[The Early Years of Nephrology at Molinette Hospital in Turin Told by Those Who Lived and Built Them].

This article, written by several authors, describes the birth and early development of the nephrology at Molinette Hospital in Torino, Italy. In particular, it supplies important information on Antonio Vercellone, very motivated and innovative clinician and one of the fathers of Italian nephrology, and on Giuseppe Piccoli, his right-hand man and then his successor. This article also shows the strong professional and human engagement that was requested to the young doctors who, in the early Sixties and Seventies of the past century, had chosen to devote their professional lives to the patients with kidney diseases: from endless workdays without schedules to the anguish caused by the shortage of artificial kidneys to the cure of very fragile and unfortunate patients, and much more.

Prevalence and correlates of erectile dysfunction in men on chronic haemodialysis: a multinational cross-sectional study.

BACKGROUND: Factors associated with erectile dysfunction in men on haemodialysis are incompletely identified due to suboptimal existing studies. We determined the prevalence and correlates of erectile dysfunction and identified combinations of clinical characteristics associated with a higher risk of erectile dysfunction using recursive partitioning and amalgamation (REPCAM) analysis. METHODS: We conducted a multinational cross-sectional study in men on haemodialysis within a collaborative network. Erectile dysfunction and depressive symptoms were evaluated using the erectile function domain of the International Index of Erectile Function questionnaire and the Center for Epidemiological Studies-Depression Scale, respectively. RESULTS: Nine hundred and forty-six (59%) of 1611 eligible men provided complete data for erectile dysfunction. Eighty-three per cent reported erectile dysfunction and 47% reported severe erectile dysfunction. Four per cent of those with erectile dysfunction were receiving pharmacological treatment. Depressive symptoms were the strongest correlate of erectile dysfunction [adjusted odds ratio 2.41 (95% confidence interval (CI) 1.57-3.71)]. Erectile dysfunction was also associated with age (1.06, 1.05-1.08), being unemployed (1.80, 1.17-2.79) or receiving a pension (2.05, 1.14-3.69) and interdialytic weight gain (1.9-2.87 kg, 1.92 [CI 1.19-3.09]; >2.87 kg, 1.57 [CI 1.00-2.45]). Married men had a lower risk of erectile dysfunction (0.49, 0.31-0.76). The prevalence of erectile dysfunction was highest (94%) in unmarried and unemployed or retired men who have depressive symptoms. CONCLUSIONS: Most men on haemodialysis experience erectile dysfunction and are untreated. Given the prevalence of this condition and the relative lack of efficacy data for pharmacological agents, we suggest that large trials of pharmacological and non-pharmacological interventions for erectile dysfunction and depression are needed.

Blood and ultrafiltrate dosage of citrate as a useful and routine tool during continuous venovenous haemodiafiltration in septic shock patients.

BACKGROUND: Citrate anticoagulation is gaining popularity in renal replacement therapies (RRT) for critically ill patients. In order to study whether citrate accumulates in septic shock patients, we determined citrate in plasma and dialysate during continuous venovenous haemodiafiltration (CVVHDF). METHODS: An automated routine determination of citrate was set up using a commercial kit (citrate lyase method). Twelve patients with septic shock on CVVHDF and citrate anticoagulation were studied ex vivo for citrate levels in systemic and circuit blood and in the ultrafiltrate (at 0, 0.5, 1, 3, 6, 9, 12, 24, 48 and 72 h). RESULTS: In vitro blood studies showed a near unit correlation between the plasma measured and predicted citrate concentrations for an exclusive extracellular distribution of citrate. Median systemic arterial citratemias were 0.09 (0.06-0.12) mmol/L (Time 0) and 0.23 (0.18-0.31) mmol/L during treatment; median sieving coefficient for citrate was 0.95 (0.88-1.02) and did not change with different volumes of CVVHDF effluent (from 1350 to 5100 mL/h). Net citrate and calcium removal by filter significantly correlated with effluent volume (r = 0.85 and 0.78, respectively). Median citrate load entering in the patients' bloodstream was 13.60 (9.1-19.6, n = 68) mmol/h. Although cost analysis of the citrate test demonstrated a minimally increased daily cost (from 2.96 to 3.51€), saving costs could be potentially relevant with more extended use of citrate anticoagulation. CONCLUSIONS: In septic shock patients with liver dysfunction citratemia is useful in guiding clinical application of RRT, where the citrate losses in the ultrafiltrate can be efficiently modulated by increasing the effluent volume.

