Rol de la oxitocina en patología psiquiátrica / Role of oxytocin in psychiatric pathology

Oxytocin is a neuropeptide that in mammals has important functions on different reproductive stages and socialization behaviors. In humans, its importance has been recognized in processes of social regulation such as social memory, affiliation, mentality and empathy. The objective of this work is to perform an updated review of the evidence about the role of oxytocin in psychiatric disorders. A bibliographic search was carried out on this topic through the Medline / PubMed and SciELO databases. The results show evidence on the possible etiopathogenic role of oxytocin in different clinical conditions. In addition, research has sought answers in this hormone to understand the different symptomatic profiles, such as emotional regulation, the recognition of emotions, the capacity for mentalization and the response to stress, which could operate as targets for possible therapeutic uses of oxytocin. Although the data are still incipient and inconclusive, oxytocin has been positioned as an important focus of neurobiological and therapeutic study in psychiatry for future research.

Identidad de género y salud mental / Gender identity and mental health

Resumen Este artículo tiene como objetivo revisar las implicaciones de la identidad de género en la construcción psíquica y la salud mental, sin pretender ser una revisión exhaustiva, dada la complejidad del tema. Se realiza un recorrido por las definiciones conceptuales de la identidad de género, pasando por algunos modelos explicativos de la misma, como una forma de comprender esta experiencia. Además, se abordará la realidad transgénero como factor de estrés psicosocial y, desde una perspectiva clínica, sus repercusiones psíquicas, enfatizando la diferenciación de las identidades trans con la entidad diagnóstica llamada disforia de género. Finalmente, se caracterizará la disforia de género, con énfasis en el malestar subjetivo secundario a la discordancia de género, sus relaciones con otros diagnósticos psiquiátricos, sus repercusiones psicosociales y las barreras de atención médica que este grupo de personas experimenta.

This article aims to review the implications of gender identity in psychic construction and mental health, without intending to be an exhaustive review, given the complexity of this issue. A tour of the conceptual definitions of gender identity is made, going through some explanatory models of it, as a way to understand this experience. Also, transgender reality as a psychosocial stress factor will be addressed and, from a clinical perspective, its psychic repercussions, emphasizing the differentiation of trans identities with the diagnostic entity called gender dysphoria. Finally, gender dysphoria will be characterized, focusing on the subjective disconfort secondary to gender discordance, its relationships with other psychiatric diagnoses, its psychosocial repercussions and the health care barriers that this group of people experiences.

Eosinofilia inducida por Olanzapina: A propósito de un caso / Olanzapine-induced eosinophilia: A case report

Resumen Se han descrito una serie de reacciones adversas asociadas a antipsicóticos, entre las que destacan las reacciones adversas hematológicas propias de algunos antipsicóticos atípicos. Las más renombradas han sido clásicamente las discrasias sanguíneas asociadas al uso de olanzapina. En este trabajo nos enfocamos en una reacción adversa poco común: eosinofilia en un paciente esquizofrénico paranoide usuario de olanzapina, situación documentada en contadas publicaciones a lo largo de la historia de uso de este medicamento. Se trata de una reacción adversa infrecuente, y por lo mismo poco conocida y estudiada.

Many adverse effects of antipsychotic drugs have been described, among which hematologic adverse effects stand out. Classically, blood discrasias have been associated to the use of olanzapine. On this paper we will focus on an uncommon adverse reaction: eosinophilia in a patient diagnosed with a paranoid schitzophrenia, who had been using olanzapine. There have been just a few reported cases of eosinophilia secondary to the use of olanzapine, which makes this an infrequent, rarely known and even less studied adverse reaction.

Trastorno por déficit atencional e hiperactividad (TDAH) y su relación con el síndrome de apnea obstructiva del sueño (SAOS) en pediatría / Attention deficit hyperactivity disorder (ADHD) and its relationship with obstructive sleep apnea syndrome (OSAS) in pediatrics

La importancia de la patología psiquiátrica en la infancia y la adolescencia ha ido en ascenso, debido al aumento en su diagnóstico y a sus implicancias socioculturales. El Trastorno por Déficit Atencional e Hiperactividad es el trastorno neurobiológico más diagnosticado en la práctica clínica infanto-juvenil, tanto así que debe ser conocido y manejado en la Atención Primaria por los médicos generales. Se ha descrito cierto grado de sobrediagnóstico influenciado, entre otros motivos, por las altas expectativas sociales respecto del rendimiento escolar/conductual de los niños, así como la presencia de otras patologías que se pueden manifestar con síntomas TDAH-like. En este sentido, la relación entre SAOS y TDAH, cobra gran relevancia, puesto que ambas patologías presentan una amplia prevalencia en nuestro país y un alto nivel de comorbilidad psiquiátrica/médica, además de relacionarse a través de una compleja y aún no muy bien conocida interacción neuropsicológica.

