Mantovani Alessandro, Targher Giovanni
Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.
Department of Medicine, University of Verona, Verona, Italy.
Liver Int. 2025 Mar;45(3):e16010. doi: 10.1111/liv.16010. Epub 2024 Jun 14.
Accumulating epidemiological evidence shows that the patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 G allele, which is the most robust genetic variant associated with greater susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD), is significantly associated with impaired kidney function in both adults and children, regardless of the presence of common renal risk factors, MASLD severity, and other potential confounders. Although some prospective studies have reported a significant association between the PNPLA3 rs738409 G allele and the increased risk of developing chronic kidney disease (CKD), the epidemiological evidence about a possible direct effect of the PNPLA3 rs738409 G allele on the risk of developing CKD is still limited. Experimentally, PNPLA3 is expressed in renal podocytes, pericytes, and proximal tubule cells, thus supporting the notion that the mutant PNPLA3 protein may play a role in developing renal steatosis and fibrosis. However, it cannot be ruled out that a part of the adverse effect of the PNPLA3 rs738409 G allele on kidney function may be driven by a direct impact of this genetic variant on the development and progression of MASLD. It is possible to hypothesize that identifying the PNPLA3 genotype might help identify individuals at higher risk of CKD and those at greater risk of advanced MASLD. In this narrative minireview, we summarize the current epidemiological data about the association between the PNPLA3 rs738409 G allele and the risk of CKD and abnormal albuminuria. We also briefly discuss the putative biological mechanisms underpinning this association and its potential and future clinical implications.
越来越多的流行病学证据表明，含patatin样磷脂酶结构域蛋白3（PNPLA3）rs738409 G等位基因是与代谢功能障碍相关脂肪性肝病（MASLD）易感性增加最密切相关的基因变异，无论是否存在常见肾脏危险因素、MASLD严重程度及其他潜在混杂因素，该等位基因都与成人和儿童的肾功能受损显著相关。尽管一些前瞻性研究报告了PNPLA3 rs738409 G等位基因与慢性肾脏病（CKD）发生风险增加之间存在显著关联，但关于PNPLA3 rs738409 G等位基因对CKD发生风险可能的直接影响的流行病学证据仍然有限。在实验中，PNPLA3在肾足细胞、周细胞和近端小管细胞中表达，因此支持了突变型PNPLA3蛋白可能在肾脂肪变性和纤维化发展中起作用的观点。然而，不能排除PNPLA3 rs738409 G等位基因对肾功能的部分不良影响可能是由该基因变异对MASLD发展和进展的直接影响所驱动。可以推测，识别PNPLA3基因型可能有助于识别CKD高风险个体以及晚期MASLD高风险个体。在这篇叙述性综述中，我们总结了目前关于PNPLA3 rs738409 G等位基因与CKD风险及异常白蛋白尿之间关联的流行病学数据。我们还简要讨论了支持这种关联的假定生物学机制及其潜在的和未来的临床意义。
