P1781CONVERSION TO SIROLIMUS IN ADVANCED STAGES OF CHRONIC ALLOGRAFT NEPHROPATHY. A RANDOMIZED CLINICAL TRIAL

Background and Aims Some studies have shown that proteinuria more than 800 mg per day and glomerular filtration rate (GFR) less than 40 ml/min are the most important relative contraindications for mTOR inhibitors prescription. There is no pathophysiologic reason to put aside mTOR inhibitors in more advanced stages of chronic allograft nephropathy(CAN). To clarify the safety of conversion to mTOR inhibitors in more advanced stages of CAN we conduct a randomized clinical trial Method Among 1911 renal transplant recipients which was performed from May 1989 to May 2016, patients (pts) with CAN included to the study. CAN was defined by pathology results and rule out of other causes of renal dysfunction and GFR less than 60 ml/min. pts with recent acute rejection, chronic Ab mediated rejection, active viral infection, malignancy, advanced cardiac, liver and respiratory diseases, obstructive uropathy and non-adherence were excluded from the study. After exclusion there were 211 pts with CAN. Among CAN pts 112 pts have GFR less than 40 ml/min. These patients were assigned in two group randomly. Group 1 continued their immunosuppression which consists of mycophenolate mofetil/myfortic, Cyclosporin A /Tacrolimus and prednisolone. Group B which received Sirolimus 2 mg daily instead of CyclosporinA / tacrolimus. All pts followed for 18 months. allograft function and pts morbidity and mortality were monitored every two months. results were recorded in clinic sheets and were analyzed using SPss version 22 Results G1 consist of 53 and G2 59 pts. There were no differences in two group in respect to sex (M/F was 0.89 and 0.84 in G1 and G2 respectively), and age (mean age was 41 6 9.5 and 43 6 8.23 in G1 and G2 respectively). there were no differences in admission rate for medical reasons (0.43 and 0.39 admission per pts per year in G1 and G2 respectively p=0.23). There was no difference between two group in respect to cardiovascular events (0.23 and 0.27 events per pts per year in G1 and G2 respectively p=0.31). The average trough level of SRL was 8.38± 3.12 ng/mL at 18 months. At 18 months, the incidence of acute rejection was not higher in G2 (21% vs. 18.8 %, p = 0.21) and renal function was superior in patients converted to SRL (eGFR 32.3 vs. 23.4 mL/min/ 1.73 m2, p = 0.019) compared to those maintained on CsA/TAC. There were no significant differences in pts survival (one death in each group) Graft loss was higher in G1( 5 versus 2 at 18 months p= 0.014). there were no significant differences in respect to liver, respiratory, GI, hematologic and infectious complications. pts in G2 group had lower BP and uric acid levels. Conclusion Conversion to mTOR inhibitors in more advanced stages of CAN is safe and has beneficial effect on renal allograft function with no more side effect.

P1615IDENTIFICATION OF URINARY PROTEOMIC PROFILE OF PATIENTS WITH CHRONIC ALLOGRAFT NEPHROPATHY

Background and Aims Chronic allograft nephropathy (CAN) is a major complication that occurs post-transplantation. At present, the diagnosis of chronic allograft nephropathy (CAN) is based on renal biopsy. Therefore, there is an ultimate need to identify more specific and sensitive noninvasive methods for the early diagnosis of CAN. Recently, proteomic-based modalities have been developed to discover biomarkers of CAN. Method Urine samples from 75 participants were collected. Participants were divided into 3 groups: Group I: 25 patients with chronic allograft nephropathy, group II: 25transplanted patients with stable renal functions, and group III: 25 healthy control subjects matched for age and sex. Each group was divided into training set and test set. Specimens were purified with magnetic beads-based weak cation exchange chromatography and analyzed in a MALDI-TOF MS. Results A Genetic Algorithm (GA) was used to set up the classification models. Five peaks represented the proteomic profile that differentiates between the CAN patients and the control group with sensitivity of 100%, specificity of 100%, recognition capability of 100 % and cross-validation91.7 % and five peaks differentiate between the transplant patients with normal renal functions and the control groups with sensitivity of96.8 %, specificity of 95.5 %, recognition capability of 98 % and cross-validation of 100 %. Conclusion We identified a pattern for CAN and transplant patients with normal renal functions by proteomic profiling using MALDI-TOF-MS and magnetic beads.

Senescence in chronic allograft nephropathy

Despite increasing numbers of patients on dialysis, the numbers of renal transplants performed yearly have remained relatively static. During the last 50 years, there have been many advances in the pharmacology of prevention of organ rejection. However, most patients will suffer from a slow but steady decline in renal function leading to graft loss. The most common cause of long-term graft loss is chronic allograft nephropathy (CAN). Therefore, elucidating and understanding the mechanisms involved in CAN is crucial for achieving better posttransplant outcomes. It is thought that the development of epithelial to mesenchymal transition (EMT) in proximal tubules is one of the first steps towards CAN, and has been shown to be a result of cellular senescence. Cells undergoing senescence acquire a senescence associated secretory phenotype (SASP) leading to the production of interleukin-1 alpha (IL-1α), which has been implicated in several degenerative and inflammatory processes including renal disease. A central mediator in SASP activation is the production of reactive oxygen species (ROS), which are produced in response to numerous physiological and pathological stimuli. This review explores the connection between SASP and the development of EMT/CAN in an effort to suggest future directions for research leading to improved long-term graft outcomes.