Para-aminohippurate Clearance Research Articles

Renal Glucose Release after Unilateral Renal Denervation during a Hypoglycemic Clamp in Pigs with an Altered Hypothalamic Pituitary Adrenal Axis after Late-Gestational Dexamethasone Injection.

Previously, we demonstrated in pigs that renal denervation halves glucose release during hypoglycaemia and that a prenatal dexamethasone injection caused increased ACTH and cortisol concentrations as markers of a heightened hypothalamic pituitary adrenal axis (HPAA) during hypoglycaemia. In this study, we investigated the influence of an altered HPAA on renal glucose release during hypoglycaemia. Pigs whose mothers had received two late-gestational dexamethasone injections were subjected to a 75 min hyperinsulinaemic-hypoglycaemic clamp (<3 mmol/L) after unilateral surgical denervation. Para-aminohippurate (PAH) clearance, inulin, sodium excretion and arterio-venous blood glucose difference were measured every fifteen minutes. The statistical analysis was performed with a Wilcoxon signed-rank test. PAH, inulin, the calculated glomerular filtration rate and plasma flow did not change through renal denervation. Urinary sodium excretion increased significantly (p = 0.019). Side-dependent renal net glucose release (SGN) decreased by 25 ± 23% (p = 0.004). At 25 percent, the SGN decrease was only half of that observed in non-HPAA-altered animals in our prior investigation. The current findings may suggest that specimens with an elevated HPAA undergo long-term adaptations to maintain glucose homeostasis. Nonetheless, the decrease in SGN warrants further investigations and potentially caution in performing renal denervation in certain patient groups, such as diabetics at risk of hypoglycaemia.

#3840 THE SYSTEMIC AND RENAL HAEMODYNAMIC EFFECTS OF APELIN IN HEALTH AND CHRONIC KIDNEY DISEASE

Abstract Background and Aims Chronic kidney disease (CKD) is a leading cause of global morbidity and mortality and is independently associated with cardiovascular disease. Indeed, patients with CKD are more likely to die of cardiovascular disease than they are to progress to kidney failure. Despite current standard of care, outcomes remain poor and newer therapies are needed. Apelin, an endothelium-dependent vasodilator and potent inotrope, is a potential novel treatment for CKD. There are no clinical studies of the renal actions of apelin, but pre-clinical data show that it regulates glomerular haemodynamics and promotes aquaresis. We investigated the cardiovascular and renal actions of apelin in healthy volunteers and in patients with CKD. Method Patients with stable, non-diabetic CKD and age- and sex-matched healthy volunteers were recruited to a prospective, randomised, double-blind and placebo-controlled study. Subjects received either pyroglutamated apelin-13 ([Pyr1]apelin-13, 1 nmol/min and 30 nmol/min) or placebo on two separate visits. Cardiovascular assessments included blood pressure, impedance cardiography and pulse wave velocity; iohexol and para-aminohippurate clearance were used to assess glomerular filtration rate (GFR) and renal blood flow, respectively. Tubular function was examined via urinary sodium, potassium and free water excretion. Results Twelve patients with CKD and 12 healthy volunteers were recruited and completed both phases of the study protocol. Baseline characteristics are shown in Table 1. Whilst infusion of 1 nmol/min [Pyr1]apelin-13 did not affect systemic haemodynamics, 30 nmol/min [Pyr1]apelin-13 led to significant changes. Compared to placebo, mean arterial pressure fell by 3 mmHg and 4 mmHg in health and CKD, respectively (p&amp;lt;0.05 for both groups), and systemic vascular resistance index fell by 309 dynes*s*cm−5 m2 and 407 dynes*s*cm−5 m2, respectively (p&amp;lt;0.01 for both groups). Cardiac index increased by 0.3 L/min/m2 and 0.2 L/min/m2, respectively (p&amp;lt;0.05 for both groups compared to placebo). In contrast, both 1 nmol/min and 30 nmol/min [Pyr1]apelin-13 had similar effects on renal haemodynamics. Effective renal blood flow increased by ∼15% in health and CKD (p&amp;lt;0.01 compared to placebo for both groups). GFR fell by ∼4 mL/min compared to placebo in patients with CKD (p&amp;lt;0.01) but we observed no change in healthy volunteers. As a result of these changes in effective renal blood flow and GFR, filtration fraction fell by ∼3% in CKD, reflected by a fall in proteinuria of ∼25% (p&amp;lt;0.001 compared to placebo for both). Both low and high doses of [Pyr1]apelin-13 promoted natriuresis and free water clearance in health and CKD. In comparison to placebo, sodium excretion increased by ∼30% and free water clearance by ∼15% in both groups (p&amp;lt;0.05 for all comparisons). Overall, the effects of apelin were prolonged in CKD. Conclusion Apelin offers systemic and renal haemodynamic benefits to patients with CKD. If these effects were maintained longer-term they would translate to improved cardiovascular and renal outcomes in this at-risk patient group. Clinical trials of long-acting, oral apelin analogues are now justified in CKD and other conditions with impaired salt and water balance.

Renal and Vascular Effects of Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition.

