Knol Martine G E, Bais Thomas, Geertsema Paul, Connelly Margery A, Bakker Stephan J L, Gansevoort Ron T, van Gastel Maatje D A
Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Labcorp, Morrisville, NC, USA.
Nephrol Dial Transplant. 2024 Apr 26;39(5):838-847. doi: 10.1093/ndt/gfad239.
Dysregulated energy metabolism is a recently discovered key feature of autosomal dominant polycystic kidney disease (ADPKD). Cystic cells depend on glucose and are poorly able to use other energy sources such as ketone bodies. Raising ketone body concentration reduced disease progression in animal models of polycystic kidney diseases. Therefore, we hypothesized that higher endogenous plasma beta-hydroxybutyrate (BHB) concentrations are associated with reduced disease progression in patients with ADPKD.
We analyzed data from 670 patients with ADPKD participating in the Developing Intervention Strategies to Halt Progression of ADPKD (DIPAK) cohort, a multi-center prospective observational cohort study. BHB was measured at baseline using nuclear magnetic resonance spectroscopy. Participants were excluded if they had type 2 diabetes, were using disease-modifying drugs (e.g. tolvaptan, somatostatin analogs), were not fasting or had missing BHB levels, leaving 521 participants for the analyses. Linear regression analyses were used to study cross-sectional associations and linear mixed-effect modeling for longitudinal associations.
Of the participants, 61% were female, with an age of 47.3 ± 11.8 years, a height-adjusted total kidney volume (htTKV) of 834 [interquartile range (IQR) 495-1327] mL/m and an estimated glomerular filtration rate (eGFR) of 63.3 ± 28.9 mL/min/1.73 m2. The median concentration of BHB was 94 (IQR 68-147) µmol/L. Cross-sectionally, BHB was associated neither with eGFR nor with htTKV. Longitudinally, BHB was positively associated with eGFR slope {B = 0.35 mL/min/1.73 m2 [95% confidence interval (CI) 0.09 to 0.61], P = .007}, but not with kidney growth. After adjustment for potential confounders, every doubling in BHB concentration was associated with an improvement in the annual rate of eGFR by 0.33 mL/min/1.73 m2 (95% CI 0.09 to 0.57, P = .008).
These observational analyses support the hypothesis that interventions that raise BHB concentration could reduce the rate of kidney function decline in patients with ADPKD.
能量代谢失调是最近发现的常染色体显性多囊肾病（ADPKD）的一个关键特征。囊性细胞依赖葡萄糖，且利用酮体等其他能量来源的能力较差。提高酮体浓度可减缓多囊肾病动物模型的疾病进展。因此，我们推测内源性血浆β-羟基丁酸酯（BHB）浓度升高与ADPKD患者疾病进展减缓有关。
我们分析了参与“停止ADPKD进展的发展干预策略（DIPAK）队列研究”的670例ADPKD患者的数据，这是一项多中心前瞻性观察性队列研究。在基线时使用核磁共振波谱法测量BHB。如果参与者患有2型糖尿病、正在使用疾病修饰药物（如托伐普坦、生长抑素类似物）、未禁食或BHB水平缺失，则将其排除，最终纳入521名参与者进行分析。采用线性回归分析研究横断面关联，并采用线性混合效应模型研究纵向关联。
参与者中，61%为女性，年龄为47.3±11.8岁，身高校正后的总肾体积（htTKV）为834[四分位间距（IQR）495 - 1327]mL/m，估计肾小球滤过率（eGFR）为63.3±28.9 mL/min/1.73 m²。BHB的中位浓度为94（IQR 68 - 147）µmol/L。横断面分析中，BHB与eGFR及htTKV均无关联。纵向分析中，BHB与eGFR斜率呈正相关{B = 0.35 mL/min/1.73 m²[95%置信区间（CI）0.09至0.61]，P = 0.007}，但与肾脏生长无关。在对潜在混杂因素进行校正后，BHB浓度每增加一倍，eGFR的年增长率改善0.33 mL/min/1.73 m²（95% CI 0.09至0.57，P = 0.008）。
这些观察性分析支持了这样一种假设，即提高BHB浓度的干预措施可降低ADPKD患者的肾功能下降速率。
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