Paolo Malvezzi

Conversion to mammalian target of rapamycin inhibitors increases risk of de novo donor-specific antibodies

In kidney transplantation, conversion to mammalian target of rapamycin (mTOR) inhibitors may avoid calcineurin inhibitor (CNI) nephrotoxicity, but its impact on post‐transplant allo‐immunization remains largely unexplored. This retrospective cohort study analyzed the emergence of donor‐specific antibodies (DSA) in kidney transplant recipients relative to their immunosuppressive therapy. Among 270 recipients without pretransplant immunization who were screened regularly for de novo DSA, 56 were converted to mTOR inhibitors after CNI withdrawal. DSA emergence was increased in patients who were converted to mTOR inhibitors (HR 2.4; 95% CI 1.06–5.41, P = 0.036). DSA were mainly directed against donor HLA‐DQB1 antigens. The presence of one or two DQ mismatches was a major risk factor for DQ DSA (HR 5.32; 95% CI 1.58–17.89 and HR 10.43; 95% CI 2.29–47.56, respectively; P < 0.01). Rejection episodes were more likely in patients converted to mTOR inhibitors, but this difference did not reach significance (16% vs. 7.9%, P = 0.185). Concerning graft function, no significant change was observed one year after conversion (P = 0.31). In conclusion, conversion to mTOR inhibitors may increase the risk of developing class II DSA, especially in the presence of DQ mismatches: this strategy may favor chronic antibody‐mediated rejection and thus reduce graft survival.

The safety of calcineurin inhibitors for kidney-transplant patients

Introduction: Cyclosporine-A and tacrolimus are the cornerstones in modern immunosuppression after organ transplantation. They are potent inhibitors of calcineurin, that is, so-called calcineurin-inhibitors (CNIs). However, because these drugs have narrow therapeutic windows, they are associated with many side-effects, with some being dose related. Areas covered: The most frequent side-effect of CNIs is nephrotoxicity, which in the long term can contribute, to allograft deterioration. Other frequent side-effects include metabolic disorders (new onset of diabetes, dyslipidemia), neurotoxicity, or promoting of de novo cancers. Expert opinion: In kidney transplantation, many strategies have been developed to minimize nephrotoxicity while maintaining efficacy of immunosuppression: for example, the minimization of CNI in addition to either full-dose mycophenolic acid or low doses of m-TOR inhibitors, mainly everolimus (EVR). Attempts made to eliminate CNIs by replacing them with m-TOR inhibitors have been unsuccessful because of occurrence of de novo donor-specific alloantibodies in a substantial number of patients, associated with antibody-mediated rejection. Conversely, CNI-avoidance by replacing them by Belatacept is feasible with very good renal function in the long term despite a significant increase in acute cellular rejections within the first-year posttransplantation. Other side-effects of CNIs, such as neurologic disorders, diabetes, dyslipidemia, viral infections, and cancer, seem to be less frequent in low-dose or CNI-free immunosuppressive regimens. Thus, although CNIs remain the major immunosuppressive treatment, their dosage should be minimized by using them with either full-dose MPA or reduced-dose EVR.

Influence of intention to adhere, beliefs and satisfaction about medicines on adherence in solid organ transplant recipients.

Introduction Nonadherence to immunosuppressive (IS) therapy is associated with poor outcomes. Identifying factors predicting poor adherence is therefore essential. The primary objective of this study was to test whether parameters of a model adapted from the theory of planned behavior, and more specifically attitudes that are influenced by beliefs and satisfaction with medication, could predict adherence in solid organ transplant patients. Methods Adherence was assessed with a self-reported medication adherence scale and IS blood trough concentrations over 6 months, in four transplant units. Satisfaction and beliefs were assessed using the Treatment Satisfaction with Medicines Questionnaire (SATMED-Q) and Beliefs about Medicines Questionnaire (BMQ), respectively. Theory of planned behavior was assessed with a specific questionnaire exploring intentions, subjective norms, attitudes and perceived behavioral control. Treatment characteristics and socioeconomic data were also collected. Results One hundred and fifty-three solid organ transplant patients were enrolled, including lung (n=33), heart (n=43), liver (n=42), and kidney (n=44) patients. Satisfaction and positive beliefs about medication were higher in adherent than those in nonadherent patients. Factors independently associated with an increased risk of nonadherence were negative general beliefs about medications (odds ratio [OR]=0.89 [0.83–0.97]), living alone (OR=2.78 [1.09–7.09]), heart transplantation (OR=3.49 [1.34–9.09]), and being on everolimus (OR=5.02 [1.21–20.8]). Conclusion Negative beliefs toward medications were shown to be an independent risk factor of poor adherence. Therefore, the BMQ could be an effective, easy to implement tool, for use in everyday practice, to identify patients needing interventions to improve adherence to IS.

