Cancer Incidence in Heart Transplant Recipients With Previous Neoplasia History.

Neoplasm history increases morbidity and mortality after solid organ transplantation and has disqualified patients from transplantation. Studies are needed to identify factors to be considered when deciding on the suitability of a patient with previous tumor for heart transplantation. A retrospective epidemiological study was conducted in heart transplant (HT) recipients (Spanish Post-Heart Transplant Tumor Registry) comparing the epidemiological data, immu-nosuppressive treatments and incidence of post-HT tumors between patients with previous malignant noncardiac tumor and with no previous tumor (NPT). The impact of previous tumor (PT) on overall survival (OS) was also assessed. A total of 4561 patients, 77 PT and 4484 NPT, were evaluated. The NPT group had a higher proportion of men than the PT group (p < 0.001). The incidence of post-HT tumors was 1.8 times greater in the PT group (95% confidence interval [CI] 1.2-2.6; p < 0.001), mainly due to the increased risk in patients with a previous hematologic tumor (rate ratio 2.3, 95% CI 1.3-4.0, p < 0.004). OS during the 10-year posttransplant period was significantly lower in the PT than the NPT group (p = 0.048) but similar when the analysis was conducted after a first post-HT tumor was diagnosed. In conclusion, a history of PT increases the incidence of post-HT tumors and should be taken into account when considering a patient for HT.

Health-related quality of life, social support, and caregiver burden between six and 120 months after heart transplantation: a Spanish multicenter cross-sectional study.

A multicenter cross-sectional study was conducted to determine the current heart transplant (HTx) outcomes in Spain. Clinical and functional status, health-related quality of life (HRQoL), social support, and caregiver burden were analyzed in 303 adult transplant recipients (77.9% males) living with one functioning graft. Mean age at time of HTx (SD) was 56.4 (11.4) years, and the reason for transplantation in all patients was congestive heart failure. All patients had received a first heart transplant 6 (± 1), 12 (± 2), 36 (± 6), 60 (± 10), or 120 (± 20) months previously. Participants completed the Kansas City Cardiomyopathy Questionnaire (KCCQ), the EQ-5D, the Duke-UNC Functional Social Support Questionnaire, and the Zarit Caregiver Burden Scale. Reasonable HRQoL, social support, and caregiver burden levels were found at all time points, although a slight decrease in HRQoL was recorded at 120 months (p ≤ 0.033). Multivariate regression analyses showed that complications, comorbidities, and hospitalizations were associated with HRQoL (EQ-5D: 48.4% of explained variance, F4,164 = 38.46, p < 0.001; KCCQ overall summary score: 45.0%, F3,198 = 54.073, p < 0.001). Patient functional capabilities and complications affected caregiver burden (p < 0.05). In conclusion, HTx patients reported reasonable levels of HRQoL with low caregiver burden. Clinical variables related to these outcomes included functional status, complications, and number of admissions.

Chronic renal dysfunction in maintenance heart transplant patients: the ICEBERG study.

Chronic renal dysfunction (CRD) is a major complication after heart transplantation. We sought to describe the renal function over time, to assess the risk factors associated with CRD development, and to evaluate the clinical attitudes on diagnosis and treatment of CRD. A retrospective, cross-sectional, multicenter study was conducted in 13 outpatient clinics in Spain. A total of 244 heart recipients who survived more than 2 years after transplantation were included. Post-transplantation follow-up was 7.7 years (range: 2-22 years). CRD was diagnosed in 32.4% of patients at a mean of 3.3 years after transplantation. Serum creatinine increased 0.1 ± 0.2 mg/dL per year in CRD group compared with 0.0 ± 0.2 mg/dL per year in non-CRD group (P = .003) and glomerular filtration rate decreased -1.5 ± 4.3 mL/min/1.73 m(2) per year in CRD group versus -0.1 ± 4.8 mL/min/1.73 m(2) per year in non-CRD group (P = .027). After CRD diagnosis, major changes in immunosuppression based on calcineurin inhibitors reduction were instituted in 46.8% of patients. Multivariate model identified recipient age (P < .0001), female sex (P = .0398), and time since transplant (P < .0001) as predictors of CRD. In conclusion, the prevalence of CRD in long-term heart recipient survivors was quite high. CRD was associated with nonmodifiable factors (age, gender, and time since transplant).

