Systemic immunosuppression in limbal stem cell transplantation: best practices and future challenges.

The objective of this study was to evaluate systemic immunosuppression regimens used for patients undergoing ocular surface stem cell transplantation, including their benefits and adverse effects in the adjunctive management of limbal stem cell deficiency (LSCD). A systematic literature review was conducted using the MEDLINE and EMBASE databases (1980-2015). Data were collected on surgical intervention(s), type of immunosuppressive agent(s), duration of immunosuppression, percentage with stable ocular surface at last follow-up, mean follow-up time, and demographics. Data were also collected on adverse ocular and systemic outcomes. Sixteen reports met the inclusion criteria. There were no randomized controlled studies. Three studies were noncomparative prospective case series, whereas the majority were retrospective case series. Bilateral severe LSCD was the most common disease (50%), and keratolimbal allograft was the most common intervention (80%). Immunosuppressive regimens showed a progression from early studies using oral cyclosporine to later studies using combinations of mycophenolate mofetil and tacrolimus. Most studies included a course of high-dose systemic corticosteroids. For patients adherent to long-term systemic immunosuppression, stable ocular surface rates of 70%-80% at last follow-up were reported. Adverse effects included hypertension, diabetes mellitus, and biochemical abnormalities managed with pharmacotherapy or discontinuation of offending agents. There were no cases of mortality related to immunosuppression. However, the current literature does not elucidate which immunosuppressive regimen is most efficacious for different categories of LSCD or graft types. Evidence-based guidelines for systemic immunosuppression in limbal allograft therapy would benefit from randomized controlled and/or additional prospective studies. Long-term immunosuppression would benefit from close collaboration between ophthalmologists and transplant specialists to individualize treatments.

Benefits of a transfer clinic in adolescent and young adult kidney transplant patients.

BACKGROUND: Adolescent and young adult kidney transplant recipients have worse graft outcomes than older and younger age groups. Difficulties in the process of transition, defined as the purposeful, planned movement of adolescents with chronic health conditions from child to adult-centered health care systems, may contribute to this. Improving the process of transition may improve adherence post-transfer to adult care services. OBJECTIVE: The purpose of this study is to investigate whether a kidney transplant transfer clinic for adolescent and young adult kidney transplant recipients transitioning from pediatric to adult care improves adherence post-transfer. METHODS: We developed a joint kidney transplant transfer clinic between a pediatric kidney transplant program, adult kidney transplant program, and adolescent medicine at two academic health centers. The transfer clinic facilitated communication between the adult and pediatric transplant teams, a face-to-face meeting of the patient with the adult team, and a meeting with the adolescent medicine physician. We compared the outcomes of 16 kidney transplant recipients transferred before the clinic was established with 16 patients who attended the clinic. The primary outcome was a composite measure of non-adherence. Non-adherence was defined as either self-reported medication non-adherence or displaying two of the following three characteristics: non-attendance at clinic, non-attendance for blood work appointments, or undetectable calcineurin inhibitor levels within 1 year post-transfer. RESULTS: The two groups were similar at baseline, with non-adherence identified in 43.75 % of patients. Non-adherent behavior in the year post-transfer, which included missing clinic visits, missing regular blood tests, and undetectable calcineurin inhibitor levels, was significantly lower in the cohort which attended the transfer clinic (18.8 versus 62.5 %, p = 0.03). The median change in estimated glomerular filtration rate (eGFR) in the year following transfer was smaller in the group that attended the transition clinic (-0.9 ± 13.2 ml/min/1.73 m(2)) compared to those who did not (-12.29 ± 14.9 ml/min/1.73 m(2)), p = 0.045. CONCLUSIONS: Attendance at a single kidney transplant transfer clinic was associated with improved adherence and renal function in the year following transfer to adult care. If these changes are sustained, they may improve long-term graft outcomes for adolescent kidney transplant recipients.

