Renal HEIR Study: Renal Hemodynamics, Energetics and Insulin Resistance in Youth Onset Type 2 Diabetes Study
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 100
- 试验地点
- 1
- 主要终点
- Effective renal plasma flow (ERPF)
研究概览
简要总结
Type 2 diabetes (T2D) in youth is increasing in prevalence in parallel with the obesity epidemic. In the US, almost half of patients with renal failure have DKD, and ≥80% have T2D. Compared to adult-onset T2D, youth with T2D have a more aggressive phenotype with greater insulin resistance (IR), more rapid β-cell decline and higher prevalence of diabetic kidney disease (DKD), arguing for separate and dedicated studies in youth-onset T2D. Hyperfiltration is common in youth with T2D, and predicts progressive DKD. Hyperfiltration may also be associated with early changes in intrarenal hemodynamic function, including increased renal plasma flow (RPF) and glomerular pressure. Despite the high prevalence and gravity of DKD in youth-onset T2D, widely effective therapeutic options are lacking. The investigators' preliminary data support a strong association between IR and hyperfiltration in youth-onset T2D, but the pathology contributing to this relationship remains unclear. A better understanding of the pathophysiology underlying hyperfiltration and its relationship with IR is critical to inform development of new therapeutics. The investigators' overarching hypotheses are that: 1) hyperfiltration in youth-onset T2D is associated with changes in intrarenal hemodynamics, resulting in increased renal oxygen demand, 2) the demand is unmet by the inefficient fuel profile associated with IR (decreased glucose oxidation and increase free fatty acid [FFA] oxidation), resulting in renal hypoxia and ultimately renal damage. To address these hypotheses, the investigators will measure peripheral insulin sensitivity, adipose insulin sensitivity (FFA suppression), glomerular filtration rate (GFR), RPF, and renal oxygenation in youth with T2D (n=60), obesity (n=20) and in lean (n=20) controls. To further investigate the mechanisms of renal damage in youth with T2D, two optional procedures are included in the study: 1) kidney biopsy procedure and 2) induction of induced pluripotent stem cells (iPSCs) to assess morphometrics and genetic expression of renal tissue.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Obese youth with and without T2D (≥54 kg) and lean controls
- •Age 12-21 years
- •Weight <300 lbs., no implanted metal devices
- •HbA1c < 11% and no recent diabetic ketoacidosis or hyperosmolar hyperglycemia
- •No anemia
- •BMI >5th percentile for lean controls
排除标准
- •T2D onset (diagnosis) > 18 years of age
- •Prepubertal
- •eGFR <60ml/min/1.73m2 or creatinine > 1.5mg/dl or history of ACR≥300mg/g
- •ACE inhibitors, angiotensin receptor blockers (ARB), diuretics, sodium-glucose co-transport (SGLT) 2 or 1 blockers, daily NSAIDs or aspirin, sulfonamides, procaine, thiazosulfone or probenecid.
- •Seafood or iodine allergy
- •Pregnancy
- •MRI scanning contraindications (claustrophobia, implantable devices, >300 lbs)
- •Additional exclusion criteria for participants undergoing optional kidney biopsy:
- •Evidence of bleeding disorder or complications from bleeding
- •Use of aspirin, NSAIDS or other blood thinner that cannot be safely stopped for a sufficient time period before and after the biopsy so as to add no additional risk of bleeding
- •Blood urea nitrogen (BUN) > 80 gm/dL
- •INR > 1.4
- •PTT > 35 seconds
- •Hemoglobin (Hgb) < 10 mg/dL
- •Platelet count < 100,000 / µL
- •Uncontrolled or difficult to control hypertension (> 150/90 mmHg at the day of biopsy)
- •eGFR < 40 mL/min/1.73m2
- •Single kidney (either by history, documented by prior imaging or ultrasound performed prior to the biopsy)
- •> 2 cm discrepancy between left and right kidney sizes based on largest longitudinal diameter determined by ultrasound performed prior to the biopsy.
- •Kidney size: One or both kidneys < 9 cm
- •Hydronephrosis or other important renal ultrasound findings such as significant stone disease
- •Any evidence of a current urinary tract infection as indicated on day of biopsy
- •Clinical evidence of non-diabetic renal disease
- •Positive urine pregnancy test or pregnancy
研究组 & 干预措施
Clinical Investigation
All participants will undergo GFR (Iohexol Inj 300 MG/ML), ERPF (Aminohippurate Sodium Inj 20%) in addition to renal BOLD and ASL MRI.
干预措施: Aminohippurate Sodium Inj 20% (Drug)
Clinical Investigation
All participants will undergo GFR (Iohexol Inj 300 MG/ML), ERPF (Aminohippurate Sodium Inj 20%) in addition to renal BOLD and ASL MRI.
干预措施: Iohexol Inj 300 MG/ML (Drug)
Clinical Investigation
All participants will undergo GFR (Iohexol Inj 300 MG/ML), ERPF (Aminohippurate Sodium Inj 20%) in addition to renal BOLD and ASL MRI.
干预措施: Renal Biopsy (Procedure)
结局指标
主要结局
Effective renal plasma flow (ERPF)
时间窗: 4 hours
Measured by PAH clearance
Glomerular filtration rate (GFR)
时间窗: 4 hours
Measured by iohexol clearance
次要结局
- Renal oxygenation(60 min)
- Insulin sensitivity(4 hours)
- Renal perfusion(10 min)