Long-term trajectory of kidney function in autosomal-dominant polycystic kidney disease
Long-term trajectory of kidney function in autosomal-dominant polycystic kidney disease
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DOI：
10.1016/j.kint.2018.12.023
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发表时间：
2019-05-01
影响因子：
19.6
通讯作者：
Bennett, William M.
中科院分区：
文献类型：
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作者：
Yu, Alan S. L.;Shen, Chengli;Bennett, William M.
常染色体显性遗传性多囊肾病（ADPKD）的特征是囊肿和肾脏生长，这被假设为导致功能性肾脏质量丧失并最终导致终末期肾病。然而，肾小球滤过率（GFR）下降的时间过程定义不清。多囊肾病放射成像研究联盟研究是一项为期14年的观察性队列研究，纳入241名ADPKD成人。作为肾脏生长速率的估计值，根据基线年龄和磁共振成像测量的总肾脏体积（TKV），根据Alzzabal方法将参与者分为5个亚类。使用混合多项式模型重建并拟合了跨越40年生命的GFR轨迹，并使用HALT-PKD研究的数据进行了验证。GFR轨迹是非线性的，在大多数参与者中有一段相对稳定的时期，然后加速下降。这些轨迹的形状和斜率与基线Escherzabal类密切相关。与PKD 2突变或未检测到突变的患者相比，PKD 1突变患者的GFR下降幅度更大，这主要是由基因型对Escherzabal分类的影响介导的。因此，ADPKD的GFR下降是非线性的，其在整个成年期的轨迹可以从肾脏体积的单一测量来预测。这些模型可用于临床验证、临床试验设计和临床干预的患者选择。我们的研究结果支持肾体积增长和GFR下降之间的因果关系，增加了在临床试验中使用TKV作为替代终点的支持。
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst and kidney growth, which is hypothesized to cause loss of functioning renal mass and eventually end-stage kidney disease. However, the time course of decline in glomerular filtration rate (GFR) is poorly defined. The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease study is a 14-year observational cohort study of 241 adults with ADPKD. As an estimate of the rate of kidney growth, participants were stratified into 5 subclasses based on baseline age and magnetic resonance imaging measurements of total kidney volume (TKV) according to the method of Irazabal. GFR trajectories spanning over four decades of life were reconstructed and fitted using mixed polynomial models, which were validated using data from the HALT-PKD study. GFR trajectories were nonlinear, with a period of relative stability in most participants, followed by accelerating decline. The shape and slope of these trajectories were strongly associated with baseline Irazabal class. Patients with PKD1 mutations had a steeper GFR decline than patients with PKD2 mutations or with no detected mutation, largely mediated by the effect of genotype on Irazabal class. Thus, GFR decline in ADPKD is nonlinear, and its trajectory throughout adulthood can be predicted from a single measurement of kidney volume. These models can be used for clinical prognostication, clinical trial design, and patient selection for clinical interventions. Our findings support a causal link between growth in kidney volume and GFR decline, adding support for the use of TKV as a surrogate endpoint in clinical trials.