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Renal Hemodynamic Function and RAAS Activation Over the Natural History of Type 1 Diabetes
Yuliya Lytvyn1, Petter Bjornstad2, Julie A Lovshin3
1Division of Nephrology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
Rationale & Objective:
The renin-angiotensin-aldosterone system (RAAS) is associated with renal and cardiovascular disease in diabetes. Unfortunately, early RAAS blockade in patients with type 1 diabetes mellitus (T1DM) does not prevent the development of complications. We sought to examine the role of hyperfiltration and RAAS activation across a wide range of T1DM duration to better understand renal hemodynamic status in patients with T1DM.
Study Design:
Post hoc analysis of blood samples.
Setting & Participants:
148 Canadian patients with T1DM: 28 adolescents (aged 16.2±2.0 years), 54 young adults (25.4±5.6 years), and 66 older adults (65.7±7.5 years) studied in a clinical investigation unit.
Exposure:
Angiotensin II infusion (1ng/kg/min; a measure of RAAS activation) during a euglycemic clamp.
Outcomes:
Glomerular filtration rate measured using inulin clearance, effective renal plasma flow measured using para-aminohippurate, afferent (RA) and efferent (RE) arteriolar resistances, and glomerular hydrostatic pressure estimated using the Gomez equations.
Results:
In a stepwise fashion, glomerular filtration rate, effective renal plasma flow, and glomerular hydrostatic pressure were higher, while renal vascular resistance and RA were lower in adolescents versus young adults versus older adults. RE was similar in adolescents versus young adults but was higher in older adults. Angiotensin II resulted in blunted renal hemodynamic responses in older adults (renal vascular resistance increase of 3.3% ± 1.6% vs 4.9% ± 1.9% in adolescents; P<0.001), suggesting a state of enhanced RAAS activation.
Limitations:
Homogeneous study participants limit the generalizability of findings to other populations. Studying older adult participants with T1DM may be associated with a survivorship bias.
Conclusions:
A state of relatively low RAAS activity and predominant afferent dilation rather than efferent constriction characterize early adolescents and young adults with T1DM. This state of endogenous RAAS inactivity in early T1DM may explain why pharmacologic blockade of this neurohormonal system is often ineffective in reducing kidney disease progression in this setting. Older adults with long-standing T1DM who have predominant afferent constriction and RAAS activation may experience renoprotection from therapies that target the afferent arteriole. Further work is required to understand the potential role of non-RAAS pharmacologic agents that target RA in patients with early and long-standing T1DM.
Insights
Renin-angiotensin-aldosterone system (RAAS) activity differs in type 1 diabetes mellitus (T1DM) across age groups. Early T1DM shows low RAAS activity and afferent dilation, while long-standing T1DM exhibits afferent constriction and RAAS activation.
Area of Science:
- Nephrology
- Endocrinology
- Cardiovascular Medicine
Background:
- The renin-angiotensin-aldosterone system (RAAS) is implicated in diabetic kidney and cardiovascular disease.
- Early RAAS blockade in type 1 diabetes mellitus (T1DM) has not consistently prevented complications.
- Understanding RAAS activation and hyperfiltration across T1DM duration is crucial for managing renal hemodynamics.
Purpose of the Study:
- To investigate the role of hyperfiltration and RAAS activation in T1DM across different durations.
- To elucidate the renal hemodynamic status in patients with T1DM of varying disease durations.
Main Methods:
- A post hoc analysis of blood samples from 148 Canadian T1DM patients (adolescents, young adults, older adults).
- Angiotensin II infusion was used to measure RAAS activation during a euglycemic clamp.
- Glomerular filtration rate, effective renal plasma flow, arteriolar resistances, and glomerular hydrostatic pressure were assessed.
Main Results:
- Adolescents and young adults with T1DM exhibited higher glomerular filtration rate, effective renal plasma flow, and glomerular hydrostatic pressure, with lower renal vascular resistance and afferent arteriolar resistance (RA) compared to older adults.
- Older adults showed similar efferent arteriolar resistance (RE) to younger groups but higher overall.
- Angiotensin II infusion revealed blunted renal hemodynamic responses in older adults, indicating enhanced RAAS activation.
Conclusions:
- Early T1DM is characterized by low RAAS activity and afferent dilation, potentially explaining the limited efficacy of RAAS blockade.
- Older adults with long-standing T1DM display afferent constriction and heightened RAAS activation, suggesting potential benefit from therapies targeting the afferent arteriole.
- Further research is needed on non-RAAS agents targeting RA in T1DM patients with varying disease durations.
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