Roberto Zubani

Predictors of Renal and Patient Outcomes in Atheroembolic Renal Disease: A Prospective Study

Atheroembolic renal disease (AERD) is part of a multisystemic disease accompanied by high cardiovascular comorbidity and mortality. Interrelationships between traditional risk factors for atherosclerosis, vascular comorbidities, precipitating factors, and markers of clinical severity of the disease in determining outcome remain poorly understood. Patients with AERD presenting to a single center between 1996 and 2002 were followed-up with prospective collection of clinical and biochemical data. The major outcomes included end-stage renal disease (ESRD) and death. Ninety-five patients were identified (81 male). AERD was iatrogenic in 87%. Mean age was 71.4 yr. Twenty-three patients (24%) developed ESRD; 36 patients (37.9%) died. Cox regression analysis showed that significant independent predictors of ESRD were long-standing hypertension (hazard ratio [HR] = 1.1; P < 0.001) and preexisting chronic renal impairment (HR = 2.12; P = 0.02); use of statins was independently associated with decreased risk of ESRD (HR = 0.02; P = 0.003). Age (HR = 1.09; P = 0.009), diabetes (HR = 2.55; P = 0.034), and ESRD (HR = 2.21; P = 0.029) were independent risk factors for patient mortality; male gender was independently associated with decreased risk of death (HR = 0.27; P = 0.007). Cardiovascular comorbidities, precipitating factors, and clinical severity of AERD had no prognostic impact on renal and patient survival. It is concluded that AERD has a strong clinical impact on patient and renal survival. The study clearly shows the importance of preexisting chronic renal impairment in determining both renal and patient outcome, this latter being mediated by the development of ESRD. The protective effect of statins on the development of ESRD should be evaluated in a prospective study.

Long-term Effects of Arteriovenous Fistula Closure on Echocardiographic Functional and Structural Findings in Hemodialysis Patients: A Prospective Study

BACKGROUND The arteriovenous fistula (AVF) provides an effective vascular access for hemodialysis; however, the associated hemodynamic effects may alter cardiac structure and function. The objective of this study is to evaluate the effect of AVF closure on functional and structural echocardiographic findings. STUDY DESIGN Prospective observational study. SETTING & PARTICIPANTS In a single center between 2003 and 2006, we enrolled 25 consecutive hemodialysis patients with AVF malfunction who underwent AVF closure and conversion to a tunneled central venous catheter because of exhaustion of alternative vascular sites and 36 matched controls with a well-functioning AVF. PREDICTOR AVF closure. OUTCOMES & MEASUREMENTS Outcomes were changes in findings on echocardiograms obtained before and 6 months after AVF closure for patients in the AVF-closure group and at baseline and 6 months later for controls. Echocardiographic measurements included left ventricular (LV) internal diastolic diameter, interventricular septum thickness, diastolic posterior wall thickness, LV mass (LVM), LVM index (LVMi), and LV ejection fraction (LVEF). Dialysis modality and scheme were unchanged. RESULTS In the AVF-closure group, LVM decreased from 225 +/- 55 to 206 +/- 51 g (P < 0.001) and LVMi decreased from 135 +/- 40 to 123 +/- 35 g/m(2) (P < 0.001). LV internal diastolic diameter, interventricular septum thickness, and diastolic posterior wall thickness decreased significantly, whereas LVEF increased from 56% +/- 7% to 59% +/- 6% (P < 0.001). No significant changes were observed in controls. In patients with AVF closure, LV morphologic characteristics showed a decrease in both eccentric and concentric hypertrophy in favor of normalization or a pattern of concentric remodeling. No significant changes were observed in controls. LIMITATIONS Use of matched rather than randomized controls. CONCLUSIONS Closure of an AVF determines a significant decrease in LV internal diastolic diameter, interventricular septum thickness, and diastolic posterior wall thickness. This is associated with significant improvement in LVEF, a significant decrease in LVM and LVMi, and a more favorable shift of cardiac geometry toward normality.

