Antonio Lupo

Long-Term Outcome in Continuous Ambulatory Peritoneal Dialysis: A 10-Year Survey by the Italian Cooperative Peritoneal Dialysis Study Group

Over a 10-year period, 1,990 end-stage renal disease patients in 30 centers were treated with continuous ambulatory peritoneal dialysis by the Italian Cooperative Peritoneal Dialysis Study Group. At the start of treatment, patients had an average age of 58.4 years, with a 66% prevalence of one or more clinical risk factors for premature death. Patient survival was 51% and 33% at 4 and 8 years on continuous ambulatory peritoneal dialysis, respectively, and technique survival was 62% and 48%, respectively. Occurrences of peritonitis progressively reduced until they reached an incidence of 0.50 episodes/yr in the last 5 years (1985 to 1989). Hernias and catheter-related problems did not influence the dropout rates. These Italian Cooperative Peritoneal Dialysis Study Group results demonstrate that continuous ambulatory peritoneal dialysis is a viable dialysis technique for long-term treatment of chronic renal failure and that it is an effective alternative to hemodialysis, especially for older and high-risk patients.

Endovascular versus Surgical Preemptive Repair of Forearm Arteriovenous Fistula Juxta-Anastomotic Stenosis: Analysis of Data Collected Prospectively from 1999 to 2004

Surgery is the traditional treatment for juxta-anastomotic stenoses in forearm arteriovenous fistulas (AVF), but percutaneous transluminal angioplasty (PTA) is a suitable alternative. No prospective comparative trials between the two have been reported to date, however. A retrospective analysis of prospectively, concurrently collected data was performed to compare the outcome and cost of surgery and PTA in the preemptive repair of juxta-anastomotic stenosis in lower forearm AVF. Sixty-four AVF with >50% venous juxta-anastomotic stenosis were considered: 21 were treated surgically (11 proximal neo-anastomosis and 10 polytetrafluoroethylene interposition graft) and 43 by PTA. After treatment, AVF were monitored by quarterly ultrasound dilution access blood flow measurement. End points were restenosis and procedure failure rate (re-intervention by another technique or access loss), and determinants were analyzed using Cox hazard model. Initial procedural success was 100% for surgery and 95% for PTA (P = 0.539). Restenosis rate was 0.168 and 0.519 events/AVF-year for surgery and PTA, respectively (P = 0.009). The type of procedure was the only variable that was significantly associated with restenosis, the adjusted relative risk being 2.77-fold higher (95% confidence interval 1.07 to 7.17; P = 0.036) after PTA than surgery. The procedure failure rate was 0.110 and 0.097 events/AVF-year for surgery and PTA, respectively (P = 0.736). The cost profile also was similar for the two procedures. This prospective comparative study confirms a higher restenosis rate after PTA than surgery, but with strict surveillance for restenosis, the two procedures show similar assisted primary patency and cost, suggesting that they should be considered equally valid, complementary alternatives in the preemptive treatment of juxta-anastomotic stenosis in forearm AVF.

Hepcidin is not useful as a biomarker for iron needs in haemodialysis patients on maintenance erythropoiesis-stimulating agents

