Alberto Albertazzi

Serum Levels of Soluble Adhesion Molecules in Chronic Renal Failure and Dialysis Patients

Besides cell-bound adhesion molecules, which are of fundamental importance to a large number of physiological and pathological processes, soluble forms of adhesion molecules have been detected in the circulating blood in recent years. Circulating soluble adhesion molecules appear to be biologically active, and raised levels have been reported in a variety of disorders. In the present study, we used ELISA to measure the serum levels of four soluble adhesion molecules in 23 undialyzed patients with chronic renal failure (CRF), 13 patients on continuous ambulatory peritoneal dialysis (CAPD), 17 on chronic hemodialysis (HD) and 18 healthy controls having a similar mean and distribution of ages. The investigated soluble (s) molecules included intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1), sE-selectin and sP-selectin. sICAM-1 was found to be elevated in patients with CRF (p < 0.05), on CAPD (p < 0.02) and HD (p < 0.0001) compared with the controls but levels did not differ between the three patient groups. The higher sVCAM-1 values found in CRF (p < 0.02), CAPD (p < 0.05) and HD (p < 0.0001) as compared to controls again failed to differentiate the three groups of patients. Soluble E-selectin was also raised in the three groups (p < 0.0001) with no difference between them. Increased sP-selectin was found in CRF (p < 0.05), CAPD (p < 0.02) and in HD patients (p < 0.0001) compared to controls, and levels in HD were significantly higher (p < 0.02) than in CRF patients. Predialysis serum molecule levels did not differ between HD patients treated with cuprophan or with polyacrylonitrile dialyzers. HD sessions with both dialyzers had no effect on sICAM-1, while a decrease (p < 0.02) in sP-selectin was found after dialysis with cuprophan. In undialyzed patients with CRF, regression analysis showed a strong linear correlation between serum creatinine and serum levels of each soluble molecule. These results demonstrate that serum levels of soluble adhesion molecules ICAM-1, VCAM-1, E-selectin and P-selectin are elevated in both undialyzed patients with CRF and patients on CAPD or HD. The elevated serum levels of these proteins probably reflect inadequate clearance as well as enhanced synthesis/release.

Genotype-Renal Function Correlation in Type 2 Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder that affects approximately 1 in 1000 live births. Mutations of two genes, PKD1 and PKD2, account for the disease in approximately 80 to 85% and 10 to 15% of the cases, respectively. Significant interfamilial and intrafamilial renal disease variability in ADPKD has been well documented. Locus heterogeneity is a major determinant for interfamilial disease variability (i.e., patients from PKD1-linked families have a significantly earlier onset of ESRD compared with patients from PKD2-linked families). More recently, two studies have suggested that allelic heterogeneity might influence renal disease severity. The current study examined the genotype-renal function correlation in 461 affected individuals from 71 ADPKD families with known PKD2 mutations. Fifty different mutations were identified in these families, spanning between exon 1 and 14 of PKD2. Most (94%) of these mutations were predicted to be inactivating. The renal outcomes of these patients, including the age of onset of end-stage renal disease (ESRD) and chronic renal failure (CRF; defined as creatinine clearance < or = 50 ml/min, calculated using the Cockroft and Gault formula), were analyzed. Of all the affected individuals clinically assessed, 117 (25.4%) had ESRD, 47 (10.2%) died without ESRD, 65 (14.0%) had CRF, and 232 (50.3%) had neither CRF nor ESRD at the last follow-up. Female patients, compared with male patients, had a later mean age of onset of ESRD (76.0 [95% CI, 73.8 to 78.1] versus 68.1 [95% CI, 66.0 to 70.2] yr) and CRF (72.5 [95% CI, 70.1 to 74.9] versus 63.7 [95% CI, 61.4 to 66.0] yr). Linear regression and renal survival analyses revealed that the location of PKD2 mutations did not influence the age of onset of ESRD. However, patients with splice site mutations appeared to have milder renal disease compared with patients with other mutation types (P < 0.04 by log rank test; adjusted for the gender effect). Considerable renal disease variability was also found among affected individuals with the same PKD2 mutations. This variability can confound the determination of allelic effects and supports the notion that additional genetic and/or environmental factors may modulate the renal disease severity in ADPKD.

Everolimus with very low-exposure cyclosporine a in de novo kidney transplantation: a multicenter, randomized, controlled trial.

Background. In combination with everolimus (EVL), cyclosporine A (CsA) may be used at low exposure, so reducing the risk of renal dysfunction in renal transplant recipients (RTR). We evaluated whether higher exposure of EVL could allow a further reduction of CsA. Methods. De novo RTR were randomized to standard exposure EVL (C0 3–8 ng/mL) with low-concentration CsA (C2 maintenance levels 350–500 ng/mL, group A) or higher EVL exposure (C0 8–12 ng/mL) with very low-concentration CsA (C2 maintenance levels 150–300 ng/mL, group B). The primary endpoints were 6-month creatinine clearance (CrCl) and biopsy-proven acute rejection (BPAR) rate. After 6 months, patients were followed up (observational extension) to 12 months. Results. Two hundred eighty-five RTR (97% from deceased donors) were enrolled. Two patients per group died (1.4%). The 6-month death-censored graft survival was 90.2% in group A and 97.9% in group B and was unchanged at 12 months (P=0.007). There was no significant difference between groups at 6 months in CrCl (59.9 vs. 57.8 mL/min) and BPAR rates (14.7% vs. 11.9%) and also at 12 months (CrCl 62.5±20.7 vs. 61.3±22.0 mL/min, BPAR 14.7% vs. 14.1%). No significant differences were seen in treated acute rejections, steroid-resistant acute rejections, treatment failures, or delayed graft function, although there was a trend to better results in group B. Conclusions. EVL given at higher exposure for 6 months plus very low CsA concentration may obtain low acute rejection rate and good graft survival in De novo renal transplantation. However, there was no difference between groups in CrCl.

