Impact of basal heart rate on long‐term prognosis of heart transplant patients

Previous studies in patients with heart failure have shown that an elevated basal heart rate (HR) is associated with a poor outcome. Our aim with this study was to investigate if this relationship is also present in heart transplantation (HTx) recipients. From 2003 until 2010, 256 HTx performed in our center were recruited. Patients who required pacemaker, heart‐lung transplants, pediatrics, retransplants, and those patients with a survival of less than 1 year were excluded. The final number included in the analysis was 191. Using the HR obtained by EKG during elective admission at 1 year post‐HTx and the survival rate, an ROC‐curve was performed. The best point under the curve was achieved with 101 beats per minute (bpm), so patients were divided in two groups according to their HR. A comparison between survival curves of both groups was performed (Kaplan–Meier). Subsequently, a multivariate analysis considering HR and other variables with influence on survival according to the literature was carried out. A total of 136 patients were included in the group with HR ≤100 bpm, and 55 in the one with HR >100 bpm. There were no basal differences in both groups except for primary graft failure, which was more frequent in the >100 bpm group (30.9 vs. 17%, P = 0.033). Patients with ≤100 bpm had a better long prognosis (P < 0.001). The multivariate analysis proved that high HR was an independent predictor of mortality. Our study shows that HR should be considered as a prognosis factor in HTx patients.     

High‐sensitive Troponin T measurements early after heart transplantation predict short‐ and long‐term survival

Following heart transplantation, cardiac biomarkers remain elevated for several weeks eventually as a result of membrane leakage of the donor organ. We now test the predictive power of blood levels of troponin T (TNT) measured by the new hsTNT assay (Roche Diagnostics, Roche Diagnostics, Mannheim, Germany) early after heart transplantation. TNT was determined in 141 cardiac allograft recipients and 40 controls. Our findings demonstrate that patients who died within the first year after transplantation had significantly higher median hsTNT serum levels 6 weeks after transplantation (156 ng/l ± 203 vs. 29 ng/l ± 21, P = 0.0002). Using ROC analysis, a serum hsTNT concentration of 33.55 ng/l 6 weeks after transplantation was found to be the best cutoff to predict death at 1 year (HR 0.16, 95%CI:0.05–0.46, P = 0.001) with a sensitivity of 90.91% and a specificity of 70.97%. In addition, survival at 5 years (HR 0.15, 95% CI 0.06–0.35, P < 0.0001) was significantly better among patients below that cutoff value. In multivariate analysis, hsTNT serum level 6 weeks after transplantation emerged as an independent predictor for first‐year mortality (hsTNT–HR 0.90, 95% CI: 0.81–1.00, P = 0.03). Cardiac troponin T concentrations early after transplantation as measured with a highly sensitive assay represent a strong and independent risk predictor of death after heart transplantation.     

Donor‐specific anti‐HLA antibodies detected by Luminex: predictive for short‐term but not long‐term survival after heart transplantation

In heart transplantation, the clinical significance of pretransplant donor‐specific antibodies (DSA) detected by solid phase assay (SPA), which is more sensitive than the conventional complement‐dependent cytotoxicity (CDC) assays, is unclear. The aim was to evaluate SPA performed on pretransplant sera for survival after heart transplantation. Pretransplant sera of 272 heart transplant recipients were screened for anti‐HLA antibodies using CDC and SPA. For determination of pretransplant DSA, a single‐antigen bead assay was performed. The presence of anti‐HLA antibodies was correlated with survival. Secondary outcome parameters were acute cellular rejection, graft coronary vasculopathy and ejection fraction. In Kaplan–Meier analysis, SPA‐screening did not predict survival (P = 0.494), this in contrast to CDC screening (P = 0.002). However, the presence of pretransplant DSA against HLA class I was associated with decreased short‐term survival compared to non‐DSA (P = 0.038). ROC curve analysis showed a sensitivity of 76% and specificity of 73% at a cutoff of 2000 MFI. In contrast, the presence of anti‐HLA antibodies had no influence on long‐term survival, rejection incidence, and graft function. Thus, detection of DSA class I in pretransplant serum is a strong predictor of short‐term, but not long‐term survival and may help in the early management of heart transplant patients.     

