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Circulating Metabolites in Relation to the Kidney Allograft Function in Posttransplant Patients.

ABSTRACT: End-stage kidney disease is preferably treated by kidney transplantation. The suboptimal function of the allograft often results in misbalances in kidney-controlled processes and requires long-term monitoring of allograft function and viability. As the kidneys are organs with a very high metabolomic rate, a metabolomics approach is suitable to describe systematic changes in post-transplant patients and has great potential for monitoring allograft function, which has not been described yet. In this study, we used blood plasma samples from 55 patients after primary kidney transplantation identically treated with immunosuppressants with follow-up 50 months in the mean after surgery and evaluated relative levels of basal plasma metabolites detectable by NMR spectroscopy. We were looking for the correlations between circulating metabolites levels and allograft performance and allograft rejection features. Our results imply a quantitative relationship between restricted renal function, insufficient hydroxylation of phenylalanine to tyrosine, lowered renal glutamine utilization, shifted nitrogen balance, and other alterations that are not related exclusively to the metabolism of the kidney. No link between allograft function and energy metabolism can be concluded, as no changes were found for glucose, glycolytic intermediates, and 3-hydroxybutyrate as a ketone body representative. The observed changes are to be seen as a superposition of changes in the comprehensive inter-organ metabolic exchange, when the restricted function of one organ may induce compensatory effects or cause secondary alterations. Particular differences in plasma metabolite levels in patients with acute cellular and antibody-mediated allograft rejection were considered rather to be related to the loss of kidney function than to the molecular mechanism of graft rejection since they largely follow the alterations observed by restricted allograft function. In the end, we showed using a simple mathematical model, multilinear regression, that the basal plasmatic metabolites correlated with allograft function expressed by the level of glomerular filtration rate (with creatinine: p-value = 4.0 × 10^-26 and r = 0.94, without creatinine: p-value = 3.2 × 10^-22 and r = 0.91) make the noninvasive estimation of the allograft function feasible.

SUBMITTER: Baranovicova E

PROVIDER: S-EPMC9318187 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundInvestigation of circulating metabolites associated with kidney function and chronic kidney disease (CKD) risk could enhance our understanding of underlying pathways and identify new biomarkers for kidney function.MethodsWe selected participants from the population-based Rotterdam Study with data on circulating metabolites and estimated glomerular filtration rate based on serum creatinine (eGFRcreat) available at the same time point. Data on eGFR based on serum cystatin C (eGFRcys) and urine albumin-to-creatinine ratio (ACR) were also included. CKD was defined as eGFRcreat <60 ml/min per 1.73 m2. Data on circulating metabolites (ntotal = 1381) was obtained from the Nightingale and Metabolon platform. Linear regression, linear mixed, and Cox proportional-hazards regression analyses were conducted to study the associations between metabolites and kidney function. We performed bidirectional two-sample Mendelian randomization analyses to investigate causality of the identified associations.ResultsWe included 3337 and 1540 participants with data from Nightingale and Metabolon, respectively. A total of 1381 metabolites (243 from Nightingale and 1138 from Metabolon) were included in the analyses. A large number of metabolites were significantly associated with eGFRcreat, eGFRcys, ACR, and CKD, including 16 metabolites that were associated with all four outcomes. Among these, C-glycosyltryptophan (HR 1.50, 95%CI 1.31;1.71) and X-12026 (HR 1.46, 95%CI 1.26;1.68) were most strongly associated with CKD risk. We revealed sex differences in the associations of 11-ketoetiocholanolone glucuronide and 11-beta-glucuronide with the kidney function assessments. No causal associations between the identified metabolites and kidney function were observed.ConclusionOur study indicates that several circulating metabolites are associated with kidney function which are likely to have potential as biomarkers, rather than as molecules involved in the pathophysiology of kidney function decline.

Project description:BackgroundAdvanced chronic kidney disease is associated with muscle wasting, but how glomerular filtration rate (GFR) recovery after kidney transplantation is associated with muscle mass is unknown.MethodsWe took advantage of the simultaneous measurement of GFR (using iohexol plasma clearance; ioGFR) and creatinine excretion rate (a surrogate marker of muscle mass; CER) performed 3 months after transplantation and at a later time point at our institution to investigate the interplay between allograft function, muscle mass, and outcome in kidney transplant recipients.ResultsBetween June 2005 and October 2019, 1319 successive kidney transplant recipients (mean age 50.4 ± 14.6; 38.7% female) underwent GFR measurement at our institution 3 months after kidney transplantation. CER (CER3 ) and ioGFR (ioGFR3 ) were 7.7 ± 2.6 μmol/min and 53 ± 17.1 mL/min/1.73 m2 , respectively. Multivariable analysis identified female gender, older donor and recipient age, reduced body mass index, coronary disease, dialysis history, proteinuria, and reduced ioGFR3 as independent predictors of low CER3 (ioGFR3 : β coefficient 0.19 [95% confidence interval 0.14 to 0.24]). A total of 1165 patients had a subsequent CER measurement after a median follow-up of 9.5 months. Of them, 373 (32%) experienced an increase in CER > 10%, while 222 (19%) showed a CER decrease of more than 10%. Multivariable analysis adjusted for CER3 and other confounders identified ioGFR3 as an independent predictor of CER at follow-up (β coefficient 0.11 [95% confidence interval 0.07 to 0.16]). In multivariable Cox analysis, reduced CER at 3 months or at follow-up were consistently associated with mortality (hazard ratio [95% confidence interval] at 3 months: 0.82 [0.74 to 0.91]; at follow-up: 0.79 [0.69 to 0.99]) but not with graft loss.ConclusionsGlomerular filtration rate recovery is a determinant of muscle mass variation after kidney transplantation. Early interventions targeting muscle mass gain may be beneficial for kidney transplant recipients.

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Circulating Metabolites in Relation to the Kidney Allograft Function in Posttransplant Patients.

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