A High Calcium-Phosphate Product Is Associated with High C-Reactive Protein Concentrations in Hemodialysis Patients

Background: An elevated Ca×PO₄ product and C-reactive protein (CRP) have been associated with coronary artery calcification and increased cardiovascular mortality in hemodialysis (HD) patients. However, it has not been defined, so far, whether and how both parameters are related to each other. For this reason we have evaluated in a cross-sectional and in an interventional study the possible correlation between Ca×PO₄ and CRP and the effect of the correction of a high Ca×PO₄ on CRP levels. Methods: 47 uremic patients (age 65 ± 16 years) on regular chronic HD were selected from a total population of 125 prevalent patients treated at our Institution. Patients had no clinical evidence of either acute infectious or inflammatory diseases for at least 4 weeks before the study. They were on regular bicarbonate HD for 6–329 months (median 42). CRP, hemoglobin (Hb), serum albumin (sAlb), protein catabolic rate (PCRn), serum calcium (Ca), serum phosphorus (PO₄), Ca×PO₄, intact PTH, Kt/V, presence of ischemic heart disease (IHD) and/or peripheral vascular disease (PVD) were recorded. CRP was Ln-transformed in all statistical analyses because of positive skewness. Results: The main findings were: LnCRP 2.17 ± 0.77 mg/l, Ca 10.1 ± 0.4 mg/dl, PO₄ 5.8 ± 0.6 mg/dl, Ca×PO₄ 59 ± 6 mg²/dl², andPTHint 218 ± 195 ng/ml. 18/47 had IHD, 18/47 PVD. A significant hyperbolic correlation between Ca×PO₄ and CRP was observed. A piecewise linear regression model analysis identified a break-point for Ca×PO₄ at 55 mg²/dl². Comparison of CRP levels after the division of the patients into two groups according to Ca×PO₄ break-point (group A, Ca×PO₄ ≤55 mg²/dl², n = 16 patients; group B, Ca×PO₄ >55 mg²/dl², n = 31 patients) showed that CRP levels were significantly lower in patients in group A (LnCRP 1.43 ± 0.22 mg/l) than in group B (LnCRP 2.55 ± 0.67 mg/l, p < 0.0001). Multiple regression analysis bearing LnCRP as dependent variable confirmed Ca×PO₄ as the most significant variable among the other variables examined. In 22 patients with Ca×PO₄ ≧60 mg²/dl², we performed intensive lowering of the Ca×PO₄ product in order to reach and maintain a Ca×PO₄ ≤55 mg²/dl² for 3 months. At the end of observation, a significant reduction in Ca×PO₄ and LnCRP was observed (Ca×PO₄ pre 62.8 ± 1.9 vs. post 46.3 ± 6.2 mg²/dl²: p < 0.0001; LnCRP pre 2.32 ± 0.36 vs. post 1.83 ± 0.14 mg/l: p < 0.0001). No significant variation in the other biochemical parameters was observed. Conclusions: Our data show that in chronic HD patients in steady clinical conditions with no clinical evidence of either infectious or inflammatory diseases, a high Ca×PO₄ is associated with high CRP concentrations. Intensive lowering of Ca×PO₄ reduces CRP.

A prospective randomized trial on azathioprine addition to cyclosporine versus cyclosporine monotherapy at steroid withdrawal, 6 months after renal transplantation

BACKGROUND Many attempts have been made to withdraw steroid therapy in renal transplant patients in order to avoid its many side effects. Results have been, so far, controversial. In this randomized prospective study, we compare the efficacy of azathioprine adjuncts to cyclosporine at the time of steroid withdrawal, 6 months after transplantation, versus Cyclosporine monotherapy, in preventing acute rejection. METHODS One hundred and sixteen kidney transplant patients with good and stable renal function (creatininemia <2 mg/dl) received, in the first 6 months, cyclosporine + steroid. They were then randomized into two groups (A and B), and steroid therapy was withdrawn over 2 months. Group A (58 patients) continued on cyclosporine monotherapy, whereas group B (58 patients) added azathioprine (1 mg/kg/day) at the beginning of randomization and continued on cyclosporine + azathioprine. In both groups, patients resumed steroid therapy at the first episode of acute rejection. Follow-up after randomization was 5.3+/-1.6 years. RESULTS After 5 years, the incidence of steroid resumption was 57% in group A and 29% in group B (P<0.02); of those, 68% and 88% of them were within 6 months from randomization. Anti-rejection therapy was always successful. Five-year patient and graft survival rates were 90% and 88% in group A and 100% and 91% in group B. Creatininemia did not differ, at follow-up. Side effects differed only for mild and reversible leukopenia caused by azathioprine in group B. CONCLUSION Cyclosporine plus azathioprine is more effective than cyclosporine monotherapy in reducing the incidence of acute rejection after steroid withdrawal. Graft loss as a result of chronic rejection, mild in both groups, did not differ. Steroid withdrawal is feasible and advantageous, and the addition of azathioprine allowed 71% of our selected patients to remain steroid-free.

