Introduction: We previously demonstrated universal glomerular abnormalities in kidney biopsies after orthotopic liver transplantation (OLT). We hypothesize that these changes exist prior to OLT and may play an important role in the development of renal failure after OLT. We investigated the mechanism of kidney disease in patients listed for OLT by immunohistopathologic and genomic analysis of kidney biopsies (KB). Methods: Analysis of clinical and pathological data of 21 cirrhotic patients (pts) listed for OLT who underwent KB. The Gene expression profile of KB specimens was studied by Affymetric HuGene 1.0 ST expression assay and was compared with pre-implantation living donor KBs. Results: Etiology of liver disease: hepatitis C (71%), alcoholic hepatitis (24 %) and autoimmune hepatitis (5%). Mean MELD, serum creatinine, GFR and proteinuria were 17± 5, 1.9 ±0.7 mg/dl, 42±17 ml/min and 0.5±0.8 gm/day, respectively. Twelve pts had low complement levels. Mesangial proliferation was seen in 20 KBs by light microscopy. Five pts had nodular glomerulosclerosis (3 DM), 2 FSGS and 1 MPGN. Immunofluorescence staining showed mesangial, capillary wall or tubular basement-membrane deposition of IgG (16), IgM (18), IgA (10), C1Q (11) and C3 (12). Electron microscope in 16 pts showed effacement of podocytes (15) and duplication and widening of glomerular basement membranes (10). Gene expression profiles by Gene Ontology revealed significant up-regulation of genes implicated in immune response, including T-cell, leucocyte and platelet activation and differentiation. Pathogenesis-based transcripts revealed significantly increased expression of quantitative cytotoxic T-cell, quantitative macrophage, B-cell, natural killer cell, and endothelial cell associated transcripts, indicating an ongoing inflammatory immune response.

Conclusion: This study demonstrates the universal presence of glomerular abnormalities in KBs of cirrhotic patients. The majority had increases in mesangial matrix, podocyte effacement, and widening and duplication of glomerular basement membrane, as is also seen in patient’s post-OLT. The increased gene expression profiles related to immune activity could indicate immune-mediated mechanisms in development of kidney disease in cirrhotic patients.

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