Haifa Lyster

Chronic kidney disease after heart transplantation

BACKGROUND Chronic kidney disease (CKD) is a complication of heart transplantation related to calcineurin inhibitor nephrotoxicity. However, it is unclear whether early ciclosporin (CsA) exposure influences CKD in the long term. METHODS We analysed risk factors for CKD in 352 patients who underwent orthotopic heart transplantation (1995-2005). In 2000, we reduced our target CsA levels in the first year after transplantation. RESULTS Actuarial patient survival was 79% at 1 year and 62% at 10 years. Estimated median glomerular filtration rate (eGFR) by the four-variable Modification of Diet in Renal Disease formula was 64 ml/min/1.73 m2 before transplantation, inter-quartile range (IQR) 54-78. After transplantation, the eGFR was 48 (IQR 37-61) at Year 1, and 41(35-57) at Year 10. The cumulative probability of eGFR <45 ml/min/1.73 m2 was 45% at Year 1, 71% at Year 5 and 83% at Year 10. A multivariable logistic regression model was constructed for the development of eGFR <45 ml/min/1.73 m2 by 3 years. The risk factors were post-operative renal replacement therapy for acute renal failure (ARF), P < 0.001; pretransplant diabetes, P = 0.005; increasing recipient age, P < 0.001; female recipient, P = 0.029; female donor, P = 0.04, but not CsA regimen. The cumulative probability of developing stage 5 CKD (eGFR <15) was 3% at Year 5 and 12% at Year 10. Although lower ciclosporin initial levels were associated with less renal dysfunction at Year 1 (P = 0.008), there was no significant effect by Year 3 (P = 0.7). CONCLUSION The incidence of CKD increased with time and was not influenced by the CsA regimen. Some risk factors are not modifiable but measures to reduce the incidence of post-operative ARF may help to reduce CKD.

Late antibody-mediated rejection after heart transplantation following the development of de novo donor-specific human leukocyte antigen antibody.

Background. Antibody-mediated rejection (AMR) is an important problem after heart transplantation. Most cases seem to occur in sensitized recipients with preformed donor-specific human leukocyte antigen antibody (DSA) early after transplantation. Few data exist on AMR in patients who form de novo DSA. We describe the clinical features and treatment outcome for late AMR secondary to de novo DSA. Methods. This was a retrospective, observational cohort study. All heart transplant patients treated for symptomatic AMR secondary to de novo DSA between November 2005 and August 2011. Results. Fifteen patients were treated for AMR giving an incidence of 3.1 cases per 1000 person years and a prevalence of 1.4%. All had evidence of heart failure on presentation and de novo DSA at diagnosis. There was a spectrum of histologic and immunohistochemical findings. Despite treatment with immunepheresis, intravenous immunoglobulin, and rituximab, and in some cases total lymph node irradiation (n=3) and bortezomib (n=2), clinical outcomes were poor. DSA antibody levels, measured using Labscreen single antigen kits, were reduced by a mean of 76% with a median of 77% and a range of 35% to 99%, but were not eliminated. Forty-six percent had persistent cardiac allograft dysfunction. Mean and median survival was 1.3 and 0.8 years after diagnosis of AMR. Only 40% were alive at the end of the study period. Conclusion. Late cardiac AMR caused by de novo DSA was an uncommon but serious problem. Despite treatment consistent with current best practice, 46% of patients developed persistent cardiac dysfunction and their medium-term survival was poor.