The importance of psychiatric disorders in childhood and adolescence has been increasing due to the increase in its diagnosis and its cultural implications. The Attention Deficit Hyperactivity Disorder is the neurobiological disorder most commonly diagnosed in the child-adolescent clinical practice, so much so that must be managed in primary care. It described some degree of overdiagnosis influenced by high school-social expectations and behavioral performance of children, and the presence of other conditions. In this sense, the relationship between OSA and ADHD, is very relevant, because both disorders share a wide prevalence in our country and a high level of psychiatric and medical comorbidity. In adittion, these interact through a complex and still not well known neuropsychological mechanism.

Real Time Central Assessment of Kidney Transplant Indication Biopsies by Microarrays: The INTERCOMEX Study.

The authors conducted a prospective trial to assess the feasibility of real time central molecular assessment of kidney transplant biopsy samples from 10 North American or European centers. Biopsy samples taken 1 day to 34 years posttransplantation were stabilized in RNAlater, sent via courier overnight at ambient temperature to the central laboratory, and processed (29 h workflow) using microarrays to assess T cell- and antibody-mediated rejection (TCMR and ABMR, respectively). Of 538 biopsy samples submitted, 519 (96%) were sufficient for microarray analysis (average length, 3 mm). Automated reports were generated without knowledge of histology and HLA antibody, with diagnoses assigned based on Molecular Microscope Diagnostic System (MMDx) classifier algorithms and signed out by one observer. Agreement between MMDx and histology (balanced accuracy) was 77% for TCMR, 77% for ABMR, and 76% for no rejection. A classification tree derived to provide automated sign-outs predicted the observer sign-outs with >90% accuracy. In 451 biopsy samples where feedback was obtained, clinicians indicated that MMDx more frequently agreed with clinical judgment (87%) than did histology (80%) (p = 0.0042). In 81% of feedback forms, clinicians reported that MMDx increased confidence in management compared with conventional assessment alone. The authors conclude that real time central molecular assessment is feasible and offers a useful new dimension in biopsy interpretation. ClinicalTrials.gov NCT#01299168.

Actualización en psicodermatología / Update in psychodermatology

Psychodermatology is an area of dermatology dedicated to the connection between this medical discipline and psychiatry. Its importance is based in that emotional factors can exacerbate skin diseases and psychiatric disorders may manifest as skin lesions. This relationship can be described as an intricate network involving psychological, social, neuroendocrine, immune and skin factors, as reflected in the complexity of the management of these patients. Is important to increase research and interest in this important issue, as an integrative and multidisciplinary approach allows for interventions in the vicious circle between psychiatric dysfunction and skin symptoms, improving significantly the quality of life of patients...

Low serum mannose-binding lectin levels are associated with inflammation and apoptosis in early surveillance allograft biopsies.

INTRODUCTION: Mannose-binding lectin (MBL) is a protein of the innate immune system that participates in host defense and the tissue injury/repair process, enhancing the clearance of apoptotic cells by macrophages. The aim is to characterize the relationship between pre-transplant MBL levels, histological lesions and number of apoptotic cells in early surveillance renal allograft biopsies. PATIENTS AND METHODS: Consecutive renal transplant recipients were recruited and MBL levels were classified into tertiles. The first tertile was considered the low MBL group. Surveillance biopsies were done during the first 6 months and were evaluated according to Banff criteria. Renal inflammatory infiltrates were studied by immunohistochemical techniques. Apoptosis was studied using morphological methods in renal tubular cells and was expressed as the number of apoptotic cells/mm(2). RESULTS: MBL was determined in 126 patients and a surveillance biopsy with sufficient tissue was obtained in 41 of them. Patients with low pre-transplant MBL levels showed a higher acute Banff index (3.14 ± 1.96 vs. 1.88 ± 1.56, p = 0.044) and an increased proportion of biopsies with tubular cell apoptosis The proportion of biopsies with tubular cell apoptosis was higher in patients with low pre-transplant MBL levels in comparison with patients with high MBL levels (4.3 ± 3.6 versus 0.2 ± 0.9 p = 0.012) and increased interstitial number of inflammatory cells and significantly the macrophages/mm(2) (109 ± 118 vs. 32 ± 46; p = 0.04). CONCLUSION: Low pre-transplant serum MBL levels are associated with more severe inflammation and increased apoptosis in early surveillance renal allograft biopsies suggesting that MBL modulates renal inflammation after transplantation.

