The balance between under- and over-immunosuppression after heart transplantation with emphasis on acute cellular rejection and chronic kidney disease. Experiences from Skåne University Hospital in Lund 1988-2010

Abstract: Background and aims:Heart transplantation (HT) constitutes the ultimate treatment choice for end-stage heart failure. Following HT, patients require life-long immunosuppressive treatment to prevent allograft rejection. Although survival has steadily increased over the last few decades, issues related to under- and over-immunosuppression remain common and continue to represent one of the most important limiting factors for long-term outcome. This important act of balance is also a major reason for the debate on whether or not newly available generic immunosuppressants, which may provide economic advantages, should be introduced.HTs have been performed at Skåne University Hospital in Lund (SUS-Lund) since 1988. Since the beginning of the transplant program, patients have undergone extensive follow-up including renal function measurements using the iohexol clearance method, and endomyocardial biopsies (EMBs) to detect acute cellular rejection (ACR).The present thesis consists of four papers. Paper I-III aimed to study the incidence, predictors and outcome of ACR and chronic kidney disease (CKD) after HT – two of the most relevant issues related to the balance between under- and over-immunosuppression. An additional aim was to evaluate two guideline recommended glomerular filtration rate (GFR) estimating equations in HT patients (CKD-EPI and Schwartz formulae). Lastly, paper IV investigated the safety and efficacy of switching to two generic immunosuppressants, namely Myfenax Teva® and Tacrolimus Sandoz®.Methods:All papers were retrospective in design. Paper I-III were based on all 215 HT patients followed at SUS-Lund 1988-2010, whereas paper IV concerned a smaller cohort of 55 patients.Results:The frequency and severity of ACR was low and decreased with time post-HT. The findings however indicated that late (>1 year) more often than early (<1 year) ACR remains undetected, and that both types of ACR influence outcome. CKD was moreover common and appeared to have a negative impact on survival. Interestingly, the results also indicated that the CKD-EPI and Schwartz formulae both overestimate GFR in HT patients and thus could lead to diagnostic delay if solely relied upon. In paper IV, data reassuringly indicated that switching to Myfenax Teva® and/or Tacrolimus Sandoz® several years post-HT appeared safe, at least in the short-term perspective.Conclusions:The present thesis, focusing on the HT population at SUS-Lund 1988-2010, provides a useful in-depth overview on the incidence, predictors, and outcome of two of the most relevant issues related to the difficult balance between under- and over-immunosuppression after HT – namely ACR and CKD. Valuable initial experience on the conversion from branded to generic immunosuppressants is also presented.