Higher circulating levels of non-esterified fatty acids are associated with faster kidney function decline in post-menopausal women with type 2 diabetes: a pilot prospective study.

AIMS: Currently, there is little and inconsistent evidence regarding the possible adverse effects of circulating levels of non-esterified fatty acids (NEFA) on kidney function decline in patients with type 2 diabetes mellitus (T2DM). METHODS: We followed for a median of 4.6 years 85 post-menopausal women with non-insulin-treated T2DM and preserved kidney function at baseline. Serum NEFA concentrations were measured using an enzymatic colorimetric method. Glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS: Enrolled patients had a baseline mean eGFRCKD-EPI of 83 ± 12 mL/min/1.73 m2 and a median serum NEFA concentration of 662 uEq/L (interquartile range 524-842 uEq/L). During the follow-up period, 13 patients developed kidney function decline at follow-up (defined as an eGFRCKD-EPI decline ≥ 30% from baseline). In Cox proportional hazards regression analyses, higher serum NEFA levels were significantly associated with an increased risk of developing kidney function decline (adjusted-hazard ratio 3.67, 95% CI 1.64-8.22, p < 0.001; for each 1-SD increment, i.e., 262 uEq/L), even after adjustment for waist circumference, hemoglobin A1c, C-reactive protein, HOMA-estimated insulin resistance, hypertension, dyslipidemia, microalbuminuria, baseline eGFRCKD-EPI, as well as temporal changes in HbA1c levels or the use of renin-angiotensin system inhibitors over the follow-up. CONCLUSIONS: The findings of this exploratory prospective study show that in post-menopausal women with T2DM and preserved kidney function at baseline, higher circulating levels of NEFA were strongly associated with a faster kidney function decline, even after adjustment for established renal risk factors and potential confounders.

Association between PNPLA3 rs738409 variant and 5-year estimated glomerular filtration rate decline in post-menopausal women with type 2 diabetes: A panel-data analysis.

BACKGROUND AND AIMS: Little is known about the relationship between patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 variant and decline in estimated glomerular filtration rate (eGFR) over time in individuals with type 2 diabetes (T2DM). METHODS AND RESULTS: We enrolled an outpatient sample of 46 post-menopausal women with T2DM and preserved kidney function at baseline (in 2017), who were followed through 2022. eGFR and albuminuria were measured annually. Genotyping of PNPLA3 rs738409 was performed by TaqMan-based RT-PCR system. Overall, 25 (54.3%) patients had PNPLA3 rs738409 CC (homozygous wild-type) genotype and 21 had CG or GG genotypes. During the 5-year follow-up, the presence of rs738409 CG/GG genotypes was associated with faster eGFR decline (coefficient: -6.55; 95% CI -11.0 to -2.08; p = 0.004 by random-effects panel data analysis). This association remained significant even after adjustment for 5-year changes in age, hemoglobin A1c, hypertension status, albuminuria and use of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists. CONCLUSIONS: This pilot study suggests that in post-menopausal T2DM women with preserved kidney function at baseline, the risk allele (G) of PNPLA3 rs738409 is associated with a faster eGFR decline during a 5-year follow-up, independent of annual changes in common renal risk factors and use of certain glucose-lowering medications.