Giovanni Cancarini

Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments

The Oxford Classification of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as independent predictors of outcome. Whether it applies to individuals excluded from the original study and how therapy influences the predictive value of pathology remain uncertain. The VALIGA study examined 1147 patients from 13 European countries that encompassed the whole spectrum of IgAN. Over a median follow-up of 4.7 years, 86% received renin–angiotensin system blockade and 42% glucocorticoid/immunosuppressive drugs. M, S, and T lesions independently predicted the loss of estimated glomerular filtration rate (eGFR) and a lower renal survival. Their value was also assessed in patients not represented in the Oxford cohort. In individuals with eGFR less than 30 ml/min per 1.73 m2, the M and T lesions independently predicted a poor survival. In those with proteinuria under 0.5 g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2 g/day or more. The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression (net reclassification index 11.5%). The VALIGA study provides a validation of the Oxford classification in a large European cohort of IgAN patients across the whole spectrum of the disease. The independent predictive value of pathology MEST score is reduced by glucocorticoid/immunosuppressive therapy.

Cardiovascular Comorbidity and Late Referral Impact Arteriovenous Fistula Survival: A Prospective Multicenter Study

Autologous arteriovenous fistulas (AVF) have the best 5-yr patency and the lowest complication rate among hemodialysis vascular accesses. However, maturation requirements to optimize survival are unknown. A longitudinal cohort study was conducted to ascertain risk factors for failure, maturation time, and survival of the first AVF. All patients who initiated hemodialysis between January 1, 1997, and December 31, 2002, in three centers were included in this study. Analysis was restricted to patients who received an AVF. Cox regression was used to estimate the association between predictors of interest and primary and secondary AVF survival. Of the 535 patients enrolled (mean age, 66.5 yr; 57.8% male; 26.7% diabetic), 513 (96%) received an AVF. Patients who initiated with catheters (47%) cannulated their AVF earlier (median maturation period, 0.78 versus 1.80 mo; P < 0.001). Median primary and secondary survivals were longer than 50 and 72 mo, respectively. After adjustment for confounding factors, cardiovascular disease (hazard ratio [HR], 1.84; 95% confidence interval [CI], 1.26 to 2.67), utilization earlier than 1 mo after placement (HR, 1.94; 95% CI, 1.34 to 2.82), and referral within 3 mo of dialysis start (HR, 1.55; 95% CI, 1.04 to 2.32) were associated with a reduction in primary AVF survival. Presence of cardiovascular disease (HR, 2.21; 95% CI, 1.38 to 3.55), maturation time <15 d (HR, 2.12; 95% CI, 1.20 to 3.73), and presence of catheters at hemodialysis initiation (HR, 1.79; 95% CI, 1.13 to 2.84) were associated with lower secondary AVF survival. It is concluded that cardiovascular disease, late referral, temporary catheters, and early cannulation are associated with impaired AVF survival. It is recommended that AVF be allowed to mature at least 1 mo before cannulation.

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.

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.

Myocardial Ultrasound Tissue Characterization in Patients with Chronic Renal Failure

The objective of this study was to detect ultrastructural changes in myocardium related to collagen content by ultrasound tissue characterization in patients with chronic kidney disease (CKD) and in uncomplicated hypertensive control subjects. In 25 hemodialysis (HD) patients, in 25 patients with moderate to severe chronic renal failure (CRF), and in 10 patients with essential hypertension (EH) and normal renal function matched for age, BP, and left ventricular mass index, left ventricular anatomy and function were evaluated by conventional echocardiography, and integrated backscatter signal (IBS) was analyzed by acoustic densitometry. IBS mean reflectivity increased from 48% in patients with EH to 56% in patients with CRF to 62% in HD patients (ANOVA P < 0.01). IBS mean cyclic variation was progressively increased from 4.35 +/- 1.2 dB in HD patients to 5.27 +/- 0.90 in patients with CRF to 6.50 +/- 1.6 dB in patients with EH (ANOVA P < 0.01). At multivariate analysis, IBS mean reflectivity was positively related to age and serum creatinine (beta 0.351, P = 0.036; and beta = 0.408, P = 0.016, respectively). IBS mean cyclic variation was inversely related to age and serum creatinine (beta = -0.274, P = 0.025; and beta = -0.262, P = 0.025, respectively) and positively related to left ventricular midwall fractional shortening and transmitral E/A ratio (beta = 0.269, P < 0.05; and beta = 0.314, P < 0.001, respectively). The data support the hypothesis that interstitial collagen deposition may appear early in the course of CKD and suggest that acoustic densitometry may represent a useful tool for the assessment of myocardial tissue changes in patients with CKD.

Hepatocyte growth factor/scatter factor released during peritonitis is active on mesothelial cells.

Peritonitis causes mesothelial detachment that may result in persistent peritoneal denudation and fibrosis. We investigated whether hepatocyte growth factor (HGF), a scatter factor that induces detachment from substrate and fibroblastic transformation of several cell types, is produced during peritonitis and is active on mesothelial cells. We studied 18 patients on peritoneal dialysis, 9 uncomplicated, 9 with peritonitis. HGF was measured in serum, peritoneal fluid, and supernatant of peripheral blood mononuclear cells and peritoneal mononuclear cells. Primary culture of human peritoneal mesothelial cells and the human mesothelial cell line MeT-5A were conditioned with recombinant HGF, serum, and peritoneal fluid. HGF levels were significantly higher in serum and peritoneal fluid of peritonitic than uncomplicated patients. Mononuclear cells of peritonitic patients produced more HGF than cells of uncomplicated patients. Recombinant HGF, serum, and peritoneal fluid of peritonitic patients caused mesothelial cell growth, detachment, transformation from epithelial to fibroblast-like shape, overexpression of vimentin, and synthesis of type I and III collagen. In conclusion, HGF released during peritonitis causes a change in mesothelial cell phenotype and function. HGF may affect the healing process facilitating repair through mesothelial cell growth, but may contribute to peritoneal fibrosis inducing cell detachment with mesothelial denudation and collagen synthesis.

