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Glomerular Hyperfiltration in Diabetes

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Glomerular Hyperfiltration in Diabetes BRIEF REVIEW www.jasn.org Glomerular Hyperfiltration in Diabetes: Mechanisms, Clinical Significance, and Treatment Lennart Tonneijck,* Marcel H.A. Muskiet,* Mark M. Smits,* Erik J. van Bommel,* † ‡ Hiddo J.L. Heerspink, Daniël H. van Raalte,* and Jaap A. Joles *Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands; †Department of Clinical Pharmacology, University Medical Center Groningen, Groningen, The Netherlands; and ‡Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands ABSTRACT An absolute, supraphysiologic elevation in GFR is observed early in the natural characterized by an absolute, supraphy- history in 10%–67% and 6%–73% of patients with type 1 and type 2 diabetes, siologic increase in whole-kidney GFR respectively. Moreover, at the single-nephron level, diabetes-related renal hemo- (i.e., the sum of filtration in all function- dynamic alterations—as an adaptation to reduction in functional nephron mass and/ ing nephrons) (Figure 1). This early or in response to prevailing metabolic and (neuro)hormonal stimuli—increase glo- clinical entity, known as glomerular hy- merular hydraulic pressure and transcapillary convective flux of ultrafiltrate and perfiltration, is the resultant of obesity macromolecules. This phenomenon, known as glomerular hyperfiltration, classically and diabetes-induced changes in struc- has been hypothesized to predispose to irreversible nephron damage, thereby con- tural and dynamic factors that deter- tributing to initiation and progression of kidney disease in diabetes. However, ded- mine GFR.5 Reported prevalences of icated studies with appropriate diagnostic measures and clinically relevant end hyperfiltration at the whole-kidney level points are warranted to confirm this assumption. In this review, we summarize the vary greatly: between 10% and 67% in hitherto proposed mechanisms involved in diabetic hyperfiltration, focusing on type 1 diabetes mellitus (T1DM) (with ultrastructural, vascular, and tubular factors. Furthermore, we review available ev- GFR values up to 162 ml/min per 1.73 m2), idence on the clinical significance of hyperfiltration in diabetes and discuss currently and 6%–73% in patients with type 2 dia- available and emerging interventions that may attenuate this renal hemodynamic betes (T2DM) (up to 166 ml/min per abnormality. The revived interest in glomerular hyperfiltration as a prognostic and 1.73 m2, Table 1). In general, GFR in- pathophysiologic factor in diabetes may lead to improved and timely detection of creases by about 27% and 16% in recently (progressive) kidney disease, and could provide new therapeutic opportunities in diagnosed patients with T1DM6 and alleviating the renal burden in this population. T2DM,7 respectively. The prevailing hy- pothesis is that hyperfiltration in diabetes J Am Soc Nephrol 28: 1023–1039, 2017. doi: 10.1681/ASN.2016060666 precedes the onset of albuminuria and/or decline in renal function, and predisposes to progressive nephron damage by increas- ing glomerular hydraulic pressure (PGLO) 3 Driven by the ever-increasing prevalence and without albuminuria. Despite in- and transcapillary convective flux of of diabetes, diabetic kidney disease creased efforts that stabilized incidence ultrafiltrate and, although modestly, (DKD) has become the most common rates for ESRD attributable to DKD in cause of CKD, leading to ESRD, cardio- the United States over the last 5 years, vascular events, and premature death in the number of patients with renal impair- L.T. and M.H.A.M. contributed equally to this work. developed and developing countries.1 In ment due to diabetes is still increasing.4 order to reduce the onset and progres- Therefore, improved and timely strategies Published online ahead of print. Publication date sion of DKD, current management fo- are needed. available at www.jasn.org. cuses on prevention, early identification, In addition to albuminuria, reduced Correspondence: Dr. Lennart Tonneijck, Diabetes and treatment. Diabetes and nephrology GFR is a pivotal marker in predicting the Center, Department of Internal Medicine, VU Uni- versity Medical Center (VUMC), De Boelelaan 1117, guidelines advocate strict glycemic risk for ESRD and renal death in diabetes, 1081 HV Amsterdam, Amsterdam, The Nether- and BP targets, the latter for which renin- whereas the role of increased GFR is un- lands. Email: [email protected] fi angiotensin system (RAS) inhibitors are certain. In the classic, ve-stage, protei- Copyright © 2017 by the American Society of recommended in diabetes patients with2 nuric pathway of DKD, the initial phase is Nephrology J Am Soc Nephrol 28: 1023–1039, 2017 ISSN : 1046-6673/2804-1023 1023 BRIEF REVIEW www.jasn.org inulin