Madsen Mia Gebauer
Department of Urology, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus N, Denmark.
Dan Med J. 2013 Feb;60(2):B4582.
Hydronephrosis is diagnosed in 0.5-1% of all newborns, and ureteropelvic junction obstruction (UPJO) accounts for 35% of those cases. A urinary tract obstruction that occurs during early kidney development affects renal morphogenesis, maturation, and growth, and in the most severe cases, this will ultimately lead to progressive renal tubular atrophy and interstitial fibrosis with the loss of nephrons. The clinical management of these patients remains a controversial topic. The aim is to preserve renal function by identifying the 15-20% of children who require early surgical intervention from those for whom watchful waiting may be appropriate because of spontaneous resolving/stabilization without significant loss of renal function. Although the patients attend regular follow-ups, including repetitive blood tests, ultrasonographies, and the more invasive diuretic renograms, the surgeons still miss reliably biomarkers that could be used as predictors for renal parenchymal damage and decreased renal function, and thereby provide more clear indications for surgical intervention. The aim of this PhD thesis was to further elucidate the pathophysiology of obstructive nephropathy (study I) and to search for potential candidate biomarkers that may have a predictive and/or diagnostic value in the management of hydronephrosis (study II). Study I: Urine and kidney cytokine profiles in experimental unilateral acute and chronic hydronephrosis.
To study the dynamics of the urinary secretion of cytokines after the release of unilateral ureteral obstruction, and to study whether the urinary concentrations of these compounds reliably reflects changes in the renal parenchyma. This was tested in 2 experimental rat models: an acute obstruction model and a chronic obstruction model.
The acute obstruction model demonstrated significant differences in the renal levels of IL-1β, IL-6, TNF-α, and IL-10 in comparison with controls, and these differences were associated with similar differences in their urinary excretion. Such results were not obtained in the chronic obstruction model in which significant differences were only demonstrated in the urinary concentrations of IL-6. Study II: Candidate urinary biomarkers in hydronephrosis - a clinical study.
To study the dynamics of the urinary excretion of selected potential biomarkers in children after the relief of UPJO, and to compare their findings with healthy controls.
Twenty-eight children with UPJO were included in the study from 2007-2011 together with 13 healthy children. Pre-, peri- and post-operatively (1 year) urine samples were collected. The median age of the patients was 8.1 (3.5-14.5) years. Five proteins (EGF, IP-10, MCP-1, RANTES, and MIP-1α) were examined in study IIa, and 4 proteins (NGAL, CyC, βM-2, and OPN) were examined in study IIb. In brief, significantly increased urinary concentrations of EGF and MCP-1 were demonstrated in children with UPJO compared to controls, which was followed by a decline in the post-operative period to levels similar to the controls. This indicates that the urinary concentrations of EGF and MCP-1 are regulated as a response to the obstruction, suggesting that they may have a potential as urinary biomarkers in hydronephrosis. In general, urine from the obstructed kidney exhibited higher concentrations of the proteins compared to urine from the nonobstructed kidney. Furthermore, CyC, β-2M, and OPN were negatively correlated with age, and IP-10 and MCP-1 were negatively correlated with DRF. In conclusion, this PhD study confirmed increased concentrations of selected proteins in urine from kidneys suffering from obstruction. Interestingly, it was observed that some urinary proteins had an age-dependent excretion. Further investigations are required to test the ability of the examined proteins to identify an obstruction and reveal disease progression and, thereby, be useful clinical tools.
在所有新生儿中，肾盂积水的诊断率为0.5%-1%，其中输尿管肾盂连接部梗阻（UPJO）占这些病例的35%。早期肾脏发育过程中发生的尿路梗阻会影响肾脏形态发生、成熟和生长，在最严重的情况下，这最终会导致进行性肾小管萎缩和间质纤维化，伴有肾单位丧失。这些患者的临床管理仍然是一个有争议的话题。目的是通过识别15%-20%需要早期手术干预的儿童，将其与那些由于自发缓解/稳定且肾功能无明显丧失而可能适合密切观察等待的儿童区分开来，从而保留肾功能。尽管患者会定期进行随访，包括重复的血液检查、超声检查以及更具侵入性的利尿肾图检查，但外科医生仍然未能找到可靠的生物标志物，这些生物标志物可作为肾实质损伤和肾功能下降的预测指标，从而为手术干预提供更明确的指征。本博士论文的目的是进一步阐明梗阻性肾病的病理生理学（研究I），并寻找可能在肾盂积水管理中具有预测和/或诊断价值的潜在候选生物标志物（研究II）。研究I：实验性单侧急性和慢性肾盂积水中尿液和肾脏细胞因子谱。
研究单侧输尿管梗阻解除后细胞因子的尿分泌动态，并研究这些化合物的尿浓度是否能可靠反映肾实质的变化。在2种实验大鼠模型中进行了测试：急性梗阻模型和慢性梗阻模型。
与对照组相比，急性梗阻模型显示IL-1β、IL-6、TNF-α和IL-10的肾脏水平存在显著差异，这些差异与它们的尿排泄量的相似差异相关。在慢性梗阻模型中未获得此类结果，其中仅在IL-6的尿浓度中显示出显著差异。研究II：肾盂积水中的候选尿生物标志物——一项临床研究。
研究UPJO解除后儿童中选定潜在生物标志物的尿排泄动态，并将其结果与健康对照进行比较。
2007年至2011年期间，28例UPJO患儿和13例健康儿童纳入研究。收集术前、术中及术后（1年）的尿液样本。患者的中位年龄为8.1（3.5-14.5）岁。在研究IIa中检测了5种蛋白质（表皮生长因子（EGF）、干扰素诱导蛋白10（IP-10）、单核细胞趋化蛋白-1（MCP-1）、调节激活正常T细胞表达和分泌因子（RANTES）和巨噬细胞炎性蛋白-1α（MIP-1α）），在研究IIb中检测了4种蛋白质（中性粒细胞明胶酶相关脂质运载蛋白（NGAL）、胱抑素C（CyC）、β2微球蛋白（βM-2）和骨桥蛋白（OPN））。简而言之，与对照组相比，UPJO患儿的EGF和MCP-1尿浓度显著升高，术后下降至与对照组相似的水平。这表明EGF和MCP-1的尿浓度是对梗阻的一种调节反应，表明它们可能具有作为肾盂积水尿生物标志物的潜力。一般来说，梗阻侧肾脏的尿液中蛋白质浓度高于非梗阻侧肾脏的尿液。此外，CyC、β2微球蛋白和OPN与年龄呈负相关，IP-10和MCP-1与滤过率（DRF）呈负相关。总之，本博士研究证实了梗阻肾脏尿液中选定蛋白质浓度升高。有趣的是，观察到一些尿蛋白具有年龄依赖性排泄。需要进一步研究来测试所检测蛋白质识别梗阻和揭示疾病进展的能力，从而成为有用的临床工具。
