Potential association between elevated serum human epididymis protein 4 and renal fibrosis A systemic review and meta-analysis

Background: Human epididymis protein 4 (HE4), a matrix metalloprotease 2 (MMP2), and a matrix metalloprotease 9 (MMP9) inhibitor, promotes renal fibrosis by inhibiting the degradation of type I collagen. However, the predictive value of HE4 for renal fibrosis remains controversial, even though it has been identified as one of the most upregulated genes in cultured fibrosis-associated myofibroblasts. This systematic review and meta-analysis was conducted to investigate the potential association between circulating HE4 and renal fibrosis. Methods: Original and review articles published until January 2017 that analyzed the performance of serum HE4 in renal fibrosis were systematically searched for in PubMed (1966-2017.1), Cochrane Library, Web of Science, EMBASE (1980-2017.1), China National Knowledge Infrastructure, Wanfang Database, and VIP (Weipu Database). The meta-analysis was performed using RevMan 5.3 version. Pertinent studies were reviewed and the standardized mean difference (SMD) with 95% confidence interval was extracted. A total of 5 studies reporting 460 participants were included in the final analysis. Subgroup and sensitivity analyses were performed to explore the potential sources of between-study heterogeneity. Results: The results demonstrated that elevated serum HE4 favored the diagnosis of renal fibrosis across all trials (SMD = 1.41; 95% confidence interval, 0.82-2.01; P<.001). The bubble graph indicated statistically robust result. The pooled SMD was similar after removing any single study for sensitivity analysis. Conclusion: The present study suggests a positive association between circulating HE4 and renal fibrosis. Further studies are needed to investigate the effects of interventions on HE4, and the value of HE4 as a biomarker.