Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations.

Solid organ transplant (SOT) recipients are especially at risk of developing infections by multidrug resistant (MDR) Gram-negative bacilli (GNB), as they are frequently exposed to antibiotics and the healthcare setting, and are regulary subject to invasive procedures. Nevertheless, no recommendations concerning prevention and treatment are available. A panel of experts revised the available evidence; this document summarizes their recommendations: (1) it is important to characterize the isolate's phenotypic and genotypic resistance profile; (2) overall, donor colonization should not constitute a contraindication to transplantation, although active infected kidney and lung grafts should be avoided; (3) recipient colonization is associated with an increased risk of infection, but is not a contraindication to transplantation; (4) different surgical prophylaxis regimens are not recommended for patients colonized with carbapenem-resistant GNB; (5) timely detection of carriers, contact isolation precautions, hand hygiene compliance and antibiotic control policies are important preventive measures; (6) there is not sufficient data to recommend intestinal decolonization; (7) colonized lung transplant recipients could benefit from prophylactic inhaled antibiotics, specially for Pseudomonas aeruginosa; (8) colonized SOT recipients should receive an empirical treatment which includes active antibiotics, and directed therapy should be adjusted according to susceptibility study results and the severity of the infection.

Hiponatremia e insuficiencia cardiaca congestiva refractaria a tratamiento diurético. Utilidad del tolvaptán / Hyponatraemia and congestive heart failure refractory to diuretic treatment. Utility of tolvaptan

La insuficiencia cardiaca (IC) constituye actualmente uno de los problemas sociosanitarios más importantes en nuestro país, con una prevalencia en continuo crecimiento. Los avances en el conocimiento de las distintas respuestas biológicas que favorecen el remodelado cardiaco y de la congestión venopulmonar constituyen la base del tratamiento actual. En este artículo elaborado por miembros de los grupos de IC de las sociedades españolas de Cardiología y Medicina Interna se comentan las estrategias terapéuticas actuales para el paciente congestivo refractario a tratamiento diurético, introduciendo nuestra experiencia clínica con el uso de tolvaptán como tratamiento adicional en la congestión asociada a hiponatremia. Para ello se propone un algoritmo sobre el uso de tolvaptán en pacientes con IC congestiva, natremia inferior a 130mEq/l y mala respuesta al tratamiento diurético convencional (AU)

Heart failure (HF) is currently one of the most significant healthcare problems in Spain and has a continuously increasing prevalence. Advances in our understanding of the various biological responses that promote cardiac remodelling and pulmonary venous congestion constitute the basis of current treatment. This article, prepared by members of the HF groups of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine, discusses the current therapeutic strategies for patients with congestion refractory to diuretic treatment. The article includes our clinical experience with the use of tolvaptan as an additional treatment for congestion associated with hyponatraemia. To this end, we propose an algorithm for the use of tolvaptan in patients with congestive HF, natraemia <130mEq/l and poor response to conventional diuretic treatment (AU)

Hyponatraemia and congestive heart failure refractory to diuretic treatment. Utility of tolvaptan. / Hiponatremia e insuficiencia cardiaca congestiva refractaria a tratamiento diurético. Utilidad del tolvaptán.

Heart failure (HF) is currently one of the most significant healthcare problems in Spain and has a continuously increasing prevalence. Advances in our understanding of the various biological responses that promote cardiac remodelling and pulmonary venous congestion constitute the basis of current treatment. This article, prepared by members of the HF groups of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine, discusses the current therapeutic strategies for patients with congestion refractory to diuretic treatment. The article includes our clinical experience with the use of tolvaptan as an additional treatment for congestion associated with hyponatraemia. To this end, we propose an algorithm for the use of tolvaptan in patients with congestive HF, natraemia <130mEq/l and poor response to conventional diuretic treatment.

Management of cytomegalovirus infection in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations.

Cytomegalovirus (CMV) infection remains a major complication of solid organ transplantation. Because of management of CMV is variable among transplant centers, in 2011 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, new publications have clarified or questioned the aspects covered in the previous document. For that reason, a panel of experts revised the evidence on CMV management, including immunological monitoring, diagnostics, prevention, vaccines, indirect effects, treatment, drug resistance, immunotherapy, investigational drugs, and pediatric issues. This document summarizes the recommendations.

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.

Randomized controlled trial of sirolimus conversion in cardiac transplant recipients with renal insufficiency.

