Association of fructose-1,6-diphosphatase 1 with the progression of diabetic kidney disease

Diabetic Kidney Disease (DKD) is one of the most serious complications of diabetes mellitus, and a main cause of end-stage kidney disease (ESKD). The identification of clinically applicable molecular biomarkers for monitoring DKD progression has become increasingly essential. In this study, we aim to investigate the relationship between the expression of fructose-1,6-bisphosphatase 1 (FBP1), a rate-limiting enzyme in gluconeogenesis, and DKD.

A two-sample Mendelian randomization (MR) analysis was conducted using plasma protein quantitative trait loci data obtained from deCODE genetics and DKD genome-wide association study data acquired from the Finnish Biobank Alliance to assess the causal relationship between FBP1 and DKD. In parallel, a retrospective cohort study was performed involving 107 patients with biopsy-confirmed DKD, in which DKD progression was defined as a composite endpoint consisting of serum creatinine doubling or ESKD. For this endpoint, a predictive nomogram was subsequently developed.

MR results suggested that a genetically predicted higher level of circulating FBP1 was associated with a low risk of DKD (OR 0.57, 95% CI 0.33-0.98; P = 0.04) in diabetic patients. The expression level of renal FBP1 decreased with the progression of DKD pathological stage. Its expression level was positively correlated with estimated glomerular filtration rate (eGFR) (r = 0.717, P < 0.001) and expression of renal carnitine palmitoyl transferase 1 A (a rate-limiting enzyme in fatty acid oxidation) (r = 0.745, P < 0.001). During a median follow-up of 26 months, 41 (38%) patients suffered from DKD progression. Multivariate Cox regression indicated that a reduced renal expression level of FBP1 was correlated with an increased risk of DKD progression (HR 0.325, 95% CI 0.107-0.986, P = 0.047). Finally, the integration of FBP1 with 24-h urine protein and eGFR into a nomogram significantly improved the prediction of 1-year and 3-year event-free survival in DKD (C-index: 0.871 vs. 0.794, P = 0.011), demonstrating its additive prognostic value.

Renal FBP1 might be a potential biomarker reflecting the severity of renal function and kidney progression in biopsy-proven DKD stages II to IV.