Carl Söderlund

Immunosuppressive therapies after heart transplantation — The balance between under- and over-immunosuppression

Since the first heart transplantation (HT) in 1967, survival has steadily improved. Issues related to over- and under-immunosuppression are, however, still common following HT. Whereas under-immunosuppression may result in rejection, over-immunosuppression may render other medical problems, including infections, malignancies and chronic kidney disease (CKD). As such complications constitute major limiting factors for long-term survival following HT, identifying improved diagnostic and preventive methods has been the focus of many studies. Notably, research on antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) has recently led to the development of nomenclatures that may aid in their diagnosis and treatment. Moreover, novel immunosuppressants (such as mammalian target of rapamycin [m-TOR] inhibitors) and strategies aimed at minimizing the use of calcineurin inhibitors (CNIs) and corticosteroids (CSs), have provided alternatives to the traditional combination maintenance immunosuppressive therapy of CSs, cyclosporine (CSA) or tacrolimus (TAC), and azathioprine (AZA) or mycophenolate mofetil (MMF). Research within this field of medicine is not only extensive, but also in constant progress. The purpose of the present review was therefore to summarize some major points regarding immunosuppressive therapies after HT and the balance between under- and over-immunosuppression. Transplant immunology, rejection, common medical problems related to over-immunosuppression, as well as induction and maintenance immunosuppressive drugs and therapies, are addressed.

Acute cellular rejection the first year after heart transplantation and its impact on survival: a single‐centre retrospective study at Skåne University Hospital in Lund 1988–2010

Acute cellular rejection (ACR) the first year after heart transplantation (HT) and its impact on survival was investigated. All 215 HT patients at our centre 1988–2010, including 219 HTs and 2990 first‐year endomyocardial biopsies (EMBs), were studied. ‘Routine’ EMBs obtained 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 32, 40 and 52 weeks after HT, and ‘additional clinically indicated’ (ACI) EMBs, were graded according to the 1990‐ISHLT‐WF. The frequency and severity of first‐year ACRs was low, with 6.5% of routine EMBs and 14.1% of ACI EMBs showing ACR ≥ grade 2. Proportionally more (P < 0.05) first‐year ACRs ≥ grade 2 were found among EMBs in HTs performed during 1988–1999 (9.6%) than 2000–2010 (5.5%), EMBs performed during 16–52 weeks (8.8%) than 1–12 weeks (6.3%) after HT, EMBs in HTs with paediatric (11.3%) than adult (7.1%) donors, and EMBs in sex‐mismatched (10.4%) than sex‐matched (6.3%) HTs. Five‐ and ten‐year survival was furthermore lower (P < 0.05) among HTs with ≥1 compared with 0 first‐year ACRs ≥ grade 3A/3B (82% vs. 92% and 69% vs. 82%, respectively). Ten‐year survival was 74% compared with 53% in the ISHLT registry. In conclusion, our results indicate that first‐year ACRs ≥ grade 3A/3B affect long‐term survival. We believe frequent first‐year EMBs may allow early ACR detection and continuous immunosuppressive adjustments, preventing low‐grade ACRs from progressing to ACRs ≥ grade 3A/3B, thereby improving survival.

Impact of postoperative pulmonary hypertension on outcome after heart transplantation

Abstract Objectives: We wanted to investigate the effects of postoperative pulmonary hypertension (PHpostop: mean pulmonary artery pressure [MPAP] ≥ 25 mmHg), diastolic pressure gradient (DPG), pulmonary vascular resistance (PVR), and repeated hemodynamic measurements on long-term survival after heart transplantation (HT). Design: Eighty-nine patients who underwent HT at Skåne University Hospital in Lund in the period 1988–2010 and who were evaluated with right-heart-catheterization at rest, prior to HT and repeatedly during the first postoperative year, were grouped based on their MPAP, DPG, and PVR. Results: One year after HT, survival was lower in patients with PHpostop than in those without, in patients with DPG ≥7 mmHg than in those with DPG <7 mmHg, and in patients with PVR >3 WU than in those with PVR ≤3 WU. Moreover, compared to patients with no PHpostop or with PHpostop at one evaluation during the first year after HT, PHpostop at repeated evaluations was associated with higher mortality (hazard ratio 3.4, 95% CI 1.4–8.0). There was no significant difference in acute cellular rejection between patients with and without PHpostop, but postoperative kidney function was worse in patients with repeated PHpostop. Conclusions: When defined according to present guidelines, PH one year after HT may emerge as a prognostic marker for long-term outcome after HT. Moreover, PHpostop at repeated evaluations during the first year after HT had stronger prognostic value than PHpostop at a single examination, illustrating a means of identifying a high-risk population. However, confirmation in larger multi-center studies is warranted.

Acute cellular rejection later than one year after heart transplantation : A single-center retrospective study at Skåne University Hospital in Lund 1988-2010

Routine endomyocardial biopsy (EMB) to detect acute cellular rejection (ACR) late (>1 year) after heart transplantation (HT) remains debated. To gain knowledge on late ACR and thereby approach this issue, we studied the incidence, predictors, and outcome of late ACR. 815 late EMBs from 183 patients transplanted 1988‐2010 were retrospectively reviewed until June 30, 2012. Only 4.4% of the routine and 17.6% of the additional clinically indicated late EMBs showed ACR ≥ grade 2. With time post‐HT, there was a clear trend toward fewer ACRs, a lower incidence of ACR per patient per year, and a deceleration in the decrease in the proportion of patients free from ACR. Sex‐mismatching and first‐year ACR were associated with an increased risk of late ACR, which also was associated with worse outcome. Although rare, when compared to our previous study on first‐year EMBs, it appears as if late more often than early ACR remains undetected and that also late and not only early ACR influences outcome. Extended EMB surveillance >1 year post‐HT therefore still seems reasonable in “high‐risk” patients, as also suggested in the International Society for Heart and Lung Transplantation guidelines. These should include, but not be limited to, the two risk groups above.

Safety and efficacy of the switch to generic mycophenolate mofetil and tacrolimus in heart transplant patients

Generic immunosuppressants may offer economic advantages, but their use is still controversial. At our center, 55 heart transplant patients were switched from CellCept® to Myfenax Teva® (MT) (n = 51, 18% female, 8.1 ± 6.6 yr post‐transplantation) and/or Prograf® to Tacrolimus Sandoz® (TS) (n = 17, 41% female, 6.6 ± 5.8 yr post‐transplantation).