BACKGROUND It has been suggested that hepcidin may be useful as a tool for managing iron therapy in haemodialysis (HD) patients on erythropoiesis-stimulating agents (ESA). METHODS We used SELDI-TOF mass spectrometry assay to measure serum hepcidin-25 (Hep-25) and hepcidin-20 (Hep-20) in 56 adult HD patients on maintenance ESA to assess their ability to predict haemoglobin (Hb) response after 1 g intravenous iron (62.5 mg ferric gluconate at 16 consecutive dialysis sessions) and their relationship with markers of iron status, inflammation and erythropoietic activity. RESULTS At multivariate analysis (in a model that also included Hb, reticulocyte, ESA dose, HFE genotype, soluble transferrin receptor [sTfR] and C-reactive protein), Hep-25 independently correlated with ferritin (β = 0.03, P = 0.01) and the percentage of hypochromic red blood cells [%Hypo] (β = 1.84, P = 0.01), suggesting that Hep-25 may be a useful biomarker for iron stores and bone marrow iron availability. Hep-20 correlated independently with Hep-25 (β = 0.159, P < 0.001) and ferritin (β = 0.006, P = 0.05), suggesting that it may be a useful additional biomarker for iron stores. On receiver operating characteristics curve analysis, neither Hep-25 nor Hep-20 significantly predicted who will increase their Hb after iron loading (AUC = 0.52 ± 0.09 and 0.54 ± 0.08, P = 0.612), and the same applied to ferritin and transferrin saturation (AUC = 0.55 ± 0.08 and 0.59 ± 0.08, P = 0.250), whereas %Hypo and reticulocyte Hb content were significant predictors (AUC = 0.84 ± 0.05 and 0.70 ± 0.08, P < 0.01). At multivariate logistic regression analysis, %Hypo was the only biomarker independently associated with iron responsiveness. CONCLUSIONS Although our study suggests an important role for hepcidin in regulating iron homeostasis in HD patients on ESA, our findings do not support its utility as a predictor of iron needs, offering no advantage over established markers of iron status.

Adding access blood flow surveillance to clinical monitoring reduces thrombosis rates and costs, and improves fistula patency in the short term: a controlled cohort study

BACKGROUND Access blood flow (Qa) measurement is the recommended method for fistula (AVF) surveillance for stenosis, but whether it may be beneficial and cost-effective is controversial. METHODS We conducted a 5-year controlled cohort study to evaluate whether adding Qa surveillance to unsystematic clinical monitoring (combined with elective stenosis repair) reduces thrombosis and access loss rates, and costs in mature AVFs. We prospectively collected data in 159 haemodialysis patients with mature AVFs, 97 followed by unsystematic clinical monitoring (Control) and 62 by adding Qa surveillance to monitoring (Flow). Indications for imaging and stenosis repair were clinically evident access dysfunction in both groups and a Qa < 750 ml/min or dropping by >20% in Flow. RESULTS Adding Qa surveillance prompted an increase in access imaging (HR 2.96, 95% CI 1.79-4.91, P < 0.001), stenosis detection (HR 2.55, 95% CI 1.48-4.42, P = 0.001) and elective repair (HR 2.26, 95% CI 1.16-4.43, P = 0.017), and a reduction in thromboses (HR 0.27, 95% CI 0.09-0.79, P = 0.017), central venous catheter placements (HR 0.14, 95% CI 0.03-0.42, P = 0.010) and access losses (HR 0.35, 95% CI 0.11-1.09, P = 0.071). In the Kaplan-Meier analysis, adding Qa surveillance only extended short-term cumulative patency (P = 0.037 in the Breslow test). Mean access-related costs were 1213 Euro/AVF-year in Control and 743 in Flow (P < 0.001). CONCLUSIONS Our controlled cohort study shows that adding Qa surveillance to monitoring in mature AVFs is associated with a better detection and elective treatment of stenosis, and lower thrombosis rates and access-related costs, although the cumulative access patency was only extended in the first 3 years after fistula maturation. We are aware of the limitations of our study (non-randomization and the possible centre effect) and that further, better-designed trials are needed to arrive at a definitive answer concerning the role of Qa surveillance for fistulae.

