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Background: The use of alemtuzumab as induction immunosuppression for renal transplantation introduces the possibility of long-term tacrolimus monotherapy, avoiding maintenance with both corticosteroids and mycophenolate mofetil (MMF)., Methods: We conducted a single-center, prospective, open-label, randomized controlled trial comparing two steroid avoidance regimens between December 2006 and November 2010. One hundred and sixteen adult patients were randomized to either basiliximab induction followed by tacrolimus and MMF maintenance or to alemtuzumab induction followed by tacrolimus monotherapy. The primary endpoint was noninferiority of isotopic glomerular filtration rate at 1 year; secondary endpoints included patient and graft survival, incidence of delayed graft function, and incidence and severity of biopsy-proven acute rejection., Results: The two groups were well matched for all baseline demographics. Isotopic glomerular filtration rate was comparable between the groups at 1 year (57±26 mL/min for alemtuzumab group and 53±21 mL/min for basiliximab group; P=0.42). Secondary endpoints were also similar between the groups. The rate of biopsy-proven acute rejection by 12 months was lower in the alemtuzumab group (n=6 vs. n=14 in basiliximab arm) just reaching statistical significance (P=0.049); however, a single extra case in the alemtuzumab arm included when considering clinically treated rejection removes this significance (P=0.082). Similar rates of cardiovascular, infective, and neoplastic complications were observed in both groups. Forty-seven (81.0%) of the patients in the alemtuzumab group remained on tacrolimus monotherapy at 12 months., Conclusions: Renal transplantation with alemtuzumab induction followed by tacrolimus monotherapy leads to good graft and patient outcomes, with no major differences detected compared with basiliximab induction and tacrolimus/MMF maintenance at 1 year.

Background: Late-onset proteinuria after renal transplantation has been universally associated with poor allograft outcomes. However, the significance of early low-grade posttransplant proteinuria remains uncertain., Methods: We analyzed the effect of proteinuria 3 months posttransplantation on death-censored graft loss, death with a functioning graft, vascular events within the graft's life, and estimated glomerular filtration rate at 5 years. Four hundred seventy-seven renal transplants from a single center (1988-2003) with a mean follow-up of 122 months were divided into four groups based on the median protein creatinine ratio (PCR) during the 3rd posttransplant month (PCR<0.15 [group 1, n=85]; PCR 0.15-0.5 [group 2, n=245]; PCR 0.5-1.00 [group 3, n=96]; PCR>1.00 [group 4, n=51]). Cox proportional hazards analysis was performed to study the impact of proteinuria on the various outcomes., Results: Multivariate analysis revealed that even low-level proteinuria at 3 months predicted death-censored graft failure (group 1 [reference]--hazard ratio [HR]=1, group 2--HR=7.1, group 3--HR = 10.5, group 4--HR 16.0; P=0.001). The impact on death and the occurrence of vascular events was only significant for group 4 (HR: 2.6; P=0.01 for death and HR: 2.2; P=0.04 for vascular events). Estimated glomerular filtration rate at 5 years was group 1, 48.5 mL/min; group 2, 41.2 mL/min; group 3, 31.1 mL/min; and group 4, 24.5 mL/min (P<0.001). Continued observation of group 2 to 1 year revealed adverse outcomes with increasing proteinuria., Conclusions: Low-grade proteinuria at 3 months is associated with adverse clinical outcomes and identifies high-risk group of patients who may benefit from further intervention.