Effect of post-dilutional on-line haemodiafiltration on serum calcium, phosphate and parathyroid hormone concentrations in uraemic patients

BACKGROUND Strict control of serum calcium and phosphate concentrations is paramount to prevent secondary hyperparathyroidism in haemodialysis (HD) patients. Standard intermittent low-flux HD (Lf-HD) is not sufficient to reach this goal. The aim of this study was to evaluate the effect of on-line haemodiafiltration (Ol-HDF) on serum calcium (sCa), phosphate (sPO4) and parathyroid hormone (PTHint) concentrations. METHODS Of the 220 patients screened, 65 met the inclusion criteria for the study; 30 of whom agreed to participate in the study (Study group), the others were considered as the control group (Controls). Protocol for Study the group consisted of 6 months conventional Lf-HD (Period 1) and 6 months of post-dilutional Ol-HDF (Period 2). Controls continued their usual Lf-HD and were followed for 12 months. The main variables evaluated at the start and at the end of each period were sCa, sPO(4) and PTHint. RESULTS The switchover from Lf-HD to Ol-HDF resulted in a significant reduction of sPO4 (from 5.1 ± 1.0 to 4.0 ± 0.7; P < 0.0001) and PTHint concentrations (from 307 ± 167 to 194 ± 98; P < 0.0001), no significant changes were found in both sCa concentrations (from 9.1 ± 0.7 to 8.9 ± 0.6) and phosphate binder dose. Kt/Vurea increased significantly, and beta(2) microglobulin concentrations decreased significantly. In the Controls, no significant variations of the same variables were observed over time, except for a significant increase in sevelamer intake. CONCLUSION This study supports the idea that Ol-HDF could be better than Lf-HD in controlling mineral metabolism in HD patients.

Magnitude of end-dialysis overweight is associated with all-cause and cardiovascular mortality: a 3-year prospective study.

Background: We hypothesized that the difference between the prescribed end-dialysis body weight, defined end-dialysis over-weight (edOW; kg), and the body weight which is actually attained could impact survival in hemodialysis (HD) patients. The aim of this prospective observational study was to evaluate if edOW could influence survival in a cohort of prevalent HD patients, controlled for multiple dialysis and clinical risk factors and followed for 3 years. Methods: One hundred and eighty-two patients (117 men, age 65 ± 13 years) on regular HD treatment for at least 6 months [median 48 months (range: 6-366)] were followed from January 1, 2008 to December 31, 2010. Eighty-four patients (46%) did not achieve their prescribed dry body weight (dBW); their median edOW was 0.4 kg (range: 0.1-1.4). Ninety-eight died during observation, mainly from cardiovascular reasons (69%). Multivariate Cox regression analysis was utilized to evaluate the effect edOW, ultrafiltration rate (UFR), interdialytic weight gain (IDWG), age, sex, dialytic vintage, cardiovascular disease, antihypertensive therapy, diabetes, duration of HD, dBW, BMI, mean arterial blood pressure, Kt/V, and protein catabolic rate (PCRn) had on mortality. Results: Age (HR: 1.04; CI: 1.03-1.05; p <0.0001), IDWG (HR: 2.62; CI: 2.06-3.34; p < 0.01), UFR (HR: 1.13; CI: 1.09-1.16; p< 0.01), PCRn (HR: 0.02; CI: 0.01-0.04; p <0.001), and edOW (HR: 2.71; CI: 1.95-3.75; p < 0.02) were independently correlated to survival. The relative receiver operating characteristic curve identified a cutoff value of 0.3 kg for edOW in predicting death. Conclusions: High edOW is independently associated with an increased long-term risk of all-cause and cardiovascular mortality in HD patients. Better survival was observed in patients with edOW <0.3 kg. For patients with higher edOW, longer or more frequent dialysis sessions should be considered in order to prevent the deleterious consequences of excessive body fluid expansion.