Prevalence of CKD in Northeastern Italy: Results of the INCIPE Study and Comparison with NHANES

BACKGROUND AND OBJECTIVES Sufficiently powered studies to investigate the CKD prevalence are few and do not cover southern Europe. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS For the INCIPE study, 6200 Caucasian patients ≥40 years old were randomly selected in northeastern Italy in 2006. Laboratory determinations were centralized. The albumin to creatinine ratio in urine and estimated GFR from calibrated creatinine (SCr) were determined. A comparison with 2001 through 2006 NHANES surveys was performed. RESULTS Prevalence of CKD was 13.2% in northeastern (NE) Italy (age and gender standardized to the U.S. 2007 Caucasian population). Prevalence of CKD in U.S. Caucasians is higher (20.3%), the major difference being in CKD 3. Risk factors for CKD are more prevalent in the United States than in Italy. With use of CKD 3a and 3b stages, CKD prevalence decreased in NE Italy (8.5%) and in the United States (12.8%). CONCLUSIONS The prevalence of CKD is high in NE Italy, but lower than that in the United States. A large part of the difference in CKD prevalence in NE Italy versus that in the United States is due to the different prevalence of CKD 3. The higher prevalence of a number of renal risk factors in persons from the United States explains in part the different dimensions of the CKD problem in the two populations.

Hypertension of Polycystic Kidney Disease: Mechanisms and Hemodynamic Alterations

32 polycystic kidney disease (PKD) patients, 16 with normal 16 with variably decreased renal function, were studied; 12 were normotensive, 20 were hypertensive. Mean arterial pressure (MAP) was 90 +/- 8 mm Hg in the normotensive group and 117 +/- 17 in hypertensive patients; plasma renin activity (PRA) was similar. The glomerular filtration rate (GFR) was lower, but not significantly, in the hypertensive group and plasma volume (PV) was higher in hypertensive patients (normotensive 40.25 +/- 3.47 ml/kg body weight; hypertensive 46.30 +/- 3.54). No correlation was found between MAP, and PRA or GFR but MAP correlated with PV. Cardiac output was higher in hypertensive patients (normotensive 3.48 +/- 0.70 l/min/m2; hypertensive 3.89 +/- 1.47), also total peripheral resistance was higher in the hypertensive group (normotensive 2,035 +/- 503 dyn/s/cm-5/m2; hypertensive 2,577 +/- 808). Cardiac output and PV showed a high degree of correlation, but no correlation was seen between total peripheral resistance and PV, or PRA. The hypertensive patients were divided into two groups: one with hypertension of less than 2 years duration and one with more than 2 years but with similar GFR, PRA, PV and hemodynamic pattern. Our data indicate that hypertension in PKD is volume-dependent; that the increase in PV was not related to the loss of GFR, and that the role of the renin-angiotensin system in maintaining the hypertensive state is not well defined. Hemodynamically hypertension is characterized by high cardiac output and total peripheral resistance independent of the duration of hypertension.

Heparanase and Syndecan-1 Interplay Orchestrates Fibroblast Growth Factor-2-induced Epithelial-Mesenchymal Transition in Renal Tubular Cells

Background: FGF-2 induces EMT in PTECs, and HPSE regulates HS/syndecans. Results: The lack of HPSE prevents FGF-2-induced EMT; FGF-2 induces EMT through PI3K/AKT and produces an autocrine loop. Conclusion: HPSE is necessary for FGF-2 to produce EMT, to activate FGF-2 intracellular signaling, and to regulate its autocrine loop. Significance: HPSE is an interesting pharmacological target for the prevention of renal fibrosis. The epithelial-mesenchymal transition (EMT) of proximal tubular epithelial cells (PTECs) into myofibroblasts contributes to the establishment of fibrosis that leads to end stage renal disease. FGF-2 induces EMT in PTECs. Because the interaction between FGF-2 and its receptor is mediated by heparan sulfate (HS) and syndecans, we speculated that a deranged HS/syndecans regulation impairs FGF-2 activity. Heparanase is crucial for the correct turnover of HS/syndecans. The aim of the present study was to assess the role of heparanase on epithelial-mesenchymal transition induced by FGF-2 in renal tubular cells. In human kidney 2 (HK2) PTEC cultures, although FGF-2 induces EMT in the wild-type clone, it is ineffective in heparanase-silenced cells. The FGF-2 induced EMT is through a stable activation of PI3K/AKT which is only transient in heparanase-silenced cells. In PTECs, FGF-2 induces an autocrine loop which sustains its signal through multiple mechanisms (reduction in syndecan-1, increase in heparanase, and matrix metalloproteinase 9). Thus, heparanase is necessary for FGF-2 to produce EMT in PTECs and to sustain FGF-2 intracellular signaling. Heparanase contributes to a synergistic loop for handling syndecan-1, facilitating FGF-2 induced-EMT. In conclusion, heparanase plays a role in the tubular-interstitial compartment favoring the FGF-2-dependent EMT of tubular cells. Hence, heparanase is an interesting pharmacological target for the prevention of renal fibrosis.