Background:The cardiorenal effects of sodium-glucose cotransporter 2 inhibition (empagliflozin 25 mg QD) combined with angiotensin-converting enzyme inhibition (ramipril 10 mg QD) were assessed in this mechanistic study in patients with type 1 diabetes with potential renal hyperfiltration.Methods:Thirty patients (out of 31 randomized) completed this double-blind, placebo-controlled, crossover trial. Recruitment was stopped early because of an unexpectedly low proportion of patients with hyperfiltration. Measurements were obtained after each of the 6 treatment phases over 19 weeks: (1) baseline without treatment, (2) 4-week run-in with ramipril treatment alone, (3) 4-week combined empagliflozin-ramipril treatment, (4) a 4-week washout, (5) 4-week combined placebo-ramipril treatment, and (6) 1-week follow-up. The primary end point was glomerular filtration rate (GFR) after combination treatment with empagliflozin-ramipril compared with placebo-ramipril. GFR was corrected for ramipril treatment alone before randomization. At the end of study phase, the following outcomes were measured under clamped euglycemia (4 to 6 mmol/L): inulin (GFR) and para-aminohippurate (effective renal plasma flow) clearances, tubular sodium handling, ambulatory blood pressure, arterial stiffness, heart rate variability, noninvasive cardiac output monitoring, plasma and urine biochemistry, markers of the renin-angiotensin-aldosterone system, and oxidative stress.Results:Combination treatment with empagliflozin-ramipril resulted in an 8 mL/min/1.73 m2 lower GFR compared with placebo-ramipril treatment (P=0.0061) without significant changes to effective renal plasma flow. GFR decrease was accompanied by a 21.3 mL/min lower absolute proximal fluid reabsorption rate (P=0.0092), a 3.1 mmol/min lower absolute proximal sodium reabsorption rate (P=0.0056), and a 194 ng/mmol creatinine lower urinary 8-isoprostane level (P=0.0084) relative to placebo-ramipril combination treatment. Sodium-glucose cotransporter 2 inhibitor/angiotensin-converting enzyme inhibitor combination treatment resulted in additive blood pressure–lowering effects (clinic systolic blood pressure lower by 4 mm Hg [P=0.0112]; diastolic blood pressure lower by 3 mm Hg [P=0.0032]) in conjunction with a 94.5 dynes × sex/cm5 lower total peripheral resistance (P=0.0368). There were no significant changes observed to ambulatory blood pressure, arterial stiffness, heart rate variability, or cardiac output with the addition of empagliflozin.Conclusions:Adding sodium-glucose cotransporter 2 inhibitor treatment to angiotensin-converting enzyme inhibitor resulted in an expected GFR dip, suppression of oxidative stress markers, additive declines in blood pressure and total peripheral resistance. These changes are consistent with a protective physiologic profile characterized by the lowering of intraglomerular pressure and related cardiorenal risk when adding a sodium-glucose cotransporter 2 inhibitor to conservative therapy.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02632747.

20-OR: The Renal and Vascular Effects of Combined SGLT2 and Angiotensin Converting Enzyme Inhibition

The goal of this mechanistic trial was to determine the kidney and cardiovascular effects of combined treatment with an SGLT2i (empagliflozin 25mg QD) and an ACEi (ramipril 10mg QD) for 4 weeks in patients at risk of renal hyperfiltration. In this randomized, double-blind, placebo-controlled, cross-over trial, measurements were obtained following each of the 4 treatment phases: 1) no treatment, 2) 4-week ramipril treatment alone, 3) 4-week empagliflozin-ramipril combination treatment, and 4) 4-week placebo-ramipril combination treatment. The primary endpoint was GFR after empagliflozin-ramipril treatment compared to placebo-ramipril. At the end of each study phase the following measurements were performed under clamped euglycemia (4-6 mmol/L) : inulin (GFR) and paraaminohippurate (effective renal plasma flow, ERPF) clearances, tubular sodium handling, ambulatory blood pressure, arterial stiffness, heart rate variability, non-invasive cardiac output monitoring, plasma and urine biochemistry. Empagliflozin-ramipril treatment resulted in an 8ml/min/1.73m2 lower GFR (p=0.0061) , lower absolute proximal fluid reabsorption rate (p=0.0092) , lower absolute proximal sodium reabsorption rate (p=0.0056) , and lower urinary 8-isoprostane (p=0.0084) relative to placebo-ramipril treatment. Empagliflozin-ramipril treatment resulted in additive blood pressure lowering effects (SBP p=0.0112; DBP p=0.0032) and a lower total peripheral resistance (p=0.0368) . There were no other significant changes observed with the addition of empagliflozin. SGLT2i-ACEi combination treatment resulted in an expected GFR “dip”, suppression of oxidative stress markers, and additive declines in blood pressure and total peripheral resistance in this mechanistic study. These changes are consistent with a protective physiological profile characterized by the lowering of intraglomerular pressure and related cardiorenal risk when adding an SGLT2i to conservative therapy. Disclosure Y. Lytvyn: None. K. Kimura: Employee; 3Boehringer Ingelheim Canada Ltd./Ltée. N. Peter: Employee; Boehringer Ingelheim Pharma GmbH &amp; Co.KG. V.S. Lai: Advisory Panel; Baxter. J. Tse: None. L. Cham: None. B.A. Perkins: Advisory Panel; Abbott Diabetes, Insulet Corporation, Sanofi. Board Member; Novo Nordisk. Research Support; BMO Bank of Montreal, Novo Nordisk. Other Relationship; Abbott Diabetes, Insulet Corporation, Medtronic, Novo Nordisk. N. Soleymanlou: Employee; Boehringer Ingelheim Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals Inc. D. Cherney: Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research &amp; Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk, Mitsubishi Tanabe Pharma Corporation, Sanofi. Funding Boehringer Ingelheim and CIHR, Diabetes Canada and the Heart and Stroke Richard Lewar Centre of Excellence and the Heart and Stroke Foundation of Canada

Renal negative pressure treatment as a novel therapy for heart failure-induced renal dysfunction.

