Ramipril and Cardiovascular Outcomes in Patients on Maintenance Hemodialysis: The ARCADIA Multicenter Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Renin-angiotensin system (RAS) inhibitors reduce cardiovascular morbidity and mortality in patients with CKD. We evaluated the cardioprotective effects of the angiotensin-converting enzyme inhibitor ramipril in patients on maintenance hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this phase 3, prospective, randomized, open-label, blinded end point, parallel, multicenter trial, we recruited patients on maintenance hemodialysis with hypertension and/or left ventricular hypertrophy from 28 Italian centers. Between July 2009 and February 2014, 140 participants were randomized to ramipril (1.25-10 mg/d) and 129 participants were allocated to non-RAS inhibition therapy, both titrated up to the maximally tolerated dose to achieve predefined target BP values. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the single components of the primary end point, new-onset or recurrence of atrial fibrillation, hospitalizations for symptomatic fluid overload, thrombosis or stenosis of the arteriovenous fistula, and changes in cardiac mass index. All outcomes were evaluated up to 42 months after randomization. RESULTS: At comparable BP control, 23 participants on ramipril (16%) and 24 on non-RAS inhibitor therapy (19%) reached the primary composite end point (hazard ratio, 0.93; 95% confidence interval, 0.52 to 1.64; P=0.80). Ramipril reduced cardiac mass index at 1 year of follow-up (between-group difference in change from baseline: -16.3 g/m2; 95% confidence interval, -29.4 to -3.1), but did not significantly affect the other secondary outcomes. Hypotensive episodes were more frequent in participants allocated to ramipril than controls (41% versus 12%). Twenty participants on ramipril and nine controls developed cancer, including six gastrointestinal malignancies on ramipril (four were fatal), compared with none in controls. CONCLUSIONS: Ramipril did not reduce the risk of major cardiovascular events in patients on maintenance hemodialysis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ARCADIA, NCT00985322 and European Union Drug Regulating Authorities Clinical Trials Database number 2008-003529-17.

[Nephrologic workforce. Who we are? Where do we go? A project by SIN]. / La Workforce nefrologica in Italia. Chi siamo e dove andiamo: un progetto SIN.

The SIN Workforce Working Group has carried out an initial demographic study project that highlights the situation of nephrological workforce in European and non-European countries, noting in particular the apparent discrepancies between the number of nephrologists in other health systems and in the Italian one. Italy seems to have the highest number of nephrologists per capita: in fact, the number of nephrologists has decreased in recent years due to the number of retirements far higher than the entry of new specialists. The project arises from the need to define the actual number of nephrologists in Italy in relation to the population and the epidemiology of chronic renal disease, taking into account the trends of ageing and feminization of our specialty. The tools used to collect data on the demographics of Italian nephrologists are a database for demographic data collection by presidents of SIN regional sections and a questionnaire for a survey to describe demography, workload, the adhesion to the discipline and the recruitment and retirement programs of the Italian nephrological community.

[The history of peritoneal dialysis at the Molinette Hospital in Turin, Italy]. / La storia della dialisi peritoneale all'Ospedale Molinette di Torino.

In the Renal Unit of the Molinette Hospital of Turin, peritoneal dialysis (PD) was introduced in the mid 1960s to treat patients suffering from acute renal failure. The peritoneal catheter, which was then a stiff catheter, was inserted by a surgeon at each dialysis session. Between 1966 and 1970 there were a series of improvements, such as the first cycler for intermittent PD, fast-shift DP, and a homemade machine for automatic PD. During the early 1970s, a new type of stiff peritoneal catheter was introduced, which was used also for patients suffering from chronic renal failure. Towards the end of the 1970s the soft Tenckhoff peritoneal catheter started to be used, as well as continuous ambulatory peritoneal dialysis (CAPD), which made it possible to treat a large number of patients at home. The 1980s brought a new surgical technique for the insertion of the catheter, and in the 1990s new peritoneal catheters were introduced which reduced the number of early and late complications. Around the turn of the century, the PD service was reorganized and improved, with dedicated personnel and facilities. Moreover, automated PD was introduced and the treatment of peritonitis was standardized according to international guidelines.

Macrophage stimulating protein may promote tubular regeneration after acute injury.

