Abstract
Despite potent immunosuppression, clinical and biopsy confirmed acute renal allograft rejection (AR) still occurs in 10–15% of recipients, ~30% of patients demonstrate subclinical rejection on biopsy, and ~50% of them can show molecular inflammation, all which increase the risk of chronic dysfunction and worsened allograft outcomes. Mitochondria represent intracellular endogenous triggers of inflammation, which can regulate immune cell differentiation, and expansion and cause antigen-independent graft injury, potentially enhancing the development of acute rejection. In the present study, we investigated the role of mitochondrial DNA encoded gene expression in biopsy matched peripheral blood (PB) samples from kidney transplant recipients. Quantitative PCR was performed in 155 PB samples from 115 unique pediatric (<21 years) and adult (>21 years) renal allograft recipients at the point of AR (n = 61) and absence of rejection (n = 94) for the expression of 11 mitochondrial DNA encoded genes. We observed increased expression of all genes in adult recipients compared to pediatric recipients; separate analyses in both cohorts demonstrated increased expression during rejection, which also differentiated borderline rejection and showed an increasing pattern in serially collected samples (0–3 months prior to and post rejection). Our results provide new insights on the role of mitochondria during rejection and potentially indicate mitochondria as targets for novel immunosuppression.
Highlights
Kidney transplantation is the treatment of choice for most patients with end-stage renal disease
A total of 155 peripheral blood (PB) samples were collected from 115 unique patients at Stanford (36/36 samples/patients), University of California Los Angeles (UCLA) (62/24 samples/patients), Emory (28/26 samples/patients), and University of Pittsburgh Medical Center (UPMC) (29/29 samples/ patients) and analyzed for mitochondrial gene expression (Table 1, Patient Demographics)
62 had matching biopsies that met Banff classification criteria for acute renal allograft rejection (AR) [16]: 12 were classified as borderline rejection (BL-AR); 5 were antibody mediated (AMR) rejection with lesions in the glomeruli and peritubular capillary (PTC) compartments paired with positive C4d staining at PTC; 40 rejections were T-cell mediated (TCMR), and 5 showed a mixed type of antibody mediated rejection (AMR) + TCMR rejection
Summary
Kidney transplantation is the treatment of choice for most patients with end-stage renal disease. Using quantitative real-time PCR (qPCR), we analyzed 155 peripheral blood (PB) samples collected from 115 unique renal transplant recipients from 4 transplant centers in the U.S for the expression of 11 mitochondrial DNA encoded genes, 9 encoded on the respiratory complexes I, III, IV, and V, and 2 rRNA, of Abbreviations: AR, acute rejection; AMR, antibody mediated rejection; ATN, acute tubular nephritis; ATP, adenosine-tri-phosphatase; Basi, basiliximab; BL, borderline acute rejection; CNI, calcineurin inhibitor; COX, cyclooxygenase; CS, corticosteroids; CYB, cytochrome B; DAC, daclizumab; DAMPS, damageassociated molecular patterns; GFR, glomerular filtration rate; HLA, human leukocyte antigen; IF/TA, interstitial fibrosis/tubular atrophy; IRI, ischemia reperfusion injury; IS, immunosuppression; MMF, mycophenolate mofetil; Mt, mitochondrial; NADH, sodium-dehydrogenase; No-AR, absence of rejection on biopsy; PB, peripheral blood; PBMC, peripheral blood mononuclear cells; PTC, peritubular capillary; Thymo, thymoglobuline
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