ABSTRACT: Glomerular abnormalities have been demonstrated in kidney biopsies of patient after orthotopic liver transplantation (OLT). We hypothesize that these changes exist prior to OLT and may play a role in the development of renal failure after OLT. We use gene expression microarrays to investigate the mechanism of kidney disease in patients listed for OLT. Gene expression profiles of biopsies of cirrhotic patients were compared with pre-implantation living donor biopsies. Glomerular abnormalities were seen in 92% of the biopsies, the most common being increase in mesangial matrix. Electron microscope showed effacement of podocytes (93%) and duplication (35%) and widening of glomerular basement membrane (45%). Gene Ontology analysis revealed significant up-regulation of genes implicated in immune response, including T-cell, leucocyte and platelet activation and differentiation. Pathogenesis-based transcripts analysis revealed significantly increased expression of cytotoxic T-cell, macrophage, B-cell, natural killer cell, and endothelial cell associated transcripts, indicating an ongoing inflammatory immune response. Eight patients with cirrhotic livers listed for transplantation were referred to the kidney transplant clinic at Montefiore Medical Center, Bronx, New York, for evaluation of renal dysfunction between April 2010 and March 2013. Patients consented prior to clinically indicated kidney biopsy for enrollment into the study. Information and lab results were collated for each patient including: age, sex, race, etiology of liver disease, history of diabetes mellitus (DM) and hypertension (HTN), metabolic profile, liver function tests, glycosylated hemoglobin (HgbA1c), C3 and C4 complement concentrations, antinuclear antibody titers and spot urine protein to creatinine ratio. Patients completed a 24-hr urine collection for protein and creatinine, which was used to assess proteinuria and creatinine clearance. eGFR was calculated using the Modified Diet of Renal Disease (MDRD) formula. Hematuria was defined as presence of any red cells in urine analysis. Proteinuria was defined as protein excretion of greater than 100mg in 24 hour. HTN and DM were defined by use of anti-hypertensive and insulin or oral hypoglycemic agents respectively in past or at time of kidney biopsy. Biopsies from cirrhotic patients were then compared to nine pre-implantation biopsies from living kidney donors. The de-identified patient clinical characteristics are provided in each sample records; For Hematuria, HTN, MM (mesangial matrix expansion), MC (mesangial cell increase), II (interstitial inflammation), podocyte, BM (basement membrane thickening), the value 0 and 1 represents 'ABSENT' and 'PRESENT', respectively. For C3 and C4, the value 0 and 1 represents NORMAL and LOW C3 (or C4) LEVELS, repectively. For TA (tubular atrophy), IF (interstital fibrosis), AS (arteiosclerosis), the value 0, 1, and 2 represents ABSENT, PRESENT MILD, and PRESENT MODERATE, respectively. For IgG, IgA, IgM, C, and EmPE, the values represent 1 (ABSENT), 1 (MILD STAINING), 2 (MODERATE), 3 (SEVERE), NA (NOT AVAILABLE), P (PENDING). For BMWId, BMd, and EDD, the values represent 0 (ABSENT), 1 (PRESENT), NA (NOT AVAILABLE), P (PENDING).