Factors Influencing the Decision to Start Renal Replacement Therapy: Results of a Survey Among European Nephrologists

BACKGROUND Little is known about the criteria nephrologists use in the decision of when to start renal replacement therapy (RRT) in early referred adult patients. We evaluated opinions of European nephrologists on the decision for when to start RRT. STUDY DESIGN European web-based survey. PREDICTORS Patient presentations described as uncomplicated patients, patients with unfavorable clinical and unfavorable social conditions, or patients with specific clinical, social, and logistical factors. SETTING & PARTICIPANTS Nephrologists from 11 European countries. OUTCOMES & MEASUREMENTS We studied opinions of European nephrologists about the influence of clinical, social, and logistical factors on decision making regarding when to start RRT, reflecting practices in place in 2009. Questions included target levels of kidney function at the start of RRT and factors accelerating or postponing RRT initiation. Using linear regression, we studied determinants of target estimated glomerular filtration rate (eGFR) at the start of RRT. RESULTS We received 433 completed surveys. The median target eGFR selected to start RRT in uncomplicated patients was 10.0 (25th-75th percentile, 8.0-10.0) mL/min/1.73 m(2). Level of excretory kidney function was considered the most important factor in decision making regarding uncomplicated patients (selected by 54% of respondents); in patients with unfavorable clinical versus social conditions, this factor was selected by 24% versus 32%, respectively. Acute clinical factors such as life-threatening hyperkalemia refractory to medical therapy (100%) and uremic pericarditis (98%) elicited a preference for an immediate start, whereas patient preference (69%) and vascular dementia (66%) postponed the start. Higher target eGFRs were reported by respondents from high- versus low-RRT-incidence countries (10.4 [95% CI, 9.9-10.9] vs 9.1 mL/min/1.73 m(2)) and from for-profit versus not-for-profit centers (10.1 [95% CI, 9.5-10.7] vs 9.5 mL/min/1.73 m(2)). LIMITATIONS We were unable to calculate the exact response rate and examined opinions rather than practice for 433 nephrologists. CONCLUSIONS Only for uncomplicated patients did half the nephrologists consider excretory kidney function as the most important factor. Future studies should assess the weight of each factor affecting decision making.

The Kind of Vascular Access Influences the Baseline Inflammatory Status and Epoetin Response in Chronic Hemodialysis Patients

Background: Arteriovenous grafts (AVG) and tunneled permanent catheters (TPC) are increasingly being used in hemodialysis (HD) patients. However, their role in baseline inflammatory status has not been fully evaluated. Aim of the study was to evaluate the influence of the current kind of vascular access on the baseline inflammatory status, marked by serum C-reactive protein (CRP), and the response to epoetin therapy in a group of iron-replete HD patients, under steady clinical conditions, without evidence of acute infections and/or inflammatory diseases. Methods: We studied 79 patients who had been on bicarbonate HD for 8–410 months and were receiving epoetin therapy. They all had adequate iron stores and stable hemoglobin (Hb) levels. Exclusion criteria were fever, signs of infection, white blood cell count (WBC) >10 × 1,000/µl, for at least 4 weeks before study. 48 patients (group A) had arteriovenous fistula (AVF), 18 patients (group B) AVG, 13 patients (group C) TPC. CRP, Hb, transferrin saturation, serum ferritin, WBC, serum albumin, protein catabolic rate, Kt/V, and epoetin dose (U/kg body weight/week) were measured. CRP values were log-transformed to normalize the distribution. Results: Log-transformed CRP values among the 3 groups were significantly different: group A 1.81 ± 0.48; group B 2.12 ± 0.50, and group C 3.00 ± 0.25 (group A vs. B p < 0.003; group B vs. C p < 0.001; group A vs. C p < 0.0001). CRP and the epoetin dose were directly correlated (r = 0.519; p < 0.0001). The epoetin doses among the 3 groups were significantly different. Multiple regression analysis confirmed AVG and TPC as factors independently influencing CRP levels. Conclusions: AVG and TPC have a higher degree of chronic inflammation than AVF. The epoetin requirement is increased in TPC and AVG compared with AVF.

Predicting the risk of diabetic retinopathy in type 2 diabetic patients.

AIMS Diabetic retinopathy (DR) is often asymptomatic even in its more advanced stages. Timely and repeated screening for DR avoids a late diagnosis of DR, but the high number of diabetic patients precludes a frequent screening; thus, the need for a method to identify patients at higher risk for DR becomes crucial. METHODS A prospective analysis of 5034 type 2 diabetic patients followed from 1996 to 2007 and not affected by retinopathy at the time of the recruitment was performed. Patients were randomly divided (ratio 2:1) into two groups: the train data set and the test set (3327 and 1707 patients, respectively). Factors associated with the occurrence of DR were assessed by the Coxs proportional hazard model. RESULTS Duration of diabetes, glycosylated hemoglobin, systolic blood Pressure, male gender, albuminuria and diabetes therapy other than diet were all significantly associated with the occurrence of DR. CONCLUSIONS The nomogram could help in ranking the type 2 diabetic patients at higher risk to develop DR and thus with a need for more frequent ophthalmologic checks, without enhancing neither the time nor the costs.

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.