Remote Ischemic Conditioning for the Treatment of Diabetic Kidney Disease

The Safety and Efficacy of Remote Ischemic Conditioning for the Treatment of Diabetic Kidney Disease: a Single-center Double-blinded Randomized Controlled Study

Chronic kidney disease (CKD) is a growing epidemic affecting 10% of the population worldwide. Significantly, diabetic kidney disease (DKD) is the main cause of CKD and affects approximately 40% of patients with diabetes. Approximately 10% of patients with early-stage CKD and approximately half of patients with advanced-stage CKD suffer progression to renal failure and require dialysis or transplantation to survive. Moreover, DKD progresses particularly rapidly and has a poor prognosis, accounting for almost 50% of end-stage renal disease (ESRD) cases. Dialysis in particular is a burdensome therapy associated with poor patient outcomes and high societal and economic costs. Clinical studies using RIP have demonstrated protection against ischemic target renal damage in a variety of acute and chronic clinical settings . In the renal setting, RIP performed in dialysis patients is known to abrogate brain, heart and liver ischemia occurring during hemodialysis treatments. RIP may play a role in reducing the incidence of cardiac surgery-associated acute kidney injury. However, whether RIP can improve the renal function of patients with DKD is unclear and is worthy of further study.

Our overarching hypothesis is that RIP, performed in DKD patients, could delay progression to renal failure by abrogating progressive ischemic damage in the failing kidney. The present proposal is a pilot study addressing this hypothesis and is aimed at generating proof-of-concept and feasibility data on the benefits of RIP in patients with DKD.

Chronic kidney disease (CKD) is a growing epidemic affecting 10% of the population worldwide. Significantly, diabetic kidney disease (DKD) is the main cause of CKD and affects approximately 40% of patients with diabetes. Approximately 10% of patients with early-stage CKD and approximately half of patients with advanced-stage CKD suffer progression to renal failure and require dialysis or transplantation to survive. Moreover, DKD progresses particularly rapidly and has a poor prognosis, accounting for almost 50% of end-stage renal disease (ESRD) cases. Dialysis in particular is a burdensome therapy associated with poor patient outcomes and high societal and economic costs. Strategies to prevent progression to renal failure focus on exquisite blood pressure control, renin-angiotensin-aldosterone system (RAAS) inhibition for proteinuria DKD, and glycemic control with the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in patients with diabetes. Even so, despite the optimization of these parameters, many high-risk DKD patients will progress to renal failure. Recurrent ischemic damage to the failing and fibrotic kidney appears to be one of the final common pathways of progressive kidney damage in late-stage DKD, irrespective of the original cause of kidney disease. Specific strategies to alter this pathway in DKD have not yet been developed. In this context, it is crucial to seek novel pharmaceutical or nonpharmaceutical approaches to optimize the treatment of DKD.

With the progression of DKD, renal interstitial fibrosis intensifies, leading to severe ischemia and hypoxia of kidney cells and ultimately leading to ESRD. Therefore, effectively delaying the process of renal fibrosis can slow or even reverse the process of DKD. Hypoxia is characterized by an insufficient supply of oxygen to organs, and hypoxia-inducible factor (HIF) regulates gene transcription in hypoxia. Appropriate renal hypoxia can activate HIF-1α and suppress HIF-2α, improving the ability of the kidney to adapt to hypoxia, reducing transforming growth factor (TGF)-β pathway activity and further inhibiting fibrosis development. Therefore, increasing the expression of HIF-1 in renal tissue may be a new method to delay renal interstitial fibrosis and the progression of DKD to ESRD. Previous studies have provided evidence that HIF-1α participates in remote ischemic preconditioning (RIP). HIF-1α levels are significantly increased in the peripheral blood after RIP is implemented. Therefore, we speculated that RIP may have a therapeutic effect on DKD.

Ischemic conditioning occurs when a transient episode of ischemia reduces the effect of a subsequent larger ischemic insult. Similar levels of protection can be achieved by RIP. RIP is a noninvasive physical therapy that induces remote vital organs to adapt to ischemia through repeated, short-term ischemia-reperfusion training on nonvital organs such as limbs, thereby improving their tolerance to ischemic injury and enabling them to withstand subsequent fatal ischemic events. Clinical studies using RIP have demonstrated protection against ischemic target renal damage in a variety of acute and chronic clinical settings. In the renal setting, RIP performed in dialysis patients is known to abrogate brain, heart and liver ischemia occurring during hemodialysis treatments. RIP may play a role in reducing the incidence of cardiac surgery-associated acute kidney injury. However, whether RIP can improve the renal function of patients with DKD is unclear and is worthy of further study.

Our overarching hypothesis is that RIP, performed in DKD patients, could delay progression to renal failure by abrogating progressive ischemic damage in the failing kidney. The present proposal is a pilot study addressing this hypothesis and is aimed at generating proof-of-concept and feasibility data on the benefits of RIP in patients with DKD.

Inclusion Criteria:

• History of type 2 diabetes and receiving at least 1 antidiabetic medication
• CKD at stage G3 or G4 (eGFR = 15-60 mL/min/1.73 m2)
• UACR ≥ 300 mg/g or urinary albumin excretion rate (UAER) ≥ 300 mg/24 h
• Patients are cognitively and physically capable and willing to interact with the device and perform self-measurements
• Ability to withstand 5 full minutes of cuff inflation during prescreening

Exclusion Criteria:

• Patients with New York Heart Association Class III or IV congestive heart failure at enrollment
• Patients with severe illness with an expected lifespan of less than 6 months
• Patients with a recent history (< 6 months) of continuous renal replacement therapy, malignant tumor, myocardial infarction, acute coronary syndrome, stroke, seizure, thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism), or a cerebrovascular accident
• Patients with known severe arterial disease of the extremities (ulcers, amputations, known symptomatic peripheral arterial disease)
• Patients at imminent risk of starting dialysis during the study period
• Patients residing in a long-term care facility
• Patients in another interventional trial that could influence the intervention or outcome of this trial