Pancreas and kidney transplantation: long‐term endocrine function

Mora M, Ricart MJ, Casamitjana R, Astudillo E, López I, Jiménez A, Fernández‐Cruz L, Esmatjes E. Pancreas and kidney transplantation: long‐term endocrine function.
Clin Transplant 2010: 24: E236–E240. © 2010 John Wiley & Sons A/S. Abstract: Objective: To describe the characteristics of metabolic control and beta‐cell function in the long‐term follow‐up of patients with type‐1 diabetes (T1D) who have undergone pancreas and kidney transplantation (PKTx). Patients and methods: Twelve patients (eight males/four females) with normal pancreas and kidney graft function for more than 15 yr were included. Patient age at the time of transplantation was 35.8 ± 6.9, with a duration of diabetes of 19.0 ± 4.6 yr and time on dialysis of 18.7 ± 12.4 months. In all the cases, bladder derivation was performed to drain exocrine secretion, with subsequent conversion to the intestinal tract in 42% of the patients. The functional evaluation was made at one, five, 10, and 15 yr after PKTx determining: glycosylated hemoglobin (HbA1c), oral glucose tolerance test (OGTT), measuring insulinemia, and anti‐GAD antibody. Results: Comparing the results between one and 15 yr after transplantation: (i) no differences were observed in either HbA1c (4.68% vs. 4.76%) or basal glycemia (71 vs. 79 mg/dL), but an increase was seen in the area under the curve (AUC) of glucose (11 983 vs. 15 875 mg/dL/120′, p = 0.02); (ii) a trend to a reduction in basal insulinemia (24 vs. 15 mU/L, p = 0.11) and a trend to a reduction in the AUC of insulinemia (8446 vs. 7057 mU/L/120′, p = 0.22) were observed. The OGTT was normal in six patients, intolerant in two and diabetic in four patients. No variations were seen in insulin resistance (FIRI, QUICKI). Anti‐GAD antibody became positive in one case. Conclusions: The results of this study demonstrate that pancreas transplantation has long‐term functional viability, being an essential strategy for the treatment of patients with T1D with end‐stage renal failure. Nevertheless, lesser response to OGTT can be expected suggesting certain deterioration in the functional capability of the pancreas graft during follow‐up.     

Early immune biomarkers and intermediate‐term outcomes after heart transplantation: Results of Clinical Trials in Organ Transplantation‐18

Clinical Trials in Organ Transplantation‐18 (CTOT‐18) is a follow‐up analysis of the 200‐subject multicenter heart transplant CTOT‐05 cohort. CTOT‐18 aimed to identify clinical, epidemiologic, and biologic markers associated with adverse clinical events past 1 year posttransplantation. We examined various candidate biomarkers including serum antibodies, angiogenic proteins, blood gene expression profiles, and T cell alloreactivity. The composite endpoint (CE) included death, retransplantation, coronary stent, myocardial infarction, and cardiac allograft vasculopathy. The mean follow‐up was 4.5 ± SD 1.1 years. Subjects with serum anti‐cardiac myosin (CM) antibody detected at transplantation and at 12 months had a higher risk of meeting the CE compared to those without anti‐CM antibody (hazard ratio [HR] = 2.9, P = .046). Plasma VEGF‐A and VEGF‐C levels pretransplant were associated with CE (odds ratio [OR] = 13.24, P = .029; and OR = 0.13, P = .037, respectively). Early intravascular ultrasound findings or other candidate biomarkers were not associated with the study outcomes. In conclusion, anti‐CM antibody and plasma levels of VEGF‐A and VEGF‐C were associated with an increased risk of adverse events. Although this multicenter report supports further evaluation of the mechanisms through which anti‐CM antibody and plasma angiogenesis proteins lead to allograft injury, we could not identify additional markers of adverse events or potential novel therapeutic targets.     

