9 major nonfatal cardiovascular events were recorded. Stepwise regression analysis showed IL-8 as the strongest independent predictor of all-cause and cardiovascular events (p = 0.0025) even after adjustment for age and dialytic age, followed by IL-6 and CRP (p < 0.01). CONCLUSION: Despite a small population and a relatively short follow-up period, this study firstly demonstrated that IL-8 is a powerful independent predictive factor for cardiovascular and overall mortality cause in ESRD patients.

In vivo and in vitro effects of simvastatin on inflammatory markers in pre-dialysis patients.

BACKGROUND: The beneficial effects of statins in reducing cardiovascular events have been attributed predominantly to their lipid-lowering effects, recent studies suggest that these effects might be due to their anti-inflammatory properties. We here investigate the in vivo and in vitro effects of simvastatin on cytokine production in pre-dialysis chronic renal failure patients. METHODS: Our clinical study has been designed as a randomized double-blind placebo controlled study. A total of 55 chronic kidney disease (CKD) patients at stages 3 and 4 (mean creatinine clearance 45 ml/min, range 15-60) were randomly assigned to receive simvastatin 40 mg/day or placebo, added to their ongoing treatment, for 6 months. Blood samples were obtained at baseline, and after 3 and 6 months of observation for the determination of lipids, inflammatory markers and renal function. For the in vitro studies, the effect of increasing doses of simvastatin on cytokine production [namely interleukin (IL)-6 and IL-8] in human cultured monocytes from 10 healthy subjects (HS) and 15 CKD patients stimulated by lipopolysaccharide (LPS) was investigated. RESULTS: A significant reduction in total cholesterol from 221+/-44 mg/dl to 184+/-41 mg/dl (3 months) and to 186+/-39 mg/dl (6 months) (P<0.02) and low-density lipoprotein cholesterol from 139+/-40 mg/dl to 104+/-29 mg/dl (3 months) and to 100+/-31 mg/dl (6 months) (P<0.001) was observed in the 28 patients treated with simvastatin. In this group, C-reactive protein (CRP) levels significantly decreased from 2.6 mg/l [interquartile range (IQR 4.9)] to 2.0 mg/l (IQR 1.9) (P = 0.03) at 6 months (P<0.05). A parallel reduction of IL-6 levels from 5.1 pg/ml (IQR 3.8) to 3.5 pg/ml (IQR 3.1) (P = 0.001) at 6 months was also observed. No significant reduction in inflammatory markers [CRP from 5.1 mg/l (IQR 1.9) to 5.4 mg/l (IQR 1.3) (P = NS) at 6 months] or plasma lipids [LDL-cholesterol from 127+/-32 mg/dl to 131+/-21 mg/dl (6 months)] was observed in the 27 patients of the placebo group. In the in vitro studies, the average value for cell-associated IL-6 and IL-8 was higher in CKD (155+/-95 pg/ml monocytes for IL-6 and 722+/-921 pg/ml monocytes for IL-8) vs HS (137+/-87 pg/ml monocytes and 186+/-125 pg/ml monocytes) (P<0.01) and was not affected by simvastatin alone. LPS resulted in a significant increase in cytokine production (IL-6: 1954+/-321 pg/ml monocytes for CKD and 1451+/-237 pg/ml monocytes for HS; P<0.001); the simultaneous addition of increasing doses of simvastatin to these cultures induced a dose-dependent inhibition of IL-6 and IL-8 production in stimulated peripheral blood mononuclear cells in all groups. CONCLUSIONS: These results indicate that simvastatin in commonly used doses has an in vitro and in vivo anti-inflammatory effect in CKD patients, and may play an important role in counteracting the mechanisms involved on the pathogenesis of cardiovascular disease.