Macrophage-stimulating protein (MSP) exerts proliferative and antiapoptotic effects, suggesting that it may play a role in tubular regeneration after acute kidney injury. In this study, elevated plasma levels of MSP were found both in critically ill patients with acute renal failure and in recipients of renal allografts during the first week after transplantation. In addition, MSP and its receptor, RON, were markedly upregulated in the regenerative phase after glycerol-induced tubular injury in mice. In vitro, MSP stimulated tubular epithelial cell proliferation and conferred resistance to cisplatin-induced apoptosis by inhibiting caspase activation and modulating Fas, mitochondrial proteins, Akt, and extracellular signal-regulated kinase. MSP also enhanced migration, scattering, branching morphogenesis, tubulogenesis, and mesenchymal de-differentiation of surviving tubular cells. In addition, MSP induced an embryonic phenotype characterized by Pax-2 expression. In conclusion, MSP is upregulated during the regeneration of injured tubular cells, and it exerts multiple biologic effects that may aid recovery from acute kidney injury.

Polymyxin-B hemoperfusion inactivates circulating proapoptotic factors.

OBJECTIVE: To test the hypothesis that extracorporeal therapy with polymyxin B (PMX-B) may prevent Gram-negative sepsis-induced acute renal failure (ARF) by reducing the activity of proapoptotic circulating factors. SETTING: Medical-Surgical Intensive Care Units. PATIENTS AND INTERVENTIONS: Sixteen patients with Gram-negative sepsis were randomized to receive standard care (Surviving Sepsis Campaign guidelines) or standard care plus extracorporeal therapy with PMX-B. MEASUREMENTS AND RESULTS: Cell viability, apoptosis, polarity, morphogenesis, and epithelial integrity were evaluated in cultured tubular cells and glomerular podocytes incubated with plasma from patients of both groups. Renal function was evaluated as SOFA and RIFLE scores, proteinuria, and tubular enzymes. A significant decrease of plasma-induced proapoptotic activity was observed after PMX-B treatment on cultured renal cells. SOFA and RIFLE scores, proteinuria, and urine tubular enzymes were all significantly reduced after PMX-B treatment. Loss of plasma-induced polarity and permeability of cell cultures was abrogated with the plasma of patients treated with PMX-B. These results were associated to a preserved expression of molecules crucial for tubular and glomerular functional integrity. CONCLUSIONS: Extracorporeal therapy with PMX-B reduces the proapoptotic activity of the plasma of septic patients on cultured renal cells. These data confirm the role of apoptosis in the development of sepsis-related ARF.

Severe course of primary hyperoxaluria and renal failure after domino hepatic transplantation.

We report herein a domino orthotopic liver transplantation (LT), from a 38-year-old woman undergoing liver-kidney transplantation (LKT) for primary hyperoxaluria type I (PH1) to a recipient with cirrhosis and hepatocellular carcinoma. Delayed onset of PH1 and renal failure and 10% residual alanine-glyoxylate aminotransferase (AGT) activity in domino liver justified its use for domino procedure. The clinical course after LKT was similar to that described in other series, including ours. Renal function started promptly and maintained despite sustained hyperoxaluria from dissolution of oxalotic deposits. Conversely, the domino recipient manifested severe hyperoxaluria and developed nephrolithiasis and renal insufficiency with rapid progression over 2 months. A new LT resulted in slow decrease of oxaluria and improvement of renal function. Therefore, PH1 behaved quite differently in these two patients, leading us to conclude that domino LT using livers from PH1 patients should be considered very carefully, only as a bridge to definitive LT in recipients with critical clinical conditions.

Continuum of therapy in progressive renal diseases (from predialysis to transplantation): analysis of a new organizational model.

In the aging of Western populations, decreased mortality is counterbalanced by an increase in morbidity, particularly involving chronic diseases such as most renal diseases. The price of the successful care of chronic conditions, such as cardiovascular diseases or diabetes, is a continuous increase in new dialysis patients. However, the increased survival of patients on chronic renal replacement therapies poses new challenges to nephrologists and calls for new models of care. Since its split from internal medicine, nephrology has seen a progressive trend toward super specialization and the differentiation into at least 3 major branches (nephrology, dialysis, and transplantation), following a path common to several other fields of internal medicine. The success in the care of chronic patients is owed not only to a careful technical prescription, but also to the ability to teach self-care and attain compliance; this requires good medical practice and a sound patient-physician relationship. In this context, the usual models of care may fail to provide adequate coordination and, despite valuable single elements, could end up as an orchestra without a conductor. We propose an integrated model of care oriented to the type of patient (tested in our area especially for diabetic patients): the patient is followed-up by the same team from the first signs of renal disease to eventual dialysis or transplantation. This model offers an interesting alternative both for patients, who usually seek continuity of care, and for nephrologists who prefer a holistic and integrated patient-physician approach.