Use of mTOR inhibitors in chronic heart transplant recipients with renal failure: calcineurin-inhibitors conversion or minimization?

BACKGROUND: In the last decade, mTOR inhibitors (mTOR-is) have become the cornerstone of the calcineurin inhibitor (CNI)-reduced/free regimens aimed to the preservation of post-transplant renal function. We compared utility and safety of the total replacement of calcineurin inhibitors with a mTOR-i with a strategy based on calcineurin inhibitor minimization and concomitant use of m-TOR-i. METHODS: In a retrospective multi-center cohort of 394 maintenance cardiac recipients with renal failure (GFR<60 mL/min/1.73 m(2)), we compared 235 patients in whom CNI was replaced with a mTOR-i (sirolimus or everolimus) with 159 patients in whom mTOR-is were used to minimize CNIs. A propensity score analysis was carried out to balance between group differences. RESULTS: Overall, after a median time of 2 years from mTOR-i initiation, between group differences for the evolution of renal function were not observed. In a multivariate adjusted model, improvement of renal function was limited to patients with mTOR-i usage within 5years after transplantation, particularly with the conversion strategy, and in those patients who could maintain mTOR-i therapy. Significant differences between strategies were not found for mortality, infection and mTOR-i withdrawal due to drug-related adverse events. However, conversion group tended to have a higher acute rejection incidence than the minimization group (p=0.07). CONCLUSION: In terms of renal benefits, our results support an earlier use of mTOR-is, irrespective of the strategy. The selection of either a conversion or a CNI minimization protocol should be based on the clinical characteristics of the patients, particularly their rejection risk.

Andalusian registry of heart transplantation: first official adult heart transplant report 2010.

This is the first official report of the Andalusian Registry of Heart Transplantation. Since 1986, two centers in the community have been authorized to perform adult heart transplantation. Until 2010, 854 adult heart transplantation procedures were performed, which constitute the basis of the present report. Clinical features and survival are analyzed. The leading reason for heart transplantation was ischemic cardiomyopathy (34%) and nonischemic dilated cardiomyopathy (34%). The mean age of the recipients was 46 ± 16 years and the mean age of the donors was 29 ± 13 years. After a median follow-up of 106 months, the mean survival was 13.4 ± 0.6 years.

Improvement in chronic renal failure after mycophenolate mofetil introduction and cyclosporine dose reduction: four-year results from a cohort of heart transplant recipients.

Chronic renal failure (CRF) due to calcineurin inhibitor (CNI) nephrotoxicity is a frequent complication among heart transplant (HT) recipients. Small studies have suggested that the introduction of mycophenolate mofetil (MMF) can help to reduce CNI doses thereby to maintaining or improving renal function. We conducted a 4-year, prospective, multicenter study in 89 maintenance HT recipients at 5.6 ± 2.7 years postgrafting who displayed CRF (serum creatinine > 1.4 mg/dL) and were undergoing treatment with cyclosporine and prednisone ± azathioprine. We introduced MMF and reduced cyclosporine to level below 100 ng/mL. Creatinine clearance (CrCl), acute rejection episodes, and survival were through retrospectively compared with a contemporary cohort of HT recipients who were not treated with MMF (control group; n = 38). After conversion to MMF, a rapid increase was observed in the CrCl, which was maintained over the follow-up: namely, CrCl at month 6 and at 4 years were 51.0 ± 15.6 and 54.1 ± 15.6 mL/min versus 41.9 ± 11.1 mL/min at baseline (P < .0001). No renal function changes were observed among the control group. Acute rejection rates were 5.6% and 2.6% in the MMF versus control groups (P = NS) with 4-year survivals >85%. In conclusion, the introduction of MMF allowed a safe reduction of cyclosporine and significantly improved renal function after 4 years.

Risk factors associated with cytomegalovirus infection in heart transplant patients: a prospective, epidemiological study.

