Olabisi Opeyemi A, Barrett Nadine J, Lucas Anika, Smith Maurice, Bethea Kenisha, Soldano Karen, Croall Stephanie, Sadeghpour Azita, Chakraborty Hrishikesh, Wolf Myles
Division of Nephrology, Duke University School of Medicine, Durham, North Carolina, USA.
Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Kidney Int Rep. 2024 Jun 27;9(9):2677-2684. doi: 10.1016/j.ekir.2024.06.033. eCollection 2024 Sep.
Individuals of recent West African ancestry develop focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (HTN-ESKD) at 4 times the rate of White Americans. Two protein-coding variants of the Apolipoprotein L1 (APOL1) gene, G1 and G2, explain 50% to 70% of the excess risk of HTN-ESKD and FSGS among this group. Increased expression of G1 and G2 in the kidney, mediated by Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling, drive pathogenesis of these kidney diseases. Baricitinib is an orally active inhibitor of JAK1/2 that blocks APOL1 synthesis. The Janus kinase-STAT Inhibition to Reduce APOL1-Associated Kidney Disease (JUSTICE) trial is evaluating the antiproteinuric efficacy and safety of baricitinib in patients with APOL1-associated FSGS and HTN-attributed chronic kidney disease (HTN-CKD).
JUSTICE is a single-center, randomized, double-blind, placebo-controlled, pilot phase 2 trial of baricitinib in patients with proteinuria, APOL1-associated FSGS or APOL1-associated HTN-CKD without diabetes. A total of 75 African American patients with APOL1-associated CKD, including 25 with FSGS and 50 with HTN-CKD, aged 18 to 70 years will be randomized 2:1 to daily treatment with baricitinib or placebo, respectively.
The primary efficacy end point will be percent change in urine albumin-to-creatinine ratio (UACR) from baseline to end of month 6. The primary safety end point will be incidence of clinically significant decreases in hemoglobin of ≥ 1g/dl.
The phase 2 JUSTICE study will characterize the antiproteinuric efficacy and safety of JAK1/2 inhibition with baricitinib in patients with APOL1-associated FSGS and APOL1-associated HTN-CKD.
近期有西非血统的个体发生局灶节段性肾小球硬化（FSGS）和高血压所致终末期肾病（HTN-ESKD）的几率是美国白人的4倍。载脂蛋白L1（APOL1）基因的两种蛋白质编码变体G1和G2，解释了该群体中HTN-ESKD和FSGS额外风险的50%至70%。由Janus激酶/信号转导和转录激活因子（JAK-STAT）信号介导的G1和G2在肾脏中的表达增加，推动了这些肾脏疾病的发病机制。巴瑞替尼是一种口服活性JAK1/2抑制剂，可阻断APOL1合成。Janus激酶-STAT抑制以减少APOL1相关肾病（JUSTICE）试验正在评估巴瑞替尼对APOL1相关FSGS和高血压所致慢性肾病（HTN-CKD）患者的抗蛋白尿疗效和安全性。
JUSTICE是一项单中心、随机、双盲、安慰剂对照的2期试点试验，研究对象为无糖尿病的蛋白尿、APOL1相关FSGS或APOL1相关HTN-CKD患者。总共75名18至70岁的患有APOL1相关CKD的非裔美国患者，包括25名FSGS患者和50名HTN-CKD患者，将按2:1随机分组，分别接受巴瑞替尼或安慰剂每日治疗。
主要疗效终点将是从基线到第6个月末尿白蛋白与肌酐比值（UACR）的变化百分比。主要安全终点将是血红蛋白临床显著降低≥1g/dl的发生率。
2期JUSTICE研究将描述巴瑞替尼抑制JAK1/2对APOL1相关FSGS和APOL1相关HTN-CKD患者的抗蛋白尿疗效和安全性。
