PDF(Pubmed)
Abstract：
UNASSIGNED: Nephritis is a pivotal catalyst in chronic kidney disease (CKD) progression. Although epidemiological studies have explored the impact of plasma circulating metabolites and drugs on nephritis, few have harnessed genetic methodologies to establish causal relationships.
UNASSIGNED: Through Mendelian randomization (MR) in two substantial cohorts, spanning large sample sizes, we evaluated over 100 plasma circulating metabolites and 263 drugs to discern their causal effects on nephritis risk. The primary analytical tool was the inverse variance weighted (IVW) analysis. Our bioinformatic scrutiny of GSE115857 (IgA nephropathy, 86 samples) and GSE72326 (lupus nephritis, 238 samples) unveiled anomalies in lipid metabolism and immunological characteristics in nephritis. Thorough sensitivity analyses (MR-Egger, MR-PRESSO, leave-one-out analysis) were undertaken to verify the instrumental variables\' (IVs) assumptions.
UNASSIGNED: Unique lipoprotein-related molecules established causal links with diverse nephritis subtypes. Notably, docosahexaenoic acid (DHA) emerged as a protective factor for acute tubulointerstitial nephritis (ATIN) (OR1 = 0.84, [95% CI 0.78-0.90], p1 = 0.013; OR2 = 0.89, [95% CI 0.82-0.97], p2 = 0.007). Conversely, multivitamin supplementation minus minerals notably increased the risk of ATIN (OR = 31.25, [95% CI 9.23-105.85], p = 0.004). Reduced α-linolenic acid (ALA) levels due to lipid-lowering drugs were linked to both ATIN (OR = 4.88, [95% CI 3.52-6.77], p < 0.001) and tubulointerstitial nephritis (TIN) (OR = 7.52, [95% CI 2.78-20.30], p = 0.042). While the non-renal drug indivina showed promise for TIN treatment, the use of digoxin, hydroxocobalamin, and liothyronine elevated the risk of chronic tubulointerstitial nephritis (CTIN). Transcriptome analysis affirmed that anomalous lipid metabolism and immune infiltration are characteristic of IgA nephropathy and lupus nephritis. The robustness of these causal links was reinforced by sensitivity analyses and leave-one-out tests, indicating no signs of pleiotropy.
UNASSIGNED: Dyslipidemia significantly contributes to nephritis development. Strategies aimed at reducing plasma low-density lipoprotein levels or ALA supplementation may enhance the efficacy of existing lipid-lowering drug regimens for nephritis treatment. Renal functional status should also be judiciously considered with regard to the use of nonrenal medications.
UNASSIGNED: Through Mendelian randomization (MR) in two substantial cohorts, spanning large sample sizes, we evaluated over 100 plasma circulating metabolites and 263 drugs to discern their causal effects on nephritis risk. The primary analytical tool was the inverse variance weighted (IVW) analysis. Our bioinformatic scrutiny of GSE115857 (IgA nephropathy, 86 samples) and GSE72326 (lupus nephritis, 238 samples) unveiled anomalies in lipid metabolism and immunological characteristics in nephritis. Thorough sensitivity analyses (MR-Egger, MR-PRESSO, leave-one-out analysis) were undertaken to verify the instrumental variables\' (IVs) assumptions.
UNASSIGNED: Unique lipoprotein-related molecules established causal links with diverse nephritis subtypes. Notably, docosahexaenoic acid (DHA) emerged as a protective factor for acute tubulointerstitial nephritis (ATIN) (OR1 = 0.84, [95% CI 0.78-0.90], p1 = 0.013; OR2 = 0.89, [95% CI 0.82-0.97], p2 = 0.007). Conversely, multivitamin supplementation minus minerals notably increased the risk of ATIN (OR = 31.25, [95% CI 9.23-105.85], p = 0.004). Reduced α-linolenic acid (ALA) levels due to lipid-lowering drugs were linked to both ATIN (OR = 4.88, [95% CI 3.52-6.77], p < 0.001) and tubulointerstitial nephritis (TIN) (OR = 7.52, [95% CI 2.78-20.30], p = 0.042). While the non-renal drug indivina showed promise for TIN treatment, the use of digoxin, hydroxocobalamin, and liothyronine elevated the risk of chronic tubulointerstitial nephritis (CTIN). Transcriptome analysis affirmed that anomalous lipid metabolism and immune infiltration are characteristic of IgA nephropathy and lupus nephritis. The robustness of these causal links was reinforced by sensitivity analyses and leave-one-out tests, indicating no signs of pleiotropy.