Comparison of clinical and economic outcomes of two antibiotic prophylaxis regimens for sternal wound infection in high-risk patients following coronary artery bypass grafting surgery: a prospective randomised double-blind controlled trial

Objective: Prospective studies show a 10% incidence of sternal wound infection (SWI) after 90 days of follow-up, compared with infection rates of 5% reported by the National Nosocomial Infections Surveillance System after only 30 days of follow-up. This incidence increases 2–3 times in high-risk patients. Design: Prospective randomised double-blind controlled clinical trial. Setting: Cardiothoracic centre, UK. Patients: Patients were eligible if they were undergoing median sternotomy for primary isolated coronary artery bypass grafting, with at least one internal thoracic artery used for coronary grafting and having one or more of the following three risk factors: (1) obesity, defined as body mass index 30 kg/m2; (2) diabetes mellitus; or (3) bilateral internal thoracic artery grafts (ie, the use of the other internal thoracic artery). Interventions: The study group received a single dose of gentamicin 2 mg/kg, rifampicin 600 mg and vancomycin 15 mg/kg, with three further doses of 7.5 mg/kg at 12-hour intervals. The control group received cefuroxime 1.5 g at induction and three further doses of 750 mg at 8-hour intervals. Main outcome measures: The primary end point was the incidence of SWI at 90 days. The secondary end point was the antibiotic and hospital costs. Results: During the study period, 486 patients underwent isolated coronary artery bypass grafting with a 30-day SWI of 7.6%. 186 high-risk patients were recruited and analysed: 87 in the study group and 99 in the control group. 90-day SWI was significantly reduced in 8 patients in the study group (9.2%; 95% CI 3.5% to 15.3%) compared with 25 patients in the control group (25.2%; 95% CI 19.5% to 39.4%; p = 0.004). The study group had a significantly lower cost of antibiotics (21.2% reduction—US

Mycophenolate mofetil may allow cyclosporine and steroid sparing in de novo heart transplant patients

96/patient; p<0.001), and a significantly lower hospital cost (20.4% reduction in cost—US

Management of an ABO-Incompatible Lung Transplant

3800/patient; p = 0.04). Conclusions: Longer and broader-spectrum antibiotic prophylaxis significantly reduces the incidence of SWI in high-risk patients, with a significant economic benefit in costs of antibiotics as well as hospital costs.

De Novo HLA Sensitization and Antibody Mediated Rejection Following Pregnancy in a Heart Transplant Recipient

Background. Mycophenolate mofetil (MMF) provides superior prophylaxis against acute rejection when compared with azathioprine (AZA) in heart and renal transplantation. However, it remains unclear whether this results in improved survival or reduced morbidity after heart transplantation. Method. In a sequential study, 240 cardiac transplant patients were treated with either MMF (n=119) or AZA (n=121) both in combination with cyclosporine and corticosteroids after rabbit antithymocyte globulin induction. Results. By protocol lower cyclosporine levels were targeted in the MMF group during the first year (e.g. 203±52 ng/mL MMF vs. 236±59 ng/mL AZA, P=0.0006 at 6 months). Patient survival at 1 year (82% MMF vs. 79% AZA, P=0.55) and at 3 years was similar in both groups. The cumulative probability of receiving antirejection treatment within 1 year was lower in the MMF group, as was biopsy-proven acute rejection with International Society of Heart and Lung Transplantation grade ≥3A (24% vs. 35%, P=0.03). The MMF group also had fewer episodes requiring cytolytic therapy (6% vs. 13%, P=0.04) and more patients had steroids withdrawn by 1 year (66% vs. 32%, P<0.001). Renal function was better in the MMF group with lower creatinine levels at 1 year (133±45 vs. 155±46 &mgr;mol/L, P=0.0004). Calculated creatinine clearance (Cockcroft and Gault formula) at 1 year was also better (MMF 74±32 mL/min vs. AZA 62±24 mL/min, P=0.004). Conclusion. Our results suggest that immunosuppression with MMF rather than AZA may allow lower cyclosporine levels, better renal function, and increased steroid weaning at 1 year while also achieving better control of acute rejection.

ATP-binding cassette subfamily B member 1 polymorphisms do not determine cyclosporin exposure, acute rejection or nephrotoxicity after heart transplantation.

