The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus

Har, Ronnie; Scholey, James W.; Daneman, Denis; Mahmud, Farid H; Dekker, R.A.; Lai, Vesta; Elia, Yesmino; Fritzler, Mark L.; Sochett, Etienne; Reich, Heather N.; Cherney, David Z.I.

doi:10.1007/s00125-013-2857-5

Cited by 54 publications

(53 citation statements)

References 44 publications

(78 reference statements)

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“…124 The high urinary levels of eotaxin and RANTES, from hyperfiltration in the diabetic kidney, occur as result of high intraglomerular pressure which causes renal inflammation, inflammation being a component of DN. 123 Finally, some investigators reported high IL-8 and MCP-1 levels in early and late stages of DN in T2DM patients, respectively, 125 while another study on T2DM patients with …”

Section: Biomarkers Of Inflammationmentioning

confidence: 99%

“…121 Serum and urinary G-CSF levels are also increased in the early stages of DN, 122 while urinary RANTES (or CCL-5) and eotaxin excretion rates were noted to be significantly higher in hyperfiltering than in normofiltering T1DM patients. 123 Like RANTES which is a chemotactic cytokine, eotaxins are a chemotactic cytokine subfamily of eosinophil chemotactic proteins consisting of eotaxin-1 (CCL-11), eotaxin-2 (CCL-24), and eotaxin-3 (CCL-26). 124 The high urinary levels of eotaxin and RANTES, from hyperfiltration in the diabetic kidney, occur as result of high intraglomerular pressure which causes renal inflammation, inflammation being a component of DN.…”

Section: Biomarkers Of Inflammationmentioning

confidence: 99%

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The role of novel biomarkers in predicting diabetic nephropathy: a review

Uwaezuoke

2017

IJNRD

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Diabetic nephropathy (DN) is one of the microvascular complications of the kidney arising commonly from type 1 diabetes mellitus (T1DM), and occasionally from type 2 diabetes mellitus (T2DM). Microalbuminuria serves as an early indicator of DN risk and a predictor of its progression as well as cardiovascular disease risk in both T1DM and T2DM. Although microalbuminuria remains the gold standard for early detection of DN, it is not a sufficiently accurate predictor of DN risk due to some limitations. Thus, there is a paradigm shift to novel biomarkers which would help to predict DN risk early enough and possibly prevent the occurrence of end-stage kidney disease. These new biomarkers have been broadly classified into glomerular biomarkers, tubular biomarkers, biomarkers of inflammation, biomarkers of oxidative stress, and miscellaneous biomarkers which also include podocyte biomarkers, some of which are also considered as tubular and glomerular biomarkers. Although they are potentially useful for the evaluation of DN, current data still preclude the routine clinical use of majority of them. However, their validation using high-quality and large longitudinal studies is of paramount importance, as well as the subsequent development of a biomarker panel which can reliably predict and evaluate this renal microvascular disease. This paper aims to review the predictive role of these biomarkers in the evaluation of DN.

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Section: Biomarkers Of Inflammationmentioning

confidence: 99%

Section: Biomarkers Of Inflammationmentioning

confidence: 99%

The role of novel biomarkers in predicting diabetic nephropathy: a review

Uwaezuoke

2017

IJNRD

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“…First, the definition of hyperfiltration in our previous work is GFR≥135 ml/min/1.73m 2 during clamped euglycemia. [8][9][10][11]22,23 This definition based on ambient euglycemia is important because acute induction of modest hyperglycemia can induce a hyperfiltration response, possibly through neurohormonal activation, especially in normofiltering individuals. 10,24 Our second reason for controlling ambient glycemic conditions was to separate the effects of systemic hyperglycemia resulting in glucosuria (ie, essentially uncontrolled diabetes mellitus) from increased glucosuria with simultaneous euglycemia.…”

Section: Experimental Designmentioning

confidence: 99%

Renal Hemodynamic Effect of Sodium-Glucose Cotransporter 2 Inhibition in Patients With Type 1 Diabetes Mellitus

