[Interviewing Professor Enrico Malizia, one of the fathers of Italian nephrology].

This article contains an interview to Professor Enrico Malizia (born in 1926), who played an important role in the birth of nephrology in Italy. On April 27th, 1957 Professor Malizia was in fact among the founders of the Italian Society of Nephrology, which he also served as secretary for some years, together with Professor Luigi Migone (1912-2002). In addition, he participated in the organization of the First International Congress of Nephrology, which took place in Geneva and Evian from September 1st to 4th, 1960. Professor Malizia devoted himself to nephrology for many years, both as clinician and as researcher, by publishing many original papers and monographs on different nephrological topics, a few of which are described in detail in the present article. In addition, his interest in renal diseases led him to frequent the institutions of eminent renal scientists of the period such as the physiologist Homer Smith (1895-1962) and the pathologist Jean Oliver (1889-1976) in the United States, and the clinician Jean Hamburger (1909-1992) in Paris.

Evaluation of the Impact of a New Synthetic Vitamin E-Bonded Membrane on the Hypo-Responsiveness to the Erythropoietin Therapy in Hemodialysis Patients: A Multicenter Study.

BACKGROUND: Oxidative stress has been related to hypo-response to erythropoiesis-stimulating agents (ESAs) in hemodialysis (HD) patients. The aim of this study was to verify whether vitamin E (ViE) on a synthetic polysulfone dialyzer can improve ESA responsiveness. METHODS: This controlled, multicenter study involved 93 HD patients on stable ESA therapy, who were randomized to either ViE-coated polysulfone dialyzer or to a low-flux synthetic dialyzer. The primary outcome measure was the change in ESA resistance index (ERI) from baseline. RESULTS: Mean ERI decreased in the ViE group by 1.45 IU/kg*g/dl and increased in the control group by 0.53 IU/kg*g/dl, with a mean difference of 1.98 IU/kg*g/dl (p = 0.001 after adjusting for baseline ERI, as foreseen by the study protocol). Baseline ERI was inversely related to its changes during follow-up only in the control group (R2 = 0.29). CONCLUSIONS: The ViE dialyzer can improve ESA response in HD patients. Changes in ERI during follow-up are independent from baseline ERI only in the ViE group. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=453442.

[Best practices on peritoneal dialysis: the audit of Lazio Region]. / Best practices in dialisi peritoneale: l'audit della regione Lazio.

The diffusion of peritoneal methodology can not be something out of the real organizational context and the regional directive can not be the only means to encourage the diffusion. There is the need to provide effective and sustainable levels of assistance through a clinical scientific support and sharing of best-practises. On one side, the aim is to provide an aid by the centers with great expertise in the methodology, recognized as reference points; on the other side, to establish the shared K.P.I.s (Key Performance Index), to asses the clinical effectiveness and measure the objectives to be achieved, through a modality of valuation to establish the real applicability. For this purpose, a scientific board was founded, composed by the heads of UU.OO, that provide the peritoneal dialysis, to determine which aspects to investigate and identify factors of supply improvement. The selected method was the clinical audit. The analysis of the 2011 data has allowed us to capture the situation of the peritoneal dialysis in the Lazio Region. The formative procedure has enabled the centers to share and standardize protocols and therapeutic procedures, identify the strengths of peritoneal dialysis in the Lazio Region and define the KPIs through whose compare and monitor the centers over time. The conclusive analysis of the audit has enabled to identify a series of activities to be undertaken together in order to improve the situation of the peritoneal dialysis in the Lazio Region. In the following years, surveys will be carried out to verify the KPIs trend.

Outcomes in patients with chronic kidney disease not on dialysis receiving extended dosing regimens of darbepoetin alfa: long-term results of the EXTEND observational cohort study.