Congestion is the primary pathophysiological lesion in most heart failure (HF) hospitalizations. Renal congestion increases renal tubular pressure, reducing glomerular filtration rate (GFR) and diuresis. Because each nephron is a fluid-filled column, renal negative pressure therapy (rNPT) applied to the urinary collecting system should reduce tubular pressure, potentially improving kidney function. We evaluated the renal response to rNPT in congestive HF. Ten anesthetized ∼80-kg pigs underwent instrumentation with bilateral renal pelvic JuxtaFlow catheters. GFR was determined by iothalamate clearance (mGFR) and renal plasma flow (RPF) by para-aminohippurate clearance. Each animal served as its own control with randomization of left versus right kidney to -30 mmHg rNPT or no rNPT. mGFR and RPF were measured simultaneously from the rNPT and no rNPT kidney. Congestive HF was induced via cardiac tamponade maintaining central venous pressure at 20-22.5 mmHg throughout the experiment. Before HF induction, rNPT increased natriuresis, diuresis, and mGFR compared with the control kidney (P < 0.001 for all). Natriuresis, diuresis, and mGFR decreased following HF (P < 0.001 for all) but were higher in rNPT kidney versus control (P < 0.001 for all). RPF decreased during HF (P < 0.001) without significant differences between rNPT treatments. During HF, the rNPT kidney had similar diuresis and natriuresis (P > 0.5 for both) and higher fractional excretion of sodium (P = 0.001) compared with the non-rNPT kidney in the no HF period. In conclusion, rNPT resulted in significantly increased diuresis, natriuresis, and mGFR, with or without experimental HF. rNPT improved key renal parameters of the congested cardiorenal phenotype.

Application of dynamic contrast enhanced ultrasound in the assessment of kidney diseases.

Many forms of acute and chronic disease are linked to changes in renal blood flow, perfusion, vascular density and hypoxia, but there are no readily available methods to assess these parameters in clinical practice. Dynamic contrast enhanced ultrasound (DCE-US) is a method that provides quantitative assessments of organ perfusion without ionising radiation or risk of nephrotoxicity. It can be performed at the bedside and is suitable for repeated measurements. The purpose of this review is to provide updates from recent publications on the utility of DCE-US in the diagnosis or assessment of renal disease, excluding the evaluation of benign or malignant renal masses. DCE-US has been applied in clinical studies of acute kidney injury (AKI), renal transplantation, chronic kidney disease (CKD), diabetic kidney disease and to determine acute effects of pharmacological agents on renal haemodynamics. DCE-US can detect changes in renal perfusion across these clinical scenarios and can differentiate healthy controls from those with CKD. In sepsis, reduced DCE-US measures of perfusion may indicate those at increased risk of developing AKI, but this requires confirmation in larger studies as there can be wide individual variation in perfusion measures in acutely unwell patients. Recent studies in transplantation have not provided robust evidence to show that DCE-US can differentiate between different causes of graft dysfunction, although it may show more promise as a prognostic indicator of graft function 1 year after transplant. DCE-US can detect acute haemodynamic changes in response to medication that correlate with changes in renal plasma flow as measured by para-aminohippurate clearance. DCE-US shows promise and has a number of advantages that make it suitable for the assessment of patients with various forms of kidney disease. However, further research is required to evidence its reproducibility and utility before clinical use can be advocated.

The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve hard renal outcomes in type 2 diabetes. This is possibly explained by the fact that SGLT2i normalize the measured glomerular filtration rate (mGFR) by increasing renal vascular resistance, as was shown in young people with type 1 diabetes and glomerular hyperfiltration. Therefore, we compared the renal hemodynamic effects of dapagliflozin with gliclazide in type 2 diabetes. The mGFR and effective renal plasma flow were assessed using inulin and para-aminohippurate clearances in the fasted state, during clamped euglycemia (5 mmol/L) and during clamped hyperglycemia (15 mmol/L). Filtration fraction and renal vascular resistance were calculated. Additionally, factors known to modulate renal hemodynamics were measured. In 44 people with type 2 diabetes on metformin monotherapy (Hemoglobin A1c 7.4%, mGFR 113 mL/min), dapagliflozin versus gliclazide reduced mGFR by 5, 10, and 12 mL/min in the consecutive phases while both agents similarly improved Hemoglobin A1c (-0.48% vs -0.65%). Dapagliflozin also reduced filtration fraction without increasing renal vascular resistance, and increased urinary adenosine and prostaglandin concentrations. Gliclazide did not consistently alter renal hemodynamic parameters. Thus, beyond glucose control, SGLT2i reduce mGFR and filtration fraction in type 2 diabetes. The fact that renal vascular resistance was not increased by dapagliflozin suggests that this is due to post-glomerular vasodilation rather than pre-glomerular vasoconstriction.

