Serum metabolites are associated with all-cause mortality in chronic kidney disease

Abstract

Chronic kidney disease (CKD) involves significant metabolic abnormalities and has a high mortality rate. Because the levels of serum metabolites in patients with CKD might provide insight into subclinical disease states and risk for future mortality, we determined which serum metabolites reproducibly associate with mortality in CKD using a discovery and replication design. Metabolite levels were quantified via untargeted liquid chromatography and mass spectroscopy from serum samples of 299 patients with CKD in the Modification of Diet in Renal Disease (MDRD) study as a discovery cohort. Six among 622 metabolites were significantly associated with mortality over a median follow-up of 17 years after adjustment for demographic and clinical covariates, including urine protein and measured glomerular filtration rate. We then replicated associations with mortality in 963 patients with CKD from the African American Study of Kidney Disease and Hypertension (AASK) cohort over a median follow-up of ten years. Three of the six metabolites identified in the MDRD cohort replicated in the AASK cohort: fumarate, allantoin, and ribonate, belonging to energy, nucleotide, and carbohydrate pathways, respectively. Point estimates were similar in both studies and in meta-analysis (adjusted hazard ratios 1.63, 1.59, and 1.61, respectively, per doubling of the metabolite). Thus, selected serum metabolites were reproducibly associated with long-term mortality in CKD beyond markers of kidney function in two well characterized cohorts, providing targets for investigation.

Allantoin induces pruritus by activating MrgprD in chronic kidney disease

“…The results showed that the allantoin concentration obviously increased in patients with CKD compared with the healthy people group (238±57 μg/ml vs. 18±13.5 μg/ml, p 0.05, n=8) ( Figure 1B ), but other purine metabolites showed no significant changes ( Table 1 ). Consistent with previous studies, the allantoin and urea in the serum of patients with CKD increased significantly rather than other purine metabolites [43, 44]. Therefore, allantoin may be a candidate to induce pruritus in nephropathy.…”

“…Human serum was obtained from the Jiangsu Provincial Hospital of Traditional Chinese Medicine. Serum samples were thawed at 4 C before experiments as in earlierresearch [43, 54]. Acetonitrile (HPLC grade, TEDIA, USA) was added into each serum sample (v/v=3:1) to precipitate protein.…”

Diet-derived fruit and vegetable metabolites suggest sex-specific mechanisms conferring protection against osteoporosis in humans

“…Hippurate, lower in men with OS, stimulated bone-forming gene expression in mice 65 . Higher plasma ribonate and kynurenine may indicate chronic kidney disease (CKD) 66 . Rats with CKD were shown to have elevated peripheral kynurenine and pathological changes in bone structure 67 .…”

Epidemiology research to foster improvement in chronic kidney disease care

“…Studies have described metabolomic fingerprints of eGFR, 85,86 causes of CKD, 87 proteinuria, 88 kidney function decline and/or incident CKD, [89][90][91] uremia, 92 kidney transplant rejection, 93 and mortality in CKD. 94 For example, the tryptophan pathway has been implicated in kidney disease progression in several studies across populations with different kidney diseases. 95 The addition of a multimetabolite panel to the conventional kidney disease risk factors (age, sex, eGFR, diabetes mellitus, hypertension, and proteinuria) significantly improved 8-year CKD risk prediction (increase in C-statistic from 0.77 to 0.83) in 1434 Framingham Heart Study participants.…”