Tissue talks: immunophenotype of cells infiltrating the graft explains histological findings and the benefits of belatacept at 10 years.

Previously, we found a substantial number of regulatory T cells (Tregs ) and fewer senescent and T helper type 17 (Th17) and a decrease in interstitial fibrosis (IF) in 12-month graft biopsies in belatacept versus cyclosporin (CNI)-treated patients [Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) study]. Seven years after kidney transplantation (KT), mean estimated glomerular filtration rate (eGFR), patient and graft survival were significantly higher with belatacept versus CNI treatment. The aim of this study was to determine whether the immunophenotypes of inflammatory and regulatory cell subsets infiltrating the grafts contribute to the BENEFIT's clinical findings a decade after KT. Twenty-three adult patients with functionally stable KT treated with belatacept and 10 treated with CNI were enrolled. Biopsies were analyzed by histomorphometry and immunohistochemistry for proliferation, senescence, apoptosis, inflammatory and regulatory cell markers in a blinded manner. Significantly lower percentages of inflammatory/fibrogenic cells [interleukin (IL)-22+ /Th17/Th2/M1 macrophages] were observed in patients treated with belatacept than in patients treated with CNI. By contrast, remarkably higher percentages of regulatory cells [Tregs /Bregs / plasmacytoid dendritic regulatory cells (pDCregs )/M2] were found in belatacept-treated patients than in CNI-treated patients. Conspicuously lower percentages of apoptosis and senescence and higher proliferation markers were found in belatacept-treated patients than in CNI-treated patients. Consequently, there was significantly more inflammation in the microvascular compartments as well as increased tubular atrophy and IF in CNI-treated patients. These findings strongly suggest that regulatory mechanisms, along with the absence of deleterious effects of CNI, contribute to the long-term graft histology and function stability in patients treated with belatacept.

Tolerability of up to 200 days of prophylaxis with valganciclovir oral solution and/or film-coated tablets in pediatric kidney transplant recipients at risk of cytomegalovirus disease.

This multicenter, open-label study evaluated the tolerability of extended prophylaxis with valganciclovir in pediatric kidney transplant recipients at risk of CMV disease. Fifty-six patients aged 4 months to 16 years received once-daily valganciclovir oral solution and/or tablets, dosed by BSA and renal function, for up to 200 days. The most common AEs on treatment were upper respiratory tract infection (33.9%), urinary tract infection (33.9%), diarrhea (32.1%), leukopenia (25.0%), neutropenia (23.2%), and headache (21.4%). There were fewer AEs during days 101-228 vs days 1-100. Twenty-seven patients (48.2%) had treatment-related AEs during valganciclovir treatment, most commonly leukopenia (21.4%), neutropenia (19.6%), anemia (7.1%), and tremor (5.4%). Treatment-related serious AEs were reported for nine patients (16.1%) and six withdrew due to AEs. Viremia was centrally confirmed in 10 patients; there was no confirmed CMV disease. One patient tested positive for a resistance mutation (UL97 L595F). Biopsy-proven acute rejection occurred in six patients (10.7%), but no graft loss or deaths occurred. In conclusion, up to 200 days of valganciclovir prophylaxis in pediatric kidney allograft recipients showed a safety profile consistent with that established in adult transplant patients.

Infiltrating cellular pattern in kidney graft biopsies translates into forkhead box protein 3 up-regulation and p16INK4α senescence protein down-regulation in patients treated with belatacept compared to cyclosporin A.

Renal allograft survival is related directly to cell senescence. In the transplantation scenario many cellular events - participating as immunological and non-immunological factors - could contribute to accelerate this biological process, responsible for the ultimate fate of the graft. Mechanisms concerned in tolerance versus rejection are paramount in this outcome. For this reason, immunosuppressive treatment constitutes an extremely important decision to prevent organ dysfunction and, finally, graft loss. This study was conducted to document the proportion of CD4(+) /interleukin (IL)-17A(+) -, CD16(+) /indoleamine 2, 3-dioxygenase (IDO(+) )-, forkhead box protein P3 (FoxP3(+))-expressing cells, senescent cells (p16(INK) (4α)) and the percentage of interstitial fibrosis (IF) in graft biopsies of kidney transplant recipients participating in the BENEFIT (Bristol-Myers Squibb IM103008) study. CD4(+) /IL-17A(+) , CD16(+) /IDO(+), FoxP3(+) and p16(INK) (4α+) cells were evaluated by immunohistochemistry, and the percentage of IF by morphometry on graft biopsies obtained at time 0 (pre-implantation) and at 12 months post-transplant. Senescent cells and CD4(+) /IL-17A(+) cells were increased among graft biopsies in subjects receiving cyclosporin A (CsA) compared to those under belatacept treatment. Meanwhile, CD16(+) /IDO(+) and FoxP3(+) -expressing cells were lower in biopsies from CsA treatment compared to patients treated with Belatacept. Histological morphometric analyses disclosed more IF in 12-month CsA-treated patients in comparison to pre-implantation biopsy findings. Summing up, renal biopsies from patients receiving belatacept showed greater amounts of FoxP3(+) cells and lower amounts of CD4(+) /IL-17A(+) and senescent cells compared to patients under CsA treatment. Along with these findings, an increase in IF in annual CsA-treated-patients biopsies compared to pre-implantation and belatacept-treated patients were observed.

Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients.

The clinical profile of belatacept in kidney transplant recipients was evaluated to determine if earlier results in the BENEFIT study were sustained at 3 years. BENEFIT is a randomized 3 year, phase III study in adults receiving a kidney transplant from a living or standard criteria deceased donor. Patients were randomized to a more (MI) or less intensive (LI) regimen of belatacept, or cyclosporine. 471/666 patients completed ≥3 years of therapy. A total of 92% (MI), 92% (LI), and 89% (cyclosporine) of patients survived with a functioning graft. The mean calculated GFR (cGFR) was ∼21 mL/min/1.73 m(2) higher in the belatacept groups versus cyclosporine at year 3. From month 3 to month 36, the mean cGFR increased in the belatacept groups by +1.0 mL/min/1.73 m(2) /year (MI) and +1.2 mL/min/1.73 m(2) /year (LI) versus a decline of -2.0 mL/min/1.73 m(2) /year (cyclosporine). One cyclosporine-treated patient experienced acute rejection between year 2 and year 3. There were no new safety signals and no new posttransplant lymphoproliferative disorder (PTLD) cases after month 18. Belatacept-treated patients maintained a high rate of patient and graft survival that was comparable to cyclosporine-treated patients, despite an early increased occurrence of acute rejection and PTLD.

A comparative study of the traditional method, and a point-score system for allocation of deceased-donor kidneys: a national multicenter study in Mexico.

BACKGROUND: The National Transplant Center in Mexico has ruled that deceased-donor kidney allocation is a function of each hospital's Internal Transplant Committee. The aim of this study was to compare and analyze results for of the traditional method and a point-score system in the allocation of deceased patient's kidneys. METHODS: The 12 major kidney transplant centers in the country having a deceased-donor program were invited to participate. Only 3 of them replied to the invitation during 2010. A point-score system was proposed to them, comprising blood group, waiting list time, HLA type, and donor and recipient ages. Once the final recipient was chosen, an explanation of reasons for the choice was requested. Thirty-eight transplants were presented. Kappa coefficient was used to measure degree of agreement in both allocation systems. Organs donated for transplantation came from patients between 4 and 54 years old, including 52% female, 52% O+ blood type, 31% A+, and 11% B+, 44% cranial-encephalic trauma, and 44% brain hemorrhage. RESULTS: Global agreement was 52.6% (kappa = 0.343), and partial agreement was 76.3% (weighted kappa = 0.204), assigning more intensity to extreme values, but with a lower correlation index. A more intense agreement, without discriminating by hospital, was found for "A" category (blood group), followed by "B" category (waiting list time). DISCUSSION: Taking into consideration the determining factors for long-term graft survival, it is indispensable to include criteria such as donor and recipient ages and HLA typife in the allocation process. This first draft of a point-score system in organ allocation included waiting list time, blood group, urgency related to vascular/peritoneal access for dialysis, clinical condition, donor/recipient age ratio, and HLA antigenic compatibility.

National survey carried out by the Mexican Society of Transplantation in 2009 regarding deceased-donor kidney allocation.

BACKGROUND: The Mexican Health Law stipulated that the criteria to be taken into account for deceased donor kidney allocation should include the following: "seriousness of recipient's condition, opportunity of transplant, expected benefits, compatibility with recipient, and all other accepted medical criteria." The practical application of these criteria has been perceived by several members of transplantation committees as allowing inequity in kidney allocation. The aims of this study were to learn the opinions of transplantation committees regarding current national allocation policies, and to obtain their opinions about the advantages of a point-score system. METHODS: A prepared questionnaire was validated with the collaboration of a team of transplantation physicians from the Mexican Society of Transplantation (MST). Ninety members of the Society, who represent transplantation groups were invited by mail to participate in the survey. RESULTS: We received 70 answered questionnaires, including 54 that represented the views of their respective internal transplantation committees. In agreement with the legislation and allocation policies currently in force were 50% of responders; however, 60% believed that a point-score system for organ allocation should be mandatory and 75% believed that only patients without a possible live donor should be included on the waiting list to compete for a deceased donor kidney. Also, 84% believed that only patients with a complete pre-transplant protocol, including recent viral serology, as well as clinically relevant pre-transplant evaluations by other specialists such as cardiology, psychiatry/psychology and urology should qualify for allocation of deceased donor organs; 76% believed that patients who compete for a deceased donor organ must have permanent support for immunosuppressive drugs as well as for short-term and long-term medical care. CONCLUSION: The answers gathered through this survey pointed out the necessity for continuous coordinated work between healthcare authorities and members of the MST to achieve the best guidelines for allocation of deceased donor kidneys including a point-score system.