肾损伤分子-1 与糖尿病肾病的肾功能丧失：1 型糖尿病患者的一个可能的因果关联。

Kidney injury molecule-1 and the loss of kidney function in diabetic nephropathy: a likely causal link in patients with type 1 diabetes.

机构信息

2nd Clinical Department, Diabetes Nutrition and Metabolic Diseases Chair, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.

出版信息

Diabetes Care. 2015 Jun;38(6):1130-7. doi: 10.2337/dc14-2330. Epub 2015 Mar 17.

DOI:10.2337/dc14-2330

PMID:25784666

Abstract

OBJECTIVE

We evaluated the predictive value and clinical benefit of urinary kidney injury molecule (KIM)-1 for progression of diabetic nephropathy (DN) in type 1 diabetes. We also investigated its causal role for the decrease of estimated glomerular filtration rate (eGFR) by a Mendelian randomization (MR) approach.

RESEARCH DESIGN AND METHODS

We followed 1,573 patients with type 1 diabetes for 6 years. KIM-1 was measured at baseline and normalized with urinary creatinine. KIM-1 predictive value was evaluated by Cox regression, while its added predictive benefit was evaluated using a panel of statistical indexes. The causality for the loss of renal function was evaluated with MR, utilizing the top signal from our genome-wide association study (GWAS) as the instrumental variable.

RESULTS

KIM-1 was not an independent predictor of progression of DN when adjusted for albumin excretion rate (AER) and added no prognostic benefit to AER or eGFR. In multiple regressions, KIM-1 was associated with lower eGFR independently of diabetes duration (β = -4.066; P < 0.0001) but not of AER. In our GWAS, rs2036402 in the KIM1 gene was strongly associated with KIM-1 (β = -0.51; P = 6.5 × 10(-38)). In the MR, KIM-1 was associated with lower eGFR, independently of diabetes duration and AER (β = -5.044; P = 0.040), suggesting a causal relationship.

CONCLUSIONS

KIM-1 did not predict progression to end-stage renal disease independently of AER and added no prognostic benefit to current biomarkers. Nevertheless, the MR showed that the inverse association of increased KIM-1 levels with lower eGFR is likely to represent a causal link.

摘要

目的

我们评估尿肾损伤分子-1（KIM-1）在 1 型糖尿病患者中预测糖尿病肾病（DN）进展的价值和临床获益。我们还通过孟德尔随机化（MR）方法研究了它对估算肾小球滤过率（eGFR）下降的因果作用。

研究设计和方法

我们随访了 1573 例 1 型糖尿病患者 6 年。在基线时测量 KIM-1，并与尿肌酐进行标准化。通过 Cox 回归评估 KIM-1 的预测价值，同时使用一系列统计指标评估其附加预测益处。利用全基因组关联研究（GWAS）的最高信号作为工具变量，通过 MR 评估肾功能丧失的因果关系。

结果

当调整白蛋白排泄率（AER）时，KIM-1 不是 DN 进展的独立预测因子，并且在 AER 或 eGFR 方面没有增加预后益处。在多元回归中，KIM-1 与 eGFR 降低独立相关，与糖尿病病程无关（β=-4.066；P<0.0001），但与 AER 无关。在我们的 GWAS 中，KIM1 基因中的 rs2036402 与 KIM-1 强烈相关（β=-0.51；P=6.5×10(-38)）。在 MR 中，KIM-1 与 eGFR 降低独立相关，与糖尿病病程和 AER 无关（β=-5.044；P=0.040），表明存在因果关系。