Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA.
Kidney Research Institute, University of Washington, Seattle, WA.
Diabetes Care. 2022 Jun 2;45(6):1416-1427. doi: 10.2337/dc21-2204.
Understanding mechanisms underlying rapid estimated glomerular filtration rate (eGFR) decline is important to predict and treat kidney disease in type 1 diabetes (T1D).
We performed a case-control study nested within four T1D cohorts to identify urinary proteins associated with rapid eGFR decline. Case and control subjects were categorized based on eGFR decline ≥3 and <1 mL/min/1.73 m2/year, respectively. We used targeted liquid chromatography-tandem mass spectrometry to measure 38 peptides from 20 proteins implicated in diabetic kidney disease. Significant proteins were investigated in complementary human cohorts and in mouse proximal tubular epithelial cell cultures.
The cohort study included 1,270 participants followed a median 8 years. In the discovery set, only cathepsin D peptide and protein were significant on full adjustment for clinical and laboratory variables. In the validation set, associations of cathepsin D with eGFR decline were replicated in minimally adjusted models but lost significance with adjustment for albuminuria. In a meta-analysis with combination of discovery and validation sets, the odds ratio for the association of cathepsin D with rapid eGFR decline was 1.29 per SD (95% CI 1.07-1.55). In complementary human cohorts, urine cathepsin D was associated with tubulointerstitial injury and tubulointerstitial cathepsin D expression was associated with increased cortical interstitial fractional volume. In mouse proximal tubular epithelial cell cultures, advanced glycation end product-BSA increased cathepsin D activity and inflammatory and tubular injury markers, which were further increased with cathepsin D siRNA.
Urine cathepsin D is associated with rapid eGFR decline in T1D and reflects kidney tubulointerstitial injury.
了解导致估算肾小球滤过率（eGFR）快速下降的机制对于预测和治疗 1 型糖尿病（T1D）患者的肾脏疾病非常重要。
我们在四个 T1D 队列中进行了一项病例对照研究，以确定与 eGFR 快速下降相关的尿蛋白。病例和对照患者分别根据 eGFR 下降≥3 和 <1 mL/min/1.73 m2/年进行分类。我们使用靶向液相色谱-串联质谱法测量了 20 种与糖尿病肾病相关蛋白的 38 个肽段。在补充的人类队列和小鼠近端肾小管上皮细胞培养物中研究了显著的蛋白。
该队列研究纳入了 1270 名参与者，中位随访时间为 8 年。在发现组中，仅组织蛋白酶 D 肽和蛋白在充分调整临床和实验室变量后具有统计学意义。在验证组中，组织蛋白酶 D 与 eGFR 下降的关联在最小调整模型中得到了复制，但在调整白蛋白尿后失去了统计学意义。在发现组和验证组的荟萃分析中，组织蛋白酶 D 与 eGFR 快速下降的关联比值比为 1.29（95%CI 1.07-1.55）。在补充的人类队列中，尿组织蛋白酶 D 与肾小管间质损伤相关，皮质间质分体积的增加与肾小管间质组织蛋白酶 D 表达相关。在小鼠近端肾小管上皮细胞培养物中，晚期糖基化终产物-BSA 增加了组织蛋白酶 D 的活性和炎症及管状损伤标志物，而用组织蛋白酶 D siRNA 进一步增加了这些标志物。
尿组织蛋白酶 D 与 T1D 患者的 eGFR 快速下降相关，反映了肾脏的肾小管间质损伤。