Introduction: With the worldwide shortage of donors, extra lengths are ongoing to enlarge the donor pool. One means has been a greater use of "expanded criteria donor" (ECD) grafts. A major concern regarding ECD kidneys is poor long-term graft survival. The aims of this study were to determine whether ECD grafts, as defined by the United Network for Organ Sharing, had a negative impact on graft survival and to identify the principle donor and recipient factors that influenced graft survival in our patient cohort., Methods: We analyzed all deceased donor renal transplants in our unit from January 1995 to October 2005, in total 1,053 transplants., Results: ECD grafts (United Network for Organ Sharing criteria) demonstrated higher rates of delayed graft function and higher early mean creatinine levels. However, there was no significant difference in 5-year graft survival. Multivariate analysis of our patient group identified donor hypertension and ischemic heart disease (IHD) as independent predictors of poor graft survival. Recipient age was significant on univariate but not on multivariate analysis. However, although younger recipients maintained acceptable 5-year graft survival despite donor hypertension, IHD, or a combination of both, these factors significantly reduced graft survival in older recipients., Conclusion: Although ECD grafts had slightly worse function, 5-year survival was comparable with standard grafts in all recipients. Donor hypertension, IHD, or a combination of both significantly reduced graft survival in older recipients, not evident in younger patients. We discuss the possible factors for improved outcome with ECD grafts in our patients and the implications of our patient analysis.

Vascular disease and chronic allograft nephropathy have prompted re-evaluation of steroids and calcineurin inhibitors (CNIs) in renal transplantation. Sirolimus (SRL) can facilitate early CNI withdrawal. We report on the Early CNI and Steroid Elimination in Leeds (ECSEL) study, which was terminated early due to poor tolerability of SRL. Basiliximab/methylprednisolone induction was used, then 2 months of tacrolimus (TAC) and mycophenolate mofetil (MMF) treatment. A total of 51 patients were randomized to continue TAC/MMF or switch to SRL/MMF. In ECSEL1, patients were switched at 2 months (n=10). In ECSEL2, SRL was introduced at months 4-6 and TAC was tapered (n=13). Median overall follow up was 701 days. All 10 ECSEL1 and 10 of 13 (77%) ECSEL2 patients discontinued SRL due to adverse events, including leucopenia, rash, mucosal ulceration, arthralgia, and possible pneumonitis. Mean end-of-study creatinine was comparable in all groups. Sirolimus should be used with caution in complete CNI and steroid withdrawal, due to the resultant intolerable adverse event profile.

Background: Renal transplant recipients have an increased risk of cardiovascular disease compared with age- and gender-matched controls. It is recommended that "high-risk" patients are treated with hydroxymethylglutaryl CoA reductase inhibitors to reduce cholesterol levels., Method: We evaluated the effect of a computer-based decision support algorithm in delivering patient-specific prompts to manage cholesterol in renal transplant outpatients. Data were analyzed retrospectively for a 2-year period with attention to changes in cholesterol levels, prescribing patterns of statins, and causes of underperformance., Results: At baseline, 36.7% of patients achieved a total serum cholesterol level less than 5.0 mmol/L, compared with 67.2% at 2 years, with mean values of 5.6+/-0.1 mmol/L and 4.8+/-0.1 mmol/L (P<0.0001). At baseline, 24% of the patients were receiving statin therapy, increasing to 61% at 2 years. There were no significant changes in creatinine phosphokinase, trough cyclosporine levels, or total cyclosporine dose. Alkaline phosphatase levels increased (166.1+/-3.6-184.6+/-6.1 mmol/L, P=0.009), but remained within the normal clinical range; creatinine clearance increased (58.6+/-1.0-61.0+/-1.2 mL/min, P=0.05). For patients followed concurrently in two units without the algorithm, serum cholesterol measurements decreased from 5.57 mmol/L and 5.34 mmol/L to 5.31 mmol/L and 5.27 mmol/L, respectively (P=0.05), both higher than that achieved contemporaneously at St. James's. Underperformance depended less on medical noncompliance than with systematic features of the methodology and patient preference/collaboration with treatment., Conclusions: The introduction of the algorithm coincided with a significant reduction in cholesterol levels, an increase in the number of patients receiving appropriate therapy, and no serious adverse effects. Our results illustrate the positive effect of computer-generated prompts and decision support software.

