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Low-grade proteinuria and systolic hypertension (SHT) are risk factors for allograft failure. Both are dynamic variables and their relationship is not independent. We have simultaneously analyzed the effects of proteinuria and SHT on graft outcomes in 805 adult Kidney Transplant Recipients and impact of their changes over time. Proteinuria and systolic blood pressure (SBP) were recorded for years 1 and 3 posttransplantation. Subjects with proteinuria >1 g/day were excluded. Patients were divided into groups based on proteinuria (Absent(A) <150 mg/day or low-grade(P)150 mg-1 g/day) and blood pressure (Normotensive-SBP <140 mmHg or hypertensive-SBP ≥ 140 mmHg). Graft survival was assessed in all four groups over 10 years by multivariate analysis. At the three annual time points (Year 1, 2 and 3) hypertensive patients with proteinuria had the worst graft survival. Patients with persistent proteinuria between years 1-2 and 2-3 had the poorest graft survival with an improvement if proteinuria regressed (P-A), especially in the Hypertensive group. The impact of proteinuria was highest in persistently hypertensive patients between years 1-3. Thus both proteinuria and SHT were associated with poor graft survival and the combination of the two led to the worst outcomes. Importantly, SHT was associated with significantly worse outcomes in patients with proteinuria. Patient cohort with SHT and low-grade proteinuria represent a selective group that might benefit from intervention., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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.

Donation after cardiac death (DCD) provides grafts in renal transplantation but is associated with increased early graft dysfunction. Cold ischemia time (CIT) is a factor that is thought to affect outcomes in renal transplantation. We sought to assess the impact of the length of CIT among our DCD cohort of renal transplants performed between April 2002 and December 2009. Since the median CIT was 15.5 hours, we formed two groups CIT < 15.5 (n = 100) and CIT > 15.5 hr (n = 98). We demonstrated an increased incidence of DGF among the extended CIT group, but the long outcomes and the mean graft function were otherwise comparable. In conclusion, CIT affects early graft function; every effort should be made to minimize it in renal transplantation using DCD kidneys., (Copyright © 2010 Elsevier Inc. All rights reserved.)

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.

Aims: To determine whether measurement of soluble CD30 (sCD30) levels predicts for early rejection in a cohort of first deceased kidney transplant recipients., Methods: Pre-transplant serum samples were analysed for sCD30 levels using a commercial ELISA kit (Biotest). A 100 U/ml cut-off for "high sCD30" was applied. Clinical outcome parameters were biopsy-proven rejection episodes, creatinine levels and glomerular filtration rate., Results: In the cohort of patients who experienced at least one episode of rejection in the first 6 months post-transplant, levels of pre-transplant sCD30 were significantly higher than in those who did not experience rejection. Despite this association, the occurrence of a high sCD30 level did not predict for rejection on an individual basis., Conclusions: The prognostic value of pre-transplant sCD30 testing is diminished by the large number of patients with high sCD30 levels who do not develop rejection. Although this limits the utility of the test in informing clinical management of individual patients, a high pre-transplant sCD30 level should still be considered a risk factor for poorer outcome.

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.

Renal transplant recipients are at increased risk for development of nonmelanoma skin carcinoma, owing to a number of causes, including ultraviolet exposure. It has been shown that, despite education, there is poor compliance by these patients with the advice given for protecting their skin from the sun. This repeat study was conducted to determine whether there had been an improvement in compliance over the last 6 years. Two hundred twenty-seven patients were invited to complete the questionnaire used in the previous study. This questionnaire was designed to establish whether patients understood the need for extra care, whether they recalled any education about protective measures, and what actual measures were taken. There was a significant increase in the proportion of patients taking appropriate precautions. Hence there has been a significant improvement in the compliance of renal transplant recipients in Yorkshire with skin protection measures since this was originally audited in 1998.

The urological complications of renal transplantation are well documented. In 1990, our experience of 507 consecutive renal transplants using the Leadbetter-Politano technique, which was unsplinted in the vast majority of patients, had a ureteric complication rate of 7.7%. Here, we report the long-term incidence and management of our ureteric complications in 1186 consecutive renal transplants done over the following 11 years using an extravesical onlay stented ureteroneocystostomy. We report a considerable reduction in the urological complications of renal transplantation to 3.8%. Furthermore, we were able to use percutaneous radiological techniques to salvage the majority (84.7%) of ureteric complications. Recourse to surgery was required rarely but enabled salvage of all treatment failures.