Costimulation Blockade in Kidney Transplantation: An Update

Abstract In the setting of solid-organ transplantation, calcineurin inhibitor (CNI)-based therapy remains the cornerstone of immunosuppression. However, long-term use of CNIs is associated with some degree of nephrotoxicity. This has led to exploring the blockade of some costimulation pathways as an efficient immunosuppressive tool instead of using CNIs. The only agent already in clinical use and approved by the health authorities for kidney transplant patients is belatacept (Nulojix), a fusion protein that interferes with cytotoxic T lymphocyte-associated protein 4. Belatacept has been demonstrated to be as efficient as cyclosporine-based immunosuppression and is associated with significantly better renal function, that is, no nephrotoxicity. However, in the immediate posttransplant period, significantly more mild/moderate episodes of acute rejection have been reported, favored by the fact that cytotoxic T lymphocyte-associated protein pathway has an inhibitory effect on the alloimmune response; thereby its inhibition is detrimental in this regard. This has led to the development of antibodies that target CD28. The most advanced is FR104, it has shown promise in nonhuman primate models of autoimmune diseases and allotransplantation. In addition, research into blocking the CD40-CD154 pathway is underway. A phase II study testing ASK1240, that is, anti-CD40 antibody has been completed, and the results are pending.

Profiling Sirolimus-Induced Inflammatory Syndrome: A Prospective Tricentric Observational Study

Background The use of the immunosuppressant sirolimus in kidney transplantation has been made problematic by the frequent occurrence of various side effects, including paradoxical inflammatory manifestations, the pathophysiology of which has remained elusive. Methods 30 kidney transplant recipients that required a switch from calcineurin inhibitor to sirolimus-based immunosuppression, were prospectively followed for 3 months. Inflammatory symptoms were quantified by the patients using visual analogue scales and serum samples were collected before, 15, 30, and 90 days after the switch. Results 66% of patients reported at least 1 inflammatory symptom, cutaneo-mucosal manifestations being the most frequent. Inflammatory symptoms were characterized by their lability and stochastic nature, each patient exhibiting a unique clinical presentation. The biochemical profile was more uniform with a drop of hemoglobin and a concomitant rise of inflammatory acute phase proteins, which peaked in the serum 1 month after the switch. Analyzing the impact of sirolimus introduction on cytokine microenvironment, we observed an increase of IL6 and TNFα without compensation of the negative feedback loops dependent on IL10 and soluble TNF receptors. IL6 and TNFα changes correlated with the intensity of biochemical and clinical inflammatory manifestations in a linear regression model. Conclusions Sirolimus triggers a destabilization of the inflammatory cytokine balance in transplanted patients that promotes a paradoxical inflammatory response with mild stochastic clinical symptoms in the weeks following drug introduction. This pathophysiologic mechanism unifies the various individual inflammatory side effects recurrently reported with sirolimus suggesting that they should be considered as a single syndromic entity.

Place of mTOR inhibitors in management of BKV infection after kidney transplantation.

Context: BK virus (BKV) viremia and BKV-associated nephropathy (BKVAN) have become a serious nuisance to kidney transplant (KT) patients since the mid-nineties, when the incidence of this disease has increased significantly. Evidence Acquisition: Directory of open access journals (DOAJ), EMBASE, Google Scholar, PubMed, EBSCO, and Web of Science have been searched. Results: Many hypothesis have been made as to why this phenomenon has developed; it is of general opinion that a more potent immunosuppression is at the core of the problem. The use of the association of tacrolimus (TAC) with mycophenolic acid (MPA) has gained momentum in the same years as the increase in BKV viremia incidence making it seem to be the most likely culprit. m-TOR inhibitors (m-TORIs) have been shown to have antiviral properties in vitro and this fact has encouraged different transplant teams to use these agents when confronted with BKV infection (viremia or nephropathy). However, the results are mitigated. There had been conflicting results for example when converting from TAC-to sirolimus-based immunosuppression in the setting of established BKVAN. Conclusions: In order to prevent BKV infection we have to minimize to some extent immunosuppression, but it is not always possible, e.g. in high immunological risk patients. Conversely, we could use m-TORIs associated with low-dose calcineurin inhibitors (CNIs). This could be actually the key to a safe immunosuppression regimen both from the immunological stand point and from the viral one.

