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Renal and Vascular Effects of Uric Acid Lowering in Normouricemic Patients with Uncomplicated Type 1 Diabetes

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Renal and Vascular Effects of Uric Acid Lowering in Normouricemic Patients with Uncomplicated Type 1 Diabetes Diabetes Volume 66, July 2017 1939 Renal and Vascular Effects of Uric Acid Lowering in Normouricemic Patients With Uncomplicated Type 1 Diabetes Yuliya Lytvyn,1,2 Ronnie Har,1 Amy Locke,1 Vesta Lai,1 Derek Fong,1 Andrew Advani,3 Bruce A. Perkins,4 and David Z.I. Cherney1 Diabetes 2017;66:1939–1949 | https://doi.org/10.2337/db17-0168 Higher plasma uric acid (PUA) levels are associated with at the efferent arteriole. Ongoing outcome trials will de- lower glomerular filtration rate (GFR) and higher blood termine cardiorenal outcomes of PUA lowering in patients pressure (BP) in patients with type 1 diabetes (T1D). Our with T1D. aim was to determine the impact of PUA lowering on renal and vascular function in patients with uncomplicated T1D. T1D patients (n = 49) were studied under euglycemic and Plasma uric acid (PUA) levels are associated with the PATHOPHYSIOLOGY hyperglycemic conditions at baseline and after PUA low- pathogenesis of diabetic complications, including cardiovas- ering with febuxostat (FBX) for 8 weeks. Healthy control cular disease and kidney injury (1). Interestingly, extracellu- subjects were studied under normoglycemic conditions lar PUA levels are lower in young adults and adolescents (n = 24). PUA, GFR (inulin), effective renal plasma flow with type 1 diabetes (T1D) compared with healthy control (para-aminohippurate), BP, and hemodynamic responses subjects (HCs) (2–4), likely due to a stimulatory effect of to an infusion of angiotensin II (assessment of intrarenal urinary glucose on the proximal tubular GLUT9 transporter, renin-angiotensin-aldosterone system [RAAS]) were mea- which induces uricosuria (2). Thus, PUA-mediated target sured before and after FBX treatment. Arterial stiffness, organinjurymaybemediatedbytheintracellularuric fl ow-mediated dilation (FMD), nitroglycerin-mediated dila- acid effects, uricosuria-related tubular cell exposure (5), tion (GMD), urinary nitric oxide (NO), and inflammatory sequestration of PUA along the vascular endothelium, or markers were measured before and after FBX treatment. PUA-mediated inflammation and activation of the renin- Gomez equations were used to estimate arteriolar affer- angiotensin (ANG)-aldosterone system (RAAS) (1). ent resistance, efferent resistance (R ), and glomerular E Consequently, even within the normal range, PUA is hydrostatic pressure (PGLO). FBX had a modest systolic BP–lowering effect in T1D patients (112 6 10 to 109 6 associated with impaired renal function (6,7), early glo- fi 9 mmHg, P = 0.049) without impacting arterial stiffness, merular ltration rate (GFR) loss (8), and an increased risk FMD, GMD, or NO. FBX enhanced the filtration fraction of the development of proteinuria in patients with T1D (9). response to hyperglycemia in T1D patients through larger Even in young adults and adolescents with T1D without increases in RE, PGLO, and interleukin-18 but without complications, higher PUA levels are associated with lower impacting the RAAS. FBX lowered systolic BP and mod- GFR (2–4), which may be driven by a PUA-mediated ulated the renal RE responses to hyperglycemia but with- increase in afferent renal arteriole resistance potentially out impacting the RAAS or NO levels, suggesting that PUA promoting ischemia to the renal microcirculation (4). Ad- may augment other hemodynamic or inflammatory mech- ditionally, accumulating evidence suggests that PUA levels anisms that control the renal response to hyperglycemia are independently associated with increased intimal medial 1Department of Medicine, Division of Nephrology, Toronto General Hospital, Uni- Received 7 February 2017 and accepted 5 April 2017. versity of Toronto, Toronto, Ontario, Canada Clinical trial reg. no. NCT02344602, clinicaltrials.gov. 2Department of Pharmacology and Toxicology, University of Toronto, Toronto, B.A.P. and D.Z.I.C. are co–senior authors. Ontario, Canada 3Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge © 2017 by the American Diabetes Association. Readers may use this article as Institute of St. Michael’s Hospital, Toronto, Ontario, Canada long as the work is properly cited, the use is educational and not for profit, and the 4Department of Medicine, Division of Endocrinology and Metabolism, Mount Sinai work is not altered. More information is available at http://www.diabetesjournals Hospital, University of Toronto, Toronto, Ontario, Canada .org/content/license. Corresponding author: David Z.I. Cherney, [email protected]. 