Drube Jens, Schiffer Eric, Mischak Harald, Kemper Markus J, Neuhaus Thomas, Pape Lars, Lichtinghagen Ralf, Ehrich Jochen H H
Department of Paediatric Nephrology, Children's Hospital, Hannover Medical School, Hannover, Germany.
Nephrol Dial Transplant. 2009 Jul;24(7):2161-9. doi: 10.1093/ndt/gfp063. Epub 2009 Feb 18.
The renal Fanconi syndrome (FS) is characterized by renal glucosuria, loss of electrolytes, bicarbonate and lactate, generalized hyperaminoaciduria and low-molecular-weight proteinuria. We studied the urinary low-molecular-weight proteome to identify excreted peptides indicative of a pathogenetic mechanism leading to tubular dysfunction.
We established a urinary proteome pattern using capillary electrophoresis mass spectrometry (CE-MS) of 7 paediatric patients with cystinosis and 6 patients with ifosfamide-induced FS as the study group, and 54 healthy volunteers and 45 patients suffering from other renal diseases such as lupus nephritis (n = 8), focal segmental glomerulosclerosis (n = 27), minimal change disease (n = 7) and membranous glomerulonephritis (n = 3) as controls. Consequently, we conducted a blinded study consisting of 11 FS patients and 9 patients with renal disease other than FS. Additionally, we applied this pattern to 294 previously measured samples of patients with different renal diseases. Amino acid sequences of some marker proteins were obtained.
Specificity for detecting FS was 89% and sensitivity was 82%. The marker peptides constituting the proteome pattern are fragments derived from osteopontin, uromodulin and collagen alpha-1.
CE-MS can be used to diagnose FS in paediatric patients and might be a future tool for the non-invasive diagnosis of FS. The reduced amount of the marker proteins osteopontin and uromodulin indicates loss of function of tubular excretion in all patients suffering from FS regardless of the underlying cause. In addition, the six different fragments of the collagen alpha-1 (I) chain were either elevated or reduced in the urine. This indicates a change of proteases in collagen degradation as observed in interstitial fibrosis. These changes were prominent irrespectively of the stages of FS. This indicates fibrosis as an early starting pathogenetic reason for the development of renal insufficiency in FS patients.
肾性范科尼综合征（FS）的特征为肾性糖尿、电解质、碳酸氢盐和乳酸丢失、全身性高氨基酸尿症以及低分子量蛋白尿。我们研究了尿低分子量蛋白质组，以鉴定可指示导致肾小管功能障碍的发病机制的排泄肽。
我们使用毛细管电泳质谱法（CE-MS）建立了7例胱氨酸病患儿和6例异环磷酰胺诱导的FS患者作为研究组的尿蛋白质组图谱，并以54名健康志愿者和45例患有其他肾脏疾病（如狼疮性肾炎（n = 8）、局灶节段性肾小球硬化症（n = 27）、微小病变病（n = 7）和膜性肾小球肾炎（n = 3））的患者作为对照。随后，我们对11例FS患者和9例非FS肾脏疾病患者进行了一项盲法研究。此外，我们将此图谱应用于294份先前测量的不同肾脏疾病患者的样本。获得了一些标记蛋白的氨基酸序列。
检测FS的特异性为89%，敏感性为82%。构成蛋白质组图谱的标记肽是源自骨桥蛋白、尿调节蛋白和胶原蛋白α-1的片段。
CE-MS可用于诊断小儿FS患者，可能成为未来FS无创诊断的工具。标记蛋白骨桥蛋白和尿调节蛋白数量减少表明，所有FS患者无论潜在病因如何，肾小管排泄功能均丧失。此外，胶原蛋白α-1（I）链的六个不同片段在尿液中要么升高要么降低。这表明在间质纤维化中观察到的胶原蛋白降解中的蛋白酶发生了变化。这些变化在FS各阶段均很突出。这表明纤维化是FS患者肾功能不全发展的早期发病原因。
