The metabolomics grail: promising although not yet holy
Authors: Ruben Poesen, Pieter Evenepoel, Björn Meijers
Journal: Kidney International (2015)

To the Editor: We read with interest the paper by Niewczas et al.,1.Niewczas M.A. Sirich T.L. Mathew A.V. et al.Uremic solutes and risk of end-stage renal disease in type 2 diabetes: metabolomic study.Kidney Int. 2014; 85: 1214-1224Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar and would like to offer the following comments. Although the era of metabolome-wide association studies is still to arrive, the study by Niewczas et al.1.Niewczas M.A. Sirich T.L. Mathew A.V. et al.Uremic solutes and risk of end-stage renal disease in type 2 diabetes: metabolomic study.Kidney Int. 2014; 85: 1214-1224Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar is a substantial step in this direction. Although p-cresyl sulfate (PCS) is a well-established nephro-vascular toxin, the authors are the first to demonstrate that PCS in non-uremic concentrations is one of the metabolites associated with poor renal outcome. Does this mean that accelerated renal disease progression in diabetic nephropathy is due to toxic metabolites, including PCS? There are at least three other explanations to explain this observation. First, as renal clearance of PCS is mainly due to tubular secretion, high PCS levels may merely reflect renal proximal tubulopathy.2.Masereeuw R. Mutsaers H.A. Toyohara T. et al.The kidney and uremic toxin removal: glomerulus or tubule?.Semin Nephrol. 2014; 34: 191-208Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar Indeed, progressors presented with significantly higher albuminuria, which either may be a consequence or a cause of proximal tubulopathy. Second, PCS serum levels and urinary excretion rates are also substantially higher in diabetic versus nondiabetic chronic kidney disease patients (Meijers et al., CJASN 2010)3.Meijers B.K. Claes K. Bammens B. et al.p-Cresol and cardiovascular risk in mild-to-moderate kidney disease.Clin J Am Soc Nephrol. 2010; 5: 1182-1189Crossref PubMed Scopus (234) Google Scholar and high PCS levels may contribute to insulin resistance, rendering the host more susceptible to development of more severe diabetes and its complications.4.Koppe L. Pillon N.J. Vella R.E. et al.p-Cresyl sulfate promotes insulin resistance associated with CKD.J Am Soc Nephrol. 2013; 24: 88-99Crossref PubMed Scopus (174) Google Scholar Finally, high PCS may point to a disturbed and potentially deleterious gut microbial metabolism. As pharmacological (e.g., acarbose) and dietary interventions (e.g., fiber intake) may differentially affect microbial metabolism and PCS levels, they should be accounted for.5.Evenepoel P. Bammens B. Verbeke K. et al.Acarbose treatment lowers generation and serum concentrations of the protein-bound solute p-cresol: a pilot study.Kidney Int. 2006; 70: 192-198Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Untargeted metabolomics will show us numerous intriguing associations. Even when in alignment with existing literature, such as for PCS, these associations may or may not point toward a causal relationship. As always, good science generates more questions.