et al. 2014

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2, n=13) at baseline. Renal function and circulating levels of renin-angiotensin-aldosterone system mediators and NO were measured under clamped euglycemic (4-6 mmol/l) and hyperglycemic (9-11 mmol/l) conditions at baseline and end of treatment. During clamped euglycemia, hyperfiltration was attenuated by −33 ml/min/1.73m 2 with empagliflozin in T1D-H, (GFR 172±23-139±25 ml/min/1.73 m 2 , P<0.01). This effect was accompanied by declines in plasma NO and effective renal plasma flow and an increase in renal vascular resistance (all P<0.01). Similar significant effects on GFR and renal function parameters were observed during clamped hyperglycemia. In T1D-N, GFR, other renal function parameters, and plasma NO were not altered by empagliflozin. Empagliflozin reduced hemoglobin A1c significantly in both groups, despite lower insulin doses in each group (P≤0.04). This distal tubular condition is sensed as a low effective circulating volume stimulus at the level of the juxtaglomerular apparatus, causing an afferent renal vasodilatory response ( Figure 1B). The consequence of this altered TGF results in supranormal glomerular filtration rate (GFR) values into the hyperfiltration range. Targeting TGF in renal hyperfiltration has shown promising results in experimental animal models by using phlorizin, a nonspecific inhibitor of the renal tubular glucose transporters SGlT1 and SGlT2. 13,14 The clinical relevance of these findings, however, could not be conclusively studied in humans, because of the poor tolerability of phlorizin resulting from its low selectivity for SGlT2, SGlT1 inhibition-related gastrointestinal side effects and very limited oral bioavailability. Conclusions-In14 Subsequent studies with selective SGlT2 inhibitors in animals have also shown similar significant effects on renal hyperfiltration. 15 More recently, several highly selective SGlT2 inhibitors have been developed for use in clinical trials in patients with type 2 diabetes mellitus (T2D). 16,17 These compounds generally do not affect SGlT1 at clinical doses and have pharmacological features that allow once daily oral dosing. In T2D, this class of drugs is well-tolerated and has consistently improved glycemic control, along with weight loss, and antihypertensive effects. 17,18 Available evidence for SGlT2 inhibitors in T1D is however limited, and is mainly derived from experimental animal models. Only 1 clinical pilot study has been conducted, which demonstrated that a single dose of remogliflozin improved postprandial glucose profiles. 19 Based on previous findings with phlorizin and other SGlT2 inhibitors in animals, the concept of altering renal hyperfiltration by blocking renal glucose absorption with SGlT2 inhibitors is intriguing, because reducing this surrogate marker of intraglomerular pressure is renal protective in experimental models of diabetes mellitus. 13,20,21 However, potential renal hemodynamic effects of these drugs in subjects with diabetes mellitus, including effects on renal hyperfiltration, remain unknown. Accordingly, the p...

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“…eGFR was calculated using the Larsson formula: eGFR = 77.24 3 cystatin C 21.2623 , where cystatin C was measured by laser immunonephelometry (Dade Behring) (12,13). As in our previous work, T1D adolescent participants were also subdivided into a normofiltration and a hyperfiltration group, where hyperfiltration was defined as eGFR $135 mL/min (14)(15)(16)(17).…”

Section: Renal Assessmentsmentioning

confidence: 99%

Association Between Plasma Uric Acid Levels and Cardiorenal Function in Adolescents With Type 1 Diabetes

et al. 2016

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OBJECTIVE The relationship between plasma uric acid (PUA) and renal and cardiovascular parameters in adolescents with type 1 diabetes (T1D) is not well understood. Our aims in this exploratory analysis were to study the association between PUA and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (ACR), blood pressure, endothelial function, and arterial stiffness in T1D adolescents. These associations were also studied in healthy control (HC) subjects. RESEARCH DESIGN AND METHODS We studied 188 T1D subjects recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) and 65 HC subjects. Baseline PUA, eGFR cystatin C , ACR, blood pressure, flow-mediated dilation (FMD), and carotid-femoral pulse wave velocity (PWV) were measured. RESULTS PUA was lower in T1D vs. HC subjects (242 6 55 vs. 306 6 74 mmol/L, respectively ; P < 0.0001). Higher PUA was inversely associated with eGFR in T1D subjects (r = 20.48, P < 0.0001) even after correction for baseline clinical demographic characteristics. PUA was not associated with ACR in T1D after adjustment for potential confounders such as eGFR. For cardiovascular parameters, PUA levels did not associate with systolic blood pressure, FMD, or PWV in T1D or HC subjects. CONCLUSIONS Even within the physiological range, PUA levels were significantly lower in T1D adolescent patients compared with HC subjects. There was an inverse relationship between PUA and eGFR in T1D, likely reflecting an increase in clearance. There were no associations observed with ACR, blood pressure, arterial stiffness, or endothelial function. Thus, in contrast with adults, PUA may not yet be associated with cardiorenal abnormalities in adolescents with T1D. Recent evidence from animal and human models suggests that plasma uric acid (PUA) levels are associated with multiple key pathways implicated in the pathogen-esis of type 1 diabetes (T1D) complications, such as metabolic abnormalities (insulin resistance and hyperglycemia), cardiovascular disease (hypertension, endothelial dysfunction, arterial stiffness, and cardiac diastolic dysfunction), and kidney dysfunc-tion (1). In healthy adult men and women, PUA is positively associated with activation of proinflammatory pathways and activation of the renin-angiotensin-aldosterone

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The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus

Cited by 54 publications

References 44 publications

The role of novel biomarkers in predicting diabetic nephropathy: a review

The role of novel biomarkers in predicting diabetic nephropathy: a review

Renal Hemodynamic Effect of Sodium-Glucose Cotransporter 2 Inhibition in Patients With Type 1 Diabetes Mellitus

Association Between Plasma Uric Acid Levels and Cardiorenal Function in Adolescents With Type 1 Diabetes

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