Banff fibrosis study: multicenter visual assessment and computerized analysis of interstitial fibrosis in kidney biopsies.

Increasing interstitial fibrosis (IF) in native and kidney transplant biopsies is associated with functional decline and serves as a clinical trial end point. A Banff 2009 Conference survey revealed a range in IF assessment practices. Observers from multiple centers were asked to assess 30 renal biopsies with a range of IF and quantitate IF using two approaches on trichrome, Periodic acid-Schiff (PAS) and computer-assisted quantification of collagen III immunohistochemistry (C-IHC) slides, as well as assessing percent of cortical tubular atrophy% (TA%) and Banff total cortical inflammation score (ti-score). C-IHC using whole slide scans was performed. C-IHC assessment showed a higher correlation with organ function (r = -0.48) than did visual assessments (r = -0.32--0.42); computerized and visual C-IHC assessment also correlated (r = 0.64-0.66). Visual assessment of trichrome and C-IHC showed better correlations with organ function and C-IHC, than PAS, TA% and ti-score. However, visual assessment of IF, independent of approach, was variable among observers, and differences in correlations with organ function were not statistically significant among C-IHC image analysis and visual assessment methods. C-IHC image analysis correlated among three centers (r > 0.90, p < 0.0001, between all centers). Given the difficulty of visual IF assessment standardization, C-IHC image could potentially accomplish standardized IF assessment in multicenter settings.

Potential impact of microarray diagnosis of T cell-mediated rejection in kidney transplants: The INTERCOM study.

We previously developed a microarray-based test for T cell-mediated rejection (TCMR) in a reference set of 403 biopsies. To determine the potential impact of this test in clinical practice, we undertook INTERCOM, a prospective international study of 300 indication biopsies from 264 patients (ClinicalTrials.gov NCT01299168). Biopsies from six centers-Baltimore, Barcelona, Edmonton, Hannover, Manchester and Minneapolis-were analyzed by microarrays, assigning TCMR scores by an algorithm developed in the reference set and comparing TCMR scores to local histology assessment. The TCMR score correlated with histologic TCMR lesions-tubulitis and interstitial infiltration. The accuracy for primary histologic diagnoses (0.87) was similar to the reference set (0.89). The TCMR scores reclassified 77/300 biopsies (26%): 16 histologic TCMR were molecularly non-TCMR; 15 histologic non-TCMR were molecularly TCMR, including 6 with polyoma virus nephropathy; and all 46 "borderline" biopsies were reclassified as TCMR (8) or non-TCMR (38). Like the reference set, discrepancies were primarily in situations where histology has known limitations, for example, in biopsies with scarring and inflammation/tubulitis potentially from other diseases. Neither the TCMR score nor histologic TCMR was associated with graft loss. Thus the molecular TCMR score has potential to add new insight, particularly in situations where histology is ambiguous or potentially misleading.

Contribution of anemia and hypertension to left ventricular hypertrophy during the initial 2 years after renal transplantation.

BACKGROUND: Cardiovascular disease is the main cause of mortality after renal transplantation. Left ventricular hypertrophy (LVH) is considered to be an independent predictor of cardiovascular events. The main risk factors for LVH after renal transplantation are anemia and hypertension. In hypertensive and renal transplant patients, ambulatory blood pressure monitoring (ABPM) has been demonstrated to be more closely related to LVH than office blood pressure. The aim of this study has to evaluate LVH after renal transplantation, particularly its association with measures derived from ABPM and cardiovascular risk factors. PATIENTS AND METHODS: Between March 2005 and October 2006, we recruited 101 consecutive kidney transplant patients to calculate left ventricular mass index (LVMI) by echocardiography at 3, 12, and 24 months. Hypertension was evaluated by office blood pressure measurements at 3, 12, and 24 months and also by ABPM at 3 months. Clinical and laboratory data were recorded during the study. RESULTS: From 3 to 24 months LVMI was reduced from 129 ± 29 g/m(2) to 121 ± 34 g/m(2) (P = .0089). Multivariate stepwise regression analysis showed independent predictors of LVMI at 3 months to be hemoglobin at 1 month, day systolic blood pressure (SBP) derived from ABPM and donor age (R = .50, P < .001). The independent predictors of LVMI at 12 months were day SBP derived from ABPM, hemoglobin at 1 month, and proteinuria at 12 months (R = .55, P < .001). Office SBP at 12 months, proteinuria at 24 months, patient age and night diastolic blood pressure derived from ABPM at 3 months were independent predictors of LVMI at 24 months (R = .71, P < .001). CONCLUSION: We observed a significant reduction in LVMI after renal transplantation. The main contributors to LVMI were anemia and elevated blood pressures measured by ABPM.