[Indications from the first audit on peritoneal dialysis in Piedmont and Aosta valley]. / Indicazioni dal primo audit sulla dialisi peritoneale in Piemonte e in Valle D'Aosta.

In March 2009 a clinical audit was held in Turin on peritoneal dialysis in order to analyze the problems that still hinder the effective deployment of the technique in Piedmont-Aosta Valley. Various data about epidemiological and clinical management were collected by means of a questionnaire that all 26 nephrology centers of the two regions responded to. The two major critical issues highlighted were the role of the outpatient facility dedicated to uremic patients and why the peritoneal technique was not chosen for new dialysis patients. With regard to the first issue, the presence of a well structured outpatient facility dedicated to chronic renal failure seems to direct more uremic patients to peritoneal dialysis, at the same time decreasing the rate of late referrals. Regarding the second issue, patient choice was the leading cause followed by problems related to the partner, while traditional clinical contraindications interfered to a lesser extent with the choice of dialysis technique. We therefore believe that it will be possible to increase the use of peritoneal dialysis by improving organizational aspects of the dialysis center and trying to remedy the lack of social support. Accurate information and early care of uremic patients by dedicated outpatient facilities are in fact able to lead more patients to choose peritoneal dialysis. The implementation of measures of support, such as financial incentives to dialysis patients following a recent decision of the Piedmont region, could help to overcome problems related to the lack or unhelpfulness of a partner.

Circulating plasma factors induce tubular and glomerular alterations in septic burns patients.

BACKGROUND: Severe burn is a systemic illness often complicated by sepsis. Kidney is one of the organs invariably affected, and proteinuria is a constant clinical finding. We studied the relationships between proteinuria and patient outcome, severity of renal dysfunction and systemic inflammatory state in burns patients who developed sepsis-associated acute renal failure (ARF). We then tested the hypothesis that plasma in these patients induces apoptosis and functional alterations that could account for proteinuria and severity of renal dysfunction in tubular cells and podocytes. METHODS: We studied the correlation between proteinuria and indexes of systemic inflammation or renal function prospectively in 19 severe burns patients with septic shock and ARF, and we evaluated the effect of plasma on apoptosis, polarity and functional alterations in cultured human tubular cells and podocytes. As controls, we collected plasma from 10 burns patients with septic shock but without ARF, 10 burns patients with septic shock and ARF, 10 non-burns patients with septic shock without ARF, 10 chronic uremic patients and 10 healthy volunteers. RESULTS: Septic burns patients with ARF presented a severe proteinuria that correlated to outcome, glomerular (creatinine/urea clearance) and tubular (fractional excretion of sodium and potassium) functional impairment and systemic inflammation (white blood cell (WBC) and platelet counts). Plasma from these patients induced a pro-apoptotic effect in tubular cells and podocytes that correlated with the extent of proteinuria. Plasma-induced apoptosis was significantly higher in septic severe burns patients with ARF with respect to those without ARF or with septic shock without burns. Moreover, plasma from septic burns patients induced an alteration of polarity in tubular cells, as well as reduced expression of the tight junction protein ZO-1 and of the endocytic receptor megalin. In podocytes, plasma from septic burns patients increased permeability to albumin and decreased the expression of the slit diaphragm protein nephrin. CONCLUSION: Plasma from burns patients with sepsis-associated ARF contains factors that affect the function and survival of tubular cells and podocytes. These factors are likely to be involved in the pathogenesis of acute tubular injury and proteinuria, which is a negative prognostic factor and an index of renal involvement in the systemic inflammatory reaction.

Guidelines audit may overcome disparities in health care: experience of an Italian region.

