Clinical outcomes with ABO antibody titer variability in a multicenter study of ABO-incompatible kidney transplantation in the United Kingdom.

BACKGROUND: ABO blood group-incompatible kidney transplantation (ABOiKTx) outcomes are good, but complications are more common than in conventional transplantation. Regimens that use extracorporeal antibody removal therapy (EART) and enhanced immunosuppression are guided by titration of ABO blood group antibodies (using hemagglutination [HA] dilution assays), and these assays vary significantly in performance between centers. This study aims to describe the differences in titer measurement and the effect on clinical practice and outcomes. STUDY DESIGN AND METHODS: This multicentre, prospective cohort study of 100 ABOiKTx recipients assessed treatment and outcome data, including HA assay results measured retrospectively in a single central laboratory. RESULTS: Patient and allograft survival at 1 year was 99% and 94%, respectively. There were significant differences in the number of pretransplantation EART sessions in centers undertaking plasma exchange (PEx), compared with immunoadsorption (IA) (median, 6 vs. 4 sessions; p = 0.007). The pre-EART HA titer in both groups was the same when centrally assayed. The local HA assay used to guide treatment yielded significantly higher titers in centers undertaking PEx compared with IA (median, 128 vs. 32; p < 0.005). Patients undergoing PEx rather than IA were significantly more likely to suffer postoperative hematoma (12.9% vs. 1.8%; p = 0.05) or any perioperative collection requiring drainage (19.4% vs. 3.6%; p = 0.02). CONCLUSION: The colinearity of HA assay sensitivity with the receipt of PEx and EART limits some conclusions regarding the likely direction of causation. However, the association of differences in clinical practice with recognized perioperative complications of ABOiKTx identifies targets for further investigation and quality improvement.

Alemtuzumab induction in renal transplantation permits safe steroid avoidance with tacrolimus monotherapy: a randomized controlled trial.

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.

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

BACKGROUND: Kidney 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/DESIGN: The 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. DISCUSSION: Late 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 REGISTRATION: ClinicalTrials.gov, NCT01120028 and ISRCTN88894088.

Summary of the British Transplantation Society Guidelines for the Prevention and Management of CMV Disease After Solid Organ Transplantation.

The third edition of the British Transplantation Society Guidelines for the Prevention and Management of CMV Disease after Solid Organ Transplantation was published in March 2011. This article summarizes the important changes and advances in management in this rapidly evolving field. The pros and cons of universal, or targeted anti-cytomegalovirus (CMV) prophylaxis, and pre-emptive anti-CMV therapy are discussed, especially with respect to advances in CMV polymerase chain reaction monitoring. The evidence for oral anti-CMV prophylaxis using valganciclovir is presented, together with a summary of the treatment of CMV disease and emerging fields such as CMV vaccination, CMV genotyping, and drug resistance.

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.

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 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.

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.

Recurrent disease in renal transplants.

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.