BACKGROUND: The objectives of this epidemiological, prospective study were to describe the characteristics of cytomegalovirus (CMV) infection in heart transplant (HT) recipients and to identify the variables that may influence the development of CMV viremia and CMV disease in these patients. METHODS: HT recipients ≥18 years of age (n=199) were included in the study. Variables studied included CMV serostatus, immunosuppressive treatment, and administration of anti-CMV prophylaxis. RESULTS: The mean age of the population was 52 years, and 84% were males. Immunosuppressive regimens were administered as induction therapy to 92.5% of patients; 88.5% of patients received calcineurin inhibitors as maintenance therapy. Anti-CMV treatment was given to 59% of 199 patients as prophylaxis (70%), preemptive therapy (10%), or to treat CMV infection (20%). Overall, 43% of patients had at least 1 positive viremia test. No patient with a high-risk serostatus (donor+/recipient-) receiving prophylaxis developed CMV syndrome, and only 2.5% of 199 patients developed CMV invasive disease. Multivariate analysis showed that having a positive donor CMV serostatus was associated with an increased risk of developing CMV viremia (P<0.012), while use of mammalian target of rapamycin (mTOR) inhibitors was associated with a decreased risk (P=0.005). CONCLUSIONS: In a population of HT recipients, the CMV infection rate was similar to that seen in previous studies, but the progression to overt CMV disease was very low. Having a CMV-positive donor was identified as an independent risk factor for developing CMV viremia, while the use of mTOR inhibitors was protective against viremia.

Temporal trends in the use of proliferation signal inhibitors in maintenance heart transplantation: a Spanish multicenter study.

Proliferation signal inhibitors (PSI; sirolimus, everolimus) are being increasingly used in heart transplantation. We performed an observational, retrospective, multicenter study in 9 Spanish centers seeking to describe the clinical context in which a PSI was used among maintenance heart recipients and its evolution over time. We collected a cohort of 548 patients in whom a PSI was prescribed from October 2001 to March 2009. The group was divided into 3 time periods. The use of PSI steeply increased in the 2005-2006 period, remaining stable thereafter. There were no significant differences over time with regard to age, gender, or time from transplantation to the introduction of the PSI. Everolimus usage overtook sirolimus from 2005 on; currently, >90% of the subjects with PSI indications are prescribed everolimus. Compared with earlier periods, patients in the more recent period (October 2006-March 2009) showed less vascular graft disease and better basal renal function, irrespective of the primary indication for the PSI prescription. Also, skin cancer overtook solid cancer as the main type of neoplasm in patients for whom malignancy was the primary indication for the use of the PSI. The actuarial incidence of PSI withdrawal owing to adverse effects did not change significantly over time.

Incidence and risk factors for nonmelanoma skin cancer after heart transplantation.

INTRODUCTION: The incidence of skin cancer in heart transplant (HT) patients is higher than in the general population, reversing the proportion of cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) with a predominance of the former. The etiologic role of new immunosuppressants is not well known. We sought to ascertain the incidence of SCC and BCC in HT patients and the risk factors for its occurrence. PATIENTS AND METHODS: We report the incidence of all types of post-HT skin cancer, SCC, and BCC among adult HT patients in Spain (4089 subjects) as well as the influence of gender, age at heart transplant, immunosuppression, and sunlight exposure. RESULTS: The incidence rates of SCC and BCC, per 1000 persons/year, were 8.5 and 5.2, respectively. Males had a higher risk of SCC but not BCC. Induction therapy increased the risk of SCC and BCC. The relative risk of mycophenolate mofetil (MMF) was 0.3 (0.2-0.6; P<.0005) and azathioprine (AZA) 1.8 (1.2-2.7; P<.0032) for SCC, whereas tacrolimus and cyclosporine showed no difference. The relative risk of BCC was not affected by any immunosuppressant. CONCLUSION: Age at transplantation>45 years, induction therapy use, and high sunshine zone were risk factors for both SCC and BCC. Different immunosuppressive agents have different risks of nonmelanoma skin cancer, as AZA increases the risk of SCC and MMF is a protective factor. The relative risk of BCC was not affected by any immunosuppressor.

[Pharmacogenetic analysis of the absorption kinetics of cyclosporine in a population of Spanish cardiac transplant patients]. / Análisis farmacogenético de la cinética de absorción de ciclosporina en una población española de pacientes trasplantados cardíacos.

