Risk and Protective Factors for Gastrointestinal Symptoms associated with Antibiotic Treatment in Children: A Population Study.

PURPOSE: Gastrointestinal symptoms are often related to antibiotic treatment. Their incidence, risk and protective conditions in children are not well defined and represent the aims of this study. METHODS: We prospectively enrolled inpatient children submitted to antibiotic treatment. Indication, type, dose and duration of treatment, probiotic supplementation and gastrointestinal symptoms were recorded at recruitment, after two and four weeks. Antibiotic-associated diarrhea (AAD) was defined as the presence of at least 3 loose/liquid stools within 14 days from antibiotic onset. RESULTS: AAD occurred in 59/289 (20.4%) of patients, with increased risk in children younger than 3 years (relative risk [RR]=4.25), in lower respiratory (RR=2.11) and urinary infections (RR=3.67), intravenous administration (RR=1.81) and previous AAD episodes (RR=1.87). Abdominal pain occurred in 27/289 (9.3%), particularly in children >6 years (RR=4.15), with previous abdominal pain (RR=7.2) or constipation (RR=4.06). Constipation was recorded in 23/289 (8.0%), with increased risk in children having surgery (RR=2.56) or previous constipation (RR=7.38). Probiotic supplementation significantly reduced AAD (RR=0.30) and abdominal pain (RR=0.36). Lactobacillus rhamnosus GG (LGG) and L. reuteri significantly reduced AAD (RR=0.37 and 0.35) and abdominal pain (RR=0.37 and 0.24). CONCLUSION: AAD occurred in 20.4% of children, with increased risk at younger age, lower respiratory and urinary tract infections, intravenous treatment and previous AAD. LGG and L. reuteri reduced both AAD and associated abdominal pain.

Testing the Cow's Milk-Related Symptom Score (CoMiSSTM) for the Response to a Cow's Milk-Free Diet in Infants: A Prospective Study.

The diagnosis of cow's milk allergy (CMA) is particularly challenging in infants, especially with non-Immunoglobulin E (IgE)-mediated manifestations, and inaccurate diagnosis may lead to unnecessary dietary restrictions. The aim of this study was to assess the accuracy of the cow's milk-related symptom score (CoMiSSTM) in response to a cow's milk-free diet (CMFD). We prospectively recruited 47 infants (median age three months) who had been placed on a CMFD due to persisting unexplained gastrointestinal symptoms. We compared data with 94 healthy controls (median age three months). The CoMiSSTM score was completed at recruitment and while on the exclusion diet. In 19/47 (40%) cases a response to the diet occurred. At recruitment CoMiSSTM was significantly higher in cases compared to controls (median score 8 vs. 3; p-value: <0.05), 9 cases had a score ≥12 and 8/9 normalized on CMFD. An oral milk challenge was performed in all 19 responders and six of these had a positive reaction to cow's milk (CM). In eight infants IgE allergy tests were positive. The receiver operation characteristic (ROC) curve identified a CoMISSTM score of 9 to be the best cut-off value (84% sensitivity, 85% specificity, 80% positive (PPV) and 88% negative predictive value (NPV)) for the response to CMFD. We found CoMiSSTM to be a useful tool to help identify infants with persisting gastrointestinal symptoms and suspected CMA that would benefit from CMFD.

Reproducibility of the Oxford classification of immunoglobulin A nephropathy, impact of biopsy scoring on treatment allocation and clinical relevance of disagreements: evidence from the VALidation of IGA study cohort.

BACKGROUND: The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive (CS/IS) treatments, and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present and central absent, local absent and central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS. RESULTS: All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy, while the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity) and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe). CONCLUSION: We conclude that differences in the scoring of MEST-C criteria between local pathologists and a central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies.

Complement related kidney diseases: Recurrence after transplantation.