538-P: Copeptin and Renin Angiotensin Aldosterone System (RAAS) Activation in Long-Standing Type 1 Diabetes (T1D)

It remains unclear why some individuals with long-standing T1D develop diabetic kidney disease (DKD) while others do not (DKD resistors). Vasopressin and its surrogate copeptin have been implicated in the pathogenesis of DKD. We hypothesized that DKD resistors would be distinguished from those with DKD by copeptin concentrations. Renal hemodynamic function, including renal vascular resistance (RVR), was measured by inulin and para-aminohippurate clearance at baseline and after intravenous infusion of angiotensin II as a measure of RAAS activation in 75 participants (65±8 years, HbA1c 7.4±0.8%) with prolonged T1D durations (≥50 years) and in equal numbers of nondiabetic controls (66±8 years). Copeptin was measured by B·R·A·H·M·S proAVP copeptin KRYPTOR assay. Participants with T1D were categorized as DKD resistors (n=50) if they had eGFR ≥60 ml/min/1.73 m2 and 24-hour urine albumin excretion (UAE) &amp;lt;30 mg/d, and as DKD (n=25) if they had eGFR &amp;lt;60 ml/min/1.73 m2 or 24-hour UAE &amp;gt;30 mg/d at their screening visit. Multivariable linear regression (adjusted for age, sex and HbA1c) was used to evaluate the relationships with copeptin. DKD resistors had lower copeptin (least square geometric means, 95% CI: 4.0 [3.4-4.8] pmol/l) compared to those with DKD (5.8 [4.5-7.6] pmol/l, p=0.02) and the nondiabetic controls (4.8 [4.1-5.5] pmol/l, p=0.01) adjusting for age, sex and HbA1c. In T1D, copeptin inversely associated with GFR (adjusted β±SE: -8.0±3.2, p=0.02) and positively with renin concentration (50.3±24.9, p=0.049) after multivariable adjustments. These relationships were not evident in nondiabetic controls. Further, copeptin inversely associated with change in RVR following exogenous angiotensin II only in participants with T1D (adjusted β±SE: -6.9±3.4, p=0.04). In longstanding T1D, copeptin associated with intrarenal RAAS activation and renal hemodynamic function, suggesting a possible interplay between vasopressin and RAAS in the pathogenesis of DKD. Disclosure P. Bjornstad: Advisory Panel; Self; Horizon, XORTX. Consultant; Self; Bayer US, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company. J.A. Lovshin: Consultant; Self; Eli Lilly and Company, Intarcia Therapeutics, Inc., Prometic Life Sciences Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. Y. Lytvyn: None. P. Wiromrat: None. L.T. Chung: None. C.L. Vinovskis: None. L. Lovblom: None. G. Boulet: Other Relationship; Self; Medtronic. V.S. Lai: None. J.M. Tse: None. L. Cham: None. A. Orszag: None. A. Weisman: None. H.A. Keenan: Employee; Self; Sanofi Genzyme. M.H. Brent: Advisory Panel; Self; AbbVie Inc., Bayer Canada, Novartis Canada. Research Support; Self; Bayer Canada, Novartis Canada, Roche Canada. N. Paul: Consultant; Self; Bayer AG. V. Bril: Advisory Panel; Self; Akcea Therapeutics, Alexion Pharmaceuticals, Inc., Alnylam, CSL Behring. Consultant; Self; Pfizer Inc. Research Support; Self; Baxter, Biogen, Grifols, UCB, Inc. B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. Funding JDRF (17-2013-312, 2-SRA-2018-627-M-B)

243-OR: ADA Presidents' Select Abstract: Dapagliflozin Reduces Measured GFR by Reducing Renal Efferent Arteriolar Resistance in Type 2 Diabetes

Introduction: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) improve hard renal outcomes in type 2 diabetes (T2D) patients. An acute and reversible drop in eGFR that stabilizes over time, as with RAS inhibitors, suggests involvement of a beneficial renal hemodynamic mechanism. In hyperfiltering T1D patients, SGLT2i lowered GFR by increasing afferent arteriolar resistance, possibly by activating tubuloglomerular feedback. We studied the renal hemodynamic effects of SGLT2i dapagliflozin in T2D patients like those included in recent outcome trials. Methods: Forty-four T2D patients on metformin monotherapy, (62.9±7.0 years, HbA1c 7.38±0.63%, GFR 113±19 mL/min) were randomized to 12 weeks dapagliflozin 10mg (DAPA, n=24) or gliclazide 30mg (GLIC, n=20) QD to achieve glycemic equipoise. At baseline and week 12, GFR and renal plasma flow (RPF) were measured by gold-standard inulin and para-aminohippurate clearances. The measurements were performed 1) in the fasting state, 2) during clamped euglycemia (90 mg/dL) and 3) hyperglycemia (270 mg/dL). Renal vascular resistance (RVR) and filtration fraction (FF) were calculated using GFR, RPF, Ht and MAP. Afferent and efferent arteriolar resistances were estimated by Gomez’ equations. Results: HbA1C decreased similarly (0.47% with DAPA and 0.65% with GLIC; p=ns), while only DAPA significantly reduced MAP by approximately 6 mmHg. DAPA reduced GFR during all three conditions by 8.9 (p&amp;lt;0.01), 9.0 (p=0.01) and 13.4 mL/min (p&amp;lt;0.001), respectively, without altering RPF, thus also reducing FF. Importantly, DAPA lowered RVR and efferent arteriolar resistance. GLIC did not alter any renal hemodynamic variables. Conclusion: We confirm that SGLT2i induces beneficial renal hemodynamic changes in T2D beyond glycemic control that are characterized by reduced GFR and FF. However, in contrast to standing opinion, this is mediated by efferent arteriolar dilation rather than afferent arteriolar constriction. Disclosure E.J. van Bommel: None. M.A. Muskiet: Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi. M.J. van Baar: None. M.H. Kramer: None. M. Nieuwdorp: Advisory Panel; Self; Caelus health. J.A. Joles: None. D.H. van Raalte: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp., Sanofi. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp., Sanofi. Funding AstraZeneca Nederland BV

