Laville Solène M, Jaisson Stéphane, Gillery Philippe, Okwieka Anaïs, Alencar de Pinho Natalia, Combe Christian, Mansencal Nicolas, Massy Ziad A, Liabeuf Sophie
MP3CV Laboratory, Jules Verne University of Picardie, Amiens, France.
Pharmacoepidemiology Unit, Department of Clinical Pharmacology, Amiens-Picardie University Medical Center, Amiens, France.
Kidney360. 2025 Apr 1;6(8):1328-1337. doi: 10.34067/KID.0000000797.
In nondialysis CKD, baseline serum homocitrulline was positively and independently linked to age, low eGFR, urea, anemia, and diuretics. A higher serum homocitrulline concentration was associated with an elevated risk of major adverse cardiovascular event and all-cause mortality rate. Targeting elevated levels of protein carbamylation may be a way of modifying the cardiovascular risk in patients with CKD.
Protein carbamylation contributes to an increase in the cardiovascular risk in certain patient populations (., in patients with CKD because of elevated urea concentrations). Homocitrulline (HCit) is a biomarker of overall protein carbamylation. In a study of a large cohort of nondialysis patients with a confirmed diagnosis of CKD and an eGFR <60 ml/min per 1.73 m, we sought to determine whether the serum HCit concentration was associated with adverse cardiovascular outcomes and all-cause mortality.
CKD-renal epidemiology and information network is a prospective cohort of patients with CKD and an eGFR <60 ml/min per 1.73 m. The baseline serum HCit concentration was centrally measured. The 2195 patients included in the analysis were divided into tertile (T) groups according to the baseline HCit concentration (T1 <292, T2=[292–429], and T3 ≥430 mol/mol lysine). Adjusted Cox proportional hazards models were used to estimate hazard ratios for the first major adverse cardiovascular event (MACE) and death before KRT.
Among the 2195 included patients, the median age was 68 years and the mean eGFR was 34.6 ml/min per 1.73 m. The median (interquartile range) serum HCit was 352 (266–481) mol/mol lysine. The HCit concentration was correlated with the eGFR (=−0.57) and the urea concentrations (=0.73). In an adjusted linear regression model, the HCit concentration was independently and positively associated with age, eGFR decrease, urea, anemia, baseline prescription of diuretics, and negatively associated with male sex and an elevated urinary albumin-to-creatinine ratio. The adjusted hazard ratio (95% confidence interval) for MACEs as a function of the baseline HCit concentration was 1.32 (0.96 to 1.84) for T2 and 1.63 (1.16 to 2.30) for T3, compared with T1. The risk of death before KRT as a function of the baseline serum HCit concentration was 2.09 (1.45 to 3.03) for T3 and 1.48 (1.04 to 2.11) for T2, compared with T1.
Our analysis of a large cohort of patients with CKD demonstrated that the serum HCit concentration was associated with a greater likelihood of a MACE and death. To confirm causality, further studies of therapeutic interventions for preventing or reducing carbamylation are now warranted.
: NCT03381950.
在非透析慢性肾脏病（CKD）患者中，基线血清同型瓜氨酸与年龄、估算肾小球滤过率（eGFR）降低、尿素、贫血及利尿剂呈正相关且具有独立性。血清同型瓜氨酸浓度升高与主要不良心血管事件风险及全因死亡率升高相关。针对蛋白质氨甲酰化水平升高进行干预可能是改善CKD患者心血管风险的一种方法。
蛋白质氨甲酰化会增加特定患者群体（如因尿素浓度升高导致的CKD患者）的心血管风险。同型瓜氨酸（HCit）是整体蛋白质氨甲酰化的生物标志物。在一项针对大量确诊为CKD且eGFR<60 ml/min/1.73 m²的非透析患者队列研究中，我们试图确定血清HCit浓度是否与不良心血管结局及全因死亡率相关。
CKD-肾脏流行病学和信息网络是一个针对CKD且eGFR<60 ml/min/1.73 m²患者的前瞻性队列研究。基线血清HCit浓度采用集中检测。纳入分析的2195例患者根据基线HCit浓度分为三分位数（T）组（T1<292、T2=[292 - 429]、T3≥430 μmol/mol赖氨酸）。采用校正的Cox比例风险模型估算首次主要不良心血管事件（MACE）及开始肾脏替代治疗（KRT）前死亡的风险比。
在纳入的2195例患者中，中位年龄为68岁，平均eGFR为34.6 ml/min/1.73 m²。血清HCit的中位数（四分位间距）为352（266 - 481）μmol/mol赖氨酸。HCit浓度与eGFR（r = -0.57）及尿素浓度（r = 0.73）相关。在校正线性回归模型中，HCit浓度与年龄、eGFR降低、尿素、贫血、利尿剂基线处方呈独立正相关，与男性及尿白蛋白/肌酐比值升高呈负相关。与T1组相比，T2组因基线HCit浓度导致的MACE校正风险比（95%置信区间）为1.32（0.96至1.84），T3组为1.63（1.16至2.30）。与T1组相比，T3组因基线血清HCit浓度导致的KRT前死亡风险为2.09（1.45至3.03），T2组为1.48（1.04至2.11）。
我们对大量CKD患者的分析表明，血清HCit浓度与发生MACE及死亡的可能性更大相关联。为证实因果关系，现在有必要进一步开展关于预防或减少氨甲酰化的治疗性干预研究。
NCT03381950