The recurrence of renal disease after renal transplantation is becoming one of the main causes of graft loss after kidney transplantation. This principally concerns some of the original diseases as the atypical hemolytic uremic syndrome (HUS), the membranoproliferative glomerulonephritis (MPGN), in particular the MPGN now called C3 glomerulopathy. Both this groups of renal diseases are characterized by congenital (genetic) or acquired (auto-antibodies) modifications of the alternative pathway of complement. These abnormalities often remain after transplantation because they are constitutional and poorly influenced by the immunosuppression. This fact justifies the high recurrence rate of these diseases. Early diagnosis of recurrence is essential for an optimal therapeutically approach, whenever possible. Patients affected by end stage renal disease due to C3 glomerulopathies or to atypical HUS, may be transplanted with extreme caution. Living donor donation from relatives is not recommended because members of the same family may be affected by the same gene mutation. Different therapeutically approaches have been attempted either for recurrence prevention and treatment. The most promising approach is represented by complement inhibitors. Eculizumab, a monoclonal antibody against C5 convertase is the most promising drug, even if to date is not known how long the therapy should be continued and which are the best dosing. These facts face the high costs of the treatment. Eculizumab resistant patients have been described. They could benefit by a C3 convertase inhibitor, but this class of drugs is by now the object of randomized controlled trials.

Update on ischemia-reperfusion injury in kidney transplantation: Pathogenesis and treatment.

Ischemia/reperfusion injury is an unavoidable relevant consequence after kidney transplantation and influences short term as well as long-term graft outcome. Clinically ischemia/reperfusion injury is associated with delayed graft function, graft rejection, chronic rejection and chronic graft dysfunction. Ischemia/reperfusion affects many regulatory systems at the cellular level as well as in the renal tissue that result in a distinct inflammatory reaction of the kidney graft. Underlying factors of ischemia reperfusion include energy metabolism, cellular changes of the mitochondria and cellular membranes, initiation of different forms of cell death-like apoptosis and necrosis together with a recently discovered mixed form termed necroptosis. Chemokines and cytokines together with other factors promote the inflammatory response leading to activation of the innate immune system as well as the adaptive immune system. If the inflammatory reaction continues within the graft tissue, a progressive interstitial fibrosis develops that impacts long-term graft outcome. It is of particular importance in kidney transplantation to understand the underlying mechanisms and effects of ischemia/reperfusion on the graft as this knowledge also opens strategies to prevent or treat ischemia/reperfusion injury after transplantation in order to improve graft outcome.

Complement involvement in kidney diseases: From physiopathology to therapeutical targeting.

Complement cascade is involved in several renal diseases and in renal transplantation. The different components of the complement cascade might represent an optimal target for innovative therapies. In the first section of the paper the authors review the physiopathology of complement involvement in renal diseases and transplantation. In some cases this led to a reclassification of renal diseases moving from a histopathological to a physiopathological classification. The principal issues afforded are: renal diseases with complement over activation, renal diseases with complement dysregulation, progression of renal diseases and renal transplantation. In the second section the authors discuss the several complement components that could represent a therapeutic target. Even if only the anti C5 monoclonal antibody is on the market, many targets as C1, C3, C5a and C5aR are the object of national or international trials. In addition, many molecules proved to be effective in vitro or in preclinical trials and are waiting to move to human trials in the future.

What's new in clinical solid organ transplantation by 2013.

Innovative and exciting advances in the clinical science in solid organ transplantation continuously realize as the results of studies, clinical trials, international conferences, consensus conferences, new technologies and discoveries. This review will address to the full spectrum of news in transplantation, that verified by 2013. The key areas covered are the transplantation activity, with particular regards to the donors, the news for solid organs such as kidney, pancreas, liver, heart and lung, the news in immunosuppressive therapies, the news in the field of tolerance and some of the main complications following transplantation as infections and cancers. The period of time covered by the study starts from the international meetings held in 2012, whose results were published in 2013, up to the 2013 meetings, conferences and consensus published in the first months of 2014. In particular for every organ, the trends in numbers and survival have been reviewed as well as the most relevant problems such as organ preservation, ischemia reperfusion injuries, and rejections with particular regards to the antibody mediated rejection that involves all solid organs. The new drugs and strategies applied in organ transplantation have been divided into new way of using old drugs or strategies and drugs new not yet on the market, but on phase Ito III of clinical studies and trials.

Impact of donor-specific antibodies on the outcomes of kidney graft: Pathophysiology, clinical, therapy.