1940 Cardiorenal Effects of Uric Acid Lowering in T1D Diabetes Volume 66, July 2017 thickness, endothelial dysfunction, and vascular stiffness (10), promoting the development of hypertension, car- diovascular disease, and chronic kidney disease (6,11). Although not observed in adolescents with T1D, the asso- ciation between higher PUA levels within the normal range and higher blood pressure (BP) has been reported in young adults with uncomplicated T1D (2). Such relationships be- tween PUA and early renal and cardiovascular risk factors in young patients with T1D suggest that lowering PUA may be an important strategy to reduce renal and cardiovascular complications related to diabetes. From the limited data available in patients with diabetes, lowering of PUA levels may improve endothelial function (12), lower BP (13–15), slow GFR decline, reduce protein- uria, and suppress renal inflammation (1,16–18). Given the lack of effective therapy that protects against initiation and progression of diabetic complications, it is of the utmost importance to evaluate the renal and vascular effects of pharmacological PUA lowering in patients with T1D. Ac- cordingly, the goals of our physiological study were to de- termine whether PUA lowering with the xanthine oxidase Figure 1—Flow diagram for study participants. inhibitor febuxostat (FBX) modifies 1) the effect of hyper- glycemia and infused ANG II on renal hemodynamic func- tion, 2) systemic BP, and 3) arterial stiffness and endothelial function during clamped euglycemia and hyperglycemia in normoalbuminuria on a 24-h urine collection; 3) BMI of an even earlier cohort of young T1D adults without any 18–35 kg/m2; 4) normal renal and liver function; 5)normal complications. electrocardiogram; 6)clinicBP,140/90 mmHg; 7)T1D Using a study design with both euglycemic and hyper- duration .5 years; 8) normal PUA levels ,450 mmol/L glycemic clamp conditions, we wanted to assess the effects based on Clinical Reference Laboratory Guidelines at the of uricosuria-related tubular exposure that is augmented by time of study initialization; and 9) no history of renal or hyperglycemia and the consequent glycosuria. As we have cardiovascular complications and no intake of concomitant previously shown, glycosuria stimulated by hyperglycemia medications that would alter BP or cardiovascular outcomes leads to uricosuria (2). It was therefore important to com- or interfere with purine metabolism. The study was ap- pare PUA-lowering effects during euglycemic conditions proved by the University Health Network Research Ethics with those during hyperglycemic conditions. In addition, Board (Toronto, ON, Canada), and all subjects gave written unlike other PUA-lowering agents, FBX lowers PUA levels informed consent. sequestered along the vascular endothelium (1), allowing us to potentially target PUA-mediated injury mechanisms that Experimental Design are due to either paracellular or even intracellular uric acid Patients with T1D were studied at baseline (day 1, levels. Finally, because of interactions among PUA, the euglycemic; day 2, hyperglycemic) and after 8 weeks of RAAS, and inflammation, we measured plasma aldoste- FBX therapy 80-mg daily (day 3, euglycemic; day 4, rone and renin levels as well as urinary inflammatory hyperglycemic). Medication compliance was assessed by marker levels and hemodynamic responses to an exoge- pill counting and was .90% in all participants. During nous ANG II infusion to better elucidate PUA lowering as clamped euglycemic study days, the blood glucose level was a modulator of these traditional renal and cardiovascular maintained between 4 and 6 mmol/L, and during clamped injury pathways. hyperglycemic study days the blood glucose level was maintained between 9 and 11 mmol/L. Studies were RESEARCH DESIGN AND METHODS performed after 7 days on a controlled diet consisting Subject Inclusion Criteria and Study Preparation of $150 mmol/day sodium and #1.5 g/kg/day protein. Twenty-four HCs and 49 patients with T1D completed this The sodium-replete diet was used to avoid circulating vol- open-label, proof-of-principle, 8-week FBX treatment study ume contraction, RAAS activation, and between-subject het- (Fig. 1) (ClinicalTrials.gov identifier NCT02344602). T1D erogeneity and in an attempt to keep study conditions study participants included 42 patients with T1D with nor- similar to typical North American dietary patterns. Prestudy mofiltration (T1D-N; GFR ,135 mL/min/1.73 m2)and7 protein intake was modest to avoid the hyperfiltration ef- patients with T1D with hyperfiltration (T1D-H; GFR $135 fect of high-protein diets (19). Compliance was ascertained mL/min/1.73 m2). Detailed inclusion criteria were as fol- by the measurement of 24-h urine sodium and urea excre- lows: 1) male and female participants 18–40 years old; 2) tion on the seventh day prior to the studies. All study diabetes.diabetesjournals.org Lytvyn and Associates 1941 participants were instructed to avoid caffeine-containing The DPF was calculated as follows: products and to have the same light breakfast on the morn- ¼ = ing
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