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. Electronic supplementary material The online version of this article (10.1186/s12882-019-1249-6) contains supplementary material, which is available to authorized users.

The relationship between blood metabolites of the tryptophan pathway and kidney function: a bidirectional Mendelian randomization analysis

“…In an elderly population, indole-3-lactate was found to be associated not only with muscle composition but also with the renal function markers serum creatinine and blood urea nitrogen 78 . Quite recently, a study group reported that increased levels of indole-3-lactate were found to be associated with lower eGFR in a cohort of patients with ADPKD 79 . Altogether, study results support a causal relationship of low eGFR on blood indole-3-lactate levels.…”

Cardiovascular risk factors and the impact on prognosis in patients with chronic kidney disease secondary to autosomal dominant polycystic kidney disease

“…These results could be influenced not only by serum lipid levels, but also by deeper lipid disturbances, such as lipid particle number, size and density. These alterations have been related to CVD in CKD of other etiologies [32], and recently preliminary data have been published in this regard in patients with ADPKD [33].…”

Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease

“…Limited evidence supports that cellular kidney metabolism is also dysregulated in humans with ADPKD. Nontargeted metabolomics using plasma samples from patients with early-stage ADPKD who participated in the Halt Progression of PKD (HALT-PKD) Study A suggests an association between two long-chain triglycerides and height-adjusted total kidney volume (TKV) (23). Similarly, alterations in fatty acid metabolism, including the lipoxygenase pathways, have been observed using targeted analysis of bioactive lipid mediators in serum samples from HALT-PKD Study A participants (24).…”