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      Biomarkers of diabetic kidney disease

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          Abstract

          Diabetic kidney disease (DKD) remains one of the leading causes of reduced lifespan in diabetes. The quest for both prognostic and surrogate endpoint biomarkers for advanced DKD and end-stage renal disease has received major investment and interest in recent years. However, at present no novel biomarkers are in routine use in the clinic or in trials. This review focuses on the current status of prognostic biomarkers. First, we emphasise that albuminuria and eGFR, with other routine clinical data, show at least modest prediction of future renal status if properly used. Indeed, a major limitation of many current biomarker studies is that they do not properly evaluate the marginal increase in prediction on top of these routinely available clinical data. Second, we emphasise that many of the candidate biomarkers for which there are numerous sporadic reports in the literature are tightly correlated with each other. Despite this, few studies have attempted to evaluate a wide range of biomarkers simultaneously to define the most useful among these correlated biomarkers. We also review the potential of high-dimensional panels of lipids, metabolites and proteins to advance the field, and point to some of the analytical and post-analytical challenges of taking initial studies using these and candidate approaches through to actual clinical biomarker use.

          Electronic supplementary material

          The online version of this article (10.1007/s00125-018-4567-5) contains a slideset of the figures for download, which is available to authorised users.

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          Most cited references98

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          Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury.

          We report the identification of rat and human cDNAs for a type 1 membrane protein that contains a novel six-cysteine immunoglobulin-like domain and a mucin domain; it is named kidney injury molecule-1 (KIM-1). Structurally, KIM-1 is a member of the immunoglobulin gene superfamily most reminiscent of mucosal addressin cell adhesion molecule 1 (MAdCAM-1). Human KIM-1 exhibits homology to a monkey gene, hepatitis A virus cell receptor 1 (HAVcr-1), which was identified recently as a receptor for the hepatitis A virus. KIM-1 mRNA and protein are expressed at a low level in normal kidney but are increased dramatically in postischemic kidney. In situ hybridization and immunohistochemistry revealed that KIM-1 is expressed in proliferating bromodeoxyuridine-positive and dedifferentiated vimentin-positive epithelial cells in regenerating proximal tubules. Structure and expression data suggest that KIM-1 is an epithelial cell adhesion molecule up-regulated in the cells, which are dedifferentiated and undergoing replication. KIM-1 may play an important role in the restoration of the morphological integrity and function to postischemic kidney.
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            Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse.

            Although members of the fibroblast growth factor (FGF) family and their receptors have well-established roles in embryogenesis, their contributions to adult physiology remain relatively unexplored. Here, we use real-time quantitative PCR to determine the mRNA expression patterns of all 22 FGFs, the seven principal FGF receptors (FGFRs), and the three members of the Klotho family of coreceptors in 39 different mouse tissues. Unsupervised hierarchical cluster analysis of the mRNA expression data reveals that most FGFs and FGFRs fall into two groups the expression of which is enriched in either the central nervous system or reproductive and gastrointestinal tissues. Interestingly, the FGFs that can act as endocrine hormones, including FGF15/19, FGF21, and FGF23, cluster in a third group that does not include any FGFRs, underscoring their roles in signaling between tissues. We further show that the most recently identified Klotho family member, Lactase-like, is highly and selectively expressed in brown adipose tissue and eye and can function as an additional coreceptor for FGF19. This FGF atlas provides an important resource for guiding future studies to elucidate the physiological functions of FGFs in adult animals.
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              Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD.

              Serum cystatin C was proposed as a potential replacement for serum creatinine in glomerular filtration rate (GFR) estimation. We report the development and evaluation of GFR-estimating equations using serum cystatin C alone and serum cystatin C, serum creatinine, or both with demographic variables. Test of diagnostic accuracy. Participants screened for 3 chronic kidney disease (CKD) studies in the United States (n = 2,980) and a clinical population in Paris, France (n = 438). Measured GFR (mGFR). Estimated GFR using the 4 new equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both with age, sex, and race. New equations were developed by using linear regression with log GFR as the outcome in two thirds of data from US studies. Internal validation was performed in the remaining one third of data from US CKD studies; external validation was performed in the Paris study. GFR was measured by using urinary clearance of iodine-125-iothalamate in the US studies and chromium-51-EDTA in the Paris study. Serum cystatin C was measured by using Dade-Behring assay, standardized serum creatinine values were used. Mean mGFR, serum creatinine, and serum cystatin C values were 48 mL/min/1.73 m(2) (5th to 95th percentile, 15 to 95), 2.1 mg/dL, and 1.8 mg/L, respectively. For the new equations, coefficients for age, sex, and race were significant in the equation with serum cystatin C, but 2- to 4-fold smaller than in the equation with serum creatinine. Measures of performance in new equations were consistent across the development and internal and external validation data sets. Percentages of estimated GFR within 30% of mGFR for equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both levels with age, sex, and race were 81%, 83%, 85%, and 89%, respectively. The equation using serum cystatin C level alone yields estimates with small biases in age, sex, and race subgroups, which are improved in equations including these variables. Study population composed mainly of patients with CKD. Serum cystatin C level alone provides GFR estimates that are nearly as accurate as serum creatinine level adjusted for age, sex, and race, thus providing an alternative GFR estimate that is not linked to muscle mass. An equation including serum cystatin C level in combination with serum creatinine level, age, sex, and race provides the most accurate estimates.
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                Author and article information

                Contributors
                Helen.colhoun@igmm.ed.ac.uk
                Journal
                Diabetologia
                Diabetologia
                Diabetologia
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0012-186X
                1432-0428
                8 March 2018
                8 March 2018
                2018
                : 61
                : 5
                : 996-1011
                Affiliations
                [1 ]MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU UK
                [2 ]ISNI 0000000121885934, GRID grid.5335.0, Department of Paediatrics, , University of Cambridge, ; Cambridge, UK
                Article
                4567
                10.1007/s00125-018-4567-5
                6448994
                29520581
                e89a61ca-ddf9-4716-a62f-6428204641f5
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 24 October 2017
                : 3 January 2018
                Funding
                Funded by: University of Edinburgh
                Categories
                Review
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2018

                Endocrinology & Diabetes
                biomarker,diabetic kidney disease,epidemiology,nephropathy,review
                Endocrinology & Diabetes
                biomarker, diabetic kidney disease, epidemiology, nephropathy, review

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