This randomized, comparative, multinational phase 3b/4 study of patients 1-8 years postcardiac transplantation (mean 3.9 years) evaluated the effect of conversion from a calcineurin inhibitor (CNI) to sirolimus on renal function in patients with renal insufficiency. In total, 116 patients on CNI therapy with GFR 40-90 mL/min/1.73 m(2) were randomized (1:1) to sirolimus (n = 57) or CNI (n = 59). Intent-to-treat analysis showed the 1-year adjusted mean change from baseline in creatinine clearance (Cockcroft-Gault) was significantly higher with sirolimus versus CNI treatment (+3.0 vs. -1.4 mL/min/1.73 m(2) , respectively; p = 0.004). By on-therapy analysis, values were +4.7 and -2.1, respectively (p < 0.001). Acute rejection (AR) rates were numerically higher in the sirolimus group; 1 AR with hemodynamic compromise occurred in each group. A significantly higher treatment discontinuation rate due to adverse events (AEs; 33.3% vs. 0%; p < 0.001) occurred in the sirolimus group. Most common treatment-emergent AEs significantly higher in the sirolimus group were diarrhea (28.1%), rash (28.1%) and infection (47.4%). Conversion to sirolimus from CNI therapy improved renal function in cardiac transplant recipients with renal impairment, but was associated with an attendant AR risk and higher discontinuation rate attributable to AEs.

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.

Relationship between functional capacity and quality of life in heart transplant patients.

The goal of heart transplantation (HT) is not only to prolong the life of patients with end-stage heart failure, but also to offer them the sort of health they enjoyed before the disease. It is widely known that patients' functional capacity improves after HT but what about their quality of life (QoL)? Do functional capacity and QoL improve simultaneously? In the present study, we compared the progression of effort capacity and QoL in the first 2 years after HT. A prospective longitudinal study was performed in 58 heart transplant recipients (43 males, 15 females, age 51.6 ± 10 years) able to complete an effort test 2, 6, 12, and 24 months after transplantation. The studied variables included the five dimensions of the Euroqol-5D questionnaire (EQ-5D) test: mobility, self-care, daily activities, pain/discomfort, anxiety, and depression; a visual analog scale from 0 to 100; and the results (metabolic equivalent units [METs] and time of exercise) of the effort test at 2, 6, 12, and 24 months after transplantation. Analysis of variance was used to compare these variables at each point. Significance was set at P < .05. Functional capacity, measured by both METs and time of exercise, improved progressively (METs: 2 months: 5.2 ± 1.8, 6 months: 6.6 ± 2.1, 12 months: 7.5 ± 2.2, and 24 months: 8.5 ± 2.3, P < .001). As well, the result of EQ-5D questionare improved in parallel to exercise capacity. However, visual analog scale score did not change significatively during the follow-up (2 months: 78.9.3 ± 16.1, 6 months: 83.8 ± 11.3, 12 months: 83.3 ± 11.1, 24 months: 85.2 ± 14.9; P = .192), reaching a plateau at 6 to 24 months. In conclusion, the improvement in functional capacity shown by heart transplant recipients in the first 2 years after transplantation was not parallel to the feelings of well-being measured by the analog scale of the EQ-5D. Possibly long after transplantation patients will compare themselves to healthy people rather than to their state before HT, resulting in improvements the visual analog scale.

Sympathetic reinnervation 1 year after heart transplantation, assessed using iodine-123 metaiodobenzylguanidine imaging.

Complete allograft denervation occurs during heart transplantation (HT). Partial ventricular sympathetic reinnervation that may develop after transplantation can be measured using iodine-123 meta iodobenzylguanidine (MIBG) uptake. Previous studies have suggested that reinnervation is likely to be a slow process, only occurring after 1 year posttransplantation. However, the reinnervation prevalence at 1 year after HT remains unknown. This study sought to determine sympathetic reinnervation measured by MIBG at 12 months after surgery. We performed serial cardiac MIBG imaging in 45 cardiac transplant recipients, including 32 males and 13 females, early (2 months) and late (12 months) after the operation. The intensity of myocardial MIBG uptaken was quantified by heart-to-mediastinum ratios (HMR). Reinnervation was considered when the HMR was >1.3. HMR was significantly higher at 12 months: 1.16 ± 0.10 at 2 vs 1.30 ± 0.15 at 12 months (P < .001). Eighteen (40%) of 45 subjects developed visible cardiac MIBG uptake at 1 year after transplantation with HMR >1.3. In conclusion, partial sympathetic reinnervation increases with time after HT; it was seen in 40% of patients at 1 year after the operation.

