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Background and Aims:Emerging evidence suggests an association between patatinlike phospholipase domain-containing protein-3 (PNPLA3) rs738409 (I148M protein variant) and risk of chronic kidney disease (CKD), but the mechanisms underpinning this association are poorly understood. Methods:We studied 157 patients with type 2 diabetes (T2DM) who underwent ultrasonography and vibration-controlled transient elastography for diagnosing nonalcoholic fatty liver disease (NAFLD). CKD was defined as estimated glomerular filtration rate (e-GFR) <60 mL/min/1.73 m 2 and/or abnormal albuminuria. We surveyed PNPLA3 mRNA expression in human tissues, using the liver as a positive control, and also measured PNPLA3 mRNA and protein expression levels in human cell lines represented in the kidney and the liver. Results:In all, 112 patients had NAFLD and 43 had CKD. Patients homozygous for the I148M variant (n = 11) had lower e-GFR levels (60.6 ± 11.7 vs 77.8 ± 15.9 vs 83.5 ± 16.5 mL/min/1.73 m 2 , P = .0001) and higher prevalence of CKD (63.6% vs 24.2% vs 25.0%, P = .028), compared to those with I/M (n = 66) and I/I (n = 80) PNPLA3 genotype. The association of I148M homozygosity with lower e-GFR levels (P < .0001) and higher risk of CKD (adjusted-odds ratio 6.65; 95% CI 1.65-26.8, P = .008) was independent of liver disease severity (as detected by liver stiffness ≥7kPa) and other risk factors. PNPLA3 mRNA expression was greatest in liver and renal cortex, and podocytes showed high PNPLA3 mRNA and protein levels, comparable to that of hepatocytes and hepatic stellate cells respectively. Conclusions:The PNPLA3 I148M variant was associated with CKD, independently of common renal risk factors and severity of NAFLD PNPLA3 expression levels were particularly high in renal podocytes. | 1131 MANTOVANI eT Al.

CKD, chronic kidney disease CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration CRP, C-reactive protein eGFR, estimated glomerular filtration rate FIB-4, fibrosis 4 FLI, fatty liver index GGT, gamma-glutamyltransferase HOMA-IR, Homeostasis model assessment-insulin resistance MDRD, Modification of Diet in Renal Disease NAFLD, nonalcoholic fatty liver disease NASH, nonalcoholic steatohepatitis OR, odds ratio PNPLA3, patatin-like phospholipase domain-containing protein 3 SNP, single nucleotide polymorphism T2DM, type 2 diabetes mellitus ABSTRACT Aim: Evidence is emerging that PNPLA3 rs738409 polymorphism (the major genetic variant associated with susceptibility to non-alcoholic fatty liver disease [NAFLD]) is associated with chronic kidney disease (CKD) in nondiabetic individuals. Currently, little is known about this association in type 2 diabetic (T2DM) patients with and without NAFLD. Methods: We studied 101 Caucasian post-menopausal women with T2DM, consecutively attending our diabetes outpatient service during a 3-month period. Glomerular filtration rate (eGFR CKD-EPI ) was estimated using the CKD-Epidemiology Collaboration equation, whilst albuminuria was measured with an immunonephelometric assay on morning spot urine samples. NAFLD was detected either by fatty liver index (FLI≥60, n=101) or by ultrasonography (n=77). Genotyping was performed by TaqMan-Based RT-PCR system. Results: Eight patients had G/G, 41 G/C and 52 C/C PNPLA3 rs738409 genotypes, and 21 (20.8%) patients had CKD (eGFR CKD-EPI <60 ml/min/1.73 m 2 or abnormal albuminuria). Compared to those with G/C or C/C genotypes, patients with G/G genotype had significantly lower eGFR CKD-EPI (63.7±11 vs. 77.4±17 vs. 81.9±15 ml/min/1.73 m 2 , p=0.014) and higher prevalence of CKD (50% vs. 24.4% vs. 13.5%, p=0.04). After adjustment for age, diabetes duration, hemoglobin A1c, HOMA-estimated insulin resistance, systolic blood pressure, hypertension treatment and FLI≥60, rs738409 G/G genotype was independently associated with lower eGFR CKD-EPI (β coefficient: 15.5, 95%CI -26.0 to -5.0, p=0.004) and higher risk of CKD (adjusted-odds ratio 8.05, 95%CI 1.26-41.4, p=0.03). Conclusion:Regardless of the presence of NAFLD, in post-menopausal women with T2DM, the G/G genotype of rs738409 in the PNPLA3 gene was independently associated with lower eGFR CKD-EPI and higher prevalence of CKD.

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