Role of metabolic dysfunction-associated steatotic liver disease and of its genetics on kidney function in childhood obesity

Objectives: Evidence linked metabolic associated steatotic liver disease (MASLD) to kidney damage with the potential contribution of the I148M variant of the Patatin-like phospholipase containing domain 3 (PNPLA3) gene. We aimed at investigating the relationship of MASLD and of its genetics with kidney function in children with obesity. Methods: A comprehensive evaluation including genotyping for the I148M PNPLA3 polymorphism was performed in 1037 children with obesity. Fatty liver (FL) was assessed by liver ultrasound. According to MASLD criteria, subjects with obesity but without FL were included in group 1, while patients with obesity and FL (encompassing one MASLD criterion) were clustered into group 2. Group 3 included patients with obesity, FL, and metabolic dysregulation (encompassing >1 MASLD criterion). Results: Alanine transaminase levels significantly increased while estimated glomerular filtration rate (eGFR) significantly reduced from group 1 to 3. Group 3 showed a higher percentage of carriers of the I148M allele of the PNPLA3 gene compared to other groups (p < 0.0001). Carriers of group 2 and of group 3 showed reduced eGFR levels than noncarriers of group 2 (p = 0.04) and of group 3 (p = 0.02), respectively. A general linear model for eGFR variance in the study population showed an inverse association of eGFR with both MASLD and PNPLA3 genotypes (p = 0.011 and p = 0.02, respectively). An inverse association of eGFR with MASLD was also confirmed only in carriers (p = 0.006). Conclusions: The coexistence of more than 1 MASLD criterion in children with obesity seems to adversely affect kidney function. The PNPLA3 I148M allele further impacts on this association.