Background: Use of intravenous (IV) immunoglobulin (Ig) to obtain panel reactive antibody (PRA) A reduction in sensitized patients has been widely reported. Because no IVIg preparation is formulated specifically for this purpose, the authors have sought to determine whether, through laboratory testing, they could guide the rational choice of product for clinical use., Methods: Using a flow cytometric approach, the authors have quantitatively determined the capacity of 22 different IVIg preparations to cause PRA reduction., Results: IVIg preparations showed considerable variability in their individual capacity to reduce serum PRA. Protein-A pretreatment of IVIg preparations was found to reduce their capacity to cause PRA reduction., Conclusion: Laboratory screening of IVIg preparations provides a rational basis for the selection of product for administration to patients in whom the aim is to produce a PRA reduction. Experiments involving protein-A treatment of IVIg preparations indicate that immunoglobulin G is the principal factor involved in the abrogation of serum reactivity.

Background: Population data indicate that cyclosporine (CsA)-based immunosuppression has had relatively little effect on late renal allograft loss. For individual patients, however, the degree and variability of CsA exposure may be of prognostic importance. This case-control study has examined the contribution of these and other factors to the development of chronic allograft nephropathy (CAN) in patients receiving follow-up care in our unit., Methods: The electronic record was interrogated to identify adult, CsA-treated renal transplant recipients with CAN (group A) and CsA-treated controls with stable graft function for a minimum of 4 years posttransplantation and serum creatinine less than 200 micromol/L (group B). Age at transplantation, gender, years posttransplantation, donor source and age, kidney preservation time, human leukocyte antigen match, occurrence of delayed graft function, immunosuppressive regimen, weight-adjusted maintenance CsA dose, and coefficient of variation (CvarC0 ) of dose-adjusted CsA trough blood levels (C0/dose) were recorded (CvarC0 =[SD (C0/dose)/mean (C0/dose)]x100). Statistical analysis included binary logistic regression analysis., Results: Three transplant recipients were excluded because of known noncompliance with immunosuppressive medication, leaving a study population of 102 patients. Recipient age (AB, <0.01) and CsA dose (A>B, <0.02) were significantly different by univariate analysis. Only low recipient age ( P<0.001) and high CvarC0 ( P<0.02) were independent predictors of CAN in the regression model., Conclusion: Younger renal transplant recipients and those with highly variable CsA exposure are predisposed to developing CAN. Investigation of such patients may reveal correctable factors such as poor treatment compliance and lead to appropriate interventions.

Background: There is a significant Indo-Asian community in Yorkshire. The rate of end-stage renal failure is disproportionately high in this ethnic group. There have not been any large studies of this ethnic minority's access to and outcome after cadaveric renal transplantation., Methods: Three local cohorts were studied: 846 adult patients (9.1% Asian) who started renal replacement therapy 1990-1994, 822 adult patients (11.4% Asian) registered on the transplant waiting list 1985-1994; and 608 adult patients (8.6% Asian) transplanted 1985-1994., Results: At 1 year from the start of dialysis, 34% of Asian and 31% of non-Asian patients were registered onto the waiting list. After adjustment for age in a multifactorial model, Asian patients were less likely to be listed (relative risk, 0.68), although this did not reach statistical significance (P=0.06). There was a significant difference in graft rate between the groups: at 3 years 72% of non-Asians versus 55% of Asians had been transplanted from the waiting list (P<0.001). For those transplanted, HLA matching was superior for white patients: 34% versus 20% of pairings achieved a 000 mismatched or favorably matched graft (P<0.05). Transplant survival at 5 years was 71% in the non-Asian and 58% in the Asian patients (P=0.07). Asian cadaveric donation was identified in 2 of 608 transplants during a 10-year period., Conclusion: Asian patients gained access to the transplant waiting list at a similar rate to the non-Asian white majority. Because of difficulties with HLA matching, Asian patients were significantly disadvantaged in receiving a transplant once listed, and there was a trend towards reduced posttransplant survival. Cadaveric donation was uncommon from within the Asian community; the reasons for which are likely to be complex.

