Lifelong effect of therapy in young patients with the COL4A5 Alport missense variant p.(Gly624Asp): a prospective cohort study
Lifelong effect of therapy in young patients with the COL4A5 Alport missense variant p.(Gly624Asp): a prospective cohort study
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DOI：
10.1093/ndt/gfac006
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发表时间：
2022-01-12
影响因子：
6.1
通讯作者：
Gross, Oliver
中科院分区：
文献类型：
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作者：
Boeckhaus, Jan;Hoefele, Julia;Gross, Oliver
背景血管紧张素转换酶抑制剂(ACEI)已发展成为延缓Alport综合征(AS)终末期肾功能衰竭(ESRF)的一线治疗药物。本研究验证了早期血管紧张素转换酶抑制剂干预具有更好的肾脏保护潜力的假设，检验了一组带有Col4A5错义变异p.(Gly624Asp)的队列。方法在这项观察性队列研究(NCT02378805)中，以治疗为终点，对114名具有相同基因变异的个体进行ESRF年龄和预期寿命的调查。结果13例未治疗的半合子患者均发生ESRF(平均年龄48.9±13.7岁)，3例晚期治疗的半合子患者发生ESRF(51.7±4.2岁)，平均预期寿命59.2±9.6岁。28例早期治疗[估计肾小球滤过率(EGFR)和Gt；=60mL/min/1.73m(2)]的偏侧合子患者全部存活，仍未达到终末期肾功能衰竭。治疗将GFR的年损失降至最低，与健康个体的年损失相似。在65个杂合子中，4个未经治疗的个体在53.3+/-20.7岁时发生了终末期肾衰。治疗后的杂合子雌鼠均未发生ESRF。结论本研究首次表明，在AS患者中，对有错义突变的个体进行早期治疗可能具有延缓终生肾功能衰竭的潜力，从而在不需要肾脏替代治疗的情况下提高预期寿命和生活质量。一些接受治疗的患者已经到了退休年龄，肾脏仍然功能正常，而他们的未接受治疗的亲属在相同或更小的年龄就达到了ESRF。因此，在肾小球性血尿的儿童中，早期检测Alport相关基因变异可能导致及时的肾脏保护干预。
Background Angiotensin-converting enzyme inhibitors (ACEis) have evolved as a first-line therapy for delaying end-stage renal failure (ESRF) in Alport syndrome (AS). The present study tested the hypothesis of a superior nephroprotective potential of an early ACEi intervention, examining a cohort with the COL4A5 missense variant p.(Gly624Asp). Methods In this observational cohort study (NCT02378805), 114 individuals with the identical gene variant were explored for age at ESRF and life expectancy in correlation with treatment as endpoints. Results All 13 untreated hemizygous patients developed ESRF (mean age 48.9 +/- 13.7 years), as did 3 very late treated hemizygotes (51.7 +/- 4.2 years), with a mean life expectancy of 59.2 +/- 9.6 years. All 28 earlier-treated [estimated glomerular filtration rate (eGFR) >= 60 mL/min/1.73 m(2)] hemizygous patients were still alive and still had not reached ESRF. Therapy minimized the annual loss of their GFR, similar to the annual loss in healthy individuals. Of 65 heterozygotes, 4 untreated individuals developed ESRF at an age of 53.3 +/- 20.7 years. None of the treated heterozygous females developed ESRF. Conclusions For the first time, this study shows that in AS, early therapy in individuals with missense variants might have the potential to delay renal failure for their lifetime and thus to improve life expectancy and quality of life without the need for renal replacement therapy. Some treated patients have reached their retirement age with still-functioning kidneys, whereas their untreated relatives have reached ESRF at the same or a younger age. Thus, in children with glomerular haematuria, early testing for Alport-related gene variants could lead to timely nephroprotective intervention.