Retinopathy and RAAS Activation: Results From the Canadian Study of Longevity in Type 1 Diabetes.

The importance of renin-angiotensin-aldosterone system (RAAS) activation in retinopathy for long-standing diabetes is not well understood. We determined retinopathy stage and evaluated associations with other vascular complications before and after physiological RAAS activation in adults with long-standing (≥50 years duration) type 1 diabetes. Participants underwent retinal examination by digital funduscopic photography and optical coherence tomography and were classified as having nonproliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), or no diabetic retinopathy (NDR) with or without diabetic macular edema (DME). Neuropathy was measured by clinical neuropathy examination scores, electrophysiologically, and by corneal confocal microscopy. Renal function was measured by inulin and para-aminohippurate clearance methods. Arterial stiffness was measured by applanation tonometry. Renal function, blood pressure, and arterial stiffness were measured before and after RAAS activation with angiotensin II (ANGII). Associations were determined using linear regression. Twelve (16%) of the 75 participants had NDR, 24 (32%) had NPDR, and 39 (52%) had PDR. A low overall prevalence of DME (4%) was observed. Those with PDR had worse nerve function and reduced corneal nerve density, were more likely to have macrovascular disease, and had increased arterial stiffness in response to ANGII compared with those with NPDR or NDR. Prevalence of kidney disease or renal hemodynamic function did not differ by retinopathy status. PDR was associated with neuropathy severity and cardiovascular and peripheral vascular disease. In those with PDR, RAAS activation may be linked to vascular stiffening, an effect that persists in long-standing type 1 diabetes.

Atherosclerosis and Microvascular Complications: Results From the Canadian Study of Longevity in Type 1 Diabetes.

Type 1 diabetes carries a significant risk for cardiovascular mortality, but it is unclear how atherosclerosis associates with microvascular complications. We aimed to determine the relationships between atherosclerotic burden and neuropathy, retinopathy, and diabetic kidney disease (DKD) in adults with a ≥50-year history of type 1 diabetes. Adults with type 1 diabetes (n = 69) underwent coronary artery calcification (CAC) volume scoring by wide-volume computerized tomography. Microvascular complications were graded as follows: neuropathy by clinical assessment, electrophysiology, vibration and cooling detection thresholds, heart rate variability, and corneal confocal microscopy; retinopathy by ultra-wide-field retinal imaging; and DKD by renal hemodynamic function measured by inulin and para-aminohippurate clearance at baseline and after intravenous infusion of angiotensin II. The cohort was dichotomized to high (≥300 Agatston units [AU]) or low (<300 AU) CAC and was stratified by diabetes status. A comparator group without diabetes (n = 73) matched for age and sex also underwent all study procedures except for retinal imaging. CAC scores were higher in participants with type 1 diabetes (median Agatston score 1,000 [interquartile range = 222, 2,373] AU vs. 1 [0.75] AU in comparators, P < 0.001). In participants with type 1 diabetes, high CAC scores associated with markers of neuropathy and retinopathy, but not with DKD, or renal hemodynamic function at baseline or in response to angiotensin II. The presence of high CAC in adults with longstanding type 1 diabetes was associated with large nerve fiber neuropathy and retinopathy but not with renal hemodynamic function, suggesting that neuropathy, retinopathy, and macrovascular calcification share common risk factors.

The Relationships between Retinopathy and Other Vascular Complications in Adults with Long-Standing Diabetes—Results from the Canadian Study of Longevity in Type 1 Diabetes (T1D)