Histological findings in two renal transplants accomplishing operational tolerance criteria.

Operational tolerance is defined as stable renal function in transplants without immunosuppression for at least 1 year. We present histological assessments of two patients with operational tolerance. The first withdrew immunosuppression in 2005 and presents stable renal function (creatinine 1.5 mg/dL) without proteinuria. The biopsy showed mild chronic tubulointerstitial changes without inflammation. The second withdrew immunosuppression in 2009 and maintains stable renal function (creatinine 1.6 mg/dL) with mild proteinuria. Histology showed chronic humoural rejection and Class II anti-human leukocyte antigen antibodies were detected. These cases suggest that a renal biopsy may be useful to rule out subclinical pathology in patients with operational tolerance.

Banff '09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups.

The 10th Banff Conference on Allograft Pathology was held in Banff, Canada from August 9 to 14, 2009. A total of 263 transplant clinicians, pathologists, surgeons, immunologists and researchers discussed several aspects of solid organ transplants with a special focus on antibody mediated graft injury. The willingness of the Banff process to adapt continuously in response to new research and improve potential weaknesses, led to the implementation of six working groups on the following areas: isolated v-lesion, fibrosis scoring, glomerular lesions, molecular pathology, polyomavirus nephropathy and quality assurance. Banff working groups will conduct multicenter trials to evaluate the clinical relevance, practical feasibility and reproducibility of potential changes to the Banff classification. There were also sessions on quality improvement in biopsy reading and utilization of virtual microscopy for maintaining competence in transplant biopsy interpretation. In addition, compelling molecular research data led to the discussion of incorporation of omics-technologies and discovery of new tissue markers with the goal of combining histopathology and molecular parameters within the Banff working classification in the near future.

Interstitial fibrosis and tubular atrophy in renal allograft protocol biopsies as a surrogate of graft survival.

Interstitial fibrosis and tubular atrophy (IF/TA) evaluated in protocol renal allograft biopsies are associated with decreased graft survival, especially when associated with transplant vasculopathy, subclinical rejection, or transplant glomerulopathy. IF/TA evaluated in protocol biopsies has been used as a secondary efficacy variable in clinical trials, some of which have shown that the prevalence of IF/TA depends on the type of immunosuppressive treatment. These observations suggest that IF/TA may be considered a surrogate of graft survival. However, there is an important difference between a predictive and a surrogate variable. A predictive variable is associated only with the main outcome variable, whereas in case of a surrogate variable, an additional condition must be accomplished; that is, modifications of the predictive variable as a result of treatment imply changes in the main outcome variable. In a trial of cyclosporine withdrawal from a cyclosporine-sirolimus-prednisone regimen, cyclosporine discontinuation was associated with less severe chronic lesions in protocol biopsies at 3 years and also with improved graft survival at 4 years. This observation suggest that IF/TA may be a surrogate of survival. This conclusion must be confirmed in other trials before accepting IF/TA as a real surrogate of graft outcome.

Banff 07 classification of renal allograft pathology: updates and future directions.

The 9th Banff Conference on Allograft Pathology was held in La Coruna, Spain on June 23-29, 2007. A total of 235 pathologists, clinicians and scientists met to address unsolved issues in transplantation and adapt the Banff schema for renal allograft rejection in response to emerging data and technologies. The outcome of the consensus discussions on renal pathology is provided in this article. Major updates from the 2007 Banff Conference were: inclusion of peritubular capillaritis grading, C4d scoring, interpretation of C4d deposition without morphological evidence of active rejection, application of the Banff criteria to zero-time and protocol biopsies and introduction of a new scoring for total interstitial inflammation (ti-score). In addition, emerging research data led to the establishment of collaborative working groups addressing issues like isolated 'v' lesion and incorporation of omics-technologies, paving the way for future combination of graft biopsy and molecular parameters within the Banff process.

Risk factors associated with the deterioration of renal function: the role of protocol biopsies.