BACKGROUND: Extended dosing of the erythropoiesis-stimulating agent (ESA) darbepoetin alfa (DA) once biweekly or monthly reduces anaemia treatment burden. This observational study assessed outcomes and dosing patterns in patients with chronic kidney disease not on dialysis (CKD-NoD) commencing extended dosing of DA. METHODS: Adult CKD-NoD patients starting extended dosing of DA in Europe or Australia in June 2006 or later were followed up until December 2012. Outcomes included haemoglobin (Hb) concentration, ESA dosing, mortality rates and receipt of dialysis and renal transplantation. Subgroup analyses were conducted for selected outcomes. RESULTS: Of 6035 enrolled subjects, 5723 (94.8%) met analysis criteria; 1795 (29.7%) received dialysis and 238 (3.9%) underwent renal transplantation. Mean (standard deviation) Hb concentration at commencement of extended dosing was 11.0 (1.5) g/dL. Mean [95% confidence interval (CI)] Hb 12 months after commencement of extended dosing (primary outcome) was 11.6 g/dL (11.5, 11.6) overall and was similar across countries, with no differences between subjects previously treated with an ESA versus ESA-naïve subjects, subjects with versus without prior renal transplant or diabetics versus non-diabetics. Weekly ESA dose gradually decreased following commencement of extended DA dosing and was similar across subgroups. The decrease in weekly DA dose was accompanied by an increase in the proportion of patients receiving iron therapy. Hb concentrations declined following changes in ESA labels and treatment guidelines. The mortality rate (95% CI) was 7.06 (6.68, 7.46) deaths per 100 years of follow-up. Subjects alive at study end had stable Hb concentrations in the preceding year, while those who died had lower and declining Hb concentrations in their last year. CONCLUSIONS: Long-term, extended dosing of DA maintained Hb concentrations in patients already treated with an ESA and corrected and maintained Hb in ESA-naïve patients.

Management of CKD-MBD in non-dialysis patients under regular nephrology care: a prospective multicenter study.

BACKGROUND: Knowledge about mineral bone disorder (MBD) management in non-dialysis chronic kidney disease (ND-CKD) patients is scarce, although essential to identifying areas for therapeutic improvement. METHODS: We prospectively evaluated current management of CKD-MBD in two visits, performed 6 months apart, in 727 prevalent ND-CKD stage 3b-5 patients from 19 nephrology clinics. Therapeutic inertia was defined as lack of treatment despite hyperphosphatemia and/or hypocalcemia, and/or hyperparathyroidism. The primary endpoint was the prevalence of achieved target for CKD-MBD parameters and related treatments (phosphate binders, vitamin D and calcium supplements). The secondary endpoint was the assessment of prevalence and clinical correlates of therapeutic inertia. RESULTS: Over 65 % of patients did not reach parathormone (PTH) targets, while 15 and 19 % did not reach phosphate and calcium targets, respectively. The proportion of untreated patients decreased from stage 3b to 5 (at baseline, from 60 to 16 %, respectively). From baseline to the 6-month visit, the achievement of targets remained stable. Low protein diet was prescribed in 26 % of patients, phosphate binders in 17.3 % (calcium-based binders 15.5 %, aluminium binders 1.8 %), and vitamin D in 50.5 %. The overall prevalence of therapeutic inertia at the 6-month visit was 34.0 % (for hyperphosphatemia, 54.3 %). Compared to CKD stage 3, the likelihood of therapeutic inertia was 40 and 68 % lower at stage 4 and 5, respectively. CONCLUSIONS: PTH, calcium and phosphate targets were not reached in a significant proportion of patients. One-third of patients with at least one MBD parameter not-at-target remained untreated. Therapeutic inertia regarding CKD-MBD treatment may be a major barrier to optimizing the prevention and cure of CKD-MBD.

[Lazio dialysis registry: natives vs foreigners]. / Confronto delle caratteristiche demografiche, cliniche e di sopravvivenza tra dializzati nati in Italia e all'estero: risultati del registro del Lazio.

INTRODUCTION: An increasing number of foreigners was observed in Italy even among chronic dialysis patients. We compared demographic, clinical, treatment characteristics and survival probability between groups of Italian and foreign patients with chronic dialysis in Lazio. METHODS: We analysed data from the Lazio Dialysis and Transplantation Registry from 2004 to 2012 (4,076 prevalent chronic dialysis patients in 31-12-2012). Among 7,970 incident patients, we evaluated, by country of birth, survival probability by using Kaplan-Meier method and mortality risk, through multiple Cox regression. RESULTS AND CONCLUSIONS: We observed an increase of foreigners among chronic dialysis patients in Lazio from 2004 (4.4%) up to 2012 (7.6%, test for trend: p<0,001). Compared with Italians, foreign patients were younger (53.816.3 vs. 68.713.6) and more frequently: women (42.7% vs. 37.7%), HbsAg-positive (18.1% vs. 13.9%), not vaccinated if HBV susceptible (26.8% vs. 20.9%), late referral (21.6% vs. 12.9%) and suitable for kidney transplantation (21.7% vs. 9.9%). Foreigners compared with Italians had higher survival probability at 1 year (91.9% vs. 84.7%) and 5 years (74,6% vs. 51,5%) after chronic dialysis has been started. We observed a lower mortality risk (HR=0.71;IC95%:0.58-0.87) among foreign patients even after adjustment for many potential confounding factors. Our findings suggest that health status and treatment of end stage renal disease, including access to kidney transplantation, were similar between groups of Italian and foreign patients in Lazio. Observed differences in patients' characteristics were probably attributable to younger age of foreigners. However, further analyses are needed to fully explain higher survival probability in chronic dialysis among foreigners compared with Italians.

