C. Newstead

The clinical significance of early proteinuria after renal transplantation.

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 grafts 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.

Poor Tolerance of Sirolimus in a Steroid Avoidance Regimen for Renal Transplantation

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.

Campath, calcineurin inhibitor reduction and chronic allograft nephropathy (3C) study: background, rationale, and study protocol

BackgroundKidney transplantation is the best treatment for patients with end-stage renal failure, but uncertainty remains about the best immunosuppression strategy. Long-term graft survival has not improved substantially, and one possible explanation is calcineurin inhibitor (CNI) nephrotoxicity. CNI exposure could be minimized by using more potent induction therapy or alternative maintenance therapy to remove CNIs completely. However, the safety and efficacy of such strategies are unknown.Methods/DesignThe Campath, Calcineurin inhibitor reduction and Chronic allograft nephropathy (3C) Study is a multicentre, open-label, randomized controlled trial with 852 participants which is addressing two important questions in kidney transplantation. The first question is whether a Campath (alemtuzumab)-based induction therapy strategy is superior to basiliximab-based therapy, and the second is whether, from 6 months after transplantation, a sirolimus-based maintenance therapy strategy is superior to tacrolimus-based therapy. Recruitment is complete, and follow-up will continue for around 5 years post-transplant. The primary endpoint for the induction therapy comparison is biopsy-proven acute rejection by 6 months, and the primary endpoint for the maintenance therapy comparison is change in estimated glomerular filtration rate from baseline to 2 years after transplantation. The study is sponsored by the University of Oxford and endorsed by the British Transplantation Society, and 18 centers for adult kidney transplant are participating.DiscussionLate graft failure is a major issue for kidney-transplant recipients. If our hypothesis that minimizing CNI exposure with Campath-based induction therapy and/or an elective conversion to sirolimus-based maintenance therapy can improve long-term graft function and survival is correct, then patients should experience better graft function for longer. A positive outcome could change clinical practice in kidney transplantation.Trial registrationClinicalTrials.gov, NCT01120028 and ISRCTN88894088

Sequential transplant of paired kidneys following donation after cardiac death: impact of longer cold ischemia time on the second kidney on graft and patient outcome.

The United Kingdom has no national sharing scheme for kidneys received from donation after cardiac death (DCD). Therefore, both kidneys retrieved by a transplant team are implanted at a single unit, often sequentially. This study analyzes the impact of a prolonged cold ischaemia time on the second transplanted kidney and the effects on short-term and long-term outcomes in all our DCD renal implants from 2002 to 2009. Cold ischaemia time was significantly longer with the second kidney (P = .04) as was delayed graft function (P = .02). Acute rejection was increased in the first transplanted kidney (P < .001). Five-year patient survival was comparable between groups, but 5-year graft survival was higher in the second transplanted group (P = .04). The results confirm that, provided recipient centers are willing to accept higher initial rates of delayed graft function, it is acceptable to transplant DCD grafts sequentially without jeopardizing long-term graft or recipient outcome.

Kidney transplantation using the inferior epigastric vessels for multiple anastomoses from a pelvic kidney.

D T b p d m elvic kidney is a rare congenital malformation of renal scent during development. Such kidneys may be dysplasic, with suboptimal renal function. They are also known to ave multiple aberrant vessels and are associated with an ncreased risk of nephrolithiasis. If functionally normal, elvic kidney can be used for living donor kidney translantation. There are only six case reports in the transplanation literature of successful live donor renal transplantaion using pelvic kidneys in adults and one report in the ediatric setting. We report successful live donor translantation of a pelvic kidney with multiple blood vessels till functioning 4 years postoperatively, with the unique se of the inferior epigastric artery and vein to aid the nastomosis.

Impact of Cold Ischemia on Renal Transplant Outcomes Following Donation After Cardiac Death

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.

Resolution of Low‐Grade Proteinuria is Associated With Improved Outcomes After Renal Transplantation—A Retrospective Longitudinal Study

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.

Successful kidney transplantation with a well-matched donor despite a positive crossmatch; detection and management of sensitization secondary to an alternate allelic variant of 'self' HLA.

Under current UK standards of deceased donor typing, the formation by the recipient of HLA antibody against an allelic variant of a ‘self’ antigen creates a particular problem for organ allocation. In the reported case, the decision to transplant was taken in the situation of a positive flow crossmatch result attributed to allelic antibody. The potential that target antigen density contributed to this patient’s subsequent good outcome is discussed.

AGE MATCHING OF DONORS TO RECIPIENTS DOES NOT IMPACT ON OUTCOME IN RENAL TRANSPLANTATION FOLLOWING DONATION AFTER CARDIAC DEATH: 2136

Introduction. Renal grafts procured from donors after cardiac death (DCD) have increased rates of delayed graft function compared to those procured from conventional donation after brain death donors (DBD). However, patient and graft survival are comparable between DCD and DBD grafts. It is a practice in our centre to attempt to age match recipients were possible when using grafts from DCD donors DCD in an attempt not to give kidneys from older DCD donors to young recipients. This study seeks to identify the impact of age matching on graft and recipient outcomes in DCD donor kidney transplant. Methods. Donor and recipient ages were prospectively recorded to allow matching of donor and recipients for DCD transplantation. Donor:recipient age ratios were calculated and the cohort of well matched donor-recipient pairs (i.e.lying between the 25th and 75th centiles) were compared with less favourably matched donor-recipient pairs (i.e. <25th centile or >75th centile). Rates of DGF, primary non function (PNF), acute rejection (AR), 5 year graft and patient survival and estimated GFR were compared. Categorical data were compared using Χ2 or Fishers exact test; longitudinal data were compared using a Student t test; all at a 5% level of statistical significance. Results. In the study period between 2002-2009, 201 renal transplants were performed using DCD donors, all were analysed. 99 were performed between donors and recipients matched for age. Grafts matched for age had rates of AR (14% vs 20%; Χ2=1.20; p=0.27), DGF (58% vs 49%; Χ2=1.52; p=0.22) and PNF (5% vs 3%; Χ2=0.36; p=0.55) comparable to less well matched grafts. Five year recipient (95% vs 85%;Χ2=0.122; p=0.05) and graft survival (84% vs 89%; Χ2=1.835; p=0.18) was similarly comparable. Though there was a significant difference in GFR between groups at 1 year (49 vs 65ml/min; t=-3.3; p=0.001) this was not apparent by 3 or 5 years (48 vs 57 ml/min; t=-1.8; p=0.07 and 51 vs 58 ml/min; t=-0.72; p=0.48). Conclusions. The matching of DCD donors to recipients by age has no impact on rates of AR or PNF. Similarly there is no effect on medium term graft function or recipient and graft survival. The use of donor age to select a matched recipient for a DCD graft is not a useful determinant of most graft and recipient outcomes.