Remote Ischemic Conditioning for the Treatment of Diabetic Kidney Disease

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Устройство Remote ischemic conditioning
  RIC is a non-invasive therapy that performed by an electric auto-control device with cuff placed on arm. RIC procedures consist of five cycles of 5-min inflation (200 mmHg) and 5-min deflation of cuff on bilateral arm. The procedure will be performed twice daily for consecutive 6 months after enrollment.
• Устройство Sham remote ischemic conditioning
  Sham RIC will be performed by the same electric auto-control device with cuff placed on arm. Sham RIC procedures consist of five cycles of 5-min inflation (60 mmHg) and 5-min deflation of cuff on bilateral arm. The procedure will be performed twice daily for consecutive 6 months after enrollment.
• Препарат Standard medication therapy
  Standard medication therapy will be performed according to the national and international guidelines.

Первичные конечные точки

• The tolerability of RIC in patients with DKD [Срок оценки: 0-6 months]

Вторичные конечные точки (12)

• ΔSerum creatinine [Срок оценки: 0-6 months]
• ΔSerum Cystatin C [Срок оценки: 0-6 months]
• ΔHemoglobin [Срок оценки: 0-6 months]
• ΔSerum KIM-1 [Срок оценки: 0-6 months]
• ΔUrine microalbumin-creatinine ratio [Срок оценки: 0-6 months]
• ΔEstimated glomerular filtration rate [Срок оценки: 0-6 months]
• ΔSerum VEGF [Срок оценки: 0-6 months]
• ΔSerum HIF-1 [Срок оценки: 0-6 months]
• Δurine protein [Срок оценки: 0-6 months]
• Incidence of major adverse cerebral and cardiac events [Срок оценки: 0-6 months]
• Incidence of Kidney failure [Срок оценки: 0-6 months]
• Incidence of all-cause death [Срок оценки: 0-6 months]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

• Bello AK, Levin A, Tonelli M, Okpechi IG, Feehally J, Harris D, Jindal K, Salako BL, Rateb A, Osman MA, Qarni B, Saad S, Lunney M, Wiebe N, Ye F, Johnson DW. Assessment of Global Kidney Health Care Status. JAMA. 2017 May 9;317(18):1864-1881. doi: 10.1001/jama.2017.4046. PMID 28430830
• Wakashima T, Tanaka T, Fukui K, Komoda Y, Shinozaki Y, Kobayashi H, Matsuo A, Nangaku M. JTZ-951, an HIF prolyl hydroxylase inhibitor, suppresses renal interstitial fibroblast transformation and expression of fibrosis-related factors. Am J Physiol Renal Physiol. 2020 Jan 1;318(1):F14-F24. doi: 10.1152/ajprenal.00323.2019. Epub 2019 Oct 21. PMID 31630548
• Wang Y, Meng R, Song H, Liu G, Hua Y, Cui D, Zheng L, Feng W, Liebeskind DS, Fisher M, Ji X. Remote Ischemic Conditioning May Improve Outcomes of Patients With Cerebral Small-Vessel Disease. Stroke. 2017 Nov;48(11):3064-3072. doi: 10.1161/STROKEAHA.117.017691. Epub 2017 Oct 17. PMID 29042490
• Ekeloef S, Homilius M, Stilling M, Ekeloef P, Koyuncu S, Munster AB, Meyhoff CS, Gundel O, Holst-Knudsen J, Mathiesen O, Gogenur I. The effect of remote ischaemic preconditioning on myocardial injury in emergency hip fracture surgery (PIXIE trial): phase II randomised clinical trial. BMJ. 2019 Dec 4;367:l6395. doi: 10.1136/bmj.l6395. PMID 31801725
• Zarbock A, Schmidt C, Van Aken H, Wempe C, Martens S, Zahn PK, Wolf B, Goebel U, Schwer CI, Rosenberger P, Haeberle H, Gorlich D, Kellum JA, Meersch M; RenalRIPC Investigators. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA. 2015 Jun 2;313(21):2133-41. doi: 10.1001/jama.2015.4189. PMID 26024502
• Li H, Satriano J, Thomas JL, Miyamoto S, Sharma K, Pastor-Soler NM, Hallows KR, Singh P. Interactions between HIF-1alpha and AMPK in the regulation of cellular hypoxia adaptation in chronic kidney disease. Am J Physiol Renal Physiol. 2015 Sep 1;309(5):F414-28. doi: 10.1152/ajprenal.00463.2014. Epub 2015 Jul 1. PMID 26136559
• Wang L, Jia L, Huang S, Ren C, Yu Y, Wang Y, Zhao W, Ji X, Li S. Safety and efficacy of remote ischaemic preconditioning in diabetic kidney disease: a pilot randomised, parallel-arm, sham-controlled trial protocol. BMJ Open. 2025 Sep 3;15(9):e096851. doi: 10.1136/bmjopen-2024-096851. PMID 40903083

Идентификаторы

NCT: NCT06654921 · RIC-DKD

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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