Allo-antibodies, particularly when donor specific, are one of the most important factors that cause both early and late graft dysfunction. The authors review the current state of the art concerning this important issue in renal transplantation. Many antibodies have been recognized as mediators of renal injury. In particular donor-specific-Human Leukocyte Antigens antibodies appear to play a major role. New techniques, such as solid phase techniques and Luminex, have revealed these antibodies from patient sera. Other new techniques have uncovered alloantibodies and signs of complement activation in renal biopsy specimens. It has been acknowledged that the old concept of chronic renal injury caused by calcineurine inhibitors toxicity should be replaced in many cases by alloantibodies acting against the graft. In addition, the number of patients on waiting lists with preformed anti-human leukocyte antigens (HLA) antibodies is increasing, primarily from patients with a history of renal transplant failure already been sensitized. We should distinguish early and late acute antibody-mediated rejection from chronic antibody-mediated rejection. The latter often manifets late during the course of the post-transplant period and may be difficult to recognize if specific techniques are not applied. Different therapeutic strategies are used to control antibody-induced damage. These strategies may be applied prior to transplantation or, in the case of acute antibody-mediated rejection, after transplantation. Many new drugs are appearing at the horizon; however, these drugs are far from the clinic because they are in phase I-II of clinical trials. Thus the pipeline for the near future appears almost empty.

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations.

Hemolytic uremic syndrome (HUS) is a rare disease. In this work the authors review the recent findings on HUS, considering the different etiologic and pathogenetic classifications. New findings in genetics and, in particular, mutations of genes that encode the complement-regulatory proteins have improved our understanding of atypical HUS. Similarly, the complement proteins are clearly involved in all types of thrombotic microangiopathy: typical HUS, atypical HUS and thrombotic thrombocytopenic purpura (TTP). Furthermore, several secondary HUS appear to be related to abnormalities in complement genes in predisposed patients. The authors highlight the therapeutic aspects of this rare disease, examining both "traditional therapy" (including plasma therapy, kidney and kidney-liver transplantation) and "new therapies". The latter include anti-Shiga-toxin antibodies and anti-C5 monoclonal antibody "eculizumab". Eculizumab has been recently launched for the treatment of the atypical HUS, but it appears to be effective in the treatment of typical HUS and in TTP. Future therapies are in phases I and II. They include anti-C5 antibodies, which are more purified, less immunogenic and absorbed orally and, anti-C3 antibodies, which are more powerful, but potentially less safe. Additionally, infusions of recombinant complement-regulatory proteins are a potential future therapy.

Is it time to give up with calcineurin inhibitors in kidney transplantation?

Calcineurin inhibitors (CNIs) represent today a cornerstone for the maintenance immunosuppressive treatment in solid organ transplantation. Nevertheless, several attempts have been made either to minimize their dosage or to avoid CNIs at all because these drugs have the severe side effect of chronic nephrotoxicity. This issue represents a frontier for renal transplantation. The principal problem is to understanding whether the poor outcome over the long-term may be ascribed to CNIs nephrotoxicity or to the inability of these drugs to control the acute and chronic rejection B cells mediated. The authors analyze extensively all the international trials attempting to withdraw, minimize or avoid the use of CNIs. Few trials undertaken in low risk patients with an early conversion from CNIs to proliferation signal inhibitors were successful, but the vast majority of trials failed to improve CNIs side effects. To date the use of a new drug, a co-stimulation blocker, seems promising in avoiding CNIs with similar efficacy, better glomerular filtration rate and an improved metabolic profile. Moreover the use of this drug is not associated with the development of donor-specific anti-human leukocyte antigen antibodies. This point has a particular relevance, because the failure of CNIs to realize good outcomes in renal transplantation has recently ascribed to their inability to control the acute and chronic rejections B-cell mediated. This paper analyzes all the recent studies that have been done on this issue that represents the real frontier that should be overcome to realize better results over the long-term after transplantation.

Renal transplant allocation criteria, desensitization strategies and immunosuppressive therapy in retransplant renal patients.

