Haffner D, Tönshoff B, Blum W F, Vickers M, Siebler T, Cronin M J, Baxter R C, Mehls O
Division of Pediatric Nephrology, University Children's Hospital Heidelberg, Germany.
Kidney Int. 1997 Sep;52(3):802-10. doi: 10.1038/ki.1997.397.
We hypothesized that the increased glomerular permeability to serum proteins in the nephrotic syndrome might lead to alterations of the somatotropic hormone axis, thereby contributing to growth failure and catabolism in the nephrotic state. The insulin-like growth factors (IGF)-I and -II and the IGF binding proteins (IGFBP)-1, -2 and -3 were analyzed in serum and urine of 21 children with the nephrotic syndrome and normal glomerular filtration rate. Mean age-related serum IGF-I levels by RIA (-0.53 +/- 0.34 SD) were slightly, but significantly (P < 0.05) decreased compared with the reference population, whereas mean age-related serum IGF-II levels (0.68 +/- 0.21 SD) were slightly, but significantly (P < 0.005) increased. The urinary excretion rate of both peptides was enhanced fivefold. By RIA, mean age-related serum IGFBP-1 (2.05 +/- 0.19 SD) and, even more pronounced, IGFBP-2 (5.97 +/- 0.65 SD) were clearly elevated despite a 12-fold and 2-fold increase of the respective urinary excretion rate. There was a tight and specific correlation between age-related serum IGFBP-2 levels and the degree of the nephrotic syndrome, as estimated by serum albumin levels (r = -0.78, P < 0.0001). Serum immunoreactive IGFBP-3 levels were also elevated (1.79 +/- 0.33 SD) in nephrotic serum, due to an increase of low-molecular weight IGFBP-3 fragments. By FPLC analysis, there was a decrease of the 150 kDa IGFBP ternary complex in nephrotic serum, which in the presence of normal concentrations of the acid-labile subunit by RIA appears to be due to a reduction of intact IGFBP-3. Serum levels of the high-affinity GH binding protein that presumably reflects GH receptor status in tissues were normal. In summary, total serum IGFs in children with the nephrotic syndrome are normal, but the binding of IGFs to IGFBPs in the circulation is altered with a shift from the 150 kDa IGFBP complex to an excess of low molecular weight IGFBPs. Because increased unsaturated high-affinity IGFBPs in nephrotic serum have the ability to inhibit IGF action on target tissues by competing with the type 1 IGF receptor for IGF binding, this alteration is likely to contribute to growth failure and tissue catabolism in the nephrotic state.
我们推测，肾病综合征时肾小球对血清蛋白通透性增加可能导致生长激素轴的改变，从而促使肾病状态下的生长发育迟缓及分解代谢。对21例肾小球滤过率正常的肾病综合征患儿的血清和尿液进行了胰岛素样生长因子（IGF）-I、-II以及IGF结合蛋白（IGFBP）-1、-2和-3的分析。通过放射免疫分析（RIA）测定，与正常人群相比，按年龄匹配的血清IGF-I水平（-0.53±0.34标准差）虽略有下降，但差异有统计学意义（P<0.05）；而按年龄匹配的血清IGF-II水平（0.68±0.21标准差）则略有升高，且差异有极显著统计学意义（P<0.005）。两种肽的尿排泄率均增加了5倍。通过RIA检测，按年龄匹配的血清IGFBP-1（2.05±0.19标准差），尤其是IGFBP-2（5.97±0.65标准差）明显升高，尽管各自的尿排泄率分别增加了12倍和2倍。按年龄匹配的血清IGFBP-2水平与肾病综合征的严重程度（以血清白蛋白水平评估）之间存在紧密且特定的相关性（r=-0.78，P<0.0001）。肾病血清中的血清免疫反应性IGFBP-3水平也升高（1.79±0.33标准差），这是由于低分子量IGFBP-3片段增加所致。通过快速蛋白液相色谱（FPLC）分析，肾病血清中150kDa的IGFBP三元复合物减少，在RIA检测酸不稳定亚基浓度正常的情况下，这似乎是由于完整的IGFBP-3减少所致。推测反映组织中生长激素受体状态的高亲和力生长激素结合蛋白的血清水平正常。总之，肾病综合征患儿的血清总IGF水平正常，但循环中IGF与IGFBP的结合发生改变，从150kDa的IGFBP复合物转变为低分子量IGFBP过量。由于肾病血清中不饱和高亲和力IGFBP增加能够通过与1型IGF受体竞争IGF结合来抑制IGF对靶组织的作用，这种改变可能促使肾病状态下的生长发育迟缓及组织分解代谢。