Transforming growth factor beta (TGF beta 1) is a prosclerotic cytokine implicated in several disease processes. Recent reports have demonstrated a role for TGF beta 1 in experimental models of glomerulonephritis, focusing attention on the relevance of TGF beta to renal fibrogenesis in human disease. The study reported here was designed to investigate whether circulating, active TGF beta 1 could be detected in renal allograft recipients, and whether plasma levels correlated with episodes of rejection, a process involving both inflammation and fibrosis. We have developed an ELISA assay for active TGF beta 1 using commercially available antibodies, and measured plasma levels in 43 healthy controls, 11 patients with membranous nephropathy (MN) and impaired renal function, 17 transplant recipients with stable renal function, 27 patients with acute cellular rejection, 7 patients with chronic vascular rejection, and 10 patients with acute tubular necrosis and/or cyclosporine toxicity. In the last three groups diagnoses were biopsy-proved, and all samples were collected at the time of biopsy. TGF beta 1 was also measured in urine samples from 8, 11, 0, 9, 4, and 7 individuals, respectively, from each group. TGF beta 1 was not detected in plasma from any of the healthy controls or any of the MN patients, (detection limit of assay 0.1 ng/ml). By comparison, it was significantly increased in all groups of transplant recipients (unpaired t test, P < 0.01), but there were no significant differences between the transplant groups. Plasma TGF beta 1 level did not correlate with renal function (estimated by either serum creatinine or reciprocal creatinine), kidney donor age, recipient age, time since transplantation, or cyclosporine plasma trough level. TGF beta 1 was found in every urine sample tested from healthy controls, with a range from 1 ng/ml to 35 ng/ml. Among the 20 transplant patient urines tested, 2 were negative, 18 were positive but within the range determined for the healthy controls. There were no significant differences between the groups.

The object of the study presented here was to test whether measurement of blood or urine IL-6 or TNF-alpha could discriminate between the most common causes of renal allograft dysfunction, thus avoiding a biopsy. We present data here in which serum and urine IL-6 and TNF-alpha levels were measured at the same time as a diagnostic renal biopsy was performed. TNF-alpha and IL-6 were measured by sandwich ELISA. Thirty patients had acute cellular rejection, 18 had acute tubular necrosis/CsA toxicity, and 9 had chronic vascular rejection. There was no difference in the levels of IL-6 measured in serum and urine among the three categories of graft dysfunction (t < 1.31; P > 0.20). A similar result with considerable overlap between the groups was seen with TNF-alpha (t < 0.78; P > 0.44). Stratifying the results according to the precise immunosuppressive therapy, CsA dose, body weight, CsA level, body temperature, serum creatinine, the number of previous rejection episodes, original cause of renal failure, or the time elapsed since the transplant did not alter the results. The ratio of serum IL-6 divided by trough CsA level was compared among the three groups and there was no significant difference among them (t < 1.79; P > 0.09). In the light of our results, we therefore suggest that previously published reports of the clinical value of serum and or urine IL-6 and or TNF-alpha in relatively small numbers of patients, not all of whom had been biopsied and in whom rigorous clinical and statistical criteria had not been met, should be viewed with caution.

We examined the influence of donor and recipient age as well as close donor and recipient age matching by analysis of the actuarial survival of 397 consecutive first cadaveric renal transplants carried out in the years 1987 to 1990. Graft failure was defined as return to dialysis, transplant nephrectomy, or death of the recipient from any cause. Overall 1-, 2-, and 3-year actuarial graft survival was 87, 84, and 79%. No effect on graft survival in adult patients was seen of advanced age of either donor or recipient. The source of the donor whether from within or outside the North Western Regional Health Authority did not influence outcome whatever the donor age. Results from patients in whom the donor was within 5 years of the recipient's age were no different from those obtained when the age difference was greater than 5 years. These data do not support the hypothesis that close age matching influences graft survival. Age matching need not be used as a recipient selection criterion. As neither recipient nor donor age influenced early graft survival, consideration should be given to increasing the average age of both donors and recipients.