Clinical evaluation of rosuvastatin in heart transplant patients with hypercholesterolemia and therapeutic failure of other statin regimens: short‐term and long‐term efficacy and safety results

We conducted an observational study of 30 heart transplant recipients with serum low‐density lipoprotein cholesterol (LDL‐c) >100 mg/dl despite previous statin therapy, who were treated with rosuvastatin 10 mg daily (5 mg in case of renal dysfunction). Serum lipids, creatine phosphokinase (CPK), bilirubin, and hepatic enzymes were prospectively measured 2, 4, and 12 weeks after the initiation of the drug. Clinical outcomes of patients who continued on long‐term rosuvastatin therapy beyond this 12‐week period were reviewed in February 2015. Over the 12‐week period following rosuvastatin initiation, serum levels of total cholesterol (TC) and LDL‐c and the ratio TC/high‐density lipoprotein cholesterol (HDL‐c) decreased steadily (P < 0.001). Average absolute reductions of these three parameters were –48.7 mg/dl, –46.6 mg/dl, and –0.9, respectively. Seventeen (57%) achieved a serum LDL‐c < 100 mg/dl. No significant changes from baseline were observed in serum levels of triglycerides, HDL‐c, hepatic enzymes, bilirubin, or CPK. Twenty‐seven (90%) patients continued on long‐term therapy with rosuvastatin over a median period of 3.6 years, with no further significant variation in lipid profile. The drug was suspended due to liver toxicity in 1 (3.3%) patient and due to muscle toxicity in 2 (6.7%) patients. All adverse reactions resolved rapidly after rosuvastatin withdrawal. Our study supports rosuvastatin as a reasonable alternative for heart transplant recipients with hypercholesterolemia and therapeutic failure of other statin regimens.     

Metabolic risk factors and long‐term graft function after paediatric renal transplantation

The aim of this study was to evaluate metabolic risk factors and their impact on long‐term allograft function in paediatric renal transplant (RTx) patients. We reviewed the medical records of 210 RTx patients who underwent transplantation at a median age of 4.5 years (range 0.7–18.2) and a median follow‐up of 7.0 years (range 1.5–18.0). Data on lipid and glucose metabolism, uric acid levels, weight and blood pressure were collected up to 13 years post‐RTx, and the findings were correlated with the measured glomerular filtration rate (GFR). Beyond the first year, GFR showed gradual deterioration with a mean decline of 2.4 ml/min/1.73 m²/year. Metabolic syndrome, overweight, hypertension and type 2 diabetes were diagnosed in 14–19%, 20–23%, 62–87% and 3–5% of the patients, respectively. These entities showed only mild association with the concomitant or long‐term GFR values. Dyslipidaemia was common and hypertriglyceridaemia associated with a lower GFR at 1.5 and 5 years post‐RTx (P = 0.008 and P = 0.017, respectively). Similarly, hyperuricaemia was frequent and associated significantly with GFR (P < 0.001). Except for hyperuricaemia and hypertriglyceridaemia, metabolic risk factors beyond the first postoperative year associated modestly with the long‐term kidney graft function in paediatric RTx patients.     