We aimed to measure the prevalence of retinopathy in a T1D cohort of 75 adults with T1D duration of ≥50 years, and to determine association with other vascular complications. Participants underwent ultra-widefield retinal imaging and optimal coherence tomography. Neuropathy was characterized by electrophysiology and corneal confocal microscopy. Intrarenal hemodynamic function was determined by inulin and para-aminohippurate clearance, and arterial stiffness was measured by applanation tonometry, both at baseline and in responses to intravenous angiotensin II (ANGII). Participants were classified as having no diabetic retinopathy (ⱷDR), non-proliferative (NPDR), or proliferative (PDR), and associations were determined using multivariable linear regression adjusting for age, sex, and HbA1c. Thirty-nine (52%) participants had PDR, 24 (32%) had NPDR, and 12 (16%) had ⱷDR. Those without retinopathy had lower HbA1c vs. those with NDPR and PDR (6.7±0.6% vs. 7.4±0.7% and 7.5±0.9%, p=0.019). PDR was associated with lower corneal nerve fibre density, worse electrophysiology, and a greater number of signs and symptoms of neuropathy, but not with intrarenal hemodynamic function. Retinopathy severity was associated with greater response to ANGII for carotid-radial pulse wave velocity (mean change -4.9±11.4% vs. 8.2±18.5% vs. 12.9±20.2% for ⱷDR, NPDR, and PDR respectively, p=0.043). In longstanding T1D, retinopathy associated strongly with neuropathy and arterial stiffening, but not with renal hemodynamic function. Greater understanding of the co-occurrence of microvascular complications in patients with T1D, and relationships with macrovascular abnormalities such as arterial stiffness, may improve early detection and management of diabetes-related diseases. Disclosure J.A. Lovshin: Other Relationship; Self; AstraZeneca. Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Sanofi, Merck Sharp &amp; Dohme Corp.. Other Relationship; Self; Novo Nordisk Inc.. L. Lovblom: None. P. Bjornstad: Consultant; Self; Boehringer Ingelheim GmbH. Y. Lytvyn: None. G. Boulet: Advisory Panel; Self; Medtronic, Sanofi, Novo Nordisk Inc.. Other Relationship; Self; Janssen Global Services, LLC., Abbott. A. Weisman: None. V.S. Lai: None. J.M. Tse: None. L. Cham: None. A. Orszag: None. H.A. Keenan: Research Support; Self; Sanofi. Employee; Self; Sanofi Genzyme. N. Paul: None. V. Bril: Consultant; Self; Alexion Pharmaceuticals, Inc.. Research Support; Self; CSL Behring, Grifols. Advisory Panel; Self; CSL Behring. Consultant; Self; Grifols. Research Support; Self; Shire. Advisory Panel; Self; Pfizer Inc. M.H. Brent: Research Support; Self; Novartis Canada. Advisory Panel; Self; Novartis Canada. Research Support; Self; Bayer Canada. Advisory Panel; Self; Bayer Canada, Allergan Canada. Research Support; Self; Roche Canada. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc. D. Cherney: Consultant; Self; AbbVie Inc.. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company. Consultant; Self; Sanofi. Other Relationship; Self; Merck &amp; Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. Other Relationship; Self; Janssen Pharmaceuticals, Inc..

A randomized intervention study to evaluate the effect of calcitriol therapy on the renin-angiotensin system in diabetes.

Background:Prior studies suggest that vitamin D therapy may decrease cardiovascular disease risk in type 2 diabetes (T2DM) by lowering renin-angiotensin system (RAS) activity. However, randomized human intervention studies to evaluate the effect of vitamin D receptor (VDR) agonists on RAS activity are lacking.Objective:The objective of this article is to investigate the effect of direct VDR activation with calcitriol on circulating RAS activity and vascular hemodynamics in T2DM.Methods:A randomized, double-blinded, and placebo-controlled study wherein 18 participants with well-controlled T2DM without chronic kidney disease (CKD) were administered calcitriol or placebo for three weeks was conducted. Outcome measures included plasma renin activity (PRA), serum and urinary aldosterone, mean arterial pressure (MAP) before and after an infusion of angiotensin II, and renal plasma flow (RPF) via para-aminohippurate clearance.Results:Despite an increase in 1,25(OH)2D with calcitriol administration (45.4 to 61.8 pg/ml, p = 0.03) and no change with placebo, there were no significant differences in PRA, serum or urinary aldosterone, baseline and angiotensin II-stimulated MAP, or basal and angiotensin II-stimulated RPF between interventions.Conclusion:In this randomized and placebo-controlled study in participants with T2DM without CKD, calcitriol therapy to raise 1,25(OH)2D levels, when compared with placebo, did not significantly change circulating RAS activity or vascular hemodynamics.

U-shaped relationship between serum uric acid levels and intrarenal hemodynamic parameters in healthy subjects.

Hyperuricemia has been reported to affect renal hemodynamics. In a recent study, both low and high levels of serum uric acid (SUA) were found to be associated with loss of kidney function. The goal of this study was to evaluate the relationship between SUA levels and intrarenal hemodynamic parameters in healthy subjects, using plasma clearance of para-aminohippurate (CPAH) and inulin (Cin). Renal and glomerular hemodynamics were evaluated by simultaneous measurements of CPAH and Cin in 48 healthy subjects (54.6 ± 13.4 yr). Intrarenal hemodynamic parameters, including efferent and afferent (Ra) arteriolar resistance, were calculated using Gómez's formulas. Relationships of SUA levels with these intrarenal hemodynamic parameters were examined. In quadratic regression analysis, SUA levels had a significant inverse U-shaped relationship with Cin (P < 0.0001, R2 = 0.350) and CPAH (P = 0.0093, R2 = 0.188) and a U-shaped relationship with Ra (P = 0.0011, R2 = 0.262). In multiple regression analysis with normal (3.5-6.0 mg/dl) and mildly low or high (<3.5 or >6.0 mg/dl) SUA levels entered as dummy variables of zero and one, respectively, mildly low or high SUA levels were significantly and independently associated with Ra (β = 0.230, P = 0.0403) after adjustment for several factors (R2 = 0.597, P < 0.0001). Both mild hyperuricemia and mild hypouricemia are significantly associated with increased Ra, although weakly. The increase in Ra in subjects with mild hyperuricemia or hypouricemia may be related to renal hemodynamic abnormalities, possibly leading to a decline in renal function.

Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial.

Aims/hypothesisThis study aimed to investigate the acute renal effects of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide in type 2 diabetes patients.MethodsWe included overweight (BMI 25–40 kg/m2) men and postmenopausal women, aged 35–75 years with type 2 diabetes (HbA1c 48–75 mmol/mol; 6.5–9.0%) and estimated GFR ≥ 60 ml min−1 1.73 m−2. Exenatide or placebo (NaCl solution, 154 mmol/l) was administrated intravenously in an acute, randomised, double-blind, placebo-controlled trial conducted at the Diabetes Center VU University Medical Center (VUMC). GFR (primary endpoint) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance, respectively, based on timed urine sampling. Filtration fraction (FF) and effective renal vascular resistance (ERVR) were calculated, and glomerular hydrostatic pressure (PGLO) and vascular resistance of the afferent (RA) and efferent (RE) renal arteriole were estimated. Tubular function was assessed by absolute and fractional excretion of sodium (FENa), potassium (FEK) and urea (FEU), in addition to urine osmolality, pH and free water clearance. Renal damage markers, BP and plasma glucose were also determined.ResultsOf the 57 patients randomised by computer, 52 were included in the final analyses. Exenatide (n = 24) did not affect GFR (mean difference +2 ± 3 ml min−1 1.73 m−2, p = 0.489), ERPF, FF, ERVR or PGLO, compared with placebo (n = 28). Exenatide increased RA (p < 0.05), but did not change RE. Exenatide increased FENa, FEK, urine osmolality and pH, while FEU, urinary flow and free water clearance were decreased (all p < 0.05). Osmolar clearance and renal damage makers were not affected. Diastolic BP and mean arterial pressure increased by 3 ± 1 and 6 ± 2 mmHg, respectively, whereas plasma glucose decreased by 1.4 ± 0.1 mmol/l (all p < 0.05).Conclusions/interpretationExenatide infusion does not acutely affect renal haemodynamics in overweight type 2 diabetes patients at normal filtration levels. Furthermore, acute GLP-1RA administration increases proximal sodium excretion in these patients.Trial registrationClincialTrials.gov NCT01744236FundingThe research leading to these results has been funded from: (1) the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 282521 – the SAFEGUARD project; and (2) the Dutch Kidney Foundation, under grant agreement IP12.87.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3938-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Acute hemodynamic and renal effects of glucagon-like peptide 1 analog and dipeptidyl peptidase-4 inhibitor in rats

BackgroundGlucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase-4 (DPP4) inhibitors are a newer class of antidiabetics named as incretin-based therapy. In addition to the homeostatic control of glucose, the incretin-based therapy has shown beneficial effects on the cardiovascular system in preclinical and clinical studies. However, there is limited information on their renal effects. To this end, we assessed the acute hemodynamic and renal effects of a GLP-1 analog, Liraglutide, and a DPP4 inhibitor, MK-0626.MethodsExperiments were performed in anesthetized male Sprague–Dawley rats. Three ascending doses of Liraglutide (3, 9, and 27 nmol/kg/h) or MK-0626 (1 mg/kg) with or without GLP-1 peptide (2.4, 4.8, or 9.6 pmol/kg/min) were administered. Blood pressure (BP) and heart rate (HR) were recorded from an indwelling catheter. Glomerular filtration rate (GFR) and renal blood flow (RBF) were assessed by inulin and para-aminohippurate clearance, respectively. Renal excretory function was assessed in metabolic studies.ResultsBoth Liraglutide and MK-0626 plus GLP-1 evoked significant diuretic and natriuretic responses and increased GFR. MK-0626 alone increased RBF. Liraglutide at 27 nmol//kg/h and MK-0626 plus GLP-1 at 9.6 pmol/kg/min also increased HR, whereas BP was not affected.ConclusionThe results of the present study demonstrated that a GLP-1 analog and a DPP4 inhibitor may have beneficial effects on renal sodium and water handling. Additionally, the DPP4 inhibitor, MK-0626, favorably affects renal hemodynamics by increasing RBF. However, exceedingly high levels of GLP-1 receptor agonists may adversely affect the cardiovascular system in acute setting, as demonstrated by an acute increase in HR.

Evaluation of the effect of Boerhavia diffusa on gentamicin-induced nephrotoxicity in rats

Background:Ayurvedic literature claims that Boerhavia diffusa possesses rejuvenative properties especially related to the urinary system.Objective:To evaluate effect of aqueous extract of root of Boerhavia diffusa in gentamicin-induced nephrotoxicity in rats.Materials and Methods:Study was conducted in two parts, using 40 rats in each part. Rats were equally divided into five groups for each part. Group 1: Normal control, Group 2: Disease control and Groups 3, 4, and 5: α-lipoic acid (ALA) and 200 and 400 mg/kg of B. diffusa, respectively. All groups, except Group 1, concomitantly received gentamicin 150 mg/kg/day for 10 days. Parameters measured in part I were blood urea nitrogen (BUN), serum creatinine, kidney malondialdehyde (MDA), and glutathione (GSH) levels, kidney injury on histopathology; in part II, paraaminohippurate (PAH) clearance.Statistical Analysis:Mean ± SD of body weight, creatinine, BUN, MDA, GSH and PAH clearance were compared using parametric tests. Median histopathology scores were compared using Kruskal–Wallis test. ‘P’ value of < 0.05 was considered significant.Results:High dose of gentamicin caused significant elevation in BUN, serum creatinine and kidney MDA, fall in kidney GSH and histopathological damage in disease control group as compared with normal control (P < 0.05). Treatment with B. diffusa prevented changes in above parameters, comparable to ALA. Effects of both doses of B. diffusa were significantly better than disease control (P < 0.05).B. diffusa did not show significant improvement in PAH clearance, which was reduced due to gentamicin damage.Conclusion:B. diffusa exerted protection against structural and functional damage induced by gentamicin possibly due to its antioxidant properties.