The self-locating catheter: clinical experience and follow-up.

BACKGROUND: The self-locating catheter invented by Nicola Di Paolo has been used increasingly in Italy and elsewhere since 1994, with about a thousand patients currently implanted every year. Twelve grams of tungsten inserted into the tip of the conventional Tenckhoff catheter during extrusion does not significantly change its form, but suffices to keep the tip firmly in the Douglas cavity. OBJECTIVE: The aim of the present study was to confirm our preliminary results in a large population of peritoneal dialysis patients. SETTING: 16 Italian nephrology departments. RESULTS: In addition to confirming the validity of the new catheter, the present results show that patients with the new catheter have fewer episodes of peritonitis, tunnel infection, cuff extrusion, catheter malfunction, obstruction, and leakage. CONCLUSION: The present multicenter control study confirms preliminary results and demonstrates that complications of peritoneal dialysis, such as cuff extrusion, infection, peritonitis, early leakage, and obstruction, are statistically less frequent in patients with self-locating catheters than in patients with classic Tenckhoff catheters.

Vascular access survival and morbidity on daily dialysis: a comparative analysis of home and limited care haemodialysis.

BACKGROUND: Concerns about vascular access failure may have limited the widespread use of daily haemodialysis (DHD). We assessed the incidence and type of vascular access complications during DHD and other schedules, both at home and on limited care haemodialysis. METHODS: All patients were treated in a limited care and home haemodialysis unit with a stable caregiver team (November 1998-November 2002). Vascular access failure, surgical treatment, angioplasty and declotting were studied alone or in combination by univariate and multivariate models. We analysed the effects of age, sex, comorbidity, previous vascular events, schedule, setting of treatment (home, limited care), dialysis follow-up, vascular access (native vs prosthetic, first vs subsequent) and setting of vascular access creation. 'Intention to treat' and 'per protocol' analyses were performed. RESULTS: In 2160 patient-months (home dialysis: DHD 400 months, non-DHD 655 months; limited care: DHD 208 months; non-DHD 897 months), 57 adverse events occurred (27 failures), in which 30 were at home (nine DHD) and 27 were in limited care (five DHD). The probability of remaining free from adverse events at 6 and 12 months was 89% and 80% on DHD and 79% and 76% on other schedules ('intention to treat'). Univariate analyses revealed a significant difference for the setting of the vascular access creation (lower risk of vascular access complications in our centre) and sex (male sex was protective). Logistic regression and Cox analyses confirmed the role for the setting of the vascular access creation. CONCLUSIONS: Although DHD did not appear as a risk factor for vascular access morbidity or failure at home or in a limited care centre setting, the setting of vascular access creation may influence its success.

Flexibility as an implementation strategy for a daily dialysis program.

BACKGROUND: Daily hemodialysis (DHD) is an interesting dialysis option, experienced worldwide by only a few hundred patients, because of clinical and logistic limitations. This study describes the main clinical and implementation results of a flexible policy applied in starting a DHD program. METHODS: The setting is the University Nephrology Center of Turin, Italy (approximately 150 hemodialysis and 50 peritoneal dialysis (PD) patients) where in November 1998 a short daily DHD program was started. Outcome measures were logistical (enrollment rate, indications and drop-outs) and clinical (dialysis efficiency, metabolic control, hypertension and anemia control). RESULTS: 25 patients experienced DHD, 16 (11% of the hemodialysis pool) were on DHD in November 2001; overall the DHD follow-up was 409.1 months (median 18, range 0.7-36 months). Flexibility was applied to schedules (patients modulated dialysis time and could switch to 3-4 sessions/wk); treatment setting (home: 11 patients, limited care center: 13; alternate settings: one); clinical selection (23/25 patients with comorbidity). Main reasons for choice were poor tolerance of previous schedule and the search for "best" treatment. Five patients dropped out (work reasons), one died on DHD and three were grafted. As compared to baseline, dialysis efficiency increased (EKRc pre-DHD 14.5 +/- 2.1 mL/min; 17.4 +/- 2.8 mL/min and 17.7 +/- 3.5 mL/min at 1-6 months; p<0.000). Despite the potentially confusing effect of comorbidity, the main clinical data improved. CONCLUSIONS: A flexible approach allowed development of DHD in approximately 11% of hemodialysis patients, with promising clinical results, despite frequent comorbidity.