Clinical Features of Patients with Solitary Kidneys

A clinical study was performed in 2 groups of patients with solitary kidneys, followed for 11-146 months. Group 1 had 9 patients (7 males and 2 females, aged between 23 and 68 years) with unilateral renal agenesis. Group 2 had 13 patients (9 females and 4 males, aged between 27 and 70 years) who underwent unilateral nephrectomy for the following reasons: hydronephrosis secondary to ureteropelvic junction stenosis, 7 patients; renal trauma, 4 patients; benign neoplasia, 2 patients. During the follow up, urinary protein excretion of more than 300 mg/day was observed in 9 patients, 3 in group 1 and 6 in group 2. Eleven patients, 8 in group 1 and 3 in group 2, were hypertensive (diastolic blood pressure higher than 95 mm Hg). Hyperuricemia was observed in 14 patients, 10 in group 1 and 4 in group 2. Seven patients, 4 in group 1 and 3 in group 2, had a significant deterioration of renal function. Neither proteinuria nor renal failure were observed before at least 10 years had elapsed since the anatomic condition of solitary kidney had been established. A surgical renal biopsy was performed in 1 patient with unilateral renal agenesis and showed focal glomerular sclerosis. This study adds support to the view that the reduction of 50% of the renal tissue may be a risky situation in humans as well as in animals.

Lithiasis in cystic kidney disease and malformations of the urinary tract

The prevalence of renal stones in renal cystic and malformative conditions exceeds the prevalence of renal stones in the general population, suggesting that the above-mentioned cystic and malformative disorders favor stone formation. Urinary stasis is generally assumed to play a major part in the pathogenesis of the nephrolithiasis associated with distorted renal anatomy due to a delayed washout of crystals and risk of urinary infections. However metabolic factors are also important in the pathogenesis of stones in these conditions. Indeed, metabolic abnormalities have been observed in the majority of stone-forming patients with conditions such as horseshoe kidney and ureteropelvic junction obstruction. Five different models of stone formation can be identified, depending on stone composition, risk of infection stones, and pathogenesis of renal cystic and malformative conditions. A proper metabolic evaluation should be conducted to diagnose specific, treatable metabolic disorders, thereby reducing the frequency of recurrent stone disease in these conditions as well.

Evaluation of hepcidin isoforms in hemodialysis patients by a proteomic approach based on SELDI-TOF MS.

The hepatic iron regulator hormone hepcidin consists, in its mature form, of 25 amino acids, but two other isoforms, hepcidin-20 and hepcidin-22, have been reported, whose biological meaning remains poorly understood. We evaluated hepcidin isoforms in sera from 57 control and 54 chronic haemodialysis patients using a quantitative proteomic approach based on SELDI-TOF-MS. Patients had elevated serum levels of both hepcidin-25 and hepcidin-20 as compared to controls (geometric means: 7.52 versus 4.69 nM, and 4.06 versus 1.76 nM, resp., P < .05 for both). The clearance effects of a single dialysis session by different dialysis techniques and membranes were also investigated, showing an average reduction by 51.3% ± 29.2% for hepcidin-25 and 34.2% ± 28.4% for hepcidin-20 but only minor differences among the different dialysis modalities. Measurement of hepcidin isoforms through MS-based techniques can be a useful tool for better understanding of their biological role in hemodialysis patients and other clinical conditions.