BACKGROUND: A clinical audit is used to verify the application of evidence-based clinical guidelines. Our regional section of the Italian Society of Nephrology was the first to establish a region-based program of clinical audits of compliance with guidelines for treating osteodystrophy and anemia of patients on chronic dialysis. This study summarizes the main results of the 2 audits of the Piemonte region. METHODS: Structured questionnaires were sent twice to all of the 22 dialysis centers of Piemonte and to the Center of Valle D'Aosta for an Audit on Osteodystrophy (in 2000 and 2004) and for the Audit on Anemia (2003). The questionnaires were meant to evaluate the clinical schedule of treatment relative to calcium-phosphate balance and anemia in dialysis patients. RESULTS: All centers responded, showing low levels of agreement with the targets of Italian guidelines. In sum, in 2000 only 27% of centers had more than 70% of patients with serum phosphate <5.5 mg/dL, but that rate had increased to 33% in 2004. Only 35% (in 2000) and 40% (in 2004) of the centers had more than 90% of patients with Kt/V >1.2. The Audit on Anemia showed a median of 42% of patients with hemoglobin between 11 and 12 g/dL, and only 2 centers had more than 70% of patients above this target. CONCLUSIONS: The first result of our pioneering experience was that we found that compliance with minimal levels of care was still inadequate, with regard to hyperphosphatemia, dialysis adequacy and anemia. Nevertheless, the 2nd Audit on Osteodystrophy showed a relative improvement in the results. But, most importantly, this open regional report has encouraged comparisons, and motivated centers to adopt a strategy of understanding, addressing and correcting inadequate levels of care, and furthermore increased satisfaction with the care being offered.

Platelet-activating factor synthesis by neutrophils, monocytes, and endothelial cells is modulated by nitric oxide production.

Nitric oxide (NO) and platelet-activating factor (PAF) can modulate the interaction between endothelial lining and circulating leukocytes. Several studies implicated the production of PAF and NO in the pathogenesis of microcirculatory alterations occurring in septic shock. However, the reciprocal interaction between PAF and NO has not been fully elucidated. In the present study, we evaluated whether the basal synthesis of NO could modulate the production of PAF by neutrophils (PMN), monocytes (MO), and endothelial cells (EC) unstimulated or stimulated with lipopolysaccharides (LPS) or tumor necrosis factor (TNF). PMN, MO, and EC, when incubated with N(omega)-nitro-L-arginine methyl ester (L-NAME) spontaneously synthesized PAF, with an early peak at 30 min. The effective inhibition of NO production was visualized on MO cells as generation of fluorescence reactivity by cell-permeable NO reactive dye DAF-2 DA. Also, monomethyl-L-arginine (L-NMMA) induced PAF synthesis by PMN, whereas the biologically inactive D-enantiomers of NAME (D-NAME) and of NMMA (D-NMMA) did not. Stimulation of PMN with L-NAME in presence of the exogenous NO donor nitroprusside, of the NO secondary mediator cGMP, or of the NO synthase substrate L-arginine reduced PAF synthesis, suggesting the involvement of an NO-dependent pathway on the modulation of PAF synthesis. The synthesis of PAF was enhanced by combined treatment with L-NAME and TNF or LPS. These results indicate an inhibitor effect of NO on the spontaneous and TNF or LPS-induced synthesis of PAF by human PMN, MO, and EC.

Lipoprotein-apolipoprotein changes in renal transplant recipients.

Recent studies have demonstrated that the incidence of cardiovascular events occurring with renal transplantation is higher than that in the general population. Renal transplantation modifies the characteristic dyslipidemia of chronic renal failure. In this study the change in lipoprotein and lipid values of 103 transplant recipients after transplantation was investigated. The aim of our work was to examine the short-term and long-term variations in lipid metabolism. The major lipoprotein fractions (VLDL, LDL, HDL) were separated by preparative ultracentrifugation, and TG and cholesterol concentrations were determined in plasma and lipoprotein fractions. Whole plasma apolipoproteins were determined by a rate immunonephelometric technique. In the pretransplant period the patients displayed the typical picture of uremics. After transplantation the most evident alterations in the lipoprotein profile occurred in our case series after 3 mon. The major finding was a 35% reduction in plasma TG. The modifications in the TG-rich lipoproteins of our transplant recipients persisted throughout the observation period. In the initial 3-mon period, total cholesterol remained steady, whereas LDL-cholesterol and total apolipoprotein B showed a significant increase. No significant changes were found in total and transported TG and cholesterol between the 3-mon and the 6-yr values. The substantial stability of cholesterol levels after transplantation and in subsequent reports, as well as a higher incidence of cardiovascular complications, may suggest that the mechanisms responsible for vessel damage must be sought mainly in the structural and physicochemical alterations of the individual lipoprotein fractions or in other risk factors.

