Change in Urinary Myoinositol/Citrate Ratio Associates with Progressive Loss of Renal Function in ADPKD Patients

Abstract

Introduction: In autosomal dominant polycystic kidney disease (ADPKD) patients, predicting renal disease progression is important to make a prognosis and to support the clinical decision whether to initiate renoprotective therapy. Conventional markers all have their limitations. Metabolic profiling is a promising strategy for risk stratification. We determined the prognostic performance to identify patients with a fast progressive disease course and evaluated time-dependent changes in urinary metabolites.

Methods: Targeted, quantitative metabolomics analysis (1H NMR-spectroscopy) was performed on spot urinary samples at two time points, baseline (n = 324, 61% female; mean age 45 years, SD 11; median eGFR 61 mL/min/1.73 m2, IQR 42-88; mean years of creatinine follow-up 3.7, SD 1.3) and a sample obtained after 3 years of follow-up (n = 112). Patients were stratified by their eGFR slope into fast and slow progressors based on an annualized change of > -3.0 or ≤ -3.0 mL/min/1.73 m2/year, respectively. Fifty-five urinary metabolites and ratios were quantified, and the significant ones were selected. Logistic regression was used to determine prognostic performance in identifying those with a fast progressive course using baseline urine samples. Repeated-measures ANOVA was used to analyze whether changes in urinary metabolites over a 3-year follow-up period differed between fast and slow progressors.

Results: In a single urinary sample, the prognostic performance of urinary metabolites was comparable to that of a model including height-adjusted total kidney volume (htTKV, AUC = 0.67). Combined with htTKV, the predictive value of the metabolite model increased (AUC = 0.75). Longitudinal analyses showed an increase in the myoinositol/citrate ratio (p < 0.001) in fast progressors, while no significant change was found in those with slow progression, which is in-line with an overall increase in the myoinositol/citrate ratio as GFR declines.

Conclusion: A metabolic profile, measured at a single time point, showed at least equivalent prognostic performance to an imaging-based risk marker in ADPKD. Changes in urinary metabolites over a 3-year follow-up period were associated with a fast progressive disease course.

Keywords: Autosomal dominant polycystic kidney disease; Biomarker; Estimated glomerular filtration rate slope; Progression; Urine metabolites.

Fig. 1

Vulcano plot of all quantified metabolites and metabolite ratios (n = 55). This plot represents a univariate overview of the differences in the measured metabolites and metabolite ratios between fast (n = 193) and slow (n = 131) progressors in the BL cohort. The degree of significance was presented in different colors. The most statistically significant variables were represented by the green dots. The urinary alanine/citrate ratio is significantly higher in the group with fast progressive disease. Notes: p values corrected for multiple testing (Benjamini-Hochberg correction) were used. Fast and slow progressors were stratified based on an annualized change in eGFR of > or ≤ −3.0 mL/min/1.73 m²/year, respectively.

Fig. 2

Forest plot of all quantified metabolites and metabolite ratios (n = 55). This plot represents a summary of the logistic regression models for each BL metabolite and metabolite ratio. In the models, fast (n = 193) and slow (n = 131) progressors were the dependent variables. The side color bar shows the degree of significance. Note: Fast and slow progressors were stratified based on an annualized change in eGFR of > or ≤ −3.0 mL/min/1.73 m²/year, respectively.

Fig. 3

ROC curves of conventional and metabolite models to distinguish fast from slow progressors in the BL cohort (n = 324). A model including BL log htTKV (green line; AUC = 0.67 [95% CI: 0.61–0.73]) showed a similar prognostic performance as compared with a model including the urinary subset of metabolites (purple line; AUC = 0.72 [95% CI: 0.66–0.77]) for distinguishing fast from slow progressors. The prognostic value was improved when adding the metabolite profile on top of log htTKV (orange line; AUC = 0.75 [0.69–0.80]). A model with BL eGFR or age as a single predictor (red and blue lines) showed limited prognostic value. Note: Fast and slow progressors were stratified based on an annualized change in eGFR of > or ≤ −3.0 mL/min/1.73 m²/year, respectively. ROC, Receiver operating characteristic.

Fig. 4

Changes in the urinary myoinositol/citrate ratio over time at an individual level within the progressor groups (n = 112). After 3 years of follow-up, the myoinositol/citrate ratio increased in fast progressors (a) (n = 56, p < 0.001), while in slow progressors (b) (n = 56), no such tendency was observed (p = 0.38). Notes: p values for BL versus year 3 (Y3) were calculated using the Mann-Whitney U test (paired version). The dark red dots represent the scaled median values (fast progressors BL = −0.66, Y3 = −0.21; slow progressors BL = −0.86, Y3 = −0.83). Fast and slow progressors were stratified based on an annualized change in eGFR of > or ≤ −3.0 mL/min/1.73 m²/year, respectively.