Gobet R, Cisek L J, Zotti P, Peters C A
Department of Urology, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
J Urol. 1998 Sep;160(3 Pt 2):1058-62; discussion 1079. doi: 10.1097/00005392-199809020-00025.
Prenatal diagnosis allows the early detection of vesicoureteral reflux in an increasing number of newborns, some of whom are born with impaired kidney function. This situation challenges our current understanding of the pathophysiology, natural history and, therefore, treatment of reflux. We created a fetal sheep model of vesicoureteral reflux to study the mechanisms of fetal reflux nephropathy.
Vesicoureteral reflux was induced in fetal sheep at 95 days of gestation (term 140 days) by open bladder incision of the intravesical ureteral tunnel. All animals underwent urachal ligation and in female subjects mild bladder outlet obstruction was created with a gold ring.
At term reflux was detected in 18 of 28 renal units by filling cystography. Refluxing kidneys were hydronephrotic and larger than normal. At term mean kidney weight was 21.1 gm. (range 12.2 to 35.0) in male subjects with reflux compared to 8.5 gm. (range 6.5 to 11.3) in normal male subjects (p <0.001) and 11.5 gm. (range 8.5 to 15.8) in male subjects with urachal ligation only (p = 0.035). In female subjects there was no change in renal weight. Renal histology revealed a thin, structurally normal cortex with small subcortical cysts and a hypoplastic medulla with mesenchymal tissue replacing normal ducts. Total mean renal collagen content was significantly increased to 51.7 mg. (range 35 to 81) in the refluxing kidneys of male animals, while it was 23.8 mg. (range 12.1 to 38.4) in normal male animals (p = 0.03). The fractional excretion of sodium was elevated in refluxing kidneys based on sodium-to-creatinine ratios in bladder urine.
In a novel model of fetal vesicoureteral reflux we showed that prenatal reflux nephropathy is characterized by altered renal growth regulation, structural maldevelopment without overt dysplasia, excess matrix deposition and impaired excretory function.
产前诊断能够使越来越多的新生儿早期检测出膀胱输尿管反流，其中一些新生儿出生时肾功能受损。这种情况对我们目前对反流的病理生理学、自然病史以及治疗方法的理解提出了挑战。我们创建了一个膀胱输尿管反流的胎羊模型来研究胎儿反流性肾病的机制。
在妊娠95天（足月为140天）时，通过切开膀胱内输尿管隧道对胎羊进行膀胱输尿管反流诱导。所有动物均进行脐尿管结扎，对于雌性动物，用金环造成轻度膀胱出口梗阻。
足月时，通过膀胱造影术在28个肾单位中的18个检测到反流。发生反流的肾脏出现肾积水且比正常肾脏大。足月时，有反流的雄性动物平均肾脏重量为21.1克（范围为12.2至35.0克），而正常雄性动物为8.5克（范围为6.5至11.3克）（p<0.001），仅进行脐尿管结扎的雄性动物为11.5克（范围为8.5至15.8克）（p = 0.035）。雌性动物的肾脏重量没有变化。肾脏组织学显示皮质薄，结构正常，有小的皮质下囊肿，髓质发育不全，间质组织取代了正常导管。雄性动物反流肾脏的总平均肾胶原含量显著增加至51.7毫克（范围为35至81毫克），而正常雄性动物为23.8毫克（范围为12.1至38.4毫克）（p = 0.03）。根据膀胱尿液中钠与肌酐的比值，反流肾脏中钠的分数排泄升高。
在一个新的胎儿膀胱输尿管反流模型中，我们表明产前反流性肾病的特征是肾脏生长调节改变、结构发育异常但无明显发育异常、基质沉积过多和排泄功能受损。
