Plasma metabolites and lipids associate with kidney function and kidney volume in hypertensive ADPKD patients early in the disease course

Abstract

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and is characterized by gradual cyst growth and expansion, increase in kidney volume with an ultimate decline in kidney function leading to end stage renal disease (ESRD). Given the decades long period of stable kidney function while cyst growth occurs, it is important to identify those patients who will progress to ESRD. Recent data from our and other laboratories have demonstrated that metabolic reprogramming may play a key role in cystic epithelial proliferation resulting in cyst growth in ADPKD. Height corrected total kidney volume (ht-TKV) accurately reflects cyst burden and predicts future loss of kidney function. We hypothesize that specific plasma metabolites will correlate with eGFR and ht-TKV early in ADPKD, both predictors of disease progression, potentially indicative of early physiologic derangements of renal disease severity.

Methods: To investigate the predictive role of plasma metabolites on eGFR and/or ht-TKV, we used a non-targeted GC-TOF/MS-based metabolomics approach on hypertensive ADPKD patients in the early course of their disease. Patient data was obtained from the HALT-A randomized clinical trial at baseline including estimated glomerular filtration rate (eGFR) and measured ht-TKV. To identify individual metabolites whose intensities are significantly correlated with eGFR and ht-TKV, association analyses were performed using linear regression with each metabolite signal level as the primary predictor variable and baseline eGFR and ht-TKV as the continuous outcomes of interest, while adjusting for covariates. Significance was determined by Storey's false discovery rate (FDR) q-values to correct for multiple testing.

Results: Twelve metabolites significantly correlated with eGFR and two triglycerides significantly correlated with baseline ht-TKV at FDR q-value < 0.05. Specific significant metabolites, including pseudo-uridine, indole-3-lactate, uric acid, isothreonic acid, and creatinine, have been previously shown to accumulate in plasma and/or urine in both diabetic and cystic renal diseases with advanced renal insufficiency.

Conclusions: This study identifies metabolic derangements in early ADPKD which may be prognostic for ADPKD disease progression.

Clinical trial: HALT Progression of Polycystic Kidney Disease (HALT PKD) Study A; Clinical www.clinicaltrials.gov identifier: NCT00283686; first posted January 30, 2006, last update posted March 19, 2015.

Keywords: ADPKD; HALT study; Metabolomics; Progression.

Conflict of interest statement

Ethics approval and consent to participate

Eligible participants in the HALT PKD trial were enrolled at seven clinical sites from February 2006 through June 2009. All the participants provided written informed consent.

Consent for publication

Not applicable.

Competing interests

Partial funding was obtained from a grant from Dialysis Clinics Incorporated but DCI had no impact on the content of this article.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Boxplots of likelihood ratio test (LRT) p-values of 290 metabolites determining significance of each of the HALT covariates to include in the final analysis models for both (a) eGFR and (b) ht-TKV. The dashed line represents the p = 0.05 significance level

Fig. 2

Heatmap of significantly (p a) eGFR and (b) ht-TKV. Rows: patients sorted by their outcome values from high to low; Columns: metabolites. Dendrogram clustering on the X-axis indicates metabolite similarity. Expression values are log2 transformed. Red and green color intensity indicate positive and negative intensity

Fig. 3

Altered associations between a given metabolite/lipid and outcome, eGFR, by effect modifiers sex and genotype. A different color represents a different sex and genotype. The length and direction of bar indicate a degree and direction (negative or positive) of association with that metabolite/lipid respectively (see Additional file 2: Tables S1 and S2 for details)

Fig. 4

Altered associations between a given metabolite/lipid and outcome, ht-TKV, by effect modifiers sex and genotype. A different color represents a different sex and genotype. The length and direction of bar indicate a degree and direction (negative or positive) of association with that metabolite/lipid respectively (see Additional file 2: Tables S1 and S2 for details)