Extracapillary proliferation is an independent predictive factor in Immunoglobulin A nephropathy.

BACKGROUND: Oxford classification of Immunoglobulin A Nephropathy (IgAN) identifies four pathological features as predictors of renal outcome (MEST-score): mesangial proliferation (M); endocapillary proliferation (E); segmental glomerulosclerosis (S); tubular atrophy/interstitial fibrosis (T). In particular extracapillary proliferation (Ex) was not considered as an independent histological variable predicting renal outcome. Recently the VALIGA study provided a validation of the Oxford classification in a large European cohort of IgAN patients and re-stated that Ex is not associated with a worse renal prognosis. We propose a retrospective study to evaluate the predictive value of the MEST-score in a multi-centre, single region group of patients from central Italy and in addition, to investigate Ex as a marker predicting renal outcome. METHODS: One hundred and seven patients were enrolled in this study. Clinical data of each patient were available at diagnosis and follow-up. The median age at diagnosis was 36.7 years; 72% of the patients were males. Histological parameters were those included in the MEST-score of the Oxford classification; in addition, Ex was also assessed. RESULTS: Multiple linear regression models for survey were used. Statistical analysis showed a correlation between the progression of renal decline, in terms of estimated glomerular filtration rate (slope eGFR), and M, S, T. Differently from Oxford and VALIGA studies, no correlation was found with E, while Ex correlated with a decline of eGFR. CONCLUSIONS: Our results suggest that Ex represents an additional independent variable associated with a faster decline of renal function in IgAN.

An observational cohort study of extended dosing (once every 2 weeks or once monthly) regimens with darbepoetin alfa in patients with chronic kidney disease not on dialysis: the EXTEND study.

BACKGROUND: Darbepoetin alfa (DA) has been shown to be an effective treatment of anaemia in patients with chronic kidney disease (CKD) not on dialysis (NoD). EXTEND is an observational study assessing the effectiveness of DA administered once biweekly (Q2W) or monthly (QM) in a general CKD-NoD population. METHODS: Adult CKD-NoD patients starting DA Q2W/QM treatment in June 2006 or later were eligible. Retrospective and/or prospective data including haemoglobin levels and erythropoiesis-stimulating agent (ESA) dosing were collected for 6 months before and 12 months after DA initiation. Mean Hb levels were calculated every 3 months, and ESA dose was converted to a geometric mean weekly DA equivalent dose and summarized monthly. RESULTS: Data from 4278 patients showed that patients receiving ESA treatment before DA Q2W/QM initiation had a mean (95% confidence interval) Hb level of 11.9 g/dL (11.8-12.0 g/dL) at initiation and 11.6 g/dL (11.6-11.7 g/dL) at Months 10-12, with mean ESA dose of 22 µg/week (21-23 µg/week) prior to initiation, 16 µg/week (15-16 µg/week) at initiation and 16 µg/week (15-16 µg/week) at Month 12. In ESA-naive patients, Hb levels increased from 10.3 g/dL (10.2-10.3 g/dL) at initiation to 11.7 g/dL at Months 4-6 and were maintained at a mean level of 11.7 g/dL (11.7-11.8 g/dL) at Months 10-12, with mean ESA dose of 16 µg/week (16-17 µg/week) at initiation and 16 µg/week (16-17 µg/week) at Month 12. In the 85% of patients receiving DA at extended intervals (Q2W or less frequently) at Month 12, 12 patients (0.3%) experienced DA-related adverse reactions. CONCLUSION: DA Q2W/QM was an effective treatment of anaemia in the general CKD-NoD patient population and a dose increase was not required in patients switching from a previous ESA regimen.

Peripheral artery calcifications evaluated by histology correlate to those detected by CT: relationships with fetuin-A and FGF-23.

