School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 1/F, Patrick Manson Building, 7 Sassoon Road, Hong Kong, China.
School of Public Health and Health Policy, City University of New York, New York, NY, USA.
BMC Med. 2021 Mar 26;19(1):79. doi: 10.1186/s12916-021-01951-4.
Angiotensin-converting enzyme (ACE) inhibitors and/or in combination with calcium channel blockers (CCBs) are generally recommended as the first-line antihypertensive therapy for people with hypertension and kidney dysfunction. Evidence from large randomized controlled trials comprehensively comparing renal effects of different classes of antihypertensive drugs is lacking.
We used a Mendelian randomization study to obtain unconfounded associations of genetic proxies for antihypertensives with kidney function. Specifically, we used published genetic variants in genes regulating target proteins of these drugs and then applied to a meta-analysis of the largest available genome-wide association studies of kidney function (estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), and albuminuria). Inverse variance weighting was used as the main analysis and to combine estimates from different sources.
Genetically predicted ACE inhibition was associated with higher eGFR (effect size 0.06, 95% confidence interval (CI) 0.008, 0.11), while genetic proxies for beta-blockers were associated with lower eGFR (- 0.02, 95% CI - 0.04, - 0.004) when meta-analyzing the UK Biobank and CKDGen. Genetic proxies for CCBs were associated with lower UACR (- 0.15, 95% CI - 0.28, - 0.02) and lower risk of albuminuria (odds ratio 0.58, 95% CI 0.37, 0.90) in CKDGen. The associations were robust to using different analysis methods and different genetic instruments.
Our findings suggest the reno-protective associations of genetically proxied ACE inhibitors and CCBs, while genetic proxies for beta-blockers may be related to lower eGFR. Understanding the underlying mechanisms would be valuable, with implications for drug development and repositioning of treatments for kidney disease.
血管紧张素转换酶（ACE）抑制剂和/或与钙通道阻滞剂（CCB）联合使用通常被推荐为高血压和肾功能障碍患者的一线降压治疗。缺乏全面比较不同类别的降压药物对肾脏影响的大型随机对照试验证据。
我们使用孟德尔随机化研究来获得降压药物的遗传替代物与肾功能之间的无偏关联。具体来说，我们使用了调节这些药物靶蛋白的基因中已发表的遗传变异，然后应用于对最大的可用肾功能全基因组关联研究（肾小球滤过率估计值（eGFR）、尿白蛋白与肌酐比值（UACR）和蛋白尿）的荟萃分析。逆方差加权法被用作主要分析方法，并将来自不同来源的估计值结合起来。
遗传预测的 ACE 抑制与较高的 eGFR 相关（效应大小为 0.06，95%置信区间（CI）为 0.008，0.11），而当对 UK Biobank 和 CKDGen 进行荟萃分析时，β-受体阻滞剂的遗传替代物与较低的 eGFR 相关（-0.02，95%CI-0.04，-0.004）。CCB 的遗传替代物与较低的 UACR（-0.15，95%CI-0.28，-0.02）和较低的蛋白尿风险（比值比 0.58，95%CI 0.37，0.90）相关。在 CKDGen 中，这些关联在使用不同的分析方法和不同的遗传工具时都是稳健的。
我们的发现表明，遗传替代的 ACE 抑制剂和 CCB 具有肾保护作用，而β-受体阻滞剂的遗传替代物可能与较低的 eGFR 有关。了解潜在的机制将具有重要价值，对药物开发和肾脏疾病治疗的重新定位具有启示意义。
