Objective
The objective of our project is to understand how white blood cells become active by high sugars to damage kidney cells in people with T1D and early DKD. To accomplish this, we will accomplish the following, we will recruit 10 people with T1D and DKD who have good blood sugar control based on their sensor data, 10 people with T1D and DKD with less stringent blood sugar control, and 5 controls who have T1D and no DKD. We will do a blood draw from these people and study their white blood cells in the lab to test the following:
-We will find how a person's baseline blood sugars affect how their white blood cells respond to high sugars, and if this causes the white blood cells to damage kidney cells in the lab
-We will find proteins the white blood cells make in response to high sugars which can damage kidney cells
-We will find how high sugars cause white blood cells to become active
-We will test if treating white blood cells to compounds in the lab can reduce the monocyte response to high blood sugars, and prevent them from damaging kidney cells
-We will test if we can find a blood test that can reflect how white blood cells become active, so we know which people with T1D and DKD are at highest risk for kidney injury
Background Rationale
Current treatments for DKD in those with T1D can reduce the risk of kidney disease, but a high percentage of people still develop progressive DKD, which suggests there are other factors which these treatments do not address. White blood cells are known to be an important contributor to DKD in T1D, but we do not have known treatments to target them. We know factors such as high blood sugars can cause white blood cells to be active and go to the kidneys, where they cause damage to kidney cells and contribute to DKD. Much of our existing studies on white blood cells in DKD were done in animals, and we have a limited understanding of how they damage kidney cells in people. From our previous work, we found treating white blood cells to high sugars in the lab (300 mg/dl) caused these cells to be inflamed and release proteins which directly damaged kidney cells. Therefore, there is an urgent need to improve our understanding on how high sugars cause white blood cells to damage kidney cells so we can find treatments to prevent this damage, in order to reduce the residual risk of DKD in people with T1D.
Description of Project
The goal of our study is to understand how white blood cells contribute to diabetic kidney disease (DKD) in people with type 1 diabetes (T1D). Currently, we know that white blood cells are associated with DKD, but we do not understand how they can lead to kidney damage in people with T1D. We hope to gain this knowledge from our project so we can find new treatments which can prevent these cells from damaging the kidneys, thus reducing the risk of DKD in patients with T1D.
Anticipated Outcome
We predict people with T1D and DKD who have less tight blood sugar control will have more white blood cell inflammation and more damage to kidney cells in response to high sugars in the lab compared to white blood cells from people who have tighter blood sugar control. We expect these white blood cells become more active in response to high sugars to cause white blood cells to release proteins which directly damage kidney cells. We anticipate treating white blood cells to medications in the lab will reduce their inflammatory response to high sugars, thereby reducing damage to kidney cells.
Relevance to T1D
Our project is highly relevant to the field of T1D as DKD affects 30-40% of people with T1D, and is continuing to rise (1). From these people with DKD, up to 30% progress to end-stage kidney disease, which is a devastating complication (1). Despite our current standards of care medications to treat DKD, there is a high residual risk to develop DKD and have progression. This suggests there are additional factors which are not yet addressed by our current treatments. Though we know white blood cells can go to the kidneys and cause kidney injury which can contribute to DKD, none of our current treatments are known to prevent white blood cells from kidney damage. Our study will help improve our understanding of how white blood cells cause kidney damage, so we can find effective treatments to prevent this and reduce the residual risk of DKD in people with T1D.
(1) Rossing P, Groop P-H, Singh, R et al. Prevalence of Chronic Kidney Disease in Type 1 Diabetes Among Adults in the U.S. Diabetes Care. 2024;47(8):1395–1399