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

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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.


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.


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.


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.

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