北京大学张宏团队联合澳大利亚新南威尔士大学Vlado Perkovic团队研究了口服甲基强的松龙对IgA肾病患者肾功能下降或肾衰竭的影响。相关论文发表在2022年5月17日出版的《美国医学会杂志》上。

糖皮质激素对IgA肾病主要肾脏结局和不良事件的影响尚不确定。

为了评估甲基强的松龙对肾功能下降高危IgA肾病患者的疗效和不良反应，研究组进行了一项国际性、多中心、双盲、随机临床试验，2012年5月至2019年11月，在澳大利亚、加拿大、中国、印度和马来西亚的67个中心进行了至少3个月的优化背景治疗后，共招募了503名IgA肾病患者，每天蛋白尿量>=1克，估计肾小球滤过率（eGFR）为20-120 mL/min/1.73 m²，随访至2021年6月。

将参与者按1:1的比例随机分组，其中136例接受口服甲基强的松龙治疗，126例接受安慰剂治疗。262名参与者被随机分组后，发现严重感染过多，遂将药物剂量减少，并为后续参与者（口服甲基强的松龙组121名，安慰剂组120名）添加预防肺孢子虫肺炎的抗生素。主要终点是eGFR下降40%、肾功能衰竭（透析、移植）或肾脏疾病导致的死亡。有11个次要结局，包括肾衰竭。

503名随机患者的平均年龄为38岁，198名为女性（39%）；平均eGFR为61.5 mL/min/1.73 m²；平均蛋白尿水平为2.46 g/d；共有493名（98%）完成了试验。在平均4.2年的随访中，甲基强的松龙组中有74名受试者（28.8%）出现主要结局，而安慰剂组中有106名（43.1%），危险比（HR）为0.53，组间差异显著。

与每个方案中招募的安慰剂组相关参与者相比，每种剂量对主要结局的影响都是显著的 ：全剂量HR为0.58；减少剂量后HR为0.27。在11个预先指定的次要终点中，9个显示出有利于干预组的显著差异，包括肾衰竭（HR为0.59）。与安慰剂组相比，甲基强的松龙组的严重不良事件发生率为10.9%，显著高于安慰剂组的2.8%；主要在全剂量治疗组中，严重不良事件发生率为16.2%，匹配的安慰剂组为3.2%。

研究结果表明，在进展风险较高的IgA肾病患者中，与安慰剂相比，口服甲基强的松龙6至9个月，可显著降低肾功能下降、肾衰竭或肾脏疾病死亡的综合转归风险。

附：英文原文

Title: Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial

Author: Jicheng Lv, Muh Geot Wong, Michelle A. Hladunewich, Vivekanand Jha, Lai Seong Hooi, Helen Monaghan, Minghui Zhao, Sean Barbour, Meg J. Jardine, Heather N. Reich, Daniel Cattran, Richard Glassock, Adeera Levin, David C. Wheeler, Mark Woodward, Laurent Billot, Sandrine Stepien, Kris Rogers, Tak Mao Chan, Zhi-Hong Liu, David W. Johnson, Alan Cass, John Feehally, Jürgen Floege, Giuseppe Remuzzi, Yangfeng Wu, Rajiv Agarwal, Hong Zhang, Vlado Perkovic, TESTING Study Group, Mona Razavian, Martin Gallagher, Frances Daley, Samantha Hand, Helen Knight, Sarah Gallagher, Bhadran Bose, Craig Lawlor, Junie McCourt, Chen Au Peh, Eileen Scott, Robert Carroll, Toby Coates, Bronwyn Hockley, Megan Hockley, Jenny Latte, Kathy Nicholls, Michael Cai, Paul Champion de Crespigny, Therese Cronin, Maria Farrell, Peter Hughes, Rosemary Masterson, Gloria Sepe, Sven-Jean Tan, Nigel Toussaint, Rachel Wollstencroft, Bruce Cooper, Marjorie Chang, Helen Clayton, Stephanie Tan, Heidi Tsang, Joanna Sudak, Louis P Laurin, Vincent Pichette, Karine Chausse, Martine Comeau, Lucy Lepine, Marie Soliel, Stephanie Beauchemin, Emilie René, Marceline Quach, Karine Daoust

Issue&Volume: 2022/05/17

Abstract:

Importance  The effect of glucocorticoids on major kidney outcomes and adverse events in IgA nephropathy has been uncertain.

Objective  To evaluate the efficacy and adverse effects of methylprednisolone in patients with IgA nephropathy at high risk of kidney function decline.

Design, Setting, and Participants  An international, multicenter, double-blind, randomized clinical trial that enrolled 503 participants with IgA nephropathy, proteinuria greater than or equal to 1 g per day, and estimated glomerular filtration rate (eGFR) of 20 to 120 mL/min/1.73 m2 after at least 3 months of optimized background care from 67 centers in Australia, Canada, China, India, and Malaysia between May 2012 and November 2019, with follow-up until June 2021.

Interventions  Participants were randomized in a 1:1 ratio to receive oral methylprednisolone (initially 0.6-0.8 mg/kg/d, maximum 48 mg/d, weaning by 8 mg/d/mo; n=136) or placebo (n=126). After 262 participants were randomized, an excess of serious infections was identified, leading to dose reduction (0.4 mg/kg/d, maximum 32 mg/d, weaning by 4 mg/d/mo) and addition of antibiotic prophylaxis for pneumocystis pneumonia for subsequent participants (121 in the oral methylprednisolone group and120 in the placebo group).

Main Outcomes And Measures  The primary end point was a composite of 40% decline in eGFR, kidney failure (dialysis, transplant), or death due to kidney disease. There were 11 secondary outcomes, including kidney failure.

Results  Among 503 randomized patients (mean age, 38 years; 198 [39%] women; mean eGFR, 61.5 mL/min/1.73 m2; mean proteinuria, 2.46 g/d), 493 (98%) completed the trial. Over a mean of 4.2 years of follow-up, the primary outcome occurred in 74 participants (28.8%) in the methylprednisolone group compared with 106 (43.1%) in the placebo group (hazard ratio [HR], 0.53 [95% CI, 0.39-0.72]; P<.001; absolute annual event rate difference, 4.8% per year [95% CI, 8.0% to 1.6%]). The effect on the primary outcome was seen across each dose compared with the relevant participants in the placebo group recruited to each regimen (P for heterogeneity=.11): full-dose HR, 0.58 (95% CI, 0.41-0.81); reduced-dose HR, 0.27 (95% CI, 0.11-0.65). Of the 11 prespecified secondary end points, 9 showed significant differences in favor of the intervention, including kidney failure (50 [19.5%] vs 67 [27.2%]; HR, 0.59 [95% CI, 0.40-0.87]; P=.008; annual event rate difference, 2.9% per year [95% CI, 5.4% to 0.3%]). Serious adverse events were more frequent with methylprednisolone vs placebo (28 [10.9%] vs 7 [2.8%] patients with serious adverse events), primarily with full-dose therapy compared with its matching placebo (22 [16.2%] vs 4 [3.2%]).

Conclusions and Relevance  Among patients with IgA nephropathy at high risk of progression, treatment with oral methylprednisolone for 6 to 9 months, compared with placebo, significantly reduced the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease. However, the incidence of serious adverse events was increased with oral methylprednisolone, mainly with high-dose therapy.

DOI: 10.1001/jama.2022.5368

Source: https://jamanetwork.com/journals/jama/article-abstract/2792252