BACKGROUND: Calcification of arteries is a frequent occurrence in hemodialysis (HD) patients and is linked to mortality. This study was conducted to evaluate the correspondence between coronary calcification scores and calcifications observed histologically in peripheral arteries in HD patients. In addition the association of humoral parameters including fetuin-A and fibroblast growth factor 23 (FGF-23) with arterial calcifications was studied. PATIENTS AND METHODS: HD patients (n=44) were studied with multislice computed tomography (CT) and histological quantification of arterial calcifications in the lower epigastric artery sampled at the time of renal transplant. In addition, humoral assays were performed including fetuin-A and FGF-23. RESULTS: There was a significant correlation between medial calcification of the artery and Agatston scores. Natural logarithm (Ln) FGF-23 significantly correlated to Ln Agatston score but not to Ln medial calcification. A significant negative correlation between fetuin-A and Ln FGF-23 was observed, changing to borderline significance after correction for age and Ln HD age. Ln Agatston score in a multiregression analysis was predicted by Ln FGF-23 and age. CONCLUSIONS: The association found between histologically evaluated calcification of the media of a peripheral artery in HD and the multislice CT Agatston scores is in favor of a generalized arterial calcification, either intimal or of tunica media, when calcium deposits are found in the coronary arteries. The association of FGF-23 with coronary calcification score, already reported, and less so with histological medial calcification is in favor of a link between the protein and intimal more than the medial calcification. FGF-23 may be considered a potential biomarker of arterial calcification in HD patients. The negative association between fetuin-A and FGF-23 may suggest a linkage between these humoral substances, vascular calcifications and mortality. The nature of this linkage requires further studies.

Survey of determinants and effects of timing of referral to a nephrologist: the patient's point of view.

INTRODUCTION: We conducted a survey interviewing end-stage renal disease (ESRD) patients just after they began chronic dialysis (CD) to describe characteristics and factors associated with early (ER) and late referral (LR), and to analyze the consequences of timing of referral to a nephrologist. METHODS: We interviewed 673 patients via telephone starting CD between 2004 and 2006 in Lazio, Italy, to collect information about the year before CD. Multiple logistic regression was performed to evaluate the factors associated with LR. RESULTS: We found that 22% of patients reported being LRs. A lower probability for LR was found for older age, family history of renal diseases, abnormal test for renal functions, presence of hypertension, married status and awareness of a nephrology outpatient center near home. LR patients had a lower frequency of hepatitis B virus (HBV) vaccination (14.9% vs. 41.7%), arteriovenous fistula (31.8% vs. 75.6%) and information about renal replacement therapy modalities (33.8% vs. 72.6%), and they more often started CD in an emergency (85.8% vs. 41.5%). CONCLUSIONS: The percentage of self-reported LR was lower than reported in other studies. However, many patients started CD in an emergency, with a catheter as first vascular access, without vaccination against HBV and without the possibility of choosing their dialysis modality. Individual conditions facilitating contact with medical care (older age and presence of comorbidities) seem to be associated with a lower probability of LR. These findings emphasize the importance of predialysis patient training, confirming the important role that information plays in health service access, to improve early and long-term dialysis outcomes.

Asymmetric dimethylarginine, vascular calcifications and parathyroid hormone serum levels in hemodialysis patients.

BACKGROUND: Asymmetric dimethylarginine (ADMA)is an endogenous amino acid similar to l-arginine and able to inhibit the enzyme endothelial nitric oxide synthase (eNOS). It is a factor of impaired nitric oxide (NO) synthesis. Serum levels of ADMA in chronic kidney disease (CKD) increase due to defective inactivation and excretion. High ADMA levels are associated with endothelial dysfunction and cardiovascular damage. A linkage between ADMA levels and vascular calcifications of CKD can therefore be hypothesized. This study explores also a possible relation between ADMA and parathyroid hormone (PTH) serum levels, which are known to be linked to increased rates of cardiovascular death. METHODS: The study was carried out in 79 patients on hemodialysis (HD), mean age 59.25 +/- 12 years. In all patients, serum ADMA, PTH, Ca, P, bone alkaline phosphatase (BALP), cholesterol and albumin were measured. In addition, the patients were subjected to multislice computed tomography for heart calcification evaluation. RESULTS: Correlation analysis of ADMA showed a significant relation with total and coronary calcium volumes, HD vintage, body mass index (BMI), cholesterol, serum albumin, PTH, natural logarithm of PTH (LnPTH) and BALP. Multiple regression analysis selected HD vintage, albumin and PTH as predictive variables for coronary calcium volume, while ADMA was excluded. With LnPTH as dependent variable, ADMA, serum calcium and BMI were predictive variables with R2 of 0.37. ADMA as dependent variable was also predicted by PTH, HD vintage, albumin and BMI. CONCLUSIONS: Despite the results of bivariate analysis showing a linkage between ADMA and cardiac and coronary calcifications, regression analysis showed only a spurious association. The strong positive correlation between ADMA and LnPTH, validated by the regression analysis, may suggesta link between ADMA and PTH-derived vascular damage. ADMA levels could be influenced by the severity of hyperparathyroidism and contribute to cardiovascular death linked to PTH of hemodialysis patients.

Immunohistochemical localization and mRNA expression of matrix Gla protein and fetuin-A in bone biopsies of hemodialysis patients.