Protocol renal allograft biopsies allow the early detection of histological damage in the renal allograft even before renal function deterioration or proteinuria appears. Two different lesions have attracted the main interest in protocol biopsy studies: subclinical rejection, namely, the presence of tubulo-interstitial inflammation and chronic allograft nephropathy, nowadays termed interstitial fibrosis/tubular atrophy (IF/TA), and the presence of tubulo-interstitial chronic lesions. The incidence of subclinical rejection is maximal after transplantation and decreases during the first few months despite the fact that this condition persists in a proportion of cases even in late protocol biopsies done after the first year. In studies of serial protocol biopsies, the presence of subclinical rejection is associated with a higher probability of the progression of chronic tubulo-interstitial lesions and, recently, it has been shown the subclinical rejection in early protocol biopsies is associated with poorer allograft survival. The incidence of IF/TA rapidly progresses after renal transplantation, following an exponential curve. Its presence is associated with a decreased graft survival and its predictive value on outcome is independent from other predictors of survival such as serum creatinine or acute rejection. The association of IF/TA with transplant vasculopathy, subclinical rejection or transplant glomerulopathy implies a poorer outcome than IF/TA without other histological lesions. Taken together, these data suggest that protocol biopsies allow the early detection of acute and chronic lesions and the recognition of different patterns of damage that are associated with allograft survival.

Immunephenotype of glomerular and interstitial infiltrating cells in protocol renal allograft biopsies and histological diagnosis.

Patients with a protocol renal allograft biopsy simultaneously displaying interstitial fibrosis/tubular atrophy (IF/TA) and subclinical rejection (SCR) have a shortened graft survival than patients with a normal biopsy, or with a biopsy only displaying IF/TA or SCR. The poor outcome of these patients could be related with a more severe inflammation. We evaluate the immunophenotype of infiltrating cells in these diagnostic categories. Nonexhausted paraffin blocks from protocol biopsies done during the first year were stained with anti-CD45, CD3, CD20, CD68 and CD15 monoclonal antibodies. Glomerular and interstitial positive cells were counted. C4d deposition in peritubular capillaries was evaluated. Histological diagnoses were: normal (n = 80), SCR (n = 17), IF/TA (n = 42) and IF/TA + SCR (n = 17). Only interstitial CD20 positive cells were significantly increased in patients displaying IF/TA + SCR; normal (137 +/- 117), SCR (202 +/- 145), IF/TA (208 +/- 151) and IF/TA + SCR (307 +/- 180 cells/mm(2)), p < 0.01. The proportion of biopsies displaying C4d deposition was not different among groups. The upper tertile of CD20 positive interstitial cells was associated with a decreased death-censored graft survival (relative risk: 3.01, 95% confidence interval: 1.23-7.35; p = 0.015). These data suggest that B-cell interstitial infiltrates are associated with histological damage and outcome, but do not distinguish whether these infiltrates were the cause or the consequence of chronic tubulo-interstitial damage.

Donor structural and functional parameters are independent predictors of renal function at 3 months.

INTRODUCTION: Epidemiological studies have shown that demographic, clinical, and histological donor characteristics influence renal function after transplantation, but whether these variables are independent predictors has not been established. The aim of this study was to evaluate the relative contribution of different donor variables on glomerular filtration rates (GFRs) at 3 months. PATIENTS AND METHODS: We analyzed single renal transplants performed at our center from January 2000 to July 2004. Donor variables included age, gender, weight and height, cause of death, duration of brain death, serum creatinine at admission and preprocurement, history of arterial hypertension or diabetes mellitus, and smoking habit. Donor chronic damage score was calculated in preimplantation biopsies as was the addition of interstitial fibrosis, fibrous intimal thickening, and glomerulosclerosis (<10% = 0, >10% = 1). Donor and recipient GFRs were calculated according to the Cockroft-Gault formula. RESULTS: We analyzed 202 transplants obtained from 113 deceased donors. A renal biopsy was available in 111 transplants. Recipient GFR at 3 months correlated negatively with donor age (R = -0.32, P < .01) and donor chronic damage score (R = 0.32, P < .01). GFR was lower among recipients of female versus male donors (50 +/- 15 vs 60 +/- 20 mL/min; P < .01). Donor cerebrovascular accident death (53 +/- 19 vs 63 +/- 19 mL/min; P < .01) and hypertension (48 +/- 16 vs 59 +/- 20 mL/min; P < .01) were also associated with lower GFR at 3 months. There was a positive correlation between GFR at admission, GFR preprocurement, and GFR at 3 months (R = 0.32 and R = 0.18 respectively; P < .01). Stepwise regression analysis included chronic damage score, GFR at admission, and donor gender but not donor age as independent predictors of GFR at 3 months (R = 0.50; P < .01). CONCLUSION: Donor structural and functional parameters are independent predictors of renal function at 3 months.