Dynamics of colloids in confined geometries.

We discuss the Brownian dynamics of colloids in confinement with special emphasis on the influence of the solvent dynamics. We review the derivation of a dynamic density functional theory (DDFT) including some aspects of hydrodynamic interactions and its application to the micro-rheology of suspensions. In particular we discuss the failure of Stokes' law in suspensions and non-equilibrium solvent structure mediated interactions. With regard to hydrodynamic chromatography we also discuss the stationary transport of particles in narrow channels, and the reasons for the failure of DDFT in this situation.

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.

Proliferation signal inhibitors in heart transplantation: a 5-year experience.

INTRODUCTION: Calcineurin inhibitors (CNI) are associated with multiple complications, especially renal dysfunction and tumor development. Proliferation signal inhibitors (PSI) show renal protection and an antineoplastic effects, and may retard allograft vasculopathy. The objective of the current study was to present our initial experience center with PSI therapy. MATERIALS AND METHODS: We analyzed all heart transplants (HT) performed in our center who received a PSI at any time. We assessed the clinical profiles, indications for and strategies of PSI introduction, complications, causes of discontinuation, and renal functional evolutions. RESULTS: Among 604 HT performed in our center, 82 patients (13.5%) received a PSI: sirolimus (n=2) or everolimus (n=80). Their mean age was 53±12 years and 90% were men. PSI introduction occurred at 75±53 months posttransplantation. The strategy was CNI minimization in 17% of cases, and total conversion from CNI in 83%. The PSI indication was renal dysfunction (40%), tumors (38%), allograft vasculopathy (17%), and other reasons (5%). After PSI introduction, 15.8% of patients suffered a rejection episode and 20%, a significant infection. The PSI discontinuation rate was 8.5%: due to infection (2.4%), edema (1.2%), inadequate cicatrization (1.2%), and other reasons (3.7%). Creatinine was 1.68±0.64 mg/dL the year before and 1.72±0.79 mg/dL at and 1.82±1.61 mg/dL 1 year after PSI conversion. CONCLUSION: PSIs showed few complications with a low withdrawal rate, and maintained renal function. The main indications for their use were renal dysfunction, tumors, or development of allograft vasculopathy.

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.

Timing, etiology, and location of first infection in first year after heart transplantation.

BACKGROUND: Infections are the leading cause of death in the first year after heart transplantation (HTx) after the postoperative period. OBJECTIVE: To describe the timing, etiology, and location of the first infection occurring in the first year after HTx. PATIENTS AND METHODS: The study included 604 HTx procedures performed at our center from November 1987 to September 2009. Infections were classified as those requiring hospital admission or that prolonged hospital stay. Infection was established on the basis of clinical findings and supplementary test results. Etiologic diagnosis was established at microbiological culture. Infections were categorized as bacterial, viral, fungal, protozoal, or of unknown origin, and were grouped according to microorganism family. Time to occurrence of infection is given as mean (interquartile range). Locations considered were systemic, pulmonary, genitourinary, cutaneous, oropharyngeal, mediastinal, sternal, gastrointestinal, and other. RESULTS: Mean (SD) patient age was 51 (12) years, and 83.8% of patients were men. Almost half of all patients (42.9%) experienced some type of infection in the first year after HTx. The most frequently occurring infections were bacterial (49.6%) and viral (38.7%), with fewer fungal (6.3%), protozoal (1.2%), and of unknown origin (4.3%). Staphylococci were the most commonly isolated organisms (10.5%) in bacterial infections, cytomegalovirus (21.1%) in viral infections, and Candida (2.3%) and Aspergillus (2.3%) in fungal infections. Early-onset infections (n=2; 1-7 days) were caused by Candida spp, and late-onset infections (n=110; 14-182 days) by a mixed group of bacteria. The sternum was the site of early-onset infections (n=9; 6-14 days), and the genitourinary tract was the site of late-onset infections (n=110; 28-180 days). CONCLUSIONS: Nearly half of HTx recipients experience a significant infection during the first year posttransplantation. Early-onset infections occur in critical care units, are caused by nosocomial organisms, and involve the sternum or mediastinum, whereas late- onset infections have a more varied etiology and preferentially affect the skin and genitourinary tract.

Mycophenolate acid vs mycophenolate mofetil therapy.