Matrix Gla protein (MGP) and fetuin-A are inhibitors of arterial calcifications. In blood of rats, calcium-phosphate-fetuin-MGP complexes, produced in bone, have been identified. Indeed, an association between bone resorption, release of such complexes, and arterial calcifications has been reported. We have investigated the synthesis and localization of fetuin-A and MGP in bone of hemodialysis patients and the possible contribution of bone cells in arterial calcifications. Bone biopsies from 11 hemodialysis patients were used for histology, in situ hybridization of fetuin-A and MGP messenger RNA (mRNA), immunohistochemistry of fetuin-A, and total, carboxylated, and non-carboxylated MGP proteins. Patients showed various types of renal osteodystrophy, or normal bone. MGP was synthesized and expressed (total and carboxylated) by osteoblasts, osteocytes, and most osteoclasts, while fetuin-A by osteoblasts and osteocytes. Fetuin-A and carboxylated MGP proteins were positive in the calcified matrix, while total MGP was negative. Osteoid seams were negative to fetuin-A, lightly positive to carboxylated MGP, and occasionally positive to total MGP. Undercarboxylated MGP was mostly undetectable. In adult humans, fetuin-A is produced also by osteoblasts, and not only by hepatocytes, as previously believed. MGP, essentially carboxylated, is synthesized by osteoblasts and most osteoclasts. Increased bone turnover can be an important contributor to arterial calcifications.

Epidemiology of hepatitis C virus among long-term dialysis patients: a 9-year study in an Italian region.

BACKGROUND: Monitoring hepatitis C virus (HCV) antibodies (anti-HCV) in long-term dialysis patients is an important issue of public health. The aim of the study is to analyze the prevalence, seroconversion rate, and impact of HCV-positive serological test results on survival. METHODS: We studied 6,412 patients starting long-term dialysis therapy reported to Lazio Dialysis Registry (Italy) between 1995 and 2003. HCV serological status was assessed by using second- or third-generation assays. Patients who were seronegative at the beginning of a period who became seropositive at the end of the same period are defined as seroconverters. RESULTS: In 1995 to 2003, the overall prevalence of anti-HCV among long-term dialysis patients decreased from 30.6% to 15.1%; we did not observe a decrease in prevalence of anti-HCV in those starting dialysis treatment. After a decrease in the first year, HCV seroconversion rates remained stable at approximately 2 cases/100 person-years. Survival at 9 years was lower for both HCV seroconverters and those already anti-HCV positive at dialysis therapy initiation compared with HCV-negative subjects (log-rank test, P < 0.001). Results of a multiple Cox model showed that subjects who were or became anti-HCV positive had a hazard ratio of 1.29 (95% confidence interval, 1.15 to 1.44) compared with HCV-negative patients. CONCLUSION: We did not observe a significant decrease in HCV seroconversion rates in 1995 to 2003. The overall decrease in anti-HCV prevalence could be related to the lower survival probability for both HCV seroconverters and those already HCV positive at long-term dialysis therapy initiation compared with HCV-negative subjects. Our findings confirm that additional efforts should be made to minimize the risk for HCV infection before and during long-term dialysis treatment.

Contamination by hepatitis B and C viruses in the dialysis setting.

BACKGROUND: Hepatitis virus infections continue to be a major concern in the dialysis setting. We studied levels of hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) RNA contamination in dialysis units to better define the role of the dialysis environment and machines in the nosocomial transmission of hepatitis viruses. METHODS: Possible contamination by hepatitis B virus (HBV) and HCV was studied by collecting environmental samples in 3 dialysis units located in Rome, Italy. Samples and controls were tested for HBsAg by a microparticle enzyme immunoassay, and for HCV RNA, by qualitative transcription-mediated amplification assay. RESULTS: HCV RNA and HBsAg were detected in 1 of 64 (1.6%) and 1 of 64 samples (1.6%), respectively. The only HCV RNA-positive sample was found in 1 dialysis unit on the external surface of the dialysate (inlet-outlet) connector of a dialysis machine used for HCV-negative patients. The only HBsAg-positive sample was found in another dialysis unit on the internal surface of the blood pressure monitor cuff of a dialysis bed dedicated for HBsAg-positive patients. CONCLUSION: A segregation policy for HBsAg-positive patients is a necessary measure despite its high cost-effectiveness; we found HBsAg contamination in the segregated HBV-infected room. Conversely, the finding of HCV RNA contamination on a dialysis machine not dedicated to HCV-positive patients suggests that isolation of HCV-infected dialysis patients and use of dedicated machines are unjustified. Major attention should be given to strict adherence to infection control measures in the dialysis setting.

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

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