鉴定肾小球和血浆载脂蛋白M作为肾小球疾病的新型生物标志物
Identification of Glomerular and Plasma Apolipoprotein M as Novel Biomarkers in Glomerular Disease.
作者信息
Drexler Yelena, Molina Judith, Elfassy Tali, Ma Ruixuan, Christoffersen Christina, Kurano Makoto, Yatomi Yutaka, Mariani Laura H, Contreras Gabriel, Merscher Sandra, Fornoni Alessia
机构信息
Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA.
出版信息
Kidney Int Rep. 2023 Feb 4;8(4):884-897. doi: 10.1016/j.ekir.2023.01.031. eCollection 2023 Apr.
INTRODUCTION
Dysregulation of sphingolipid and cholesterol metabolism contributes to the pathogenesis of glomerular diseases (GDs). Apolipoprotein M (ApoM) promotes cholesterol efflux and modulates the bioactive sphingolipid sphingosine-1-phosphate (S1P). Glomerular ApoM expression is decreased in patients with focal segmental glomerulosclerosis (FSGS). We hypothesized that glomerular ApoM deficiency occurs in GD and that ApoM expression and plasma ApoM correlate with outcomes.
METHODS
Patients with GD from the Nephrotic Syndrome Study Network (NEPTUNE) were studied. We compared glomerular mRNA expression of ApoM (gApoM), sphingosine kinase 1 (SPHK1), and S1P receptors 1 to 5 (S1PR1-5) in patients ( = 84) and controls ( = 6). We used correlation analyses to determine associations between gApoM, baseline plasma ApoM (pApoM), and urine ApoM (uApoM/Cr). We used linear regression to determine whether gApoM, pApoM, and uApoM/Cr were associated with baseline estimated glomerular filtration rate (eGFR) and proteinuria. Using Cox models, we determined whether gApoM, pApoM, and uApoM/Cr were associated with complete remission (CR) and the composite of end-stage kidney disease (ESKD) or ≥40% eGFR decline.
RESULTS
gApoM was reduced ( < 0.01) and SPHK1 and S1PR1 to 5 expression was increased ( < 0.05) in patients versus controls, consistent with ApoM/S1P pathway modulation. gApoM positively correlated with pApoM in the overall cohort ( = 0.34, < 0.01) and in the FSGS ( = 0.48, < 0.05) and minimal change disease (MCD) ( = 0.75, < 0.05) subgroups. Every unit decrease in gApoM and pApoM (log) was associated with a 9.77 ml/min per 1.73 m (95% confidence interval [CI]: 3.96-15.57) and 13.26 ml/min per 1.73 m (95% CI: 3.57-22.96) lower baseline eGFR, respectively ( < 0.01). From Cox models adjusted for age, sex, or race, pApoM was a significant predictor of CR (hazard ratio [HR]: 1.85; 95% CI: 1.06-3.23).
CONCLUSIONS
pApoM is a potential noninvasive biomarker of gApoM deficiency and strongly associates with clinical outcomes in GD.
引言
鞘脂和胆固醇代谢失调促成了肾小球疾病（GDs）的发病机制。载脂蛋白M（ApoM）促进胆固醇流出并调节生物活性鞘脂鞘氨醇-1-磷酸（S1P）。局灶节段性肾小球硬化症（FSGS）患者的肾小球ApoM表达降低。我们推测GD中存在肾小球ApoM缺乏，且ApoM表达及血浆ApoM与疾病转归相关。
方法
对肾病综合征研究网络（NEPTUNE）中的GD患者进行研究。我们比较了84例患者和6例对照者肾小球中ApoM（gApoM）、鞘氨醇激酶1（SPHK1）以及S1P受体1至5（S1PR1 - 5）的mRNA表达。我们采用相关性分析来确定gApoM、基线血浆ApoM（pApoM）和尿ApoM（uApoM/Cr）之间的关联。我们使用线性回归来确定gApoM、pApoM和uApoM/Cr是否与基线估计肾小球滤过率（eGFR）和蛋白尿相关。使用Cox模型，我们确定gApoM、pApoM和uApoM/Cr是否与完全缓解（CR）以及终末期肾病（ESKD）或eGFR下降≥40%的复合终点相关。
结果
与对照者相比，患者的gApoM降低（P<0.01），SPHK1以及S1PR1至5的表达增加（P<0.05），这与ApoM/S1P途径的调节一致。在整个队列（r = 0.34，P<0.01）、FSGS亚组（r = 0.48，P<0.05）和微小病变病（MCD）亚组（r = 0.75，P<0.05）中，gApoM与pApoM呈正相关。gApoM和pApoM（对数）每降低一个单位，分别与基线eGFR降低9.77 ml/min/1.73m²（95%置信区间[CI]：3.96 - 15.57）和13.26 ml/min/1.73m²（95%CI：3.57 - 22.96）相关（P<0.01）。在根据年龄、性别或种族进行调整的Cox模型中，pApoM是CR的显著预测因子（风险比[HR]：1.85；95%CI：1.06 - 3.23）。
结论
pApoM是gApoM缺乏的潜在非侵入性生物标志物，且与GD的临床转归密切相关。
Zotero 插件