When should commence dialysis: focusing on the predialysis condition.

The prevalence of chronic kidney disease (CKD), as defined by the NFK-KDOQI (the national kidney foundation kidney disease outcomes quality initiative) guidelines, is a glomerular filtration rate less than 60 mL/min/1.73 m(2) or the presence of microalbuminuria. CKD is increasing worldwide, leading to an increased risk of cardiovascular disease. There is general agreement on the importance of an early referral to a nephrologist and predialysis educational programs. Establishing the protocol for an early approach may assist in preventing the progression, and the most common complications of renal disease. Predialysis education helps patients in order to choose a renal replacement therapy (hemodialysis, peritoneal dialysis, transplantation) and improve their quality of life. Furthermore, adequate predialysis care allows the nephrologist to promptly prepare for vascular or peritoneal treatment. Regrettably, patients are often referred to the nephrologist when renal failure is already fall in the advanced stage. This is caused primarily by non-nephrologists failing to identify patients at risk for imminent renal failure. Furthermore, they may be defining the patient's degree of renal failure according to the KDOQI classification. To further complicate matters, the serum creatinine alone does not provide an adequate estimate of renal function; however, both the MDRD (the modification of diet in renal disease) equation and the Cockcroft-Gault formula permit the more reliable and accurate estimation of the all-important glomerular filtration rate (GFR). Using the MDRD equation, the KDOQI guidelines recommend referral when GFR is less than 30 mL/min/1.73 m(2). Late nephrology referral is an independent risk factor for early death while on dialysis; it is also associated with a more frequent use of temporary catheters, particularly in the elderly individuals. This subject underlines the importance of a multidisciplinary predialysis approach that may bring additional benefits - beyond referral to a nephrologist - including a reduced hospitalization period and a lower mortality rate. The KDOQI guidelines recommend evaluating the benefits and risks of starting renal replacement therapy when patients reach stage 5 (estimated GFR less than 15 mL/min/1.73 m(2)), although the ideal period for initiation of the replacement therapy remained a source of debate.

Sexual dysfunction in women with ESRD requiring hemodialysis.

BACKGROUND AND OBJECTIVES: The few existing studies of sexual dysfunction in women on hemodialysis are limited by small sample size. This large, cross-sectional study evaluated the prevalence and correlates of female sexual dysfunction in advanced kidney disease. DESIGN, SETTING, PARTICIPANTS, METHODS: A total of 1472 women with ESRD undergoing hemodialysis were recruited to a multinational, cross-sectional study conducted within a collaborative dialysis network in Europe and South America. Sexual dysfunction was identified by the Female Sexual Function Index. Correlates of self-reported sexual dysfunction were identified by regression analyses. RESULTS: Of the 1472 women, 659 completed questionnaires (45%). More than half (362 of 659 [55%]) lived with a partner, and 232 of 659 (35%) reported being sexually active. Of these 659 respondents, 555 (84%) reported sexual dysfunction. Women with a partner (282 of 362 [78%]) were less likely to report sexual dysfunction than those without a partner (273 of 297 [92%]) (P<0.001). Sexual dysfunction was independently associated with age, depressive symptoms, less education, menopause, diabetes, and diuretic therapy. Nearly all women who were not wait-listed for a kidney transplant and were living without a partner (249 of 260 [96%]) reported sexual dysfunction. More than half (128 of 232 [55%]) of sexually active women reported sexual dysfunction, associated with age, depressive symptoms, menopause, low serum albumin, and diuretic therapy. CONCLUSIONS: This descriptive study suggests most women on hemodialysis experience sexual problems. Additional research on the relevance of sexual dysfunction to symptom burden and quality of life in these women is needed.

