The Spectrum of Histopathological Changes in the Renal Allograft - a 12 Months Protocol Biopsy Study

INTRODUCTION: Renal transplantation became a routine and successful medical treatment for Chronic Kidney Disease in the last 30 years all over the world. Introduction of Luminex based Single Antigen Beads (SAB) and recent BANFF consensus of histopathological phenotypes of different forms of rejection enables more precise diagnosis and changes the therapeutic approach. The graft biopsies, protocol or cause, indicated, remain a golden diagnostic tool for clinical follow up of kidney transplant recipients (KTR).AIM: The study aimed to analyse the histopathological changes in renal grafts 12 months after the surgery in KTR with satisfactory kidney function.MATERIAL AND METHODS: A 12-month protocol biopsy study was performed in a cohort of 50 Kidney transplant recipients (42 from living and 8 from deceased donors). Usual work-up for suitable donors and recipients, standard surgical procedure, basic principles of peri and postoperative care and follow up were done in all KTR. Sequential quadruple immunosuppression including induction with Anti-thymocyte globulin (ATG) or Interleukin-2R antagonist (IL-2R), and triple drug maintenance therapy with Calcineurin Inhibitors (CNI), Mycophenolate Mofetil (MMF) and Steroids were prescribed to all pts. Different forms of Glomerulonephritis (16), Hypertension (10), End Stage Renal Disease (13), Hereditary Nephropathies (6), Diabetes (3) and Vesicoureteral Reflux (2) were the underlying diseases. All biopsies were performed under ultrasound guidance. The 16 gauge needles with automated “gun†were used to take 2 cores of tissue. The samples were stained with HE, PAS, Trichrome Masson and Silver and reviewed by the same pathologist. A revised and uploaded BANFF 2013 classification in 6 categories (Cat) was used.RESULTS: Out of 48 biopsies, 15 (31%) were considered as normal, 4 (8%), Borderline (BL-Cat 3), 5 (10%) as Interstitial Fibrosis/Tubular Atrophy (IF/TA-Cat 5), 5 (10%) were classified as non-immunological (Cat 6), 2 as a pure antibody-mediated rejection (ABMR-Cat 2) and T-cell Mediated Rejection (TCMR-Cat 4). The remaining 17 samples were classified as a “mixed†rejection: 7 (41%) ABMR + IF/TA, 5 (29%) ABMR + BL + IF/TA, 2 (11%) BL + IF/TA, 1 (5%) ABMR + BL, 1 (5%) ABMR + TCMR and 1 (5%) TCMR +  IF/TA. The mean serum creatinine at the time of the biopsy was 126.7 ± 23.4 µmol/L, while GFR-MDRD 63.4 ± 20.7 ml/min, which means that the majority of the findings were subclinical. Among the non-immunological histological findings (Cat 6), 3 cases belonged to CNI toxicity, 1 to BK nephropathy and 1 to recurrence of the primary disease.CONCLUSION: Our 12-month protocol biopsy study revealed the presence of different forms of mixed subclinical rejection. Use of recent BANFF classification and scoring system enables more precise diagnosis and subsequently different approach to the further treatment of the KTR. More correlative long-term studies including Anti HLA antibodies and Endothelial Cell Activation- Associated Transcripts (ENDAT) are needed

DE NOVO ANTI HLA ANTIBODIES AFTER KIDNEY TRANSPLANTATION: CLINICAL SIGNIFICANCE AND ASSOCIATION WITH GRAFT FUNCTION

Background. Kidney transplantation (TR) is the best treatment of chronic kidney disease. Chronic cellular and antibody mediated rejections have still major impact on graft survival. Single antigen bead technology enabled detection of donor specific (DSA) and non-donor specific (Non-DSA) anti HLA antibodies (HLA-Ab). Our study investigates the impact of de novo HLA-Ab on graft function (GF) 12 months after TR. Material and methods. 50 pts with living (42) and deceased donor (8) transplantation were included in a 12-month prospective study. HLA-Ab were analyzed using LABScreen mixed kit in the 1st and 12th month after TR. According to the presence of HLA-Ab, pts were divided in group 1 (HLA+) and group 2 (HLA -). Both groups did not differ regarding gender, age, living or deceased donor, immunosuppression, underlying renal disease, rejection episodes, HLA mismatch, cold and warm ischemia time. Serum creatinine (SCr), GFR (Cockroft Gault) and proteinuria (Pr) were analyzed 1st and 12th month after TR. Results. HLA-Ab were detected in 17 pts (34%), 5 with DSA (10%) and 12 with Non-DSA (24%). Group 1 has a significant worsening of GFR (SCr increased from 112.1 to 141.5 ( p<0.002) compared with the group 2 where SCr decreased from 116.4 to 111.31 µol/L.( p<0.23). In the same time GFR decreased from 69.7 to 57.09 and increased from 67.8 to 69.3 while Pr increased from 0.42 to 0.58 ( p< 0.26) and decreased from 0.81 to 0.32 ( p<0.051) in the groups 1 and 2, respectively. Conclusion. De novo DSA and Non-DSA produce graft injuries in the first 12 months after TR. Regular follow- up of HLA-Ab together with systematic protocol graft biopsy could be essential for further therapeutic interventions

Cannabinoid receptor 1 is a major mediator of renal fibrosis

Chronic kidney disease, secondary to renal fibrogenesis, is a burden on public health. There is a need to explore new therapeutic pathways to reduce renal fibrogenesis. To study this, we used unilateral ureteral obstruction (UUO) in mice as an experimental model of renal fibrosis and microarray analysis to compare gene expression in fibrotic and normal kidneys. The cannabinoid receptor 1 (CB1) was among the most upregulated genes in mice, and the main endogenous CB1 ligand (2-arachidonoylglycerol) was significantly increased in the fibrotic kidney. Interestingly, CB1 expression was highly increased in kidney biopsies of patients with IgA nephropathy, diabetes, and acute interstitial nephritis. Both genetic and pharmacological knockout of CB1 induced a profound reduction in renal fibrosis during UUO. While CB2 is also involved in renal fibrogenesis, it did not potentiate the role of CB1. CB1 expression was significantly increased in myofibroblasts, the main effector cells in renal fibrogenesis, upon TGF-β1 stimulation. The decrease in renal fibrosis during CB1 blockade could be explained by a direct action on myofibroblasts. CB1 blockade reduced collagen expression in vitro. Rimonabant, a selective CB1 endocannabinoid receptor antagonist, modulated the macrophage infiltrate responsible for renal fibrosis in UUO through a decrease in monocyte chemoattractant protein-1 synthesis. Thus, CB1 has a major role in the activation of myofibroblasts and may be a new target for treating chronic kidney disease.SCOPUS: ar.jinfo:eu-repo/semantics/publishe