Role of Dialysis Sodium Gradient on Intradialytic Hypertension: An Observational Study

Introduction: The causes of intradialytic hypertension (IDHyper) are not well understood and this condition can complicate the clinical management of hemodialysis (HD) patients. Aim: To evaluate the potential role of intradialytic sodium gradient (NaG) on blood pressure values and IDHyper during HD. Patients and Methods: 206 prevalent HD patients on 3 times weekly HD treatment for at least 6 months (dialytic vintage 6-240 months) followed at our institution were studied. Mean age was 68 ± 14 years, 129 were men. For 2 consecutive months (24 HD sessions) after the start of observation, the following variables were evaluated in predialysis after the long interdialysis interval: pre-HD plasma sodium (pNa, mmol/l) and potassium (pK, mmol/l) concentrations (mean value of 8 determinations), pre- and post-HD systolic (SBP, mm Hg) and diastolic (DBP, mm Hg) blood pressure, dry body weight (dBW, kg), interdialytic weight gain (IDWG, kg), ultrafiltration rate (UFR, ml/kg/h), dialysis dose (Kt/V), protein catabolic rate (PCRn, g/kg/day), hemoglobin (Hb, g/dl). SBP, DBP, IDWG, UFR are the mean values of the 24 HD sessions. 76% of patients were on antihypertensive therapy, 171 patients were on bicarbonate HD, and 35 on HDF. Dialysate Na concentration was set at 140 mmol/l in all patients. Duration of HD and the blood and dialysate flow rate were kept constant during observation. Statistical Analysis: Data are expressed as mean ± SD; linear and multiple regression analysis and t test for unpaired data were employed. Significant differences were defined as p < 0.05. Results: Pre-HD pNa was 138.1 ± 2.3 mmol/l, pK 5.0 ± 0.4 mmol/l, dBW 67 ± 14 kg, IDWG 2.9 ± 0.8 kg, UFR 11.2 ± 3.7 ml/kg/h, Kt/V 1.43 ± 0.18, PCRn 1.13 ± 0.17 g/kg/day, and Hb 11.2 ± 0.8 g/dl. Pre- and post-HD SBP values were 139 ± 13 and 134 ± 12 mm Hg (p < 0.0001); pre- and post-HD DBP did not change significantly. A dialysis Na gradient (NaG) (dialysate Na - pre-HD pNa) was calculated, as well as the delta of SBP (ΔSBP) (post-HD SBP - pre-HD SBP). IDHyper was defined as ΔSBP >0. A significant direct correlation was found between NaG and ΔSBP (p < 0.0001) and multiple regression analysis with ΔSBP as dependent variable confirmed the strong correlation with NaG (p < 0.00001). According to ΔSBP behavior, 171 patients (83%) had a decrease or no change in post-HD SBP (group 1; no IDHyper); 35 patients (17%) increased their post-HD SBP (group 2; IDHyper). NaG values were significantly greater in patients in group 2 (group 1: 1.5 ± 2.2 vs. group 2: 3.3 ± 2.5, p < 0.0001). Conclusions: This study shows that the intradialytic ΔSBP is independently and strongly associated with the dialytic NaG. The more positive the NaG (net intradialytic Na gain), the more positive the ΔSBP and IDHyper.

Total Convection Affects Serum β2 Microglobulin and C-Reactive Protein but Not Erythropoietin Requirement following Post-Dilutional Hemodiafiltration

