Comment to “Proteomic analysis of human kidney biopsies unveils emerging acute kidney injury very early after liver graft reperfusion”

To editor:

We read with great interest the manuscript by Åsa Norén et al. titled “Proteomic analysis of human kidney biopsies unveils emerging acute kidney injury very early after liver graft reperfusion” [1]. The authors propose that proteomic analysis of renal tissue biopsies can identify differential expression markers for early acute kidney injury (AKI) following liver transplantation (LT) reperfusion. Their findings indicate significant early alterations in alarmins and suggest that extracellular matrix (ECM) remodeling-related proteins may be closely linked to AKI development. We commend the authors for this important clinical study, as their results have significant implications for the early identification of LT-AKI, potentially facilitating earlier intervention and providing a foundation for further mechanistic research. However, several aspects of the study warrant further attention and discussion.

First, although the kidney biopsy identified 731 differentially expressed genes, the authors only validated MMP-7, which exhibited the most prominent upregulation, without addressing the most significantly downregulated markers. The relationship between MMP-7 and AKI remains unclear, with limited studies investigating this association. A transcriptome analysis of pigs following cardiopulmonary bypass (CPB) induced AKI revealed downregulation of MMP-7 in the renal medulla [2], which may be attributable to differences in species (human vs. pig), kidney region (cortex vs. medulla), diagnostic criteria for AKI, surgical types (LT-AKI vs. CPB-AKI), and detection methodologies (transcriptome vs. proteome). The authors should include quantification and scaling of immunohistochemical analysis of MMP-7 and consider co-localization with specific markers for renal tubular epithelial cells to identify the cell types most affected by MMP-7. Moreover, as a non-invasive alternative, the authors could explore MMP-7 expression in urine, as previous studies have suggested that urinary MMP-7 may serve as a reliable marker for renal injury [3].

Second, taking into account the research on AKI to chronic kidney disease (CKD) transition [4], we recommend extending the follow-up period for the 21 patients to at least three months to evaluate whether these differential proteins and alarmins serve as biomarkers for CKD. This would further broaden the clinical relevance of the study’s findings.

Third, while circulating alarmins such as HMGB-1 are considered promising biomarkers for AKI [5], no differential expression of it was observed in the proteomics analysis, and their performance in blood samples was suboptimal. The abstract states that “HMGB-1 was found to be already upregulated (15%) 2 hours after LT in patients who later developed AKI,” but this description is inconsistent with Fig. 4, which shows no significant difference in circulating concentrations of HMGB-1 between patients who developed AKI and no-AKI in 48 h, collected 2–4 h after liver graft reperfusion. This may arise from unadjusted confounding factors in the study, including the use of immunosuppressive medications, ischemic duration, hypotension during reperfusion, and the administration of vasoactive drugs, contrast agent, aminoglycoside antibiotics, and NSAIDs.

In conclusion, the use of human kidney biopsies to identify differentially expressed AKI-related proteins in this study is clinically valuable and provides a theoretical foundation for proposing targets for mechanistic research. However, the differentially expressed proteins identified in this study require validation in larger cohorts and through basic research. As the authors note, the most effective approach to preventing AKI may involve reducing ischemia/reperfusion injury rather than targeting specific proteins, as doing so under uncertain conditions may lead to unintended side effects. We hope that the proteomic findings from kidney biopsies in this study will ultimately guide improved early detection, diagnosis, and treatment of AKI in liver transplant recipients, thereby reducing the impact of liver transplantation on distant organs.

Author contributions

Tao Chen interpreted the article and prepared the initial draft, and Tao Luo contributed to the revision and review of the manuscript.

Funding

No funding was received.

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Conflict of interest

The authors declare that there are no conflicts of interest.