Kidney function after liver transplantation: the contrasting roles of inflammation and tubular repair

Abstract

Kidney injury is a significant complication in end-stage liver disease (ESLD), leading to increased morbidity and mortality. While liver transplant alone (LTA) can promote kidney recovery (KR), non-recovery associates with adverse outcomes, but the underlying pathophysiology is still unclear. We studied 10 LTA recipients with or without kidney failure (KF) and measured serum levels of OPN and TIMP-1 (previously identified predictors of KR), 92 proinflammatory proteins (Olink), and urinary cell populations. Our findings revealed elevated OPN and TIMP-1 levels in KF patients, strongly correlated with tubular epithelial cells in urine. Proteomic analysis showed distinct profiles in KF, non-KF, and healthy donors, indicating an ongoing proinflammatory signature in KF. Cytokines correlated with OPN and TIMP-1 levels. We propose that high pre-LTA OPN and TIMP-1 levels are crucial for tubular regeneration and normalize with kidney recovery. Insufficient pre-LTA OPN levels may lead to persistent kidney failure. Our present data also newly indicate that kidney failure post-LTA is an active condition, in which tubular cells are persistently shed in the urine. The strict association between systemic inflammation and tubular cell loss suggests a pathogenic link that could offer therapeutic opportunities to promote kidney recovery.

Keywords: OPN; TIMP-1; acute kidney injury; hepatorenal; liver transplant; tubular cell.

Figure 1

Serum levels of osteopontin (OPN) and tissue inhibitor of metalloproteinases 1 (TIMP-1) and urinary cell populations. (A) OPN and (B) TIMP-1 serum levels. (C) Tubular epithelial cells (TEC), dotted line represents mean of healthy controls; (D) neutrophils, (E) CD3⁺ T cells quantified in urine by epigenetic analysis. Correlation between urinary TEC and (F) OPN or (G) TIMP-1. NKF, normal kidney function after LTA; IKF, impaired kidney function after LTA; Ctrl, healthy controls *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001.

Figure 2

Proteomic analysis of circulating inflammatory markers. (A) PCA analysis reveals a distinct separation between the two cohorts of LTA patients and healthy controls based on the differential expression of 8 cytokines. (B) Heatmap depicting the normalized level of expression (red-blue) of representative 30 cytokines between 10 patients with LTA. (C) Single-patient levels of 8 cytokines that were significantly different between NKF vs. IKF patients after adjustment for multiple comparisons. (D) Correlation between osteopontin (OPN) and Tissue Inhibitor of metalloproteinases 1 (TIMP-1), tubular epithelial cells (TEC) and 8 significantly different cytokines and urinary cells. NKF, normal kidney function after LTA; IKF, impaired kidney function after LTA. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001.