Kidney preservation with university of Wisconsin and Celsior solution: a prospective multicenter randomized study.

Background. Although the University of Wisconsin (U.W.) solution continues to be the most commonly used for intra-abdominal organs, a new solution, Celsior, already used for heart and lungs, has been proposed for kidney and liver preservation. The aim of this research was to assess the effect of Celsior as compared with U.W. on immediate graft function and a 2-year follow-up of kidney transplants. Methods. A prospective multicenter randomized study was designed to evaluate the efficacy of the Celsior solution in the clinical preservation of the kidney. In this report, we present the data collected as of September 2000. One hundred donors were included in the trial resulting in 187 renal transplants. Ninety-nine kidneys were stored in Celsior solution and 88 in U.W. solution. The groups were comparable with regard to donor and recipient characteristics. Results. Delayed graft function occurred in 31.3% of the Celsior group and in 33.9% of the U.W. group (P =n.s.). Mean serum creatinine levels and mean daily urinary output were also comparable. Two year graft survival in kidneys preserved with Celsior was 84% as compared with 75% for U.W.-preserved kidneys without any significant statistical difference. Conclusions. Our data show that the preservation of kidneys in Celsior solution in a clinical setting is equivalent to that of U.W. solution. When using Celsior during multiple-organ donor harvesting it would be possible to perform an in situ flush of all intra-abdominal and intrathoracic organs with a single cold storage solution.

Neutrophil Reactive Oxygen Species Production during Hemodialysis: Role of Activated Platelet Adhesion to Neutrophils through P-Selectin

Platelet interaction with leukocytes can occur to a significant degree during hemodialysis, but it remains to be determined what pathophysiological consequences stem from the intradialytic formation of platelet-leukocyte coaggregates. By the use of flow cytometry techniques, this study was set out to analyze intradialytic platelet-neutrophil coaggregate formation and neutrophil hydrogen peroxide production from 10 end-stage renal disease patients each dialyzed with cuprophane and polyacrylonitrile membranes. Platelet-neutrophil coaggregates increased during dialysis with cuprophane, whereas no changes occurred with polyacrylonitrile membranes. Dialysis with cuprophane, unlike that with polyacrylonitrile, also resulted in a significant increase in neutrophil hydrogen peroxide production 10 min after dialysis initiation which persisted at significantly higher levels than predialysis values through the first 20 min. We found that the increased hydrogen peroxide production by neutrophils essentially occurred in concomitance with neutrophil-platelet coaggregation. Intracellular fluorescence representing hydrogen peroxide formation significantly increased through the first 20 min of cuprophane dialysis in neutrophils aggregated to platelets. By contrast, no change occurred in neutrophils not aggregated to platelets. Neutrophils which had formed aggregates with platelets produced higher hydrogen peroxide levels, as assessed by significantly higher fluorescence values, than non-aggregate-forming neutrophils at all time points tested. The phenomenon was duplicated in vitro when ADP-activated normal platelets were incubated with neutrophil cells but was largely inhibited when ADP-activated platelets were treated with anti-P-selectin antibody before incubation with neutrophils. These results strongly suggest that platelet-neutrophil aggregates occurring during hemodialysis, representing cell-cell interactions with pathophysiological effects, may serve as a new parameter to assess biocompatibility.

Effect of a continuous erythropoietin receptor activator (C.E.R.A.) on stable haemoglobin in patients with CKD on dialysis: once monthly administration*

ABSTRACT Aims: This Phase II study aimed to determine the optimal dose and administration schedule of continuous erythropoietin receptor activator (C.E.R.A.) given subcutaneously (SC) in patients receiving dialysis converting directly from SC epoetin therapy 1–3 times/week. An extension phase examined long-term safety and efficacy. Methods: Patients were assigned to one of three C.E.R.A. dose groups determined by multiplying the previous weekly dose of epoetin by one of three ratios (0.4/150, 0.8/150, 1.2/150 for groups A, B and C, respectively). Within each group, patients were randomized to once weekly (QW), once every 3 weeks (Q3W) and once monthly (Q4W) schedules. Dose adjustments were not permitted for the first 6 weeks. The core study period was 19 weeks (21 weeks in the Q4W cohorts). Patients could enter a 12‑month extension period at the same schedule, aiming to maintain haemoglobin (Hb) at 11–12 g/dL. Results: 137 patients entered the core period, and 62 continued into the extension period. A dose-dependent relationship was seen in the primary efficacy variable, change in Hb standardized to a 6 week period ( p < 0.0001), but effect was independent of schedule. Hb levels were maintained throughout the study, with few dose changes. C.E.R.A. was generally well tolerated and the most frequent adverse event was hypotension. Conclusion: The results suggest that SC C.E.R.A. at up to once monthly intervals provides stable maintenance of Hb levels in dialysis patients converting directly from epoetin 1–3 times/week. Achieving tight Hb control with few dose adjustments at extended administration intervals may offer health benefits and improvements in resource management. Trial registration: ClinicalTrials.gov identifier: NCT00364832.

