Metabolomic Profiling in Individuals with a Failing Kidney Allograft.

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Abstract

Alteration of certain metabolites may play a role in the pathophysiology of renal allograft disease.

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Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes.

Monika A Niewczas, Tomohito Gohda, Jan Skupien … (2012)

Levels of proinflammatory cytokines associate with risk for developing type 2 diabetes but whether chronic inflammation contributes to the development of diabetic complications, such as ESRD, is unknown. In the 1990s, we recruited 410 patients with type 2 diabetes for studies of diabetic nephropathy and recorded their characteristics at enrollment. During 12 years of follow-up, 59 patients developed ESRD (17 per 1000 patient-years) and 84 patients died without ESRD (24 per 1000 patient-years). Plasma markers of systemic inflammation, endothelial dysfunction, and the TNF pathway were measured in the study entry samples. Of the examined markers, only TNF receptors 1 and 2 (TNFR1 and TNFR2) associated with risk for ESRD. These two markers were highly correlated, but ESRD associated more strongly with TNFR1. The cumulative incidence of ESRD for patients in the highest TNFR1 quartile was 54% after 12 years but only 3% for the other quartiles (P<0.001). In Cox proportional hazard analyses, TNFR1 predicted risk for ESRD even after adjustment for clinical covariates such as urinary albumin excretion. Plasma concentration of TNFR1 outperformed all tested clinical variables with regard to predicting ESRD. Concentrations of TNFRs moderately associated with death unrelated to ESRD. In conclusion, elevated concentrations of circulating TNFRs in patients with type 2 diabetes at baseline are very strong predictors of the subsequent progression to ESRD in subjects with and without proteinuria.

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Disruption of methylarginine metabolism impairs vascular homeostasis.

Sharon Rossiter, Belen Torondel, Judith Murray-Rust … (2007)

Asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA) are endogenously produced amino acids that inhibit all three isoforms of nitric oxide synthase (NOS). ADMA accumulates in various disease states, including renal failure, diabetes and pulmonary hypertension, and its concentration in plasma is strongly predictive of premature cardiovascular disease and death. Both L-NMMA and ADMA are eliminated largely through active metabolism by dimethylarginine dimethylaminohydrolase (DDAH) and thus DDAH dysfunction may be a crucial unifying feature of increased cardiovascular risk. However, despite considerable interest in this pathway and in the role of ADMA as a cardiovascular risk factor, there is little evidence to support a causal role of ADMA in pathophysiology. Here we reveal the structure of human DDAH-1 and probe the function of DDAH-1 both by deleting the DDAH1 gene in mice and by using DDAH-specific inhibitors which, as we demonstrate by crystallography, bind to the active site of human DDAH-1. We show that loss of DDAH-1 activity leads to accumulation of ADMA and reduction in NO signaling. This in turn causes vascular pathophysiology, including endothelial dysfunction, increased systemic vascular resistance and elevated systemic and pulmonary blood pressure. Our results also suggest that DDAH inhibition could be harnessed therapeutically to reduce the vascular collapse associated with sepsis.

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Uremic solutes and risk of end stage renal disease in type 2 diabetes

Monika A Niewczas, Tammy Sirich, Anna Mathew … (2014)

Here we studied plasma metabolomic profiles as determinants of progression to ESRD in patients with Type 2 diabetes (T2D). This nested case-control study evaluated 40 cases who progressed to ESRD during 8-12 years of follow-up and 40 controls who remained alive without ESRD from the Joslin Kidney Study cohort. Controls were matched with cases for baseline clinical characteristics; although controls had slightly higher eGFR and lower levels of urinary albumin excretion than T2D cases. Plasma metabolites at baseline were measured by mass spectrometry-based global metabolomic profiling. Of the named metabolites in the library, 262 were detected in at least 80% of the study patients. The metabolomic platform recognized 78 metabolites previously reported to be elevated in ESRD (uremic solutes). Sixteen were already elevated in the baseline plasma of our cases years before ESRD developed. Other uremic solutes were either not different or not commonly detectable. Essential amino acids and their derivatives were significantly depleted in the cases, whereas certain amino acid-derived acylcarnitines were increased. All findings remained statistically significant after adjustment for differences between study groups in albumin excretion rate, eGFR or HbA1c. Uremic solute differences were confirmed by quantitative measurements. Thus, abnormal plasma concentrations of putative uremic solutes and essential amino acids either contribute to progression to ESRD or are a manifestation of an early stage(s) of the disease process that leads to ESRD in T2D.

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Journal

Journal ID (iso-abbrev): PLoS ONE

Title: PloS one

Publisher: Public Library of Science (PLoS)

ISSN (Electronic): 1932-6203

ISSN (Print): 1932-6203

Publication date (Electronic): 2017

Volume: 12

Issue: 1

Affiliations

[1 ] Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States of America.

[2 ] Transplant Medicine, IRCCS Ospedale San Raffaele, Milan, Italy.

[3 ] Section on Genetics and Epidemiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, United States of America.

[4 ] San Giovanni Battista Hospital and University of Turin, Division of Nephrology, Dialysis, and Transplantation, Turin, Italy.

[5 ] Biomedical Engineering, University of Texas, Austin, TX, United States of America.

[6 ] Universita' Vita-Salute San Raffaele, Milan, Italy.

[7 ] Medicine, Al-Azhar University, Cairo, Egypt.

[8 ] Radiology, San Raffaele Scientific Institute, Milan, Italy.

[9 ] Center for Clinical Spectroscopy, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.

[10 ] Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.

Article

Publisher Item ID: PONE-D-16-15738

DOI: 10.1371/journal.pone.0169077

PMC ID: 5214547

PubMed ID: 28052095

SO-VID: 109b5236-f0f5-4073-8891-4bdf12e78928

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Metabolomic Profiling in Individuals with a Failing Kidney Allograft.

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Most cited references 41

Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes.

Disruption of methylarginine metabolism impairs vascular homeostasis.

Uremic solutes and risk of end stage renal disease in type 2 diabetes

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Cited by 16

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