Background: Inflammation and increased erythropoiesis stimulating agents (ESA) requirement are frequently associated in patients on dialysis. On-line hemodiafiltration (ol-HDF), putting together high levels of diffusion, and convection could improve both conditions. However, it is still not known which depurative component plays a major role in determining this result. The aim of the study was to evaluate the role of convection and diffusion on long-term variations of serum β2 microglobulin (Δβ2M), high-sensitive C-reactive protein (ΔhsCRP) concentrations, and ESA requirement (ΔESA) in ol-HDF. Methods: Seventy-three patients prevalent on high flux HD (hfHD) were studied. Thirty-eight patients were switched from hfHD to post-dilutional ol-HDF (Study group); the other 35 patients were considered the Control group. At 6 and 12 months, the effects of ol-HDF and hfHD on ΔhsCRP, ΔB2M, and ΔESA (U/kg/week) were evaluated. Other variables considered were body weight (BW), serum albumin (sAlb), hemoglobin (Hb), and equilibrated Kt/V (eKt/V). Iron therapy and ESA were administered intravenously according to the K/DOQI guidelines in order to maintain transferrin saturation between 20 and 40%, serum ferritin between 150 and 500 ng/ml and Hb between 11 and 12 g/dl. Qb, treatment time and Qd remained constant. Ol-HDF and hfHD were performed using membranes of size 1.9-2.1 sqm. Ultrapure dialysate and substitution fluid were employed in both HDF and HD treatments. Data are expressed as mean ± SD. Paired t test, Mann-Whitney U test, and simple and multiple regression analyses were employed for statistical evaluation. Results: Study group: total convective volume (TCV) was 22.1 ± 1.9 l/session. A significant reduction of hsCRP: from 6.8 ± 7.1 to 2.3 ± 2.4 mg/dl (p < 0.001), β2M: from 36.5 ± 14.4 to 24.7 ± 8.6 mg/dl (p < 0.0001) and ESAdose: from 107 ± 67 to 65 ± 44 U/kg/week (p < 0.005) was observed. No significant variations of Hb, BW and sAlb were seen. A significant inverse correlation was found between TCV and Δβ2M (r = -0.627; p < 0.0001), and TCV and ΔhsCRP (r = -0.514; p < 0.0001); no correlation between TCV and ΔESAdose was observed. No correlation was found between eKt/V and Δβ2M, ΔhsCRP, and ΔESAdose. Multiple regression analysis with ΔESAdose as dependent variable showed ΔhsCRP as the only significantly associated independent factor (p < 0.01). Control group: no significant variations of hsCRP, β2M, and ESAdose were observed over time. Conclusions: Ol-HDF induces a long-term significant reduction in pre-dialysis β2M and hsCRP concentrations. The magnitude of reduction is directly correlated to the amount of TCV achieved but not on eKt/V. The observed reduction in ESAdose requirement is independent either on convection or diffusion, but is directly associated to the concomitant reduction of inflammation.

Steroid-free immunosuppression regime reduces both long-term cardiovascular morbidity and patient mortality in renal transplant recipients.

Abstract:  The aim of this retrospective study was to assess the impact of steroid therapy on cardiovascular disease (CVD) and patient mortality, in 486 on‐CsA renal transplant recipients, with a follow‐up of 9.5 ± 4.3 yr. Two hundred and one patients had their steroids permanently withdrawn at sixth month after transplantation (G1); 285 patients did not (G2) as they were unable (acute rejection after suspension) or unsuitable (because of clinical criteria or immunosuppressive protocols). The CVD considered were coronary artery disease diagnosed by angiography and myocardial infarction. G1 and G2 patients were well‐matched regarding CVD risk factors, except for age (G1: 44 ± 14 yr; G2: 40 ± 12 yr; p < 0.003), incidence of male (G1: 62%; G2: 72%, p < 0.02) incidence of acute rejection (G1: 39%; G2: 83%, p < 0.0001). Both CVD and deaths occurring during the first year of transplantation were excluded from the analysis. At 20 yr, the cumulative probability of developing a CVD, was 3.8% in G1; 23.8% in G2 (p < 0.0005). Patient survival rate was 95% in G1; 62% in G2 (p < 0.003). Mortality caused by CVD was higher in G2 (4.2% vs. 0.5%; p < 0.03). The Cox analysis identified in steroid therapy the main independent risk factors for both CVD (hazard ratio 9.56 p < 0.0001) and patient mortality (hazard ratio 5.99, p < 0.0001). At 10th and 15th year after transplantation, the mean‐daily dose of steroids was 4.2 mg.

Vascular access in older patients: an Italian survey.

BACKGROUND The number of older patients starting 
hemodialysis is continuously increasing. The type of vascular access plays an important role in dialysis treatment, but it can be difficult to create in older patients. METHODS This study compared vascular access survival rates and patient survival rates in older (≥65 years) and younger (<65 years) patients starting hemodialysis in 2 Italian hospitals in 2006-2008. RESULTS The study enrolled 336 patients: 208 ≥65 years and 128 <65 years of age. The vascular accesses used, in order of frequency, were 102 distal arteriovenous fistulas (dAVFs) (49%), 55 midarm AVFs (pAVFs) (26%), 9 arteriovenous grafts (AVGs) (4%) and 42 central venous catheters (CVCs) (20%) in the older patients, and 89 dAVFs (69%), 25 pAVFs (19%), 6 AVGs (5%) and 8 CVCs (6%) in the younger patients. Survival rates of fistula and catheter did not differ between the 2 groups. AVGs failed earlier (p = 0.02) in the older patients. On Cox analysis, age (hazard ratio [HR] = 1.073; p<0.001) and CVC (HR = 4.152; p<0.001) increased the risk of death. CONCLUSION A fistula is the gold standard for hemodialysis vascular access in older patients if judged appropriately.