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      Glomerular and Tubular Damage Markers Are Elevated in Patients With Diabetes

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          Abstract

          OBJECTIVE

          We investigated in a cross-sectional study the levels of serum and urinary damage markers in diabetic patients ( n = 94) and nondiabetic control subjects ( n = 45) to study the association of glomerular (IgG), proximal tubular (kidney injury molecule [KIM]-1, N-acetyl-β- d-glucosaminidase [NAG], neutrophil gelatinase–associated lipocalin [NGAL], and cystatin C), and distal tubular (heart fatty acid–binding protein [H-FABP]) damage markers with kidney disease severity, as assessed by albuminuria and estimated glomerular filtration rate (eGFR).

          RESEARCH DESIGN AND METHODS

          Damage markers were measured in triplicate in fresh morning urine samples and in plasma.

          RESULTS

          Of the diabetic patients, 41 were normoalbuminuric, 41 were microalbuminuric, and 12 were macroalbuminuric. Urinary NAG (ninefold), NGAL (1.5-fold), and H-FABP (3.5-fold) were significantly elevated in normoalbuminuric diabetic patients compared with nondiabetic control subjects. Urinary concentrations of all markers increased per albuminuria stratum, except KIM-1. All urinary damage markers, except KIM-1, were significantly associated with albuminuria, independent of age, sex, and plasma concentrations of the corresponding biomarker (standard βs between 0.35 and 0.87; all P ≤ 0.001). All urinary damage markers, except KIM-1, were significantly associated with the eGFR in univariate models (standard βs between −0.38 and −0.21; all P < 0.04). After adjusting for age, sex, plasma concentration of the corresponding damage marker, and albuminuria, only the association of H-FABP with eGFR remained significant (standard β −0.26; P = 0.037).

          CONCLUSIONS

          Glomerular and tubular markers are associated with albuminuria, independently of eGFR, suggesting that albuminuria reflects both glomerular and tubulointerstitial damage. Only urinary H-FABP is associated with eGFR independently of albuminuria and, therefore, may be a promising urinary damage marker to assess diabetic kidney disease.

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          Most cited references20

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          KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease.

          (2007)
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            Standards of medical care in diabetes--2007.

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              What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium?

              Microalbuminuria is an important risk factor for cardiovascular disease and progressive renal impairment. This holds true in the general population and particularly in those with diabetes, in whom it is common and marks out those likely to develop macrovascular disease and progressive renal impairment. Understanding the pathophysiological mechanisms through which microalbuminuria occurs holds the key to designing therapies to arrest its development and prevent these later manifestations. Microalbuminuria arises from the increased passage of albumin through the glomerular filtration barrier. This requires ultrastructural changes rather than alterations in glomerular pressure or filtration rate alone. Compromise of selective glomerular permeability can be confirmed in early diabetic nephropathy but does not correlate well with reported glomerular structural changes. The loss of systemic endothelial glycocalyx—a protein-rich surface layer on the endothelium—in diabetes suggests that damage to this layer represents this missing link. The epidemiology of microalbuminuria reveals a close association with systemic endothelial dysfunction and with vascular disease, also implicating glomerular endothelial dysfunction in microalbuminuria. Our understanding of the metabolic and hormonal sequelae of hyperglycaemia is increasing, and we consider these in the context of damage to the glomerular filtration barrier. Reactive oxygen species, inflammatory cytokines and growth factors are key players in this respect. Taken together with the above observations and the presence of generalised endothelial dysfunction, these considerations lead to the conclusion that glomerular endothelial dysfunction, and in particular damage to its glycocalyx, represents the most likely initiating step in diabetic microalbuminuria.
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                Author and article information

                Journal
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                April 2011
                21 March 2011
                : 34
                : 4
                : 975-981
                Affiliations
                [1] 1Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
                [2] 2Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
                [3] 3Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
                [4] 4Department of Biomaterials, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
                [5] 5Diabetes Centre, Isala Clinics, Zwolle, the Netherlands
                Author notes
                Corresponding author: Ron T. Gansevoort, r.t.gansevoort@ 123456int.umcg.nl .
                Article
                1545
                10.2337/dc10-1545
                3064060
                21307379
                cdce999f-7018-44eb-9db5-2c7eb16f3cfe
                © 2011 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                : 26 August 2010
                : 8 January 2011
                Categories
                Original Research
                Pathophysiology/Complications

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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