OBJECTIVE: To determine how single nucleotide polymorphisms located on genes MDR1, CYP3A4 and CYP3A5 affect the absorption kinetics of cyclosporine in cardiac transplant patients. METHOD: We selected a sample of 30 adult patients having previously undergone a primary cardiac transplant and who had received cyclosporine as an immunosuppressant. During the first month after the transplant, we performed a pharmacokinetic study of each patient to determine values in the cyclosporine concentration area under the 12-hour curve, steady-state cyclosporine concentration, maximum cyclosporine concentration, and time to reach that concentration. Single nucleotide polymorphisms were genotyped in all patients: MDR1 3435C > T, CYP3A4-390A > G and CYP3A5 6986A > G. RESULTS: Being a carrier of the T-allele for polymorphism MDR1 3435C > T is associated with higher values in the cyclosporine concentration area under the 12-hour curve (p = 0.01) and in steady-state cyclosporine concentration (p = 0.05), compared with those from patients who do not carry that allele. DISCUSSION: Our results show that genotype differences in MDR1 3435C > T can explain part of the variability in cyclosporine absorption among individuals in the population of Spanish cardiac transplant recipients.

Análisis farmacogenético de la cinética de absorción de ciclosporina en una población española de pacientes trasplantados cardíacos / Pharmacogenetic analysis of the absorption kinetics of cyclosporine in a population of Spanish cardiac transplant patients

Objetivo: Determinar el papel de polimorfismos de nucleótido único localizados en los genes MDR1, CYP3A4 y CYP3A5 sobre la cinética de absorción de ciclosporina en pacientes trasplantados cardíacos. Método: Se seleccionó una muestra de 30 pacientes adultos sometidos a un primer trasplante de corazón que habían recibido ciclosporina como tratamiento inmunosupresor. En el primer mes después del trasplante se realizó un estudio farmacocinético a cada paciente para determinar los valores del área de concentración de ciclosporina bajo la curva de 12 h, concentración de ciclosporina en estado de equilibrio, concentración de ciclosporina máxima y el tiempo en alcanzar dicha concentración. En todos los pacientes se genotipificaron los polimorfismos de nucleótido único: MDR1 3435C > T, CYP3A4-390A > G y CYP3A5 6986A > G. Resultados: Ser portador del alelo T para el polimorfismo MDR1 3435C > T se asoció a valores mayores de área de concentración de ciclosporina bajo la curva de 12 h (p = 0,01) y de concentración de ciclosporina en estado de equilibrio (p = 0,05), en comparación con los pacientes no portadores de dicho alelo. Discusión: Nuestros resultados muestran que las diferencias genotípicas de MDR1 3435C > T podrían explicar parte de la variabilidad interindividual en la absorción de la ciclosporina en la población española de trasplantados cardíacos (AU)

Objective: To determine how single nucleotide polymorphisms located on genes MDR1, CYP3A4 and CYP3A5 affect the absorption kinetics of cyclosporine in cardiac transplant patients. Method: We selected a sample of 30 adult patients having previously undergone a primary cardiac transplant and who had received cyclosporine as an immunosuppressant. During the first month after the transplant, we performed a pharmacokinetic study of each patient to determine values in the cyclosporine concentration area under the 12-hour curve, steady-state cyclosporine concentration, maximum cyclosporine concentration, and time to reach that concentration. Single nucleotide polymorphisms were genotyped in all patients: MDR1 3435C > T, CYP3A4-390A > G and CYP3A5 6986A > G. Results: Being a carrier of the T-allele for polymorphism MDR1 3435C > T is associated with higher values in the cyclosporine concentration area under the 12-hour curve (p = 0.01) and in steady-state cyclosporine concentration (p = 0.05), compared with those from patients who do not carry that allele. Discussion: Our results show that genotype differences in MDR1 3435C > T can explain part of the variability in cyclosporine absorption among individuals in the population of Spanish cardiac transplant recipients (AU)

Usefulness of sirolimus as rescue therapy in heart transplant recipients with renal failure: analysis of the Spanish Multicenter Observational Study (RAPACOR).

