Sonoda Yuji, Gohda Tomohito, Suzuki Yusuke, Omote Keisuke, Ishizaka Masanori, Matsuoka Joe, Tomino Yasuhiko
Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan.
Clinical Research Center, Juntendo University Faculty of Medicine, Tokyo, Japan.
PLoS One. 2015 Apr 10;10(4):e0122212. doi: 10.1371/journal.pone.0122212. eCollection 2015.
The current study aimed to examine whether the levels of TNF receptors 1 and 2 (TNFR1 and TNFR2) in serum and urine were associated with other markers of kidney injury and renal histological findings, including TNFR expression, in IgA nephropathy (IgAN). The levels of the parameters of interest were measured by immunoassay in 106 biopsy-proven IgAN patients using samples obtained immediately before renal biopsy and in 34 healthy subjects. Renal histological findings were evaluated using immunohistochemistry. The levels of serum TNFRs were higher in IgAN patients than in healthy subjects. The levels of both TNFRs in serum or urine were strongly correlated with each other (r > 0.9). Serum TNFR levels were positively correlated with the urinary protein to creatinine ratio (UPCR) and four markers of tubular damage of interest (N-acetyl-β-D-glucosaminidase [NAG], β2 microglobulin [β2m], liver-type fatty acid-binding protein [L-FABP], and kidney injury molecule-1 [KIM-1]) and negatively correlated with estimated glomerular filtration rate (eGFR). Patients in the highest tertile of serum TNFR levels showed more severe renal interstitial fibrosis than did those in the lowest or second tertiles. The tubulointerstitial TNFR2-, but not TNFR1-, positive area was significantly correlated with the serum levels of TNFRs and eGFR. Stepwise multiple regression analysis revealed that elevated serum TNFR1 or TNFR2 levels were a significant determinant of renal interstitial fibrosis after adjusting for eGFR, UPCR, and other markers of tubular damage. In conclusion, elevated serum TNFR levels were significantly associated with the severity of renal interstitial fibrosis in IgAN patients. However, the source of TNFRs in serum and urine remains unclear.
本研究旨在探讨在IgA肾病（IgAN）中，血清和尿液中肿瘤坏死因子受体1和2（TNFR1和TNFR2）水平是否与其他肾损伤标志物及肾脏组织学结果（包括TNFR表达）相关。通过免疫测定法，使用肾活检前即刻采集的样本，对106例经活检证实的IgAN患者及34名健康受试者测定了相关参数水平。采用免疫组织化学评估肾脏组织学结果。IgAN患者血清TNFR水平高于健康受试者。血清或尿液中两种TNFR水平彼此高度相关（r>0.9）。血清TNFR水平与尿蛋白肌酐比值（UPCR）以及四种感兴趣的肾小管损伤标志物（N-乙酰-β-D-氨基葡萄糖苷酶[NAG]、β2微球蛋白[β2m]、肝型脂肪酸结合蛋白[L-FABP]和肾损伤分子-1[KIM-1]）呈正相关，与估计肾小球滤过率（eGFR）呈负相关。血清TNFR水平处于最高三分位数的患者比最低或第二三分位数的患者表现出更严重的肾间质纤维化。肾小管间质TNFR2阳性面积（而非TNFR1阳性面积）与血清TNFR水平和eGFR显著相关。逐步多元回归分析显示，在调整eGFR、UPCR和其他肾小管损伤标志物后，血清TNFR1或TNFR2水平升高是肾间质纤维化的重要决定因素。总之，血清TNFR水平升高与IgAN患者肾间质纤维化的严重程度显著相关。然而，血清和尿液中TNFR的来源仍不清楚。
