Urine Metabolite Profiles Predictive of Human Kidney Allograft Status

Suhre, Karsten; Schwartz, Joseph E.; Sharma, Vijay Kumar; Chen, Justin; Lee, John Y.K.; Muthukumar, Thangamani; Dadhania, Darshana; Ding, Ruchuang; Iklé, David; Bridges, Nancy D.; Williams, N.; Kastenmüller, Gabi; Karoly, Edward D.; Mohney, Robert P.; Abecassis, Michael; Friedewald, John; Knechtle, Stuart J.; Becker, Yolanda T.; Samstein, Benjamin; Shaked, Abraham; Gross, Steven S.; Suthanthiran, Manikkam

doi:10.1681/asn.2015010107

Cited by 57 publications

(61 citation statements)

References 34 publications

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“…Referring to the daily intraindividual dynamics in the urinary microbiome of an nRTX patient recovering from AKI, we hypothesize that also these shifts depended on metabolite and electrolyte excretion in urine during the recovery from AKI, as it has already been well documented in recent literature that the urinary metabolome experiences changes dependent on kidney function [49,50]. This is consistent with our metabolome analysis of this patient.…”

Section: Discussionsupporting

confidence: 90%

“…This occurs as renal transplants mostly possess a shortened ureter, which leads into a shrunken urinary bladder, which has an effect on urine outflow when compared to nRTX patients [45][46][47][48]. (iii) The urinary metabolome differs in RTX and nRTX patients and it is likely that the urinary metabolite profile has a growth enhancing or growth inhibitory effect on certain bacterial genera [49]. (iv) In addition, a difference in the urinary microbiome of RTX and nRTX patients may occur due to frequent healthcare contacts of nRTX patients.…”

Section: Discussionmentioning

confidence: 99%

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The urinary microbiome shows different bacterial genera in renal transplant recipients and non-transplant patients at time of acute kidney injury – a pilot study

et al. 2020

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Background: In the past urine was considered sterile. Through the introduction of next generation sequencing, it has become clear that a urinary microbiome exists. Acute kidney injury (AKI) represents a major threat to kidney transplant recipients. Remarkable changes in the urinary metabolome occur during AKI, which may influence the urinary microbiome. To our knowledge, this is the first study that examines the urinary microbiome in renal transplant recipients (RTX) and non-transplant recipients (nRTX) at time of AKI.Methods: In this cross-sectional pilot-study the urinary microbiome of 21 RTX and 9 nRTX with AKI was examined. Clean catch morning urine samples were obtained from all patients on the first day of AKI diagnosis. AKI was defined according to KDIGO guidelines. Urinary microbiota and the urinary metabolome during AKI were assessed in one patient. 16S rRNA sequencing was performed. Sequences were processed using UPARSE-pipeline for operational taxonomic units (OTU) and taxon finding. Results: We successfully extracted and sequenced bacterial DNA from 100% of the urine samples. All 30 patients revealed at least 106,138 reads. 319 OTU and 211 different genera were identified. The microbiotic diversity richness in the RTX group was no different from the nRTX group. Eighteen genera were solely present in nRTX and 7 in RTX. Conclusions: The urinary microbiome at time of AKI showed different bacterial genera in RTX compared to nRTX. The nRTX group exhibited no different diversity to the RTX group. Irrespective of the status of a previous renal transplantation, the urinary microbiome comprised > 210 different genera. An intraindividual change in microbiota diversity and richness was observed in one study patient during recovery from AKI.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

The urinary microbiome shows different bacterial genera in renal transplant recipients and non-transplant patients at time of acute kidney injury – a pilot study

et al. 2020

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“…The p-gain statistic indicates whether the association between the ratio of two metabolites and the outcome of interest is different than the association of the individual metabolites. 40,41 We log transformed metabolite values for analysis. To summarize the results, we plotted the distribution of untransformed metabolites in subjects with versus those without impairment in executive function.…”

Section: Statistical Analysesmentioning

confidence: 99%

Metabolic Profiling of Impaired Cognitive Function in Patients Receiving Dialysis