BACKGROUND: Mycophenolate mofetil (MMF) is included in the basic immunosuppression regimen in heart transplantation (HTx). Classically, the mycophenolic acid (MPA) concentration has not been considered to provide clinical information. OBJECTIVE: To perform a comparative analysis of MMF dosage and MPA concentration and their effect on post-HTx renal function. PATIENTS AND METHODS: Sixty patients underwent HTx between January 2007 and April 2009, and were followed up at 4 scheduled visits in 6 months. The standard MMF dose was 1000 mg/12 h, with adjustment according to clinical criteria. The MPA concentration was determined using an enzyme-multiplied immunoassay (EMIT 2000; Siemens Healthcare Diagnostics Inc, Deerfield, Illinois), without change in dosage. The correlation between mean MMF dosage and MPA concentrations at all visits vs renal function values was analyzed using serum creatinine concentration, creatinine clearance (CrCl; Modification of Diet in Renal Disease), and glomerular filtration rate (GFR; Cockcroft-Gault formula). RESULTS: Mean (SD) patient age was 50 (13) years, and 45 of 60 (75.4%) were men. Pre-HTx values were as follows: creatinine concentration, 1.13 (0.47) mg/dL; CrCl, 81.59 (36.84) mL/min/1.73 m2; and GFR, 77.46 (30.60) mL/min. In the first 6 months post-HTx, significant negative correlations were observed between mean MPA concentration and creatinine concentration (r=.42; P=.001), CrCl (r=-.36; P=.01), and GFR (r=-.45; P=.001). No correlation was observed with mean MMF dosage. CONCLUSION: There are important differences in the relationship of MPA concentration vs MMF dosage and post-HTx renal function. Although studies with a larger number of patients are needed, treatment guided by MPA concentration seems reliable for evaluation of renal function.

Clinical interest of pharmacogenetic polymorphisms in the immunosuppressive treatment after heart transplantation.

In the transplantation field, genetic changes in a single nucleotide in the genes responsible for the transport and metabolism of an immunosuppressive drug may modify the response of the patient. The aim of this study was to evaluate the effect of single nucleotide polymorphisms (SNPs) in heart transplant recipients and their donors in association with tacrolimus and cyclosporine blood levels during the first 2 weeks after transplantation. A total of 18 blood samples from heart transplant recipients and their donors (n=36) were analyzed using Sequenom to characterize the more relevant SNPs of the ABCB1 and CYP3A5 genes for correlation with C0 (trough concentration) drug blood levels. Differences between groups were evaluated with two-way analysis of variance (ANOVA) and Bonferroni post-test. In agreement with theoretical predictions, the wild type genotype in ABCB1 SNPs (CC) tended to stabilize drug levels within the therapeutic range, whereas the T variant induced a 79% mean increase in blood levels among heterozygous (CT) and 100% among homozygous (TT) recipients. These results agreed with the mean levels in various recipient/donor populations, finding significant differences between them (P<.001 in CC vs CT and P<.01 in CT vs TT), as well as a certain influence of the donor genotype.

Clinical predictors of immunotolerance in heart transplantation.

BACKGROUND AND AIM: The drugs routinely administered to prevent rejection often cause lethal side effects. Tolerant patients, therefore, should be identified to minimize these problems. The aim of this analysis was to identify clinical variables that may be associated with tolerance. METHODS: We recruited 522 heart transplants (HT), excluding combined procedures, retransplantations, pediatric recipients, and subjects who died in the first year to obtain a cohort of 375 patients. Two groups were distinguished by the presence of echocardiographic, clinical, or pathological evidence of rejection in the first year (15 echocardiograms and 10 protocol biopsies per patient); 99 tolerant patients were compared with 276 nontolerant patients. We analyzed clinical variables related to morbidity and mortality. RESULTS: The univariate analysis showed few differences between the groups. The multivariate analysis showed that only major histocompatibility complex (MHC)-A and MHC-DR matched recipients were significantly associated with tolerance. Thus, the likelihood of tolerance was increased by 1.7- and 2.8-fold if 1 or 2 MHC-I matches were present and by 3.4- and 3.7-fold if 1 or 2 MHC-DR matches were present, respectively survival curves showed significant differences (P=.034). Most deaths in both groups were related to immunosuppressive drugs; among tolerant subjects, deaths were due to infection and neoplasms and among nontolerant patients, deaths were due to chronic rejection, neoplasms, and infection. CONCLUSIONS: The only clinical parameter that can determined whether a HT recipient was tolerant was MHC-A and MHC-DR matching. If there is matching, a reduced immunosuppressive load should be prescribed to prevent drug toxicity.