Citrate anticoagulation for continuous renal replacement therapy in critically ill patients: success and limits.

Citrate anticoagulation has risen in interest so it is now a real alternative to heparin in the ICUs practice. Citrate provides a regional anticoagulation virtually restricted to extracorporeal circuit, where it acts by chelating ionized calcium. This issue is particularly true in patients ongoing CRRT, when the "continuous" systemic anticoagulation treatment is per se a relevant risk of bleeding. When compared with heparin most of studies with citrate reported a longer circuit survival, a lower rate of bleeding complications, and transfused packed red cell requirements. As anticoagulant for CRRT, the infusion of citrate is prolonged and it could potentially have some adverse effects. When citrate is metabolized to bicarbonate, metabolic alkalosis may occur, or for impaired metabolism citrate accumulation leads to acidosis. However, large studies with dedicated machines have indeed demonstrated that citrate anticoagulation is well tolerated, safe, and an easy to handle even in septic shock critically ill patients.

Normal citratemia and metabolic tolerance of citrate anticoagulation for hemodiafiltration in severe septic shock burn patients.

PURPOSE: Anticoagulation during renal replacement therapy remains an important challenge for burn patients due to their high risk of bleeding. In this study we compared the efficacy and safety of citrate anticoagulation to heparin anticoagulation for hemodiafiltration (HDF) in severe burn patients, focusing on metabolic tolerance and handling of citrate. METHODS: Retrospective observational study (January 2000-December 2007) at a university teaching hospital. Among 548 patients admitted with burns, 70 severe burn septic shock patients (median age 57.5 years, interquartile range 42-76 years; median burned surface area 40%, interquartile range 30-60%) who underwent HDF for more than 24 h were included. RESULTS: Of the 70 HDF patients, 31 at high risk of bleeding were treated with citrate and 39 with heparin, with a mortality rate of 70.9 and 71.8%, respectively. In continuous venovenous hemodiafiltration (CVVHDF), the filter survival was higher with citrate, and hemorrhagic complications were lower (0.035 vs. 0.145 episodes/day, respectively). During citrate CVVHDF [median delivered dialysis dose: 578.9 ml kg(-1) day(-1) (461.5-769.2 ml kg(-1) day(-1))] in catecholamine-supported patients (norepinephrine 0.53 µg kg(-1) min(-1)), no metabolic derangements in pH, bicarbonates, Na+, K+, Ca++, and ionized calcium were observed. Systemic citratemia was within the normal range (<0.4 mmol/l) and was associated with a marked citrate removal in the effluent (5 patients, 36-60% of infused amount). CONCLUSIONS: In septic shock burn patients, citrate for CVVHDF was efficient and safe, and superior to heparin for hemorrhagic complications and filter survival. Observed metabolic stability was most likely due to a marked loss of citrate in effluent volume and subsequent low total citrate load for the patient.

Prevention of dialysis hypotension episodes using fuzzy logic control system.

BACKGROUND: Automatic systems for stabilizing blood pressure (BP) during dialysis are few and only control those variables indirectly related to BP. Due to complex BP regulation under dynamic dialysis conditions, BP itself appears to be the most consistent input parameter for a device addressed to preventing dialysis hypotension (DH). METHODS: An automatic system (ABPS, automatic blood pressure stabilization) for BP control by fluid removal feedback regulation is implemented on a dialysis machine (Dialog Advanced, Braun). A fuzzy logic (FL) control runs in the system, using instantaneous BP as the input variable governing the ultrafiltration rate (UFR) according to the BP trend. The system is user-friendly and just requires the input of two data: critical BP (individually defined as the possible level of DH risk) and the highest UFR applicable (percentage of the mean UFR). We evaluated this system's capacity to prevent DH in 55 RDT hypotension-prone patients. Sessions with (treatment A) and without (treatment B) ABPS were alternated one-by-one for 30 dialysis sessions per patient (674 with ABPS vs 698 without). RESULTS: Despite comparable treatment times and UF volumes, severe DH appeared in 8.3% of sessions in treatment A vs 13.8% in treatment B (-39%, P=0.01). Mild DH fell non-significantly (-12.3%). There was a similar percentage of sessions in which the planned body weight loss was not achieved and dialysis time was prolonged. CONCLUSIONS: In conclusion, FL may be suited to interpreting and controlling the trend of a determined multi-variable parameter like BP. The medical knowledge of the patient and the consequent updating of input parameters depending on the patient's clinical conditions seem to be the main factors for obtaining optimal results.