Patient‐reported health outcomes in long‐term lung transplantation survivors: A prospective cohort study

During the last three decades lung transplantation (LTx) has become a proven modality for increasing both survival and health‐related quality of life (HRQoL) in patients with various end‐stage lung diseases. Most previous studies have reported improved HRQoL shortly after LTx. With regard to long‐term effects on HRQoL, however, the evidence is less solid. This prospective cohort study was started with 828 patients who were on the waiting list for LTx. Then, in a longitudinal follow‐up, 370 post‐LTx patients were evaluated annually for up to 15 years. For all wait‐listed and follow‐up patients, the following four HRQoL instruments were administered: State‐Trait Anxiety Inventory, Zung Self‐rating Depression Scale, Nottingham Health Profile, and a visual analogue scale. Cross‐sectional and generalized estimating equation (GEE) analysis for repeated measures were performed to assess changes in HRQoL during follow‐up. After LTx, patients showed improvement in all HRQoL domains except pain, which remained steady throughout the long‐term follow‐up. The level of anxiety and depressive symptoms decreased significantly and remained constant. In conclusion, this study showed that HRQoL improves after LTx and tends to remain relatively constant for the entire life span.     

Cyclophosphamide‐induced tolerance in kidney transplantation avoids long‐term immunosuppressive therapy

There has recently been remarkable progress in immunosuppressive agents, such as tacrolimus and cyclosporine. Therefore, the rate of organ establishment has improved in transplantation. However, immunosuppressive agents generally suppress the function of T cells. Thus, opportunistic infections, such as cytomegalovirus infection, are still a major problem in kidney transplantation. Induction of specific tolerance to avoid immunosuppressive drug therapy after kidney transplantation is considered as the ultimate goal of transplantation. Various factors induce tolerance that involves establishment of hematopoietic chimerism and various cell subsets. In particular, we have carried out various studies regarding the cyclophosphamide‐induced tolerance system. Tolerance is induced after establishment of hematopoietic chimerism after donor bone marrow transplantation. At the clinical stage, kidney transplantation before administration of cyclophosphamide after transfusion of bone marrow to create hematopoietic chimera is considered to be one of the most successful protocols. Furthermore, recent studies have shown the involvement of multiple populations of immune cells in preserving immunological tolerance and promoting long‐term renal grafts. The present review focuses on how cyclophosphamide and other immune factors induce tolerance in kidney transplantation.     

Antihypertensive pharmacotherapy and long‐term outcomes in pediatric kidney transplantation

Hypertension (HTN) is common in pediatric recipients following kidney transplantation (KT). We retrospectively assessed the impact of HTN on long‐term (>10‐yr) outcomes in pediatric KT recipients (aged < 18 yr) at our center. Two hundred and ninety‐three pediatric KT recipients (83% living donor [LD]) with graft survival (GS) for ≥5 yr were studied. HTN was defined by antihypertensive medication use at five yr post‐KT. One hundred and sixty (55%) recipients did not have HTN, and 133 (45%) had HTN at five yr post‐KT. There were no differences in actuarial patient survival between cohorts. Actuarial GS at 15 and 20 yr was 68% and 53% for recipients without HTN, and 53% and 33% for recipients with HTN (p = 0.006). Among LD recipients using one antihypertensive, GS at 15 yr was 100% for those using an angiotensin‐converting enzyme inhibitor (ACEI) and 44% for those not using an ACEI (p = 0.04). Among these recipients, HTN treated with no ACEI was a significant risk factor for graft failure at >5 yr (hazard ratio [HR] = 2.5, p = 0.02), but HTN treated with an ACEI was not (HR = 0.6, p = 0.7). HTN at five yr post‐KT is associated with poorer long‐term GS in pediatric recipients, but ACEI therapy may enable better outcomes and should be studied further.     

Lung transplant recipients on long‐term extracorporeal photopheresis

Extracorporeal photophoresis (ECP) is an increasingly used therapy to address chronic lung allograft dysfunction (CLAD) following lung transplantation. In 2008, we reported the first single‐center experience showing that ECP not only reduces lung function decline in patients with bronchiolitis obliterans syndrome (BOS) but results in stabilization of patients with recurrent acute cellular rejection (ACR). In this study, the original cohort was followed up further 5 years. In addition, patients with CLAD were retrospectively classified according to recently published phenotypes. The current cohort included 21 of the original 24 patients, of which nine were initially treated for CLAD, 12 were initially treated for recurrent ACR. Our results show that survival of patients treated with ECP for CLAD was inferior to patients treated for recurrent ACR (66% vs. 82% survival rate). Long‐term survivors in the CLAD subgroup were mostly classified as BOS 1 at time of ECP initiation. These long‐term data show that patients started on ECP at early BOS stages have better long‐term outcome. The subgroup of ECP patients with recurrent ACR has an overall superior survival. To assist prediction of therapy response, we agree with other authors that patients with CLAD should be aimed to be phenotyped and evaluated for an early treatment with ECP.     