CONTEXTE: L'évolution favorable du greffon est plus souvent compromise chez les adolescents et les jeunes adultes transplantés du rein que chez les enfants et les adultes ayant subi la même intervention. Ces jeunes patients qui sont en général atteints de maladies chroniques, rencontrent des difficultés au cours de la période de transition entre le moment de leur transfert des unités de soins pédiatriques vers les unités de soins pour adultes, et celles-ci pourraient contribuer à ce pronostic défavorable. Des améliorations apportées au processus de transition pourraient favoriser l'adhésion de ces jeunes patients à leur protocole de traitement à la suite leur transfert dans les services de soins pour adultes. OBJECTIF: Le but de cette étude est de vérifier si la fréquentation d'une clinique de transfert pouvait améliorer l'adhésion des adolescents et des jeunes adultes greffés du rein à leur traitement, après leur transfert d'un établissement pédiatrique vers des services de soins pour adultes. MÉTHODES: Nous avons développé, au sein de deux centres universitaires de santé, deux cliniques conjointes de transfert pour les transplantés du rein. Ces cliniques étaient formées d'un programme de transplantation rénale pédiatrique, d'un programme de greffe rénale pour adultes et d'une clinique de médecine adolescente. La mise en place d'une clinique de transfert a facilité la communication entre les équipes de transplantation pour adultes et pédiatriques, a permis aux patients adolescents de rencontrer les équipes de transplantation pour adultes et de rencontrer des spécialistes de la médecine adolescente. Nous avons comparé les résultats de 16 jeunes greffés du rein qui avaient été transférés dans les centres de soins pour adultes avant la mise en place de la clinique de transfert avec les résultats de 16 patients qui ont fréquenté la clinique de transfert avant leur transition vers les unités de soins pour adultes. Le principal résultat a été une mesure composite d'adhésion au traitement. La non-adhésion a été définie soit par l'aveu de la part du patient de sa non-observance du traitement médicamenteux, soit par la manifestation de deux des trois comportements suivants dans le suivi du patient : la non-fréquentation de la clinique de transfert, le défaut de se présenter aux rendez-vous pour les analyses sanguines ou un niveau indécelable des inhibiteurs de calcineurine dans l'année suivant le transfert vers les services de soins pour adultes. RÉSULTATS: Les patients des deux groupes présentaient des caractéristiques similaires au début de l'étude, et 43,75 % d'entre eux avaient admis ne pas adhérer entièrement au traitement. Le nombre de comportements identifiés comme signes de non-adhésion au traitement tels que manquer des rendez-vous à la clinique de transfert, ne pas se présenter pour les analyses sanguines ou un niveau d'inhibiteurs de la calcineurine indécelable dans l'année suivant le transfert, étaient nettement inférieurs dans la cohorte de patients qui fréquentait la clinique de transfert que dans celle des patients qui avaient été transférés directement dans les services de soins pour adultes (18,8 % versus 62,5 %, p = 0,03). Qui plus est, les patients ayant fréquenté la clinique de transfert présentaient une variation médiane plus faible du débit de filtration glomérulaire (−0,9 ± 13,2 ml/min/1,73 m2) lorsque comparée à celle du groupe ayant été transféré directement (−12,2 ± 14,9 ml/min/1,73 m2), p = 0,045. CONCLUSIONS: Le fait de fréquenter une clinique de transfert pour les greffés du rein, dans l'année suivant leur transfert dans un centre de soins pour adultes, donne lieu à la fidélisation des jeunes transplantés du rein à l'égard de leur traitement et ceci favorise le rétablissement de leur fonction rénale. Le maintien de ces changements de comportement pourrait améliorer le pronostic à long terme quant à l'évolution du greffon chez les adolescents et les jeunes adultes greffés du rein.

Cytomegalovirus infection post-pancreas-kidney transplantation--results of antiviral prophylaxis in high-risk patients.

BACKGROUND: Cytomegalovirus (CMV) is a major pathogen affecting solid organ transplant (SOT) recipients. Prophylactic strategies have decreased the rate of CMV infection/disease among SOT. However, data on the effect of current prophylactic strategies for simultaneous pancreas-kidney (SPK) or pancreas after kidney (PAK) transplant remain limited. We report our experience of CMV prophylaxis in SPK/PAK recipients. METHODS: A total of 130 post-SPK/PAK patients were analyzed retrospectively for the rate of CMV and the risk factors associated with the acquisition of CMV. All patients received antiviral prophylaxis. The follow-up period was one yr post-transplant or until death. RESULTS: The rate of CMV post-SPK/PAK transplant was 24%, 44%, and 8.2% among the whole cohort, the D+/R- and the R+ groups, respectively. Median time of prophylaxis was 49 (0-254) d. In the whole cohort, risk factors for CMV infection/diseases were D+/R- CMV status (odds ratio [OR] = 16.075), preceding non-CMV (infection caused by bacteria or fungi and other viruses) infection (OR = 6.362) and the duration of prophylaxis (OR = 0.984). Among the CMV D+/R- group, non-CMV infection was the only risk factor for CMV disease (OR = 10.7). CONCLUSIONS: Forty-four per cent (25/57) of the D+/R- recipients developed CMV infection/disease despite CMV prophylaxis. Current CMV prophylaxis failed to prevent CMV infection/disease in this group of patients.

A pilot study of reduced dose cyclosporine and corticosteroids to reduce new onset diabetes mellitus and acute rejection in kidney transplant recipients.

BACKGROUND: New onset diabetes mellitus (NODM) and acute rejection (AR) are important causes of morbidity and risk factors for allograft failure after kidney transplantation. METHODS: In this multi-center, open label, single-arm pilot study, 49 adult (≥18 years of age), low immunologic risk, non-diabetic recipients of a first deceased or living donor kidney transplant received early steroid reduction to 5 mg/day combined with Thymoglobulin® (Genzyme Transplant, Cambridge, MA, USA) induction, low dose cyclosporine (2-hour post-dose (C2) target of 600 to 800 ng/ml) and mycophenolic acid (MPA) therapy. RESULTS: Six months after transplantation, two patients (4%) developed NODM and one patient (2%) developed AR. Four patients had impaired fasting glucose tolerance based on 75-g oral glucose tolerance testing (OGTT). There was one patient death. There were no episodes of cytomegalovirus (CMV) infection or BK virus nephritis. In contrast, in a historical cohort of n = 27 patients treated with Thymoglobulin induction, and conventional doses of cyclosporine and corticosteroids, the incidence of NODM and AR was 18% and 15%. CONCLUSIONS: The pilot study results suggest that Thymoglobulin induction combined with early steroid reduction, reduced cyclosporine exposure and MPA, may reduce the incidence of both NODM and AR in low immunological risk patients. A future controlled study enriched for patients at high risk for NODM is under consideration. TRIAL REGISTRATION: ClinicalTrials.gov: http://NCT00706680.

Generic immunosuppression in solid organ transplantation: a Canadian perspective.

The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as "critical dose drugs" and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ transplantation is warranted.