This review covers the issue of kidney retransplantation. Patients waiting for a second transplant are increasing in number, and it is more and more difficult to find a suitable kidney. The main reasons are both clinical and immunological. Immunological problems are the most difficult to overcome. New techniques allow the identification of anti-HLA antibodies previously not easy to find. As a consequence, patients waiting for a new transplant are often hyperimmunized, and the cross-match is often positive. The authors discuss several immunosuppressive approaches for such patients and new allocation criteria to allow an easier retransplant. New allocation programs such as acceptable mismatch programs and paired kidney exchange programs are being implemented, and new drugs are now emerging allowing new desensitization criteria. Some of them are not yet on the market, but preliminary clinical studies show such drugs to be promising in a short time.

Relationship among endothelial response to hyperemia, bone marrow-derived progenitor cells, and parathyroid hormone in renal transplantation.

BACKGROUND: Endothelial dysfunction may contribute to modulate cardiovascular complications in renal transplant recipients (RTRs), and a relationship between endothelial dysfunction and parathyroid hormone (PTH) levels in RTRs has been demonstrated. We evaluated the relationship between endothelial response to hyperemia and circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) PTH, and genetic parameters in RTRs. METHODS: In 120 RTRs and in healthy subjects without (n=107, group A) and with cardiovascular risk factors (n=109, group B), we evaluated endothelial response to hyperemia through digital tonometry (peripheral arterial tonometry) detected by reactive hyperemia index (RHI) and EPCs and CPCs by flow cytometry. RESULTS: In RTRs, RHI median value was lower than in group A (P=0.05). EPC number was significantly lower in RTRs than in groups A and B (P<0.0001), whereas PTH median value was significantly higher (P<0.0001). In RTRs, RHI values were significantly lower according to the presence of three or more risk factors (P=0.04) and positively correlated with EPCs (P=0.04) but not with PTH (P=0.2). In patients who underwent dialysis for more than 5 years, lower RHI values (P=0.08), EPC number (P=0.5), and higher PTH concentrations (P=0.09) than in patients with less than 1 year dialysis time were observed. No relationship between eNOS gene -786T>C, 894G>T, and 4a/4b polymorphisms and RHI, EPC, and CPC number was found. CONCLUSIONS: This study shows an altered endothelial response, associated with reduced EPCs, and increased PTH in RTRs; the evaluation of endothelial status in RTRs may contribute to better assess the risk profile of these patients.

Good outcomes with cyclosporine very low exposure with everolimus high exposure in renal transplant patients.

INTRODUCTION: The aim of the study was to compare efficacy of cyclosporine (CsA) very low exposure with everolimus high exposure, with respect to CsA standard exposure with enteric-coated mycophenolate sodium (EC-MPS) therapy. METHODS: In a randomized, prospective, single-center, open-label study, patients were enrolled to receive either everolimus (C0 (trough level) 8-12 ng/mL) + CsA (C2 (CsA level 2 hours after drug administration) 250-300 ng/mL) + steroids, or EC-MPS (1,440 mg/day) + CsA (C2 500-700 ng/mL) + steroids. Fifty-six patients were enrolled in the everolimus group, 50 in the EC-MPS group. Efficacy was evaluated at 3 and 12 months. RESULTS: Characteristics of groups were similar. Biopsy-proven acute rejection (BPAR) rates were similar in both groups (everolimus 18.8% vs. EC-MPS 18.2%). Everolimus patients had a lower incidence of delayed graft function (DGF) than EC-MPS patients (22.6% vs. 40.9%; p<0.05; relative risk [RR] = 0.65). One-year graft survival was 95% in the everolimus group and 88% in the EC-MPS group (p=NS). CsA dose at 1 year was lower in the everolimus group (1.52 ± 0.67 vs. 2.55 ± 0.79 mg/kg; p<0.0001). Estimated glomerular filtration rate (eGFR; Cockcroft-Gault) was higher in the everolimus group (81.64 ± 32.67 vs. 62.62 ± 22.81 ml/min; p<0.001). Systolic blood pressure was lower in the everolimus group (124.9 ± 14.64 mm Hg vs. 131.1 ± 13.23 mm Hg; p=0.03). Hemoglobin blood levels were slightly lower in the everolimus group (12.62 ± 1.42 vs. 13.01 ± 1.3 g/L; p=NS; for anemia, RR=1.302). Serum cholesterol was similar in both groups (everolimus 219.1 ± 47.20 vs. EC-MPS 207.2 ± 38.8 mg/dL; p=NS), but everolimus patients used more statins (RR=1.49). Twenty-four-hour proteinuria was higher in the everolimus group (519.7 ± 77.31 vs. 296.7 ± 33.42 mg/24 hours; p=0.01). CONCLUSIONS: Everolimus regimen compared with EC-MPS regimen is associated with lower incidence of DGF, slightly better 1-year graft survival rate, a significantly higher GFR and lower systolic blood pressure.

