前列腺素 E2、渗透压调节和常染色体显性多囊肾病的疾病进展。
Prostaglandin E2, Osmoregulation, and Disease Progression in Autosomal Dominant Polycystic Kidney Disease.
机构信息
Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, Groningen, The Netherlands.
出版信息
Clin J Am Soc Nephrol. 2023 Nov 1;18(11):1426-1434. doi: 10.2215/CJN.0000000000000269. Epub 2023 Aug 14.
BACKGROUND
Prostaglandin E2 (PGE2) plays a physiological role in osmoregulation, a process that is affected early in autosomal dominant polycystic kidney disease (ADPKD). PGE2 has also been implicated in the pathogenesis of ADPKD in preclinical models, but human data are limited. Here, we hypothesized that urinary PGE2 excretion is associated with impaired osmoregulation, disease severity, and disease progression in human ADPKD.
METHODS
Urinary excretions of PGE2 and its metabolite (PGEM) were measured in a prospective cohort of patients with ADPKD. The associations between urinary PGE2 and PGEM excretions, markers of osmoregulation, eGFR and height-adjusted total kidney volume were assessed using linear regression models. Cox regression and linear mixed models were used for the longitudinal analysis of the associations between urinary PGE2 and PGEM excretions and disease progression defined as 40% eGFR loss or kidney failure, and change in eGFR over time. In two intervention studies, we quantified the effect of starting tolvaptan and adding hydrochlorothiazide to tolvaptan on urinary PGE2 and PGEM excretions.
RESULTS
In 562 patients with ADPKD (61% female, eGFR 63±28 ml/min per 1.73 m 2 ), higher urinary PGE2 or PGEM excretions were independently associated with higher plasma copeptin, lower urine osmolality, lower eGFR, and greater total kidney volume. Participants with higher baseline urinary PGE2 and PGEM excretions had a higher risk of 40% eGFR loss or kidney failure (hazard ratio, 1.28; 95% confidence interval [CI], 1.13 to 1.46 and hazard ratio, 1.50; 95% CI, 1.26 to 1.80 per two-fold higher urinary PGE2 or PGEM excretions) and a faster change in eGFR over time (-0.39 [95% CI, -0.59 to -0.20] and -0.53 [95% CI, -0.75 to -0.31] ml/min per 1.73 m 2 per year). In the intervention studies, urinary PGEM excretion was higher after starting tolvaptan, while urinary PGE2 excretion was higher after adding hydrochlorothiazide to tolvaptan.
CONCLUSIONS
Higher urinary PGE2 and PGEM excretions in patients with ADPKD are associated with impaired osmoregulation, disease severity, and progression.
背景
前列腺素 E2（PGE2）在渗透调节中发挥生理作用，这一过程在常染色体显性多囊肾病（ADPKD）的早期就受到影响。在临床前模型中，PGE2 也与 ADPKD 的发病机制有关，但人类数据有限。在这里，我们假设尿 PGE2 排泄与人类 ADPKD 的渗透调节受损、疾病严重程度和疾病进展有关。
方法
前瞻性队列研究了 ADPKD 患者的尿 PGE2 和其代谢产物（PGEM）排泄情况。使用线性回归模型评估尿 PGE2 和 PGEM 排泄与渗透调节标志物、eGFR 和身高校正总肾体积之间的相关性。Cox 回归和线性混合模型用于分析尿 PGE2 和 PGEM 排泄与疾病进展之间的纵向关系，疾病进展定义为 eGFR 损失 40%或肾衰竭，以及随时间变化的 eGFR 变化。在两项干预研究中，我们量化了开始托伐普坦和在托伐普坦的基础上加用氢氯噻嗪对尿 PGE2 和 PGEM 排泄的影响。
结果
在 562 名 ADPKD 患者（61%为女性，eGFR 为 63±28ml/min/1.73m2）中，较高的尿 PGE2 或 PGEM 排泄与较高的血浆 copeptin、较低的尿渗透压、较低的 eGFR 和更大的总肾体积独立相关。基线时尿 PGE2 和 PGEM 排泄较高的患者，eGFR 损失 40%或肾衰竭的风险更高（风险比，1.28；95%置信区间[CI]，1.13 至 1.46 和风险比，1.50；95%CI，1.26 至 1.80，每两倍升高的尿 PGE2 或 PGEM 排泄），随时间 eGFR 变化更快（-0.39[95%CI，-0.59 至-0.20]和-0.53[95%CI，-0.75 至-0.31]ml/min/1.73m2/年）。在干预研究中，开始托伐普坦后尿 PGEM 排泄增加，而在托伐普坦的基础上加用氢氯噻嗪后尿 PGE2 排泄增加。
结论
ADPKD 患者尿 PGE2 和 PGEM 排泄增加与渗透调节受损、疾病严重程度和进展有关。
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