Gobet R, Cisek L J, Chang B, Barnewolt C E, Retik A B, Peters C A
Department of Urology and Radiology, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
J Urol. 1999 Sep;162(3 Pt 2):1090-5. doi: 10.1016/S0022-5347(01)68078-9.
We assessed renal function and urodynamic status in animals with experimental congenital vesicoureteral reflux.
Vesicoureteral reflux was surgically induced in male sheep fetuses at 95 days of gestation. After birth the animals were maintained on antibiotic prophylaxis. At ages 1 week and 6 months reflux was assessed by fluoroscopic voiding cystography. Cystometrography was performed with the animals awake. Serum creatinine, inulin clearance and the excretion of urinary N-acetyl-beta-D-glucosaminidase were measured at ages 1 week, 1 month and 6 months by surveillance urine cultures. Urinary concentrating capacity was assessed by desmopressin testing at ages 1 and 6 months.
Nine animals (18 renal units) were born after the induction of reflux. There was no reflux in 2 renal units, while reflux was mild in 2, moderate in 5 and severe in 9. In the 6 animals available for followup at age 6 months only severe reflux persisted. Reflux resolution was associated with normalization of bladder urodynamics. Surveillance urine cultures were negative until age 6 months, when infection developed in 3 of the 6 lambs. In all animals serum creatinine was normal during followup. Glomerular filtration rate in the lambs with reflux was no different from normal at age 1 week but it was significantly less than normal independent of infection at age 6 months (2.7 versus 3.9 ml./kg. per minute, p = 0.002). As an indicator of renal tubular injury the ratio of N-acetyl-beta-D-glucosaminidase-to-creatinine remained significantly higher in animals with reflux than in normal animals from ages 1 week to 6 months (51.0 versus 10.2 IU/mg., p = 0.03). Maximal concentrating ability after desmopressin testing was already less than normal by age 1 month with a maximal increase of 98 versus 435 mOsm./l. in lambs with reflux versus normal lambs (p <0.0001). It was further impaired by age 6 months. Urodynamic evaluation of the animals with reflux revealed decreased bladder compliance at age 1 week with normal voiding pressure. In addition, in those with reflux there was a more pronounced immature voiding pattern with multiple phasic contractions due to sphincteric activity as well as a post-void bladder contraction.
Our model of fetal vesicoureteral reflux induces alterations in renal function that are consistent with clinical observations and marked by altered tubular function but a relatively mild decrease in glomerular filtration. Bladder dynamics are altered, consistent with observations in human neonates with high grade reflux and bladder instability. Whether this represents cause or effect remains unclear. Our model permits focused study of the interaction of these factors in neonatal reflux and may allow the application of more specific therapies, particularly those directed toward mechanisms of renal and bladder dysfunction.
我们评估了实验性先天性膀胱输尿管反流动物的肾功能和尿动力学状态。
在妊娠95天的雄性绵羊胎儿中通过手术诱导膀胱输尿管反流。出生后，动物接受抗生素预防治疗。在1周龄和6月龄时，通过荧光透视排尿膀胱造影评估反流情况。在动物清醒状态下进行膀胱测压。在1周龄、1月龄和6月龄时，通过监测尿培养来测量血清肌酐、菊粉清除率以及尿N-乙酰-β-D-氨基葡萄糖苷酶的排泄量。在1月龄和6月龄时通过去甲加压素试验评估尿浓缩能力。
诱导反流后有9只动物（18个肾单位）出生。2个肾单位无反流，2个为轻度反流，5个为中度反流，9个为重度反流。在6只6月龄可用于随访的动物中，仅重度反流持续存在。反流缓解与膀胱尿动力学正常化相关。直到6月龄，监测尿培养均为阴性，此时6只羔羊中有3只发生感染。在所有动物的随访过程中，血清肌酐均正常。有反流的羔羊在1周龄时肾小球滤过率与正常无异，但在6月龄时显著低于正常，且与感染无关（2.7对3.9毫升/千克每分钟，p = 0.002）。作为肾小管损伤的指标，从1周龄到6月龄，有反流的动物中N-乙酰-β-D-氨基葡萄糖苷酶与肌酐的比值仍显著高于正常动物（51.0对10.2国际单位/毫克，p = 0.03）。去甲加压素试验后的最大浓缩能力在1月龄时就已低于正常，有反流的羔羊最大增加量为98与正常羔羊的435毫渗量/升相比（p <0.0001）。到6月龄时进一步受损。对有反流的动物进行尿动力学评估发现，1周龄时膀胱顺应性降低，排尿压力正常。此外，在有反流的动物中，排尿模式更明显地不成熟，由于括约肌活动以及排尿后膀胱收缩而出现多次阶段性收缩。
我们的胎儿膀胱输尿管反流模型诱导了肾功能改变，这与临床观察结果一致，其特征是肾小管功能改变，但肾小球滤过率相对轻度降低。膀胱动力学发生改变，与患有重度反流和膀胱不稳定的人类新生儿的观察结果一致。这是原因还是结果尚不清楚。我们的模型允许对新生儿反流中这些因素的相互作用进行有针对性的研究，并可能允许应用更具体的治疗方法，特别是那些针对肾和膀胱功能障碍机制所采取的治疗方法。