BACKGROUND: Chronic renal failure is a common complication of heart transplantation. Sirolimus (SRL) is an immunosuppressive drug that, unlike calcineurin inhibitors (CNIs), is not associated with nephrotoxicity. METHODS: We collected efficacy and safety data from a Spanish registry of heart transplant recipients who were switched from a CNI to SRL due to renal failure. Patients were included if the serum creatinine level before switching was >1.5 mg/dL and/or the estimated creatinine clearance level was below 50 mL/min. RESULTS: Ninety-seven patients started SRL due to renal impairment. When SRL was started, CNIs were progressively tapered and in some cases withdrawn. Mean baseline creatinine level was 2.5 mg/dL and mean creatinine clearance level was 39 mL/min. Only 1 episode of acute rejection was observed in a patient receiving SRL plus cyclosporine (CsA) but the eventual allograft function remained stable. Compared with baseline, a significant improvement in renal function was observed at 6 months among patients who stopped CNIs before the third month after SRL was started, although not among those who continued taking CNIs. Upon multivariate analysis, no predictors of response were observed. SRL was withdrawn in 18% of patients due to adverse events. CONCLUSIONS: Switching to SRL was safe in heart allograft recipients, improving renal function among those previously receiving a CNI. Renal function improves if CNIs are withdrawn soon after starting SRL.

Steroid use in heart transplant patients in Spain in the current era: a multicenter survey.

OBJECTIVE: Steroid withdrawal (SW) from maintenance therapy in heart transplant patients is still a controversial subject. We designed a questionnaire to ascertain the attitudes and procedures of a number of Spanish heart transplant units (16) regarding the use/withdrawal of steroids as part of the immunosuppressive maintenance therapy. MATERIALS AND METHODS: We sent an 11-item questionnaire to the clinical director in charge of each unit. The questionnaire was completed and returned by 14 units. RESULTS: In 21.5% of the centers SW was performed in all patients, while 78.5% of the centers only performed SW in selected patients. In 57% of units SW was performed at 12 months posttransplantation and between 6 and 12 months in the rest. Fewer than 20% of patients were steroid-free in 46% of units while in 23% of units this proportion was >50%. In 11 units, the minimum prednisone dose administered was

Outcomes of heart transplantation for cardiac amyloidosis: subanalysis of the spanish registry for heart transplantation.

Amyloidosis (Am), a systemic disease, has poor prognosis because of organ damage produced by protein deposition in the extracellular space. Although heart transplantation (HTx) is possible, donor availability concerns and high mortality make this approach controversial. The Spanish Registry for Heart Transplantation includes 25 Am patients (54 +/- 9 years): 13 with AL type, 2 with AA and 10 with TTR mutation. Fifteen patients (60%) died during follow-up (4.9 +/- 1.3 years): 9 AL-Am patients, both AA-Am patients and 4 with TTR-Am. HTx survival for Am patients was similar to patients without Am at 1 month but significantly worse at 5 years: 46% versus 78% (p < 0.02). Of 10 AL-Am patients undergoing successful HTx, 4 died of systemic Am. Stem cell transplantation was performed in 3 (1 died of acute rejection). Five of 10 patients with TTR-Am underwent liver transplant; 4 remained alive at the last follow-up. Findings include poor outcome for AL-Am patients despite HTx and better survival for TTR-Am patients if HTx is associated with liver transplantation. Given the shortage of donors and poor outcome for Am patients, we would recommend that HTx be reserved for patients without or with mild systemic Am and be supplemented by additional therapies as indicated.

Malignancy after heart transplantation: incidence, prognosis and risk factors.

The Spanish Post-Heart-Transplant Tumour Registry comprises data on neoplasia following heart transplantation (HT) for all Spanish HT patients (1984-2003). This retrospective analysis of 3393 patients investigated the incidence and prognosis of neoplasia, and the influence of antiviral prophylaxis. About 50% of post-HT neoplasias were cutaneous, and 10% lymphomas. The cumulative incidence of skin cancers and other nonlymphoma cancers increased with age at HT and with time post-HT (from respectively 5.2 and 8.9 per 1000 person-years in the first year to 14.8 and 12.6 after 10 years), and was greater among men than women. None of these trends held for lymphomas. Induction therapy other than with IL2R-blockers generally increased the risk of neoplasia except when acyclovir was administered prophylactically during the first 3 months post-HT; prophylactic acyclovir halved the risk of lymphoma, regardless of other therapies. Institution of MMF during the first 3 months post-HT reduced the incidence of skin cancer independently of the effects of sex, age group, pre-HT smoking, use of tacrolimus in the first 3 months, induction treatment and antiviral treatment. Five-year survival rates after first tumor diagnosis were 74% for skin cancer, 20% for lymphoma and 32% for other tumors.

sHLA-G levels in the monitoring of immunosuppressive therapy and rejection following heart transplantation.

