Ruggenenti Piero, Bettinaglio Paola, Pinares Franck, Remuzzi Giuseppe
Clinical Research Centre for Rare Diseases Aldo e Cele Daccò, Mario Negri Institute for Pharmacological Research, Villa Camozzi, Ranica, Italy.
Clin J Am Soc Nephrol. 2008 Sep;3(5):1511-25. doi: 10.2215/CJN.04140907. Epub 2008 Jun 11.
Despite the huge amount of studies looking for candidate genes, the ACE gene remains the unique, well-characterized locus clearly associated with pathogenesis and progression of chronic kidney disease, and with response to treatment with drugs that directly interfere with the renin angiotensin system (RAS), such as angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (ARA). The II genotype is protective against development and progression of type I and type II nephropathy and is associated with a slower progression of nondiabetic proteinuric kidney disease. ACE inhibitors are particularly effective at the stage of normoalbuminuria or microalbuminuria in both type I and type II diabetics with the II genotype, whereas the DD genotype is associated with a better response to ARA therapy in overt nephropathy of type II diabetes and to ACE inhibitors in male patients with nondiabetic proteinuric nephropathies. The role of other RAS or non-RAS polymorphisms and their possible interactions with different ACE I/D genotypes are less clearly defined. Thus, evaluating the ACE I/D polymorphism is a reliable tool to identify patients at risk and those who may benefit the most of renoprotective therapy with ACE inhibitors or ARA. This may guide pharmacologic therapy in individual patients and help design clinical trials in progressive nephropathies. Moreover, it might help optimize prevention and intervention strategies at population levels, in particular, in countries where resources are extremely limited and 1 million patients continue to die every year of cardiovascular or renal disease.
尽管有大量研究在寻找候选基因，但ACE基因仍然是唯一明确与慢性肾脏病的发病机制和进展相关，且与对直接干扰肾素血管紧张素系统（RAS）的药物（如血管紧张素转换酶（ACE）抑制剂和血管紧张素II受体拮抗剂（ARA））治疗反应相关的、特征明确的基因座。II基因型对I型和II型肾病的发生和进展具有保护作用，并且与非糖尿病性蛋白尿肾病的进展较慢有关。在I型和II型糖尿病且具有II基因型的患者中，ACE抑制剂在正常白蛋白尿或微量白蛋白尿阶段特别有效，而DD基因型与II型糖尿病显性肾病对ARA治疗以及非糖尿病性蛋白尿肾病男性患者对ACE抑制剂的更好反应相关。其他RAS或非RAS多态性的作用及其与不同ACE I/D基因型可能的相互作用尚不太明确。因此，评估ACE I/D多态性是识别有风险患者以及可能从ACE抑制剂或ARA肾保护治疗中获益最多患者的可靠工具。这可以指导个体患者的药物治疗，并有助于设计进行性肾病的临床试验。此外，它可能有助于在人群层面优化预防和干预策略，特别是在资源极其有限且每年仍有100万患者死于心血管或肾脏疾病的国家。