Can skin be the first site of CMV involvement preceding a systematic infection in a renal transplant recipient?

Cytomegalovirus (CMV) is an important and well-described opportunistic virus in renal transplant recipients (RTRs) with infection occurring mainly after the first month post-renal transplant. CMV can present as primary infection, reinfection or reactivation of latent disease. Skin manifestations are rare and variable, and diagnosis is often delayed. We present one case of skin CMV ulcer of perineal areas without systemic symptoms of CMV disease and a negative quantitative polymerase chain reaction. This case serves to illustrate the protean nature of CMV disease in RTR.

Successful treatment of refractory wart with a topical activated vitamin d in a renal transplant recipient.

Warts are benign proliferations of the skin and mucosa caused by infection with human papillomavirus. They are commonly treated with destructive modalities such as cryotherapy with liquid nitrogen, local injection of bleomycin, electrocoagulation, topical application of glutaraldehyde, and local and systemic interferon-ß therapy. These treatment modalities often cause pain and sometimes scarring or pigmentation after treatment. We herein report a case with a right index finger wart, which was successfully treated with a topical activated vitamin D.

[Immunogical surveillance and oncogenesis: role of proliferation signal inhibitors]. / Sorveglianza immunologica ed oncogenesi: ruolo degli inibitori del segnale di proliferazione.

The authors review the antineoplastic effect of mTOR inhibitors and their biological basis. In normal cells mTOR is an intracellular serine/threonine kinase that is a central controller of cell growth and proliferation. mTOR integrates signals from a variety of sources as nutrients and growth factors. mTOR regulation can affect angiogenesis, cell growth, nutrient uptake and utilization, and metabolism. Growth factors such as insulin growth factor (IGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) bind to and activate receptors located on the cell surface. Receptors activate intracellular signaling cascades through PI3K-AKT-mTOR (phosphatidylinositol 3-kinase/serine-threonine kinase-mTOR), leading to protein synthesis. As a consequence, activation of the mTOR pathway is linked to increased protein synthesis by modulating elements that are important in a number of cellular processes, including growth, proliferation, angiogenesis, and nutrient uptake. Deregulation of mTOR-linked pathways increases the risk of developing cancer and has been identified in many human cancer types. Such deregulation includes overexpression of growth factors, overexpression or mutations of growth factor receptors, loss of tumor suppressor genes, and gain-of-function mutations in mTOR-linked pathways. These changes permit the survival, growth, proliferation, and migration of cancer cells and promote tumor angiogenesis. Targeting them has been a successful anticancer strategy. Targeting mTOR as well as these deregulated pathways could provide enhanced anticancer activity. The efficacy of mTOR inhibitors in preventing several types of cancer in transplanted patients, or making them regress once developed, has been documented in clinical trials and case reports.

High platelet turnover and reactivity in renal transplant recipients patients.