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: This study was conducted to assess the effect of immunosuppression conversion on progression of chronic allograft nephropathy (CAN)., Methods: Forty-two cyclosporin-treated renal transplant recipients were studied. Patients were included if they had a negatively sloping reciprocal of creatinine vs time (ROCT) plot for >6 months and biopsy-proven CAN. Patients were excluded if they had previously been treated with tacrolimus/mycophenolate mofetil (MMF) or their serum creatinine was >400 micromol/l. Subjects were randomly treated with either: (A) MMF/reduced dose cyclosporin [MMF for azathioprine 0.5-1.0 g bd; cyclosporin trough level (C(0)): 75-100 ng/ml]; (B) tacrolimus for cyclosporin (C(0): 5-10 ng/ml); or (C) continuation of standard therapy. Glomerular filtration rate (GFR) was measured at baseline and after 6 months., Results: Two patients started dialysis within 6 months (one each from groups A and B). One patient in group A was intolerant of MMF, six others reported gastrointestinal symptoms and three developed anaemia. Cyclosporin dose was reduced by 24% [interquartile range (IQR): 14-27%] in group A [end-of-study C(0): 99 ng/ml (IQR: 90-113 ng/ml)]. In group B, the end-of-study tacrolimus C(0) was 7 ng/ml (5-9 ng/ml). The end-of-study cyclosporin C(0) in group C was 163 ng/ml (145-215 ng/ml). Comparison of ROCT slopes before and after intervention revealed a treatment advantage for group A (P<0.05). The GFR analysis was supportive (P = 0.05). When patients with GFR <20 ml/min/1.73 m(2) at enrollment were excluded from the analysis, the treatment advantage for group A reached statistical significance (n = 27, P<0.05)., Conclusions: MMF/reduced dose cyclosporin is superior to tacrolimus-for-cyclosporin and standard dose cyclosporin in patients with CAN, at least in the short term. The cyclosporin dose reduction component is likely to be of particular importance. Other findings suggest that early intervention is beneficial.

Aims: To determine whether polymorphisms of the genes encoding donor or recipient interleukin 1alpha (IL-1alpha), tumour necrosis factor alpha (TNFalpha), or IL-4 have any impact on the incidence of acute rejection after renal transplantation., Methods: All donors and recipients were genotyped for three polymorphisms in the three cytokine genes: IL1A -889, TNFA -308, and IL4 -590., Results: Statistical analysis of the data obtained revealed no association between the cytokine gene polymorphisms tested and the incidence of post-transplant acute rejection. After stratification for human leucocyte antigen (HLA) matching, it was found that kidneys from donors positive for the TNFA-A allele had a significantly increased incidence of acute rejection in HLA-DR mismatched transplants., Conclusions: This finding argues for prospective TNFA genotyping of renal donors, with avoidance of allocation of kidneys from donors positive for the TNFA-A allele to HLA-DR mismatched recipients.

Histology compatible with minimal change glomerulonephritis and associated with nephrotic syndrome has been reported as an occasional curiosity post-renal transplantation. Focal segmental glomerulosclerosis (FSGS) has a recurrence rate of approximately 20%. Age <15 years, an aggressive clinical course of the original disease and diffuse mesangial proliferation on native biopsy, are considered predictive of relapse. At present there are no tests that can accurately predict the likelihood of recurrence. Data from paediatric patients whose primary disease was FSGS were, on average, 90% more likely to lose a graft from a live donor and 50% more likely to lose a graft from a cadaveric donor compared with recipients with structural disorders. Recurrence in a subsequent graft is expected if the first graft was affected, but not if the first graft did not demonstrate recurrence. The best-established and most effective treatment of recurrent disease requires both plasma exchange and cyclophosphamide. Familial focal and segmental glomerulosclerosis, although rare, is important to recognize, as it is a different syndrome to idiopathic FSGS of childhood and overall transplant survival is good. Adults with 'secondary' FSGS would not be expected to be at risk of recurrent disease in a renal transplant.

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.

Renal transplant recipients have an increased risk of developing non-melanoma skin cancer. Ultraviolet radiation is one of the major cofactors in the development of skin cancer in the immunosuppressed. In view of this, we undertook this study to determine the advice given to renal transplant recipients and their compliance with that advice. Two hundred and two renal transplant recipients were interviewed using a questionnaire. Their knowledge about the risk of non-melanoma skin cancer and preventive measures was not good, despite advice and literature given to newly transplanted patients at the time of discharge from hospital. Only 54% remembered receiving advice. Renal physicians and nurses gave advice to the majority, with dermatologists providing advice only in 17% of cases. The use of sun-protective measures such as sun avoidance and protective clothing was poor and the use of sun barrier creams was inappropriate. Only 30% of patients knew why extra precautions against sunlight were necessary. Health professionals and dermatologists in particular need to take a more active role in raising the awareness of renal transplant recipients to their increased risk of non-melanoma skin cancer.

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.

Cortical calcification in a transplanted kidney was detected by high resolution ultrasound, not visible on plain abdominal radiography. Early recognition of these sonographic appearances should lead to a more accurate diagnosis and institution of appropriate treatment in patients with post-operative transplant dysfunction.

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.