Tailoring high-cut-off membranes and feasible application in sepsis-associated acute renal failure: in vitro studies.

BACKGROUND: As removal of pro-inflammatory cytokines is limited in conventional diffusive or convective extracorporeal therapies, we studied in two polysulphone membranes with an industrial albumin sieving coefficient of 0.05 (Type A) and 0.13 (Type B) cytokine (IL-6, IL-8, IL-1beta, IL-1ra, TNF-alpha) and plasma protein (albumin, cystatin C, total proteins) permeability profiles. Based on the convective membrane permeability, we evaluated in vitro the dialytic modality that could provide an acceptable balance between high cytokine and low albumin clearances. METHODS: Cytokine and plasma protein sieving coefficient (SC) and clearance were studied in (i) post-dilutional haemofiltration mode at 20% fixed ultrafiltration rate; (ii) haemodialysis mode (dialysate flow rate of 3 and 5 l/h); and (iii) haemodiafiltration mode (dialysate flow rate of 3 or 5 l/h with 0.5 l/h of ultrafiltrate). RESULTS: In haemofiltration mode both Type A and Type B haemodialysers at QB 150 ml/min exhibited similar median SC nearly up to 1 for IL-1beta and IL-1ra, at about 0.6 for IL-6, 0.4 for IL-8 and 0.7 for TNF-alpha, with clearance values ranging from 15 to 30 ml/min. SC were independent of blood flow and were stable throughout the whole experiment. Albumin SC was higher in Type B than in Type A and rapidly decreased from 0.2 to 0.02 and from 0.5 to 0.04 within 3 h for haemodialyser Types A and B, respectively. Cytokine SC was lower in haemodialysis than in haemodiafiltration and haemofiltration mode, and by increasing dialysate flow from 3 up to 5 l/h in both haemodialysis and haemodiafiltration mode, SC for all tested cytokines decreased. However, at 5 l/h clearances were not different or were higher, since increased amounts of dialysate outlet compensated for the decreased SC. Albumin clearances in haemodialysis and haemodiafiltration mode after 360 min at 5 l/h were 0.81 and 0.91 ml/min, respectively. CONCLUSIONS: Our studies show that a mixed convective and diffusive technique ensures high cytokine clearances with an acceptable loss of albumin.

Regional citrate anticoagulation in critically ill patients treated with plasma filtration and adsorption.

BACKGROUND: In high-risk bleeding conditions conventional systemic anticoagulation with heparin is a contraindication to renal replacement therapy. We evaluate the feasibility and safety of regional citrate anticoagulation in high-risk bleeding conditions during coupled plasma filtration adsorption (CPFA). METHODS: Thirteen critically ill patients (9 severely burned, 4 polytraumas) with septic shock and acute renal failure treated with CPFA-CVVHD by using bicarbonate-based solutions (heparin-CPFA group, 58 sessions) or with CPFA-CVVHF using citrate (citrate-CPFA group, 36 sessions). RESULTS: Plasma flow and used cartridges showed no differences between the citrate-CPFA and heparin-CPFA groups, while lost clotted cartridges were significantly lower in the citrate-CPFA group. Blood ionized calcium (iCa2+), Ca2+ infusion, pH and bicarbonates remained constant during citrate-CPFA, with no difference between pre- and post-cartridge plasma citrate. A significant positive correlation between iCa2+ in blood and ultrafiltrate was present. CONCLUSIONS: These suits demonstrate the feasibility and safety of regional citrate anticoagulation in severely burned and polytrauma septic patients treated by CPFA.