Renal transplant recipients (RTRs) patients are at increased risk of cardiovascular morbidity and mortality. We aimed this study to assess reticulated platelets (RP), platelet reactivity and von Willebrand factor (vWF) levels in RTRs patients. In 150 RTRs patients [84 (56%) not on acetylsalicylic acid (ASA) treatment, group A; 66 (44%) on ASA 100 mg treatment, group B] and in 60 healthy control subjects, RP were measured by a Sysmex XE-2100 and were expressed as the percentage of RP of the total optical platelet count (immature platelet fraction; IPF), as the percentage of RP highly fluorescent (H-IPF) and as the absolute number of RP (IPF#). Platelet function was assessed by optical aggregometry (PA) induced by 1 mmol arachidonic acid (AA-PA), 2 and 10 µM ADP (ADP2-PA and ADP10-PA) and 2 µg/ml collagen (Coll-PA). vWF levels were measured by using a miniVidas analyser. Group A and group B showed significant higher values of RP than controls. At a multiple linear regression analysis IPF and IPF# were significantly and positively related to collagen-PA. By analysing group B according to residual platelet reactivity (RPR), we observed a significant higher number of RP among patients with RPR by collagen. Moreover at a multiple logistic regression analysis, IPF# significantly affected the risk of having a RPR by collagen. With regard to vWF, RTRs patients showed higher levels than control subjects. We documented a higher platelet turn-over in both groups of RTRs patients and increased platelet reactivity in RTRs patients not on ASA therapy than controls.

High pretransplant serum levels of CXCL9 are associated with increased risk of acute rejection and graft failure in kidney graft recipients.

Several clinical and experimental models have underlined the role of the CXCR3-binding chemokines in the immune-mediated kidney diseases. This study aimed to investigate the predictive value of measuring pretransplant CXCL9 levels for acute rejection (AR) onset and kidney transplantation outcome. Pretransplantation serum levels of CXCL9 were tested retrospectively in 252 kidney graft recipients, whose stratification in two groups according to CXCL9 levels (<272.1 pg/ml vs. >272.1 pg/ml) showed highly significant differences in 5-year survival rates (97.7% vs. 73.3%; P < 0.001). Multivariate analysis demonstrated that among the analysed variables, CXCL9 [relative risk (RR) 11.708] and AR (RR 3.604) had the highest predictive power of graft loss. Accordingly, patients with AR (254.4 + or - 22.1; P < 0.05) and, even more, those with anti-thymoglobulin (ATG)-treated AR also showed increased pretransplant serum CXCL9 levels (319.3 + or - 28.1, P < 0.001). Moreover, CXCL9 expression and distribution were investigated in tissue specimens obtained from 10 patients affected by AR, and wide CXCL9 expression was detected not only in infiltrating inflammatory cells but also in vascular and tubular structures. Measurement of pretransplant serum CXCL9 levels might represent the tracking of a clinically useful parameter to identify subjects at high risk of AR and graft failure. These findings might be used for the individualization of immunosuppressive therapies.

Everolimus with very low-exposure cyclosporine a in de novo kidney transplantation: a multicenter, randomized, controlled trial.

BACKGROUND: In combination with everolimus (EVL), cyclosporine A (CsA) may be used at low exposure, so reducing the risk of renal dysfunction in renal transplant recipients (RTR). We evaluated whether higher exposure of EVL could allow a further reduction of CsA. METHODS: De novo RTR were randomized to standard exposure EVL (C0 3-8 ng/mL) with low-concentration CsA (C2 maintenance levels 350-500 ng/mL, group A) or higher EVL exposure (C0 8-12 ng/mL) with very low-concentration CsA (C2 maintenance levels 150-300 ng/mL, group B). The primary endpoints were 6-month creatinine clearance (CrCl) and biopsy-proven acute rejection (BPAR) rate. After 6 months, patients were followed up (observational extension) to 12 months. RESULTS: Two hundred eighty-five RTR (97% from deceased donors) were enrolled. Two patients per group died (1.4%). The 6-month death-censored graft survival was 90.2% in group A and 97.9% in group B and was unchanged at 12 months (P=0.007). There was no significant difference between groups at 6 months in CrCl (59.9 vs. 57.8 mL/min) and BPAR rates (14.7% vs. 11.9%) and also at 12 months (CrCl 62.5+/-20.7 vs. 61.3+/-22.0 mL/min, BPAR 14.7% vs. 14.1%). No significant differences were seen in treated acute rejections, steroid-resistant acute rejections, treatment failures, or delayed graft function, although there was a trend to better results in group B. CONCLUSIONS: EVL given at higher exposure for 6 months plus very low CsA concentration may obtain low acute rejection rate and good graft survival in De novo renal transplantation. However, there was no difference between groups in CrCl.