Shock wave lithotripsy does not impair renal function in a Swine model of metabolic syndrome.

To determine whether shock wave lithotripsy (SWL) may be a risk factor for renal functional impairment in a swine model of metabolic syndrome (MetS). Nine-month-old female Ossabaw pigs were fed an excess calorie atherogenic diet to induce MetS. At 15 months of age, the MetS pigs were treated with 2000 SWs or an overtreatment dose of 4000 SWs targeted at the upper pole calyx of the left kidney (24 kV at 120 SWs/min using the unmodified Dornier HM3 lithotripter; n=5-6 per treatment group). Serum creatinine (Cr) and blood urea nitrogen (BUN) levels were measured in conscious pigs before and ∼60 days after SWL to provide a qualitative assessment of how well both kidneys were filtering (glomerular filtration rate [GFR]). Bilateral renal function was assessed at ∼65 days post-SWL in anesthetized pigs with GFR and effective renal plasma flow (ERPF) quantified by the renal clearance of inulin and para-amino hippurate, respectively. Cr and BUN values were within normal limits before SWL and remained unchanged after lithotripsy in both the 2000 SW- and 4000 SW-treated pigs. GFR and ERPF of kidneys treated with SWL at either SW dose were similar to the contralateral nontreated kidney. Chronic histological changes in the SW-treated pole of the kidney included interstitial fibrosis, sclerotic glomeruli, and dilated and atrophic tubules. Our results are consistent with the view that a single SWL session does not result in renal impairment, even in the presence of MetS.

Differential effect of T-type voltage-gated Ca2+ channel disruption on renal plasma flow and glomerular filtration rate in vivo.

Voltage-gated Ca(2+) (Cav) channels play an essential role in the regulation of renal blood flow and glomerular filtration rate (GFR). Because T-type Cav channels are differentially expressed in pre- and postglomerular vessels, it was hypothesized that they impact renal blood flow and GFR differentially. The question was addressed with the use of two T-type Cav knockout (Cav3.1(-/-) and Cav3.2(-/-)) mouse strains. Continuous recordings of blood pressure and heart rate, para-aminohippurate clearance (renal plasma flow), and inulin clearance (GFR) were performed in conscious, chronically catheterized, wild-type (WT) and Cav3.1(-/-) and Cav3.2(-/-) mice. The contractility of afferent and efferent arterioles was determined in isolated perfused blood vessels. Efferent arterioles from Cav3.2(-/-) mice constricted significantly more in response to a depolarization compared with WT mice. GFR was increased in Cav3.2(-/-) mice with no significant changes in renal plasma flow, heart rate, and blood pressure. Cav3.1(-/-) mice had a higher renal plasma flow compared with WT mice, whereas GFR was indistinguishable from WT mice. No difference in the concentration response to K(+) was observed in isolated afferent and efferent arterioles from Cav3.1(-/-) mice compared with WT mice. Heart rate was significantly lower in Cav3.1(-/-) mice compared with WT mice with no difference in blood pressure. T-type antagonists significantly inhibited the constriction of human intrarenal arteries in response to a small depolarization. In conclusion, Cav3.2 channels support dilatation of efferent arterioles and affect GFR, whereas Cav3.1 channels in vivo contribute to renal vascular resistance. It is suggested that endothelial and nerve localization of Cav3.2 and Cav3.1, respectively, may account for the observed effects.

Early determinants of acute kidney injury during experimental intra-abdominal sepsis

Sepsis-induced acute kidney injury (AKI) is an early and frequent organ dysfunction, associated with increased mortality. To evaluate the impact of macrohemodynamic and microcirculatory changes on renal function and histology during an experimental model of intra-abdominal sepsis. In 18 anaesthetized pigs, catheters were installed to measure hemodynamic parameters in the carotid, right renal and pulmonary arteries. After baseline assessment and stabilization, animals were randomly divided to receive and intra-abdominal infusion of autologous feces or saline. Animals were observed for 18 hours thereafter. In all septic animals, serum lactate levels increased, but only eight developed AKI (66%). These animals had higher creatinine and interleukin-6 levels, lower inulin and para-aminohippurate clearance (decreased glomerular filtration and renal plasma flow), and a negative lactate uptake. Septic animals with AKI had lower values of mean end arterial pressure, renal blood flow and kidney perfusion pressure, with an associated increase in kidney oxygen extraction. No tubular necrosis was observed in kidney histology. The reduction in renal blood flow and renal perfusion pressure were the main mechanisms associated with AKI, but were not associated with necrosis. Probably other mechanisms, such as microcirculatory vasoconstriction and inflammation also contributes to AKI development.