Renin-angiotensin-aldosterone system activation in long-standing type 1 diabetes

Abstract

Background: In type 1 diabetes (T1D), adjuvant treatment with inhibitors of the renin-angiotensin-aldosterone system (RAAS), which dilate the efferent arteriole, is associated with prevention of progressive albuminuria and renal dysfunction. Uncertainty still exists as to why some individuals with long-standing T1D develop diabetic kidney disease (DKD) while others do not (DKD resistors). We hypothesized that those with DKD would be distinguished from DKD resistors by the presence of RAAS activation.

Methods: Renal and systemic hemodynamic function was measured before and after exogenous RAAS stimulation by intravenous infusion of angiotensin II (ANGII) in 75 patients with prolonged T1D durations and in equal numbers of nondiabetic controls. The primary outcome was change in renal vascular resistance (RVR) in response to RAAS stimulation, a measure of endogenous RAAS activation.

Results: Those with DKD had less change in RVR following exogenous RAAS stimulation compared with DKD resistors or controls (19%, 29%, 31%, P = 0.008, DKD vs. DKD resistors), reflecting exaggerated endogenous renal RAAS activation. All T1D participants had similar changes in renal efferent arteroilar resistance (9% vs. 13%, P = 0.37) irrespective of DKD status, which reflected less change versus controls (20%, P = 0.03). In contrast, those with DKD exhibited comparatively less change in afferent arteriolar vascular resistance compared with DKD resistors or controls (33%, 48%, 48%, P = 0.031, DKD vs. DKD resistors), indicating higher endogenous RAAS activity.

Conclusion: In long-standing T1D, the intrarenal RAAS is exaggerated in DKD, which unexpectedly predominates at the afferent rather than the efferent arteriole, stimulating vasoconstriction.

Funding: JDRF operating grant 17-2013-312.

Keywords: Diabetes; Endocrinology; Nephrology.

Figure 1. Patient flow diagram.

Equal numbers of participants with T1D (n = 75) and age- and sex-matched controls (n = 75) were enrolled in this cross-sectional study. T1D participants were further classified into DKD resistors or DKD subgroups based on the presence of overt renal injury (DKD resistor = eGFR_MDRD ≥60 ml/min/1.73 m² and 24-hour urine albumin excretion <30 mg/d). Some participants were not eligible for exogenous administration of angiotensin II. The final analysis was per protocol (T1D, n = 62; controls, n = 74). DKD, diabetic kidney disease, eGFR_MDRD, estimated glomerular filtration rate modification of diet in renal disease; T1D, type 1 diabetes; V2, visit 2.

Figure 2. Percentage change in renal hemodynamic function in response to exogenous RAAS stimulation with ANGII.

Percentage change in RVR (A), R_A (B), and R_E (C) are shown for age- and sex-matched controls (n = 74), DKD resistors (n = 42), and DKD nonresistors (n = 20) at baseline, in response to low- and high-dose ANGII, and during recovery. Data represent mean ± SEM. ANGII, angiotensin II; RVR, renal vascular resistance; R_A, renal afferent arterial resistance; R_E, renal efferent arterial resistance. *P < 0.05, Student’s t test, for DKD resistors versus DKD.

Figure 3. Percentage change in systemic hemodynamic parameters response to exogenous RAAS stimulation with ANGII.

Percentage change in MAP (A) and heart rate (B) are shown for age- and sex-matched controls (n = 74), DKD resistors (n = 42), and DKD nonresistors (n = 20) at baseline, in response to low- and high-dose ANGII, and during recovery. Data represent mean ± SEM. ANGII, angiotensin II; MAP, mean arterial pressure. *P < 0.05, Student’s t test, for DKD resistors versus DKD.

Figure 4. Change in arterial stiffness in response to exogenous RAAS stimulation with ANGII.

Percentage change in radial (A) and carotid (B) AIx and percentage change in radial (C) and femoral (D) PWV are shown for age- and sex-matched controls (n = 74), DKD resistors (n = 42), and DKD nonresistors (n = 20) at baseline, in response to low- and high-dose ANGII, and during recovery. Data represent mean ± SEM. ANGII, angiotensin II; AIx, augmentation index; PWV, pulse wave velocity. *P < 0.05, Student’s t test, for DKD resistors versus DKD.

Figure 5. Endogenous RAAS activation in controls, DKD resistors, and DKD with T1D.

AT₁ receptors are predominately expressed at the renal efferent arteriole with less relative expression at the afferent arteriole. In controls, upon exogenous RAAS stimulation with intravenous infusion of ANGII, ANGII freely interacts with available AT₁ receptors at the afferent and efferent arterioles, initiating vasoconstrictive responses at the R_A and R_E, respectively. In T1D participants without DKD (DKD resistors), locally within the kidney there is relatively more endogenous intrarenal RAAS at baseline occupying AT₁ receptors (relative to controls), predominantly at the R_E compared with the R_A. Therefore, upon exogenous RAAS stimulation, ANGII can freely bind AT₁ receptors at the R_A, producing vasoconstriction to a similar degree as controls, but to a lesser degree at the R_E. In contrast, in participants with DKD, there is exaggerated presence of endogenous RAAS, both at the afferent and efferent arterioles at baseline, such that upon exogenous RAAS stimulation, there are fewer AT₁ receptors available for ANGII binding and therefore fewer vasoconstrictive changes relative to DKD resistors and controls predominantly at the R_A. ANGII, angiotensin II; DKD, diabetic kidney disease, R_A, renal afferent arteriolar vasoconstriction; RAAS, renin-angiotensin-aldosterone system; R_E, renal efferent arteriolar vasoconstriction; RVR, renal vascular resistance; T1D, type 1 diabetes.