A 24‐year‐old woman with cystic fibrosis underwent bilateral sequential lung transplantation and unintentionally received an ABO incompatible graft (blood type A1 graft into a type O recipient). The recipient had a high titer of IgG anti‐A antibody (256 by the indirect antiglobulin test). Emergency treatment included antibody removal by plasmapheresis and additional immunosuppression with mycophenolate, rabbit antithymocyte globulin and polyspecific intravenous immunoglobulin. Subsequently, immunoadsorption and the anti‐CD20 antibody rituximab were used to remove anti‐A antibody and inhibit its resynthesis. Early graft function was good; one episode of rejection at Day 46 responded promptly to treatment with methylprednisolone. Subsequently, graft function continued to improve and anti‐A antibody titers remained low. No infectious or other complications were encountered. The treatment regimen that we adopted may prove useful in other cases of unplanned ABO‐incompatible organ transplants. The successful outcome suggests that planned ABO‐incompatible lung transplants may be possible.

Transfer from ciclosporin to mycophenolate-sirolimus immunosuppression for chronic renal disease after heart transplantation: safety and efficacy of two regimens

Here we report a case wherein both donor‐specific and third‐party, paternal, HLA class II specific antibodies developed following a spontaneous miscarriage resulting in antibody‐mediated rejection in a patient who had undergone an orthotopic cardiac transplant six years earlier.

Fungal infection in cardiothoracic transplant recipients: outcome without systemic amphotericin therapy

Background. We hypothesized that genetic variation of ATP-binding cassette subfamily B member 1 (ABCB1) that encodes P-glycoprotein (involved in the uptake of cyclosporin A [CsA]) contributes to trough drug concentrations and thereby to CsAs immunosuppressive and toxic effects. Methods. Three hundred thirty-seven adult heart transplant recipients were studied retrospectively. White recipients receiving CsA at month 3 and years 1 to 5 after transplantation (n=192, 168, 156, 130, 95, and 74, respectively) were then studied with respect to ABCB1 genotype or haplotype and CsA disposition. Genotyping was performed using a gel-based polymerase chain reaction method. Dose- and weight-adjusted CsA trough concentrations ([&mgr;g/L]/[mg/kg]), time to first endomyocardial biopsy-proven acute rejection episode (grade≥3A), weaning from steroids at 1 year, and renal function at 1 year posttransplant were measured. Results. An association between dose- and weight-adjusted CsA trough concentrations and ABCB1 haplotypes was found, with 12/1236, 21/2677, 26/3435 CC/GG/CC individuals having significantly higher concentrations than TT/TT/TT individuals at years 1 and 5 (68.9±26.9 vs. 54.9±19.5 and 70.6±35 vs. 50.0±12.2 [&mgr;g/L]/[mg/kg] P<0.05, respectively) There was no difference in the incidence of acute rejection, steroid weaning, or renal impairment between the genotype or haplotype groups. Conclusions. The association of ABCB1 12/1236, 21/2677, and 26/3435 CC/GG/CC haplotype with increased CsA dose- and weight-adjusted CsA trough concentrations in this group of adult white heart transplant recipients was not consistent over time and had no effect on the incidence of acute rejection or on the development of renal impairment.

Postoperative Care of the Heart Transplant Patient

BACKGROUND Chronic kidney disease is common after heart transplantation, and is related to ciclosporin (CsA) therapy. We compared the safety and efficacy of two ciclosporin withdrawal regimens. METHODS CsA was stopped and sirolimus (SRL) commenced immediately and the transfer was covered with prednisolone. Those on azathioprine (AZA) were transferred to MMF. In protocol A, the SRL target concentration was 16 (12-20) ng/ml; in protocol B, the target concentration was 7(5-10) ng/ml, but mycophenolate (MMF) and steroids were commenced prior to the transfer. RESULTS Baseline characteristics were similar in both groups except that group B were switched later after transplantation. Renal function improved significantly in both groups; this was maintained up to 1 year. Two patients in group A experienced acute rejection (ISHLT grade 3A or 2R); none was seen in group B. Six patients (46%) remained on protocol A and 22 (85%) remained on protocol B at 1 year. CONCLUSIONS MMF-SRL substitution resulted in a rapid but partial improvement in renal function; the lower dose SRL regimen was better tolerated.