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      A Signature of Circulating Inflammatory Proteins and Development of End Stage Renal Disease in Diabetes

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          Abstract

          Chronic inflammation is postulated to be involved in development of end stage renal disease (ESRD) in diabetes, but which specific circulating inflammatory proteins contribute to this risk remains unknown. To study this we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with Type 1 and Type 2 diabetes. In each cohort we identified an extremely robust Kidney Risk Inflammatory Signature (KRIS) consisting of 17 novel proteins enriched for TNF Receptor Superfamily members that was associated with a 10-year risk of ESRD. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying ESRD development in both types of diabetes. These proteins may be used as new therapeutic targets, new prognostic tests for high risk of ESRD and as surrogate outcome measures where changes in KRIS levels during intervention can reflect the tested therapy’s effectiveness.

          One Sentence Summary:

          Proteomic profiling of circulating proteins in subjects from three independent cohorts with type 1 and type 2 diabetes, identified an extremely robust inflammatory signature, consisting of 17 proteins enriched for TNF Receptor Superfamily members that was associated with a 10-year risk of end-stage renal disease.

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          Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase.

          L Gold, C Tuerk (1990)
          High-affinity nucleic acid ligands for a protein were isolated by a procedure that depends on alternate cycles of ligand selection from pools of variant sequences and amplification of the bound species. Multiple rounds exponentially enrich the population for the highest affinity species that can be clonally isolated and characterized. In particular one eight-base region of an RNA that interacts with the T4 DNA polymerase was chosen and randomized. Two different sequences were selected by this procedure from the calculated pool of 65,536 species. One is the wild-type sequence found in the bacteriophage mRNA; one is varied from wild type at four positions. The binding constants of these two RNA's to T4 DNA polymerase are equivalent. These protocols with minimal modification can yield high-affinity ligands for any protein that binds nucleic acids as part of its function; high-affinity ligands could conceivably be developed for any target molecule.
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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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              Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury.

              Fiona Chow, Elyce Ozols, David J Nikolic-Paterson … (2004)
              Macrophage-mediated renal injury has been implicated in progressive forms of glomerulonephritis; however, a role for macrophages in type 2 diabetic nephropathy, the major cause of end-stage renal failure, has not been established. Therefore, we examined whether macrophages may promote the progression of type 2 diabetic nephropathy in db/db mice. The incidence of renal injury was examined in db/db mice with varying blood sugar and lipid levels at 8 months of age. The association of renal injury with the accumulation of kidney macrophages was analyzed in normal db/+ and diabetic db/db mice at 2, 4, 6, and 8 months of age. In db/db mice, albuminuria and increased plasma creatinine correlated with elevated blood glucose and hemoglobin A1c (HbA1c) levels but not with obesity or hyperlipidemia. Progressive diabetic nephropathy in db/db mice was associated with increased kidney macrophages. Macrophage accumulation and macrophage activation in db/db mice correlated with hyperglycemia, HbA1c levels, albuminuria, elevated plasma creatinine, glomerular and tubular damage, renal fibrosis, and kidney expression of macrophage chemokines [monocyte chemoattractant protein-1 (MCP-1), osteopontin, migration inhibitory factor (MIF), monocyte-colony-stimulating factor (M-CSF)]. The accrual and activation of glomerular macrophages also correlated with increased glomerular IgG and C3 deposition, which was itself dependent on hyperglycemia. Kidney macrophage accumulation is associated with the progression of type 2 diabetic nephropathy in db/db mice. Macrophage accumulation and activation in diabetic db/db kidneys is associated with prolonged hyperglycemia, glomerular immune complex deposition, and increased kidney chemokine production, and raises the possibility of specific therapies for targeting macrophage-mediated injury in diabetic nephropathy.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9502015
                Journal ID (pubmed-jr-id): 8791
                Journal ID (nlm-ta): Nat Med
                Journal ID (iso-abbrev): Nat. Med.
                Title: Nature medicine
                ISSN (Print): 1078-8956
                ISSN (Electronic): 1546-170X
                Publication date Nihms-submitted: 8 March 2019
                Publication date (Electronic): 22 April 2019
                Publication date (Print): May 2019
                Publication date PMC-release: 22 October 2019
                Volume: 25
                Issue: 5
                Pages: 805-813
                Affiliations
                [1 ]Research Division, Joslin Diabetes Center, Boston, MA, USA
                [2 ]Department of Medicine, Harvard Medical School, Boston, MA, USA
                [3 ]Division of Diabetes Translation, Centers for Disease Control and Prevention, Atlanta, GA, USA
                [4 ]Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland
                [5 ]Diabetes and Complications Department, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
                [6 ]Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
                [7 ]Nephrology/Internal Medicine and Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
                [8 ]Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA
                [9 ]CHU Poitiers, University of Poitiers, Inserm, Clinical Investigation Center CIC1402, Poitiers, France
                [10 ]Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA
                [11 ]Romeo ed Enrica Invernizzi Pediatric Center, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Italy
                [12 ]Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
                Author notes

                Author Contributions: M.A.N. contributed to the design of the study, supervised proteomics data collection, conducted the data analysis, interpreted the results and wrote the manuscript. J.K.S, A.S. A.S., E.S. and C.A.S. were involved in data collection, data management of the Joslin Kidney Study, performed preliminary data analyses and reviewed the manuscript. A.D., Z.I.M.D, H.S. and J.K.S. designed the Joslin study on retinopathy, contributed to eye data collection and analysis, edited and reviewed the manuscript. R.G.N., M.E.P., P.-J.S. and H.C.L. were responsible for design and implementation of the Pima Indian Study, contributed to the proteomic data collection in the Pima Indian Study, performed preliminary data analysis, and reviewed and edited the manuscript. M.K., V.N. and R.G.N. designed the expression study in Pima Indians, provided data analysis, reviewed the manuscript. J.P., C.Q. and K.S. designed the expression study (1KGP) to be used in the current study, performed the data analyses and interpreted the results and edited the manuscript. P.F. and C.F.W. were involved in the interpretation of the results of the study and edited the manuscript. K.L.D. and J.M.W. provided the samples from the baricitinib study, facilitated measurements on the Olink platform, reviewed the analysis, reviewed and edited the manuscript. A.S.K designed the whole study, supervised all aspects of the study implementation, planned and contributed the data analysis, interpreted the data, and contributed to the manuscript writing. M.A.N. and A.S.K. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of data and the accuracy of the data analysis.

                [* ]Corresponding authors: Dr. Monika A. Niewczas or Dr. Andrzej S. Krolewski, Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA, 02215: monika.niewczas@ 123456joslin.harvard.edu or Andrzej.Krolewski@ 123456joslin.harvard.edu
                Article
                Manuscript ID: NIHMS1523522
                DOI: 10.1038/s41591-019-0415-5
                PMC ID: 6508971
                PubMed ID: 31011203
                SO-VID: 14d9efb5-a3f0-474f-8083-5bb369beec52
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