Induction by anti-thymocyte globulins in kidney transplantation: a review of the literature and current usage

Context: Preventing acute rejection (AR) after kidney transplantation is of utmost importance because an AR can have a negative impact on long-term allograft survival. Evidence Acquisition: Directory of Open Access Journals (DOAJ), Google Scholar, PubMed, EBSCO, and Web of Science have been searched. Results: At the moment this can be done by using rabbit anti-thymocyte globulins (rATGs) as an induction therapy. However, because rATGs are associated with some deleterious side-effects, such as the opportunistic infections cytomegalovirus (CMV) and de novo post-transplant cancer, it is very important they are used optimally, i.e., at minimal doses that avoid many side-effects but still retain optimal treatment efficacy. Recent data show that the risk of CMV infection can be minimized using tacrolimus plus everolimus, and not tacrolimus plus mycophenolic acid, as the maintenance immunosuppression. The use of rATG is particularly valuable in; (a) sensitized patients; (b) in recipients from an expanded-criteria donor, thus enabling the introduction of calcineurin inhibitors at reduced doses; and (c) for patients where steroid avoidance is contemplated. However, we also need to consider that rATG may increase the risk of de novo cancer, even though recent data indicate this is unlikely and that any risk can be reduced by using mammalian target of rapamycin (mTOR) inhibitors instead of mycophenolic acid combined with low-dose calcineurin inhibitors. Conclusions: Even though rATGs do not improve long-term kidney-allograft survival, they may help reduce calcineurin-inhibitor dosage during the early post-transplant period and minimize the risk of AR.

Safety of renal transplantation in patients with bipolar or psychotic disorders: a retrospective study

Solid organ transplantation societies recommend a relative contraindication of transplantation for people with bipolar or psychotic disorders. Very few data are available on the outcome of kidney transplantation and the increased risk of kidney disease in those patients. We conducted a retrospective multicenter cohort study (1979–2014) including kidney allograft recipients with either bipolar (BD) or psychotic disorders prior to transplant. Objectives were kidney allograft and patient outcomes compared to a matched control group without psychiatric disorders and the evolution of psychiatric disorder at 60 months after transplantation. Forty‐seven patients including 25 women were identified, 34 with BD and 13 with psychotic disorder. Patients’ overall cumulative death rates at 60 months were not significantly different in both groups [12.2%; 95% confidence interval: (4.5–24.1) in the group with psychiatric disorder versus 5.2%; (1.7–11.7) in control group P = 0.11] as for cumulative allograft loss rates [11.7% (3.5–25.2) vs. 9.4% (4.4–16.8) in control group (P = 0.91)]. Twenty‐three patients (16 with BD and seven with psychotic disorder) experienced at least one psychiatric relapse [incidence rate: 1.8/100 persons‐ months; 95% CI; (1.2–2.7)] totaling 13 hospitalizations within 60 months of follow‐up. Four patients stopped immunosuppressive therapy leading to allograft loss in three. Our study suggests that patients with BD or psychotic disorders have to be considered for renal transplantation with close psychiatric follow‐up after transplant.

Renal transplantation in 2016: Novel approaches to improve recipient and allograft outcomes

Kidney transplantation was the focus of numerous publications in 2016. Key studies demonstrated a survival advantage of HLA-incompatible kidney transplantation and suggested that novel approaches such as co-stimulation blockade using belatacept and treatment of antibody-mediated rejection using a C1 esterase inhibitor might prove to be future game changers.

New formulations of tacrolimus and prevention of acute and chronic rejections in adult kidney-transplant recipients

ABSTRACT Introduction: As tolerance is not yet achievable, the kidney-transplanted-patients have to take on a daily-basis immunosuppressive drugs in order to avoid acute rejection-AR-. The cornerstone of immunosuppression relies on tacrolimus-therapy which is potentially nephrotoxic. Areas Covered: We identified from the studies published in the recent years those who were reporting on AR in de novo kidney-transplant recipients under tacrolimus-based therapy, as well as those who reported on the attempt to minimize tacrolimus-therapy. Results: There are many formulations of tacrolimus: immediate-release (Prograf®), slow-release (Advagraf®), or extended-release (Envarsus®). All demonstrate a very good efficacy in preventing AR episodes. Studies in which tacrolimus was minimized or even weaned-off have shown that it was unsafe, i.e. in resulting in AR episode and/or de novo donor-specific alloantibodies. Recent data show that Tacrobell®, a generic of tacrolimus, was as efficient as Prograf® in the short- and long-term. Expert-opinion: Tacrolimus-based immunosuppression is very effective in preventing rejection in kidney-transplant recipients. It might be associated with nephrotoxicity, that can be reduced by avoiding tacrolimus trough levels too high in the long-term. Conversely, tacrolimus ultraminimization should not be attempted.