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Abstract: SA-PO376

Adaptive and Pathologic Mechanisms in Diabetic Kidney Disease: A Modeling Analysis

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 301 CKD: Risk Factors for Incidence and Progression


  • Mahato, Hari shankar, University of Georgia, Athens, Georgia, United States
  • Ahlström, Christine, AstraZeneca R&D, Mölndal, Sweden
  • Jansson-Lofmark, Rasmus, AstraZeneca R&D, Mölndal, Sweden
  • Helmlinger, Gabriel, AstraZeneca Pharmaceuticals, Waltham, Massachusetts, United States
  • Hallow, Melissa, University of Georgia, Athens, Georgia, United States

Translation from preclinical animal models to human diabetic kidney disease is challenging due to species differences in disease processes and timecourses. Quantitative systems models are helpful in understanding disease mechanisms and interspecies differences. We aimed to adapt a physiological model of human renal function to mice, to incorporate adaptive and pathologic mechanisms of diabetes and nephrectomy observed in the db/db uninephrectomized (UNX) mouse model, and to explore the response to clinically renoprotective drugs.


Some renal structural/functional characteristics are preserved across species (e.g. pressures, single nephron flow rates), while others differ markedly (e.g. nephron number, tubular lengths). We reparameterized a systems model of human renal hemodynamics to represent mice, and ensured appropriate phenotypic behavior (e.g. glomerular filtration rate [GFR], blood pressure). To model the adaptive and pathologic renal effects in kidney disease, we assumed that elevated glomerular capillary pressure causes 1) glomerular capillary hypertrophy, up to a limit, 2) podocyte damage and increased protein filtration, and 3) glomerulosclerosis. The renal consequences of 1) UNX, 2) increased blood glucose (and associated increased proximal reabsorption via SGLT) and sodium intake in db/db mice, and 3) the combination, was then simulated using experimental data to inform the model.


The model implicitly reproduced the GFR rise (hyperfiltration) observed in db/db mice when glucose and Na+ intake increased, as well as the compensatory increase in single nephron GFR to keep total GFR stableafter UNX. In both cases, glomerular hypertrophy normalized glomerular pressure, so that proteinuria was minimal, as observed experimentally. However, combining UNX with diabetes increased glomerular pressure beyond the adaptive capacity and caused overt progressive proteinuria. The model also reproduced the proteinuria reduction observed in with enalapril, eplerenone and dapagliflozin.


The systems model provides insight into adaptive and pathologic renal processes in db/db UNX mice. By simulating responses to therapies for which preclinical and clinical data is available, it may aid benchmarking for clinical translation.


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