Pattern of resolution of pulmonary hypertension,long‐term allograft right ventricular function,and exercise capacity in high‐risk heart transplant recipients listed under oral sildenafil

Unresponsive pulmonary hypertension (PH) implies poor posttransplant outcomes. Data on late adaptation of the right ventricle (RV) are still few. This study evaluated three‐yr RV function and remodeling, exercise capacity, and hemodynamic data in a selected group of patients initially disqualified because of PH. Between May 2005 and December 2009, 31 consecutive patients were qualified for oral sildenafil because of unresponsive PH at baseline right heart catheterization (RHC). After a 12‐wk trial, RHC disclosed PH reversibility (mean PVR: 5.41 ± 3 Wood units, mean TPG 14.5 ± 5.6 mmHg, and mean systolic PAP 68.9 ± 15.1 mmHg), allowing listing even though as high‐risk procedures. All patients underwent heart transplantation. RV failure developed in three patients (9.6%), and hospital mortality was 3.2%. Protocol RHC disclosed pulmonary hemodynamic profile normalization within the third postoperative month, allowing weaning from sildenafil in the 30 hospital survivors. One‐ and three‐yr RHCs confirmed stable PH reversal (n = 26, all three‐yr survivors). Parameters of late RV function and remodeling proved satisfactory. Parameters of functional capacity (Vo₂ peak 19.7 ± 3.6 mL/kg/min and slope VE/Vco₂ 34.8 ± 2.7) proved homogeneous to those measured in transplant recipients with normal preoperative pulmonary artery pressure. Oral sildenafil is effective in allowing candidacy, safe transplantation, and long‐term survival in PH recipients initially disqualified.     

Significance of patient self‐monitoring for long‐term outcomes after lung transplantation

Kugler C, Gottlieb J, Dierich M, Haverich A, Strueber M, Welte T, Simon A. Significance of patient self‐monitoring for long‐term outcomes after lung transplantation.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01197.x
© 2009 John Wiley & Sons A/S. Abstract: Background: Lung transplant (LTx) recipients’ adherence to regular self‐monitoring of lung function (SMLF) is important in maintaining health. This study investigated patients’ behavior based on electronic monitoring (EM) and compared these findings with self‐reported data. Methods: This single‐center study included 269 patients following LTx. Patients reported on adherence regarding SMLF, and data were compared to electronically stored measurements for the last three months prior to self‐reporting. Results: Non‐adherence was 59.4% based on EM for a total of 22 052 measurements performed. Main reported reasons for non‐adherence were forgetfulness (22%), lack of time (19%), and good self‐perception of health status (19%). Determinants for non‐adherence were patients constraining beliefs (p ≤ 0.0001), low perceived support from the transplant center (p ≤ 0.008), a history of infections (p ≤ 0.014) and rejections (p ≤ 0.043), and bronchiolitis obliterans (p ≤ 0.006). Multiple logistic regression revealed low‐perceived support from the transplant center (OR 3.22; 95% CI 1.32–7.83; p < 0.01), and lack of support from patient organizations (OR 2.19; 95% CI 1.02–4.72; p < 0.04) as independent predictors for non‐adherence. Conclusions: LTx recipients had some difficulties maintaining SMLF on a daily basis. Non‐adherence regarding lung function monitoring may provide a clinically relevant estimate of suspect cases for critical events impacting outcomes after LTx.