Randomized Clinical Study to Analyse the Effects of Dapagliflozin on Renal Morphology and Renal Perfusion in Patients With Impaired Renal Function One Year After Kidney Transplantation
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 48
- 试验地点
- 2
- 主要终点
- renal morphology - fibroblasts
研究概览
简要总结
The aim of this study is to observe the mechanisms of dapagliflozin on the renal interstitial tissue and renal perfusion. For this purpose, renal transplanted patients as an excellent model of CKD and high cardiovascular risk (similar to patients in DAPA-CKD study) are included in this study.
The objectives of the study are to analyze the effects of dapagliflozin on renal morphology and renal perfusion in patients with impaired renal function one year after kidney transplantation. This is a randomized (1:1), single centre clinical study. Each patient will be randomly assigned in an unblinded fashion to 10 mg Dapagliflozin or not 9 months after transplantation. At least 48 patients will be randomized and included. The routine renal biopsy taken one year after kidney transplantation will allow us to determine the morphological integrity of peritubular fibroblasts, interstitial inflammatory cell density and investigate markers of inflammation, oxidative stress and nitic oxide synthase expression (iNOS).
详细描述
Chronic kidney disease (CKD) has a high prevalence globally and is a global health concern. CKD is associated with increased risks of cardiovascular morbidity, mortality and decreased quality of life in all stages of the disease. Most patients with CKD die of cardiovascular events in earlier stages before end-stage renal disease develops.
For the last years, renin-angiotensin-aldosterone blockade agents (ACEi/ARBs) were the only treatment available for managing CKD in both native and kidney transplant patients. Recently, sodium-glucose transport protein 2 inhibitors (SGLT2i) emerged as a new class of therapeutics for diabetic CKD, non-diabetic proteinuric CKD, and heart failure with and without type 2 diabetes mellitus (T2DM) in patients with native kidneys.
Dapagliflozin (SGLT2i) has been shown to be cardio- and nephroprotective in patients with and without T2DM. The DAPA-CKD trial found that patients with CKD treated with dapagliflozin had a lower risk of the primary composite outcome of a sustained decline in the estimated glomerular filtration rate (eGFR) of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes than patients who were assigned to receive placebo. Similar results have been confirmed by other SGLT2i in 2022 (Empagliflozin; EMPA-KIDNEY trial). In April 2021, Dapagliflozin became the first SGLT2i to be approved by the Food and Drug Administration (FDA) for the treatment of chronic kidney disease (CKD) regardless of diabetic status.
The anti-hyperglycaemic and anti-hypertensive effects of Dapagliflozin have been extensively studied and demonstrated in a number of clinical trials as well as in a real-world care setting. Previously,the investigators have demonstrated treatment with dapagliflozin in patients with T2DM improved diabetic control and reduced blood pressure (BP) in comparison to placebo. Furthermore, the drug was capable of reducing hyperperfusion of retinal capillaries and minimizing arteriole remodelling, factors that contribute to the progression of diabetic retinopathy, known to be linked with diabetic nephropathy. However, the precise mechanisms of its nephroprotective potential are still under discussion and needs to be elucidated.
Recently, the investigators described the intrarenal and glomerular hemodynamics of SGLT2i assessed by the clearance technique. SGLT2-inhibition impacts predominantly on post glomerular site, decreases renal vascular resistance and preserves renal perfusion in patients with type 2 diabetes and, thereby preserve renal function.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Female and male patients aged between 18 and 75 years
- •Patients with renal transplant having a stable eGFR, who are in stable condition, 9 months after transplantation, irrespective of their diabetes status
- •Females of child bearing potential must be using adequate contraceptive precautions
- •Females of childbearing potential or within two years of the menopause must have a negative urine pregnancy test at screening visit
- •Informed consent (§ 40 Abs. 1 Satz 3 Punkt 3 AMG) has to be given in written form
排除标准
- •Type 1 diabetes mellitus.
- •HbA1c > 10%
- •Use of SGLT-2 inhibitor within the past 2 months
- •Any history of stroke, transient ischemic attack, instable angina pectoris, or myocardial infarction within the last 3 months prior to study inclusion.
- •eGFR <25 ml/min/1.73m² (CKD-EPI Formula).
- •Uncontrolled arterial hypertension (RR > 180/110 mmHg).
- •Congestive heart failure (CHF) NYHA stage IV.
- •Recurrent urinary tract infections (bacterial or fungal)
- •Severe disorders of the gastrointestinal tract or other diseases which interfere the pharmacodynamics and pharmacokinetics of the drug.
- •Significant laboratory abnormalities such as SGOT or SGPT levels more than 5 x above the upper limit of normal range.
- •Antihypertensives are allowed but should be kept stable throughout the study period.
- •Statins and other antihyperlipidemic drugs are allowed but should be kept stable throughout the study period.
- •Drug or alcohol abusus
- •Pregnant or breast-feeding patients
- •Patients with contraindications to MRI
研究组 & 干预措施
Standard of care
standard of care only
Dapagliflozin
Dapagliflozin + standard of care
干预措施: Dapagliflozin 10mg Tab (Drug)
结局指标
主要结局
renal morphology - fibroblasts
时间窗: 3 months after randomization
integrity of peritubular fibroblasts (PDGFRα) assessed from the routine one year follow up biopsy of the renal transplant
renal morphology - inflammation
时间窗: 3 months after randomization
markers of inflammation (example CD3, CD68, CD163) in the interstitium from the routine one year follow up biopsy of the renal transplant
renal morphology - oxidative stress
时间窗: 3 months after randomization
markers of oxidative stress (Nox1, 8-OHdG) in the interstitium assessed from the routine one year follow up biopsy of the renal transplant
次要结局
- mRNA Expression profile of transcripts(3 months after randomization)
- renal perfusion(3 months after randomization)
- central (aortic) systolic pressurepulse pressure(3 months after randomization)
- pulse pressure(3 months after randomization)
研究者
Roland E. Schmieder
Prof. Dr. med.
University of Erlangen-Nürnberg Medical School