Poly(ADP-ribose) polymerase expression in kidney transplantation: from alfa (alpha) to Omega (Omega).

INTRODUCTION: Overactivation of the enzyme poly(ADP-ribose) polymerase (PARP-1) can be induced by ischemia-reperfusion and involved in the renal injury subsequent to kidney transplant. The poly(ADP-ribosy)lation mechanism alters free radical-induced DNA damage, which is repair by PARP-1 polymer. However, PARP-1 overexpression induces cellular necrosis. Our aim was to study the immunohistochemical PARP-1 expression in kidney transplant biopsies associated with various events. MATERIALS AND METHODS: We studied the nuclear expression of PARP-1 in kidney tubule cells by immunohistochemistry using the monoclonal antibody PAR01 in donor biopsies without acute tubular necrosis (ATN) (n = 60; controls), allografts that suffer ATN (n = 90) or an episode of acute humoral rejection (n = 12) or acute tubulointerstitial rejection (n = 25), or chronic allograft nephropathy (n = 25). Furthermore, we also studied protocol biopsies with subclinical rejection (n = 60). Renal lesions in transplant biopsies were graded blindly using 1997 Banff criteria without any clinical information. RESULTS: Biopsies without morphological features of ATN, namely acute tubulointerstitial rejection, borderline or subclinical rejection, showed lesser PARP-1 expression compared with biopsies with ATN or with ischemic mechanism of acute humoral rejection or chronic allograft nephropathys. We observed an inverse relation between PARP-1 expression and renal function (P < .001). Overall, renal biopsies showing ATN revealed greater expression of PARP-1 (r = 0.785, Pearson test). A significant relationship with PARP-1 expression was demonstrated with renal function (effective diuresis, serum creatinine levels) and pretransplant cold ischemia time (P < .001). CONCLUSION: Kidney transplant events including ischemia were associated with the highest PARP-1 expression and worse allograft renal function.

Pharmacokinetics and pharmacodynamics in renal transplant recipients under treatment with cyclosporine and Myfortic.

INTRODUCTION: Efficacious prophylaxis of acute rejection episodes (ARE) requires adequate exposure to each component of the immunosuppressive treatment from the first days after renal transplantation. The aim of the present study was to evaluate the correlation between cyclosporine (CsA) and mycophenolic acid (MPA) exposure based upon pharmacokinetics (PK) and pharmacodynamics (PD) and 6-month biopsy-proven acute rejection (BPAR) episodes and chronic allograft nephropathy on 6 month protocol biopsies. PATIENTS AND METHODS: We examined twenty-two first or second de novo renal transplant recipients treated with steroids, Sandimmune Neoral (CsA) and Myfortic (720 mg twice a day). PK (C0, C2, and AUC(0-12h)) for both drugs were determined on days 7, 90, and 180. Calcineurin activity, interleukin-2 and interferon-gamma synthesis as well as %CEM were tested at days 7 and 180. CsA dosages were adjusted by C2 monitoring. Collected data included: BPAR during the first 6 months and Banff histological parameters on the 6-month protocol biopsies. RESULTS: Eighteen of 22 patients completed 1 year follow-up under treatment. The 6-month BPAR was 18% (4/22). Six-month protocol biopsies in 50% of 14 recipients showed chronic allograft nephropathy 1. At day 7, CsA C2 and AUC median values were 138 ng/mL and 6377 ng x h/mL, while C0 MPA was 1.0 microg/mL and AUC = 23.9 microg x h/mL. CsA C2 medians at 3 and 6 months were 1468 and 1720 ng/mL. MPA-AUC reached therapeutic targets at 3 months (32.3 microg x h/mL) and was 48.3 microg x h/mL at 6 months. Patients with BPAR showed lower CsA AUC (P = .06) and a significantly lower baseline inhibition of calcineurin activity (P < .005) than patients with no BPAR. An increase in mesangial matrix in 6-month protocol biopsies correlated with higher CsA C2 (P = .01). All biomarkers evaluated were significantly inhibited compared with the standard population. CONCLUSIONS: When Myfortic is administered together with CsA, it is advisable to begin with higher doses (720 mg x 3 days) to reach adequate PK targets and improve BPAR rates. To prevent chronic allograft nephropathy, lower CsA C2 should be targeted from 3 months.