Residual Renal Function and Effective Rehabilitation in Chronic Dialysis

The results of a 1-7 years follow-up of multiple processed and recorded semiquantitative parameters in 148 cases of chronic uremia on regular dialysis treatment (RDT) are reported. Patients were grouped according to different levels of residual creatinine clearance (CCr) at the beginning of treatment (0-5, 5-15, and 15-21 ml/min). Regardless of a possible return to work and reasonable quality of life, patients on RDT with 0-5 ml/min CCr invariably present a worsening in various subclinical parameters semiquantitatively evaluated (bone biopsies; nerve conduction velocity; glucose A-V, etc.). In patients with 5-15 ml/min CCr better results are found. In patients with residual CCr above 15 ml/min, impairment in several parameters is hardly evident and even after several years of dialysis may still remain minimal. These results seem of importance as far as the effective and not the apparent dialysis rehabilitation is concerned.

The Kidney Donor Profile Index (KDPI) of marginal donors allocated by standardized pretransplant donor biopsy assessment: distribution and association with graft outcomes.

Pretransplant donor biopsy (PTDB)‐based marginal donor allocation systems to single or dual renal transplantation could increase the use of organs with Kidney Donor Profile Index (KDPI) in the highest range (e.g. >80 or >90), whose discard rate approximates 50% in the United States. To test this hypothesis, we retrospectively calculated the KDPI and analyzed the outcomes of 442 marginal kidney transplants (340 single transplants: 278 with a PTDB Remuzzi score <4 [median KDPI: 87; interquartile range (IQR): 78–94] and 62 with a score = 4 [median KDPI: 87; IQR: 76–93]; 102 dual transplants [median KDPI: 93; IQR: 86–96]) and 248 single standard transplant controls (median KDPI: 36; IQR: 18–51). PTDB‐based allocation of marginal grafts led to a limited discard rate of 15% for kidneys with KDPI of 80–90 and of 37% for kidneys with a KDPI of 91–100. Although 1‐year estimated GFRs were significantly lower in recipients of marginal kidneys (−9.3, −17.9 and −18.8 mL/min, for dual transplants, single kidneys with PTDB score <4 and =4, respectively; p < 0.001), graft survival (median follow‐up 3.3 years) was similar between marginal and standard kidney transplants (hazard ratio: 1.20 [95% confidence interval: 0.80–1.79; p = 0.38]). In conclusion, PTDB‐based allocation allows the safe transplantation of kidneys with KDPI in the highest range that may otherwise be discarded.

Contrast-Enhanced Sonography in Early Kidney Graft Dysfunction

OBJECTIVES The aim of this study was a comparison of contrast-enhanced sonography (CEUS) and power Doppler ultrasound (US) findings in renal grafts within 30 days posttransplantation. METHODS A total of 39 kidney recipients underwent CEUS (SonoVue bolus injection) and US examinations at 5 (T0), 15 (T1), and 30 (T2) days after grafting. The results were correlated with clinical findings and functional evolution. Fourteen patients displayed early acute kidney dysfunction: 10 had acute tubular necrosis (acute tubular necrosis [ATN] group); four acute rejection episodes (ARE group); 25 with normal evolution (as control, C group). Renal biopsies were performed to obtain a diagnosis in the four ATN cases and in all ARE patients. Creatinine and estimated glomerular filtration rate were used as kidney function parameters. CEUS analysis was performed both on cortical and medullary regions while US resistivity indexes (RI) were obtained on main, infrarenal, and arcuate arteries. From an analysis of CEUS time-intensity curves, we computed peak enhancement (PEAK), time to peak (TTP), mean transit time (MTT), regional blood flow (RBF) and volume (RBV), and cortical to medullary ratio of these indies (RATIO). RESULTS An increased RI was present in the ATN and ARE groups as well as a reduced PEAK and RBF. RATIO-RBV and RATIO-MTT were lower than C among ATN cases, while TTP was higher compared to C in ARE. No statistical difference was evidence for RI between ATN and ARE groups. MTT (T0) was significantly related to creatinine at follow-up (T2). CONCLUSIONS US and CEUS identified grafts with early dysfunction, but only some CEUS-derived parameters distinguished ATN from ARE, adding prognostic information.

Psychological factors associated with medication adherence following renal transplantation

Abstract:  Background:  A relationship exists between non‐adherence and clinical outcomes in health care, including renal transplantation. The aim of this study was to identify the psychological variables associated with non‐adherence to medication after renal transplantation.