Hypertensive patients exhibit an altered metabolism. A specific metabolite signature in urine is able to predict albuminuria progression

doi:10.1016/j.trsl.2016.07.003

Translational Research

Volume 178, December 2016, Pages 25-37.e7

https://doi.org/10.1016/j.trsl.2016.07.003 Get rights and content

Hypertension (HTN) is increasing in prevalence, and albuminuria is a strong indicator of cardiovascular risk and renal damage progression. Despite blood pressure control with chronic treatment, a relevant subgroup of patients develop albuminuria. However, the biological factors responsible for albuminuria development and progression are underexplored. We aimed to identify key metabolic targets and biological pathways involved in the negative progression of cardiovascular and renal damage in hypertensives undergoing chronic treatment. A series of 1533 patients were followed for 5 years to investigate the evolution of albuminuria. Patients were classified as: (1) patients with persistent normoalbuminuria; (2) patients developing de novo albuminuria; and (3) patients with maintained albuminuria. At the end of follow-up, urine from 30 nonhypertensive subjects (control group) and a representative cohort of 118 patients was collected for metabolomic analysis. Metabolic patterns of interest were identified in a first discovery phase by nuclear magnetic resonance and further confirmed by liquid chromatography-mass spectrometry. Metabolites corresponding to HTN or albuminuria were measured in a prospective study carried out in 35 individuals still in normoalbuminuria, to evaluate their potential as predictors of albuminuria development. Nine metabolites were significantly altered, linking β-alanine metabolism, arginine and proline metabolism, and tricarboxylic acid cycle. The prospective study revealed a panel composed of guanidinoacetate, glutamate, and pantothenate, which was able to predict development of albuminuria. These metabolic signatures open new possibilities in hypertensive therapy and cardiovascular risk control, providing prompt and more efficient intervention, particularly in patients with worse cardiovascular prognosis.

Introduction

Hypertension (HTN) is a multifactorial disease of increasing prevalence and a major risk factor for cardiovascular mortality, even in the presence of apparently adequate treatment.¹ Albuminuria has been clearly demonstrated to be a marker of cardiovascular damage.2, 3 Chronic suppression of the renin–angiotensin system (RAS) has been shown to facilitate blood pressure (BP) control, prevent the development of new-onset albuminuria, and diminish the amount of urinary albumin in patients with persistent high or very high albuminuria.³ However, high albuminuria has been observed in a relevant subgroup of patients undergoing chronic RAS suppression, either as maintained (MHA) or as de novo–developed albuminuria (dnA).³ These patients are likely at the highest risk of progression of cardiovascular and renal disease. The discovery of predictors of progression or development of albuminuria during chronic RAS suppression would provide a helpful tool to detect where pharmacological therapy must be intensified and also where new drugs should be tested.

We recently published a study reporting the existence of specific plasma and urinary-protein alterations able to predict albuminuria development in chronically RAS-suppressed patients.4, 5 In this project, we have hypothesized that, during chronic suppression of RAS, HTN is reflected in urinary metabolome and that this reflection may be influenced by the presence and progression of albuminuria. The metabolome is made up of the low-molecular-weight end-products of metabolism, representing the ultimate response of the body to a certain condition (eg disease). Metabolomic studies thus nicely complement genetic and protein studies. Urine is a rich resource with which to investigate molecular alterations associated with renal physiology and kidney diseases. The metabolome was previously investigated in cardiovascular6, 7, 8 and kidney diseases9, 10 by our group and others. However, very few studies have been carried out in the context of HTN, and publications dealing with human samples are particularly scarce and focused on kidney-disease progression in diabetic individuals.11, 12, 13

We present an in-depth metabolic study aimed at identifying novel metabolite targets and biological pathways involved in the negative progression of hypertensives under chronic RAS suppression. First, variable metabolic response to HTN and albuminuria was investigated. Second, the capacity of metabolites identified as predicting development albuminuria was evaluated in a prospective study carried out in normoalbuminuric individuals.

