Pathogenesis of Kidney Disease in Type 1 Diabetes: a Modern Kidney Biopsy Cohort (The PANDA Study)
University of Colorado, Denver
Summary
Diabetic kidney disease (DKD) occurs in up to 40% of people with type 1 diabetes (T1D), often leading to kidney failure and markedly magnifying risks of cardiovascular disease and premature death. Landmark T1D kidney biopsy studies identified the classic pathological lesions of DKD, which have been attributed largely to hyperglycemia. Recent advances in continuous glucose monitoring (CGM) and automated insulin delivery have facilitated improved glycemic control, but the residual risk of DKD continues to be high. In addition, obesity and insulin resistance (IR) have accompanied intensive glycemic therapy and may promote mitochondrial dysfunction and inflammation. Deciphering the molecular underpinnings of DKD in modern-day T1D and identifying modifiable risk factors could lead to more effective and targeted therapies to prevent DKD.
Description
The overall goal of this project is to characterize the molecular, morphometric, and metabolic features of DKD over the modern clinical course of T1D. The investigators hypothesize that perturbed kidney energetics and hypoxia are central metabolic pathways in the development of DKD. Kidney hypoxia stems from a mismatch between increased renal energy demand (e.g., increased glomerular filtration rate \[GFR\] and tubular reabsorption of sodium) and impaired substrate metabolism (e.g., IR and mitochondrial dysfunction) and results in activation of the hypoxia-inducible factor (HIF) system. Althou…
Eligibility
- Age range
- 18+ years
- Sex
- All
- Healthy volunteers
- No
Inclusion Criteria: * Age ≥ 18 years at enrollment (rationale: this study focuses on determinants of early DKD over the course of T1D in adults) * T1D duration \>5 years (rationale: DKD in T1D rarely manifests prior to 5 years of disease duration) * HbA1c \<11% (rationale: HbA1c ≥ 11% exceeds the average HbA1c at most academic center and would limiting the generalizability of our study findings) Exclusion Criteria: * T2D and monogenic diabetes (rationale: our study focuses on T1D) * Recent diabetic ketoacidosis, i.e., \<1 month (rationale: safety and insulin resistance and tubular dysfuncti…
Interventions
- DrugAminohippurate Sodium Inj 20% Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)
PAH (Basic Pharma, Geleen, Netherlands) has been used to measure ERPF in human research for 7 decades, and is very well tolerated and generally recognized as safe with low toxicity.
- DrugIohexol Inj 300 MG/ML Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
Iohexol (Omnipaque 300, GE Healthcare, Chicago, IL) is a nonionic, low osmolar contrast agent with a history of extensive use in Radiology practice (for contrast x-rays) that shares many qualities of an ideal GFR marker, like inulin, such as not being absorbed, metabolized, or secreted by the kidney.
Location
- Children's Hospital ColoradoAurora, Colorado