UNASSIGNED: Dyslipidemia significantly contributes to nephritis development. Strategies aimed at reducing plasma low-density lipoprotein levels or ALA supplementation may enhance the efficacy of existing lipid-lowering drug regimens for nephritis treatment. Renal functional status should also be judiciously considered with regard to the use of nonrenal medications.
摘要：
■肾炎是慢性肾病（CKD）进展的关键催化剂。尽管流行病学研究已经探讨了血浆循环代谢物和药物对肾炎的影响,很少有人利用遗传方法来建立因果关系。
■通过两个实质性队列的孟德尔随机化（MR），跨越大样本量，我们评估了超过100种血浆循环代谢物和263种药物,以辨别它们对肾炎风险的因果影响.主要分析工具是逆方差加权(IVW)分析。我们对GSE115857(IgA肾病，86个样本）和GSE72326（狼疮性肾炎，238个样品）揭示了肾炎中脂质代谢和免疫学特征的异常。彻底的敏感性分析(MR-Egger，MR-PRESSO,留一法分析)进行验证工具变量(IVs)假设。
■独特的脂蛋白相关分子与不同的肾炎亚型建立了因果关系。值得注意的是,二十二碳六烯酸（DHA）是急性肾小管间质性肾炎（ATIN）的保护因素（OR1=0.84，[95％CI0.78-0.90]，p1=0.013；OR2=0.89，[95%CI0.82-0.97]，p2=0.007)。相反，补充多种维生素减去矿物质显着增加ATIN的风险（OR=31.25，[95％CI9.23-105.85]，p=0.004)。由于降脂药物导致的α-亚麻酸（ALA）水平降低与两种ATIN有关（OR=4.88，[95％CI3.52-6.77]，p<0.001）和肾小管间质性肾炎（TIN）（OR=7.52，[95%CI2.78-20.30]，p=0.042)。虽然非肾脏药物indivina显示出治疗TIN的希望，地高辛的使用，羟钴胺素,和甲状腺素升高了慢性肾小管间质性肾炎（CTIN）的风险。转录组剖析肯定脂质代谢异常和免疫浸润是IgA肾病和狼疮性肾炎的特点。这些因果联系的稳健性通过敏感性分析和漏检检验得到了加强，没有多效性的迹象.
■血脂异常与肾炎的发展密切相关。旨在降低血浆低密度脂蛋白水平或补充ALA的策略可能会增强现有降脂药物治疗肾炎的疗效。对于使用非肾脏药物，还应审慎考虑肾功能状态。
■通过两个实质性队列的孟德尔随机化（MR），跨越大样本量，我们评估了超过100种血浆循环代谢物和263种药物,以辨别它们对肾炎风险的因果影响.主要分析工具是逆方差加权(IVW)分析。我们对GSE115857(IgA肾病，86个样本）和GSE72326（狼疮性肾炎，238个样品）揭示了肾炎中脂质代谢和免疫学特征的异常。彻底的敏感性分析(MR-Egger，MR-PRESSO,留一法分析)进行验证工具变量(IVs)假设。
■独特的脂蛋白相关分子与不同的肾炎亚型建立了因果关系。值得注意的是,二十二碳六烯酸（DHA）是急性肾小管间质性肾炎（ATIN）的保护因素（OR1=0.84，[95％CI0.78-0.90]，p1=0.013；OR2=0.89，[95%CI0.82-0.97]，p2=0.007)。相反，补充多种维生素减去矿物质显着增加ATIN的风险（OR=31.25，[95％CI9.23-105.85]，p=0.004)。由于降脂药物导致的α-亚麻酸（ALA）水平降低与两种ATIN有关（OR=4.88，[95％CI3.52-6.77]，p<0.001）和肾小管间质性肾炎（TIN）（OR=7.52，[95%CI2.78-20.30]，p=0.042)。虽然非肾脏药物indivina显示出治疗TIN的希望，地高辛的使用，羟钴胺素,和甲状腺素升高了慢性肾小管间质性肾炎（CTIN）的风险。转录组剖析肯定脂质代谢异常和免疫浸润是IgA肾病和狼疮性肾炎的特点。这些因果联系的稳健性通过敏感性分析和漏检检验得到了加强，没有多效性的迹象.
■血脂异常与肾炎的发展密切相关。旨在降低血浆低密度脂蛋白水平或补充ALA的策略可能会增强现有降脂药物治疗肾炎的疗效。对于使用非肾脏药物，还应审慎考虑肾功能状态。
