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Drivers of progression

INFLAMMATION + FIBROSIS

Learn more about how MINERALOCORTICOID RECEPTOR (MR) overactivation affects inflammation and fibrosis for CKD Patients with T2D1

US Mechanism of Disease (MOD) Video for CKD in T2D

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Explore the drivers of CKD progression and learn how mineralocorticoid receptor over activation triggers inflammation and fibrosis in the kidney. Watch the video to learn more about the mechanism of disease (MOD) for chronic kidney disease in type 2 diabetes. For more information, please visit https://www.ckd-t2d.com/.

 

    00:06 - 00:14: Chronic kidney disease (CKD) is a progressive condition that leads to end-stage kidney disease and, eventually, death.

    00:15 - 00:20: While CKD primarily affects kidney function, it also increases a patient’s risk of cardiovascular events.

    00:21 - 00:33: In fact, patients with CKD and type 2 diabetes, T2D, are 3 times more likely to die from a cardiovascular event than patients with T2D alone.

    00:34 - 00:37: Approximately 29 million Americans have T2D.

    00:38 - 00:40: Up to 40% of these patients also have CKD.

    00:41 - 01:05: In patients with CKD and T2D, 3 major categories of pathophysiological drivers promote CKD progression:

    • Hemodynamic factors, like increased blood pressure
    • Metabolic factors, like elevated blood glucose
    • Inflammatory and fibrotic factors, like proinflammatory and profibrotic proteins

    01:06 - 01:11: But one of these is [largely] unaddressed by the current standard of care: inflammation and fibrosis.

    01:12 - 01:18: In the kidneys, the mineralocorticoid receptor, or MR, is a key trigger of inflammation and fibrosis.

    01:19 - 01:24: Under normal conditions, MR signaling regulates electrolyte and fluid balance within the kidneys.

    01:25 - 01:32: The MR may become pathologically overactivated under certain conditions, like T2D.

    01:33 - 01:50: In patients with CKD and T2D, pathological MR activation in the kidneys is believed to be due to increased expression of the MR and its activators, which leads to the production of proinflammatory and profibrotic proteins, inducing inflammation and fibrosis within the kidneys.

    01:51 - 01:59: Renal inflammation and fibrosis gradually cause thickening and hardening of the glomeruli and injure the kidneys’ tubules.

    02:00 - 02:12: Over time, inflammation and fibrosis may lead to a progressive decline in kidney function, increasing the risk of end-stage kidney disease and cardiovascular events, like myocardial infarction or stroke.

    02:13 - 02:24: Because all 3 categories of drivers contribute to CKD progression, all 3 should be addressed in order to alter the course of CKD in type 2 diabetes.

    KIDNEY FILTRATION BECOMES COMPROMISED AS INFLAMMATION AND FIBROSIS PROGRESS

    MR overactivation is a major trigger of inflammation and fibrosis, contributing to a decline in kidney function1

    For patients with chronic kidney disease (CKD) in type 2 diabetes (T2D), also known as diabetic kidney disease, unaddressed inflammation and fibrosis can lead to a variety of cellular changes that permanently alter the structure of the kidney.2,3

    In the kidney, inflammation and fibrosis can lead to tissue expansion, increased pressure within the vasculature and internal structure, and eventually, to scarring that makes effective filtration increasingly difficult.2

    INFLAMMATORY AND FIBROTIC DAMAGE IS A MAJOR CONSEQUENCE OF MR OVERACTIVATION IN THE KIDNEY1

    Under normal conditions, MR signaling regulates electrolyte and fluid balance within the kidneys. 

    However, under certain conditions, like T2D, the MR within the kidney can become pathologically overactivated. As MR activators proliferate, the cell begins producing:

    • Proinflammatory proteins
    • Profibrotic proteins

    These factors eventually lead to inflammation and fibrosis in the kidneys, causing damage. Kidney damage increases the risk of a cardiovascular (CV) event and declining kidney function.

    Normal MR Function
    Normal MR Function image
    MR Overactivation
    MR Overactivation image

    MR overactivation contributes to the risk of CV DYSFUNCTION1

    There is evidence in both preclinical and clinical trials to support the connection of MR overactivation with CV dysfunction. Though CV risk is a reality from the beginning of CKD in T2D, as CKD progresses, there is an increased chance a patient might experience a cardiac event like myocardial infarction or stroke.

    Learn more about organ damage in CKD

    Learn more about organ damage in patients with CKD in T2D

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    References:

    • Bauersachs J, Jaisser F, Toto R. Hypertension. 2015;65(2):257-263.
    • Alicic RZ, Rooney MT, Tuttle KR. Clin J Am Soc Nephrol. 2017;12(12):2032-2045.
    • National Institute of Diabetes and Digestive and Kidney Diseases. Diabetic Kidney Disease. National Institutes of Health. Updated February 2017. Accessed September 16, 2020. https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/diabetic-kidney-disease.