The aim of this study was to further determine the immediate influence, over a 12-h period, after the initiation of daily immunosuppressive treatment on the serum levels of sHLA-G in heart transplant patients during the post-transplant period (1 month). It was found that there are two patterns of patients in term of the changes observed in their levels of sHLA-G in response to the immunosuppressive treatment. One group (group A) showed no changes on sHLA-G while the other group (group B) a significant rise in sHLA-G levels was observed at 2 to 4 h post dose. Interestingly, it was observed that the patients in group B have better prognosis of acceptance of the heart graft than those of group A. On the other hand it was found that the patients with high levels of sHLA-G (77.3+/-34.8 ng/ml) in pre-transplant sera have a better prognosis of acceptance of the heart graft than those with low sHLA-G levels (9.7+/-7.1 ng/ml). In conclusion, both the intensity of changes of sHLA-G levels induced by immunosuppression and basal levels in pre-transplant could be used in the monitoring of the immunosuppression as well as the heart transplant evolution.

Soluble HLA-G in heart transplantation: their relationship to rejection episodes and immunosuppressive therapy.

The aims of this study were to quantify the level of soluble HLA-G in heart transplant patients, to determine the relationship between the sHLA-G levels and the appearance of acute rejection episodes, and to identify the influence of immunosuppressive therapy on sHLA-G levels. Analysis of sHLA-G, measured by enzyme-linked immunosorbent assay in the transplant patients, revealed the existence of two similarly sized groups of patients. One group displayed a significant increase (p < 0.001) in sHLA-G during the first month after transplantation while the other group maintained low levels of the molecule (0-30 ng/ml) throughout the study. The latter group displayed a high incidence of recurrent severe rejection. A significant increase (p < 0.01) in sHLA-G 2 hours after administration of immunosuppressive treatment (mycophenolate mofetil, cyclosporine A/FK506, corticoids) was found. These results suggest that sHLA-G participates in the induction of certain levels of immunological tolerance in these recipients.

Relationship between pharmacokinetic parameters of cyclosporin and the incidence of acute rejection after heart transplantation.

Despite two decades of use, there are limited data on the best way to monitor Cyclosporine (CsA) for heart transplantation. The aim of our study was to determine the relationships between pharmacokinetic parameters and clinical outcomes after heart transplantation and to evaluate the range of CsA trough levels provided the most effective protection against graft rejection. We retrospectively analyzed the clinical outcomes of all adult patients who received a heart transplant between January 1998 and February 2005. All had routine monitoring of CsA trough levels and scheduled endomyocardial biopsies. Rejection was defined as grade > or =3, based on International Society for Heart and Lung Transplantation (ISHLT) criteria. Follow-up period was 1 year. All patients were on CsA, corticosteroids, and azathioprine/mycophenolate mofetil with or without antilymphocyte induction (eight patients with basiliximab). Data were analyzed by unpaired Student t-test, Cox regression model, and ROC curve. Among 70 patients (60 men and 10 women) who entered the study, 34 (48.6%) had at least one acute rejection episode of grade > or =3 during the first posttransplant year. Mean CsA trough level (C(0)) measured at first week posttransplant was significantly lower in the rejection than the no-rejection group (125.17 +/- 56.9 ng/mL versus 169.33 +/- 48.27 ng/mL, P = .001). C(0) was the strongest predictor of acute graft rejection (P = .000, HR = .985.) The risk decreased by 1.5% for each unit increase of the C(0) value. ROC analysis showed that C(0) of 150 ng/mL provided the optimal cutoff. Patients with mean C(0) >150 ng/mL over the first week had less incidence of acute rejection than patients with levels <150 ng/mL (30.3% versus 64.9%) (P = .009, Cochran-Mantel-Haenszel test). In conclusion, our data suggest that in heart transplant patients it may be crucial to target early trough levels above 150 ng/mL during the first days postsurgery to avoid rejection.