Tamura

Chertow

Depner

et al. 2016

JASN

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Retention of uremic metabolites is a proposed cause of cognitive impairment in patients with ESRD. We used metabolic profiling to identify and validate uremic metabolites associated with impairment in executive function in two cohorts of patients receiving maintenance dialysis. We performed metabolic profiling using liquid chromatography/mass spectrometry applied to predialysis plasma samples from a discovery cohort of 141 patients and an independent replication cohort of 180 patients participating in a trial of frequent hemodialysis. We assessed executive function with the Trail Making Test Part B and the Digit Symbol Substitution test. Impaired executive function was defined as a score ≥2 SDs below normative values. Four metabolites-4-hydroxyphenylacetate, phenylacetylglutamine, hippurate, and prolyl-hydroxyproline-were associated with impaired executive function at the false-detection rate significance threshold. After adjustment for demographic and clinical characteristics, the associations remained statistically significant: relative risk 1.16 (95% confidence interval [95% CI], 1.03 to 1.32), 1.39 (95% CI, 1.13 to 1.71), 1.24 (95% CI, 1.03 to 1.50), and 1.20 (95% CI, 1.05 to 1.38) for each SD increase in 4-hydroxyphenylacetate, phenylacetylglutamine, hippurate, and prolyl-hydroxyproline, respectively. The association between 4-hydroxyphenylacetate and impaired executive function was replicated in the second cohort (relative risk 1.12; 95% CI, 1.02 to 1.23), whereas the associations for phenylacetylglutamine, hippurate, and prolyl-hydroxyproline did not reach statistical significance in this cohort. In summary, four metabolites related to phenylalanine, benzoate, and glutamate metabolism may be markers of cognitive impairment in patients receiving maintenance dialysis.

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“…Consequently, personalizing immunosuppression would greatly benefit from biomarkers that are informative of alloimmune activation, are predictive of minimization outcomes, and are diagnostic for rejection without the need for invasive liver biopsy. Such biomarkers were recently explored in other organ transplant settings, including sequential monitoring of urinary cell messenger RNA (mRNA) and metabolites that can predict and diagnose renal allograft rejection . Furthermore, cell‐free donor‐specific genomic DNA from sera can be used to monitor and diagnose cardiac and pulmonary allograft rejection …”

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confidence: 99%

An ectopically expressed serum miRNA signature is prognostic, diagnostic, and biologically related to liver allograft rejection

et al. 2016

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The ability to noninvasively diagnose acute cellular rejection (ACR) with high specificity and sensitivity would significantly advance personalized liver transplant recipient care and management of immunosuppression. We performed microRNA (miRNA) profiling in 318 serum samples from 69 liver transplant recipients enrolled in the Immune Tolerance Network immunosuppression withdrawal (ITN030ST) and Clinical Trials in Organ Transplantation (CTOT-03) studies. We quantified serum miRNA at clinically indicated and/or protocol biopsy events (n 5 130). The trajectory of ACR diagnostic miRNAs during immunosuppression withdrawal were also evaluated in sera taken at predetermined intervals during immunosuppression minimization before and at clinically indicated liver biopsy (n 5 119). Levels of 31 miRNAs were significantly associated with ACR diagnosis with two miRNAs differentiating ACR from non-ACR (area under the receiver operating characteristic curve 5 90%, 95% confidence interval 5 82%-96%) and predicted ACR events up to 40 days before biopsy-proven rejection. The most differentially expressed miRNAs were low or absent in the blood of healthy individuals but highly expressed in liver tissue, indicating an ectopic origin from the liver allograft. Pathway analyses of rejection-associated miRNAs and their target messenger RNAs (mRNAs) showed induction of proinflammatory and cell death-related pathways. Integration of differentially expressed serum miRNA with concordant liver biopsy mRNA demonstrates interaction between molecules with a known role in transplant rejection. Conclusion: Distinct miRNA levels profiled from sera at the time of clinical allograft dysfunction can be used to noninvasively diagnose ACR. Predictive trajectories of the same profile during supervised immunosuppression minimization diagnosed rejection up to 40 days prior to clinical expression. The rejection-associated miRNAs in sera appear to be ectopically expressed liver and specific immune cell miRNAs that are biologically related, and the consequences of immune-mediated damage to the allograft. (HEPATOLOGY 2017;65:269-280). SEE EDITORIAL ON PAGE 15L iver transplantation is currently the only treatment option for end-stage liver failure, with patient survival rates of approximately 88% observed in the first year after transplantation.(1) Standard immunosuppression entails calcineurin inhibitorbased therapies, and for most patients is aimed at achieving and maintaining therapeutic trough levels. Recipients who have clinical evidence of allograft dysfunction, usually indicated by elevated bilirubin and/or

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Urine Metabolite Profiles Predictive of Human Kidney Allograft Status

Cited by 57 publications

References 34 publications

The urinary microbiome shows different bacterial genera in renal transplant recipients and non-transplant patients at time of acute kidney injury – a pilot study

The urinary microbiome shows different bacterial genera in renal transplant recipients and non-transplant patients at time of acute kidney injury – a pilot study

Metabolic Profiling of Impaired Cognitive Function in Patients Receiving Dialysis

An ectopically expressed serum miRNA signature is prognostic, diagnostic, and biologically related to liver allograft rejection

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