and sinistrin require labor-intensive analysis, alternative well recognized, al- though less accurate, exogenous filtration markers across GFR values are widely used in clinical practice and research, such as (125I-labeled) iothalamate, iohexol, 51Cr- labeled ethylenediaminetetra-acetic acid, and 99mTc-labeled diethylenetriaminepenta- acetic acid.19,20 “Single-Nephron” Hyperfiltration The definition of hyperfiltration at the whole-kidney level disregards conditions in single nephrons, for which two distinct Figure 1. Classic course of whole-kidney GFR and UAE according to the natural (proteinuric) (frequently co-occurring) elements seem pathway of DKD. Peak GFR may be seen in prediabetes or shortly after diabetes diagnosis, and to be involved. First, in the natural history can reach up to 180 ml/min in the case of two fully intact kidneys. Strict control of HbA1c and of DKD, with irreversible damage to initiation of other treatments (such as RAS inhibition) mitigate this initial response. Two normal progressively more glomeruli, remnant fi ltration phases can be encountered, in which GFR may be for instance 120 ml/min (indicated nephrons undergo functional and struc- with the gray line): one at 100% of nephron mass and one at approximately 50% of nephron tural hypertrophy (glomeruli and associ- mass. Thus, whole-kidney GFR may remain normal even in the presence of considerable loss of nephron mass, as evidenced by a recent autopsy study.121 Assessing renal functional reserve ated tubules), thereby striving to maintain fi and/or UAE may help identify the extent of subclinically inflicted loss of functional nephron mass. whole-kidney ltration and reabsorption 21 *Whole-kidney hyperfiltration is generally defined as a GFR that exceeds approximately within the normal range. Second, and 135 ml/min, and is indicated with the red line. Heterogeneity of single-nephron filtration regardless of renal mass, metabolic and rate and nonproteinuric pathway122 of DKD are not illustrated. (neuro)hormonal stimuli that prevail in diabetes and/or obesity (as discussed be- macromolecules (including albumin). differences between sexes and distinct low) enhance filtration in single nephrons, Furthermore, increased GFR in single ethnic populations,10 nephron endow- even when whole-kidney GFR does remnant nephrons—to compensate for re- ment at birth,12 and age-related GFR not exceed 130–140 ml/min per 1.73 m2 duced nephron numbers8,9 and/or caused decline.10,13 Identification of hyperfil- (Figure 1). Given these considerations, hy- by stimuli of the diabetes phenotype—is tration in clinical practice and systematic perfiltration has also been defined as a fil- proposed to accelerate renal function de- studies is complicated by intra- and tration fraction11,22 (FF; the ratio between cline in longer-standing diabetes. interday GFR fluctuations,14,15 and the GFR and effective renal plasma flow This review summarizes proposed inaccuracy of available serum creati- [ERPF]) above 17.7%62.8%, i.e.,the factors that underlie hyperfiltration in nine–based GFR estimates.16 As such, mean6SD in healthy 22–25–year-old hu- diabetes, and addresses evidence of this the Cockroft–Gault, Modification of mans.23 In support of such a definition, a phenomenon as predictor and patho- Diet in Renal Disease, and Chronic Kid- mean FF of 24% is observed in adolescents physiologic factor in DKD. Furthermore, ney Disease Epidemiology Collaboration with uncomplicated T1DM and a we discuss lifestyle and (emerging) 2009 equations systematically underesti- GFR of 178 ml/min per 1.73 m2,whereas pharmacologic interventions that may mate GFR in diabetes, and progres- FF is 17% in those with a GFR of attenuate hyperfiltration. sively more so with increasing GFR.16 111 ml/min per 1.73 m2.24 ERPF is mea- This seems due to changes in tubular sured using para-aminohippuric acid, creatinine secretion in the setting of obe- radioiodine-labeled hippuran, or 99mTc- DEFINITION AND MEASUREMENT sity, hyperglycemia, and hyperfiltration, labeled mercaptoacetyltriglycine, which although high glucose concentrations are removed from the circulation “Whole-Kidney” Hyperfiltration also lead to overestimation of serum cre- during a single pass through the kidney Although a generally accepted definition atinine when the Jaffe reaction is used.16 by approximately 90%,25 75%,25 or is lacking, reported thresholds to define eGFR on the basis of serum cystatin C is 55%,26 respectively. Whether FF is a valid hyperfiltration vary between 130 and suggested to more accurately reflect re- approximation of PGLO is subject to 140 ml/min per 1.73 m2 in subjects nal function in patients with diabetes debate, as the latter can only be directly with two functioning kidneys,10 which and normal or elevated GFR.17,18 Never- measured by micropuncture. However,
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