Section snippets

Patient classification and selection

Patient selection was based on a previous study showing the development of de novo albuminuria in patients during chronic RAS suppression.¹⁴ Briefly, the study tracked the evolution of 1533 patients from the Hospital 12 de Octubre Hypertension Unit who had been under chronic RAS suppression for at least 5 years (2 before arrival to the unit and 3 years of follow-up). Baseline data were recorded after a 3-month stabilization period, during which the patients received the best possible control of

A metabolite fingerprint is associated with HTN and albuminuria in patients under chronic RAS supression

We have previously shown that de novo albuminuria develops in up to 16.1% of normoalbuminuric patients during chronic RAS suppression.¹⁴ From that study, a representative cohort of 118 hypertensive patients was selected, as detailed in Material and methods Section, to investigate urine metabolic alterations. Uric acid was found significantly increased in albuminuric patients. Previous studies point to a potential capacity of uric acid as early predictor of ESRD development in type 2 diabetics,¹⁸

Discussion

RAS blockade is the most effective therapeutic approach to control BP and prevent albuminuria.²⁰ Albuminuria is a known predictor of increased cardiovascular risk, future cardiovascular events, and end-organ damage, and even more in chronically RAS-suppressed individuals.¹⁴ Negative progression in normoalbuminuric patients undergoing chronic treatment is impossible to predict, and to date, the underlying mechanisms involved in de novo development of albuminuria remain unknown. In the present

Conclusions

Our data were obtained from patients who developed albuminuria while on chronic RAS suppression; in other words, in patients in whom cardiovascular and renal disease progressed despite RAS suppression. Cardiovascular and kidney disorders have an additive effect with reflection in urine at the metabolome level, linking oxidative stress, endothelial dysfunction, cardiovascular risk, and energy metabolism in the HTN picture under chronic treatment. In particular, the identification of urinary

Acknowledgments

Conflicts of Interest: All authors have read the journal's policy on disclosure of potential conflicts of interest and disclosed accordingly. All authors have read the journal's authorship statement. These results are lined up with the Spanish initiative on the Human Proteome Project (SpHPP).

This work was supported by Instituto de Salud Carlos III, fondos FEDER/FSE (FIS, PI070537, PI11/01401, PI13/01873, PI14/01841, IF08/3667-1, PI11-02239, PI 14/0917, PI11/02432, PI13/01746, PI14/01650,

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Original ArticleHypertensive patients exhibit an altered metabolism. A specific metabolite signature in urine is able to predict albuminuria progression

Introduction

Section snippets

Patient classification and selection

A metabolite fingerprint is associated with HTN and albuminuria in patients under chronic RAS supression

Discussion

Conclusions

Acknowledgments

Int J Cardiol

Kidney Int

Kidney Int

Kidney Int

J Biol Chem

Current challenges in the clinical management of hypertension

Nat Rev Cardiol

Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis

Lancet

Microalbuminuria as a risk predictor in diabetes: the continuing saga

Diabetes Care

Urinary alpha-1 antitrypsin and CD59 glycoprotein predict albuminuria development in hypertensive patients under chronic renin-angiotensin system suppression

Cardiovasc Diabetol

Metabolomics and cardiovascular biomarker discovery

Clin Chem

KLK1 and ZG16B proteins and arginine–proline metabolism identified as novel targets to monitor atherosclerosis, acute coronary syndrome and recovery

Metabolomics

A systems view of type 2 diabetes-associated metabolic perturbations in saliva, blood and urine at different timescales of glycaemic control

Diabetologia

Metabolomics in the study of kidney diseases

Nat Rev Nephrol

Metabolomics in hypertension

J Hypertens

Discovery of early-stage biomarkers for diabetic kidney disease using ms-based metabolomics (FinnDiane study)

Metabolomics

Urine and plasma metabolites predict the development of diabetic nephropathy in individuals with type 2 diabetes mellitus

Diabet Med

Original Article
Hypertensive patients exhibit an altered metabolism. A specific metabolite signature in urine is able to predict albuminuria progression