Home hemodialysis. Revival of a superior dialysis treatment.

BACKGROUND: Home hemodialysis is usually considered a superior therapy, whose decline is related to demographic, social, psychological and financial factors as well as to competition with renal transplantation and PD. METHODS: A home hemodialysis program was started in November 1998 in the University of Torino, Italy (200-210 patients on dialysis). Its main features are the tailoring of dialysis schedules and the acceptance of patients with comorbidity. Nurses assist home sessions in case of short-term problems, while the training center ensures follow-up for long-term clinical and logistic problems. RESULTS: The program started in November 1998 on a previous one (active from 1970 to 1998; 6 patients on treatment in November 1998). Since then, 25 more patients joined the program. Out of 31 patients followed since November 1998, 4 were grafted, 2 died, and 2 dropped out from training. In June 2001, 15 patients were on home hemodialysis, 8 on training. Dialysis schedules and controls are flexible and tailored; in June 2001, range of dialysis time was 1.20-5 h; sessions: 2-6; 8 patients were on thrice-weekly dialysis, 7 on daily dialysis; all patients reached target EKRc >10 ml/min (median 15, range 11-24 ml/min). CONCLUSION: Tailored, flexible schedules allowed home hemodialysis in over 10% of our patients, confirming that there is still room for this treatment in our setting.

Daily Dialysis and Flexible Schedules: How to Assess Kt/V and EKRc ?

Despite the growing interest in daily hemodialysis (DHD), logistic and economic factors limit its dissemination. Not the least of these factors is the lack of uniform criteria for measuring efficiency. From November 1998 to November 2000, 19 patients were on DHD in our unit. The dialysis prescription was bicarbonate buffer; 6 sessions per week; 2 - 3 hours; blood flow 250 - 350 mL/min; individual K, HCO3 , and Na levels; membrane 1.6 - 2 m2 (polysulfone, polycarbonate). The prescription represented the minimum dialysis requirement; patients were free to add up to 30 minutes per session, further increase or any decreases needed confirmation by the caregivers. The aim of the study was to assess Kt/Vurea variability in this clinical setting, and to identify the minimum number of dialysis sessions required to obtain a reliable estimate of weekly Kt/Vurea [relative error (RE) < 10%]. We studied 169 dialysis sessions in 13 clinically stable patients on DHD for ≥ 3 months, with ≥ 3 Kt/Vurea measurements within 2 weeks (median: 10; range: 3 - 32 sessions), tested in the same laboratory. To assess variability, we employed the simplest formula (the Lowrie Kt/Vurea ), the widely used Daugirdas II formula, and the derived single-pool equivalent renal clearance (EKRc ), according to Casino. The variability of Kt/Vurea per session was high (Lowrie: RE = 2.5% - 22.1%; Daugirdas II and EKRc : RE = 3.6% - 24%). Averaging several dialysis sessions leads to a more reliable estimate of weekly efficiency (6 sessions: RE = 0; 3 sessions, Lowrie formula: Kt/Vurea RE = 1.1% - 9.7%; Daugirdas II and EKRc : RE = 1.6% - 10.6%). In patients with wide time variations, variability may be lower if weekly efficiency is determined on the basis of "average hourly Kt/Vurea ," which is calculated by dividing Kt/Vurea by the number of hours in the studied sessions, and then multiplying by the hours of dialysis performed in the whole week (Lowrie formula, Kt/Vurea : RE = 4.8% - 16.6% for 1 session, 2.1% - 7.3% for 3 sessions). Once again, the RE decreases sharply when data from 3 sessions are considered. Therefore, for flexible DHD, we suggest averaging the data from ≥ 3 sessions for weekly Kt/Vurea assessment.