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Current Status of Fetal Intervention for Congenital Hydronephrosis
0022-534 7/83/1304-0641$02.00/0 THE JOURNAL OF UROLOGY Copyright© 1983 by The Williams & Wilkins Co.
Vol. 130, October Printed in U.S.A.
Review Article CURRENT STATUS OF FETAL INTERVENTION FOR CONGENITAL HYDRONEPHROSIS STEPHEN A. KRAMER* From the Department of Urology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
The rationale for antenatal intervention in the fetus with congenital hydronephrosis is that unrelieved, high grade urinary obstruction in utero may produce progressive renal damage. A review is presented of the current status of fetal intervention for congenital hydronephrosis and an attempt is made to answer several pertinent medical questions that urologists must address, that is 1) how accurate is prenatal ultrasonography in the diagnosis of obstructive hydronephrosis, 2) how do we differentiate dilated, low pressure hydronephrosis from obstructive uropathy, 3) what is the relationship between obstructive uropathy and pulmonary hypoplasia, 4) is there experimental or clinical evidence to suggest that obstructive uropathy is responsible for renal dysplasia, 5) what techniques currently are available to assess fetal renal function, 6) how do we assess the extent of renal dysplasia and the potential recoverability of obstructive uropathy in the fetus, 7) how long can fetal kidneys remain obstructed before loss of function becomes irreversible, 8) what techniques currently are available for in utero intervention, and what are the risks and potential benefits of these procedures, 9) will decompression of the obstructed urinary tract early in gestation alter the outcome beneficially and 10) how do we select which fetuses with dilated upper tracts need in utero intervention? A discussion of the ethical aspects of in utero intervention is provided elsewhere. 1·2 PRENATAL EVALUATION
Recent technological advances in perinatology have been responsible for a marked decrease in prenatal morbidity and mortality. Improvements in obstetric surveillance include prenatal ultrasonography, amniocentesis and fetoscopy in selected patients. Amniocentesis can be used to detect genetic and biochemical abnormalities. Fetoscopy provides a method of direct visualization of the fetus and intrauterine contents. Although these procedures supply meaningful information they are invasive and have been associated with significant complications. 3-6 Prenatal ultrasonography is a safe and noninvasive technique that can detect a variety of congenital abnormalities in utero. 7- 18 Antenatal sonography is of proved benefit in the detection and followup of patients with oligohydramnios. 19-21 Advances in the development of high resolution, gray scale, real-time ultrasonography have permitted improved visualization of fetal anatomy, and the potential exists for detection of congenital anomalies as early as 12 to 15 weeks of gestation.22-24 Ultrasonography may identify accurately up to 90 per cent-of fetal kidneys by 17 to 20 weeks of gestation and 95 per cent by 22 weeks of gestation. The widespread use of this study during pregnancy· has led to an increased recognition of fetal hydronephrosis. 25 -28 Not all large sonolucent retroperitoneal masses in the fetal * Requests for reprints: Department of Urology, Mayo Clinic, Rochester, Minnesota 55905.
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abdomen are the result of obstructive uropathy. 29 The fetus with presumed hydronephrosis detected by prenatal ultrasonography must undergo repeated studies with real-time techniques for initial findings to be confirmed. Dilatation of the collection system may be transient and may resolve before delivery. Overdistension of the bladder may produce intermittent hydronephrosis that disappears after the fetus voids. 18 Thus, it is important to obtain ultrasonograms at several phases of bladder filling. In patients undergoing fetal ultrasonography several errors in the diagnosis of presumed obstructive uropathy have occurred, including multicystic kidney, vesicoureteral reflux, megacalycosis, ureterocele, congenital nonobstructive megaureter, prune belly syndrome, simple renal cyst, duodenal atresia, bladder outlet obstruction and physiologic hydronephrosis. In a recent study 8 of 13 patients (60 per cent) with proved obstructive uropathy at birth had an incorrect diagnosis by prenatal ultrasonography. 29 CAUSES OF COLLECTING SYSTEM DILATATION
Multicystic kidney probably is the most common entity confused with congenital ureteropelvic junction obstruction. 30 Ultrasonography in neonates and infants can often differentiate the classic multicystic kidney from obstruction at the ureteropelvic junction. 31 The morphologic appearance of ureteropelvic junction obstruction is discernible readily from the usual type of multicystic kidney secondary to pelvioinfundibular atresia (fig. 1). 32 Stuck and associates recently outlined ultrasonographic criteria for identifying multicystic kidneys: 1) presence of interfaces between cyst, 2) nonmedial location oflargest cyst, 3) absence of an identifiable renal sinus, 4) multiplicity of oval or round cysts that do not communicate and 5) absence of parenchymal tissue. 30 However, it is noteworthy that atresia of the ureter or pelvis during intrauterine development may produce the hydronephrotic type of multicystic kidney that simulates ureteropelvic junction obstruction. 33 In these selected patients the distinction between multicystic kidney and ureteropelvic junction obstruction in utero can be extremely difficult, and misdiagnosis may result in inappropriate fetal or obstetric intervention. Several children with significant vesicoureteral reflux have been presumed to have obstructive uropathy on the basis of results of prenatal ultrasonography. Children with dilatation of the renal pelvis secondary to reflux usually have ureteral dilatation, which is not present in patients with congenital ureteropelvic junction obstruction. Prune belly syndrome and nonobstructive dilatation of the collecting system have been diagnosed incorrectly as obstructive uropathy in utero (fig. 2). 34 Ultrasonographic findings in children with prune belly syndrome include an enlarged bladder, bilateral ureteral dilatation, small kidneys and oligohydramnios. Infrequently, these children have hydronephrotic kidneys. However, megaureters and megacystis should allow differentiation from ureteropelvic junction obstruction.
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FIG. 1. Parasagittal scan of left kidney demonstrates 8 cm. mass composed of multiple cystic spaces of different sizes consistent with multicystic dysplastic kidney.
adversely normal lung development. However, oligohydramnios has not been associated universally with pulmonary hypoplasia. Bellinger reported 2 fetuses with oligohydramnios who did not have postnatal pulmonary insufficiency. 38 Abnormal fetal respirations, 39 chest wall abnormalities 40 and mechanical factors 36• 41 - 43 all have been implicated in the genesis of pulmonary hypoplasia. DeLorimier and associates produced pulmonary hypoplasia in fetal lambs by creating a diaphragmatic hernia in utero. 40 Recent evidence suggests that pulmonary hypoplasia may be related to diminished epithelial growth factor in utero. 44 This polypeptide hormone is responsible for pulmonary growth and differentiation in fetal rabbits and lambs, and it appears to afford protection against the development ofhyaline membrane disease in these animals. 45 •46 Human ,6-urogastrone, 47 a peptide isolated from human urine and similar in structure and action to epithelial growth factor, may be deficient in the amniotic fluid of patients with oligohydramnios and this deficiency may contribute to pulmonary hypoplasia. Bilateral congenital hydronephrosis may produce urinary ascites with elevation of the diaphragms and cause secondary mechanical compression of the fetal thorax. Harrison and associates produced congenital hydronephrosis in fetal lambs by obstruction of the urethra and ligation of the urachus. 41 These investigators found that lambs that underwent obstruction during the third trimester were born with hypoplastic lungs and had a higher incidence of fetal mortality. 48 Conversely, lambs that underwent in utero decompression of urinary tract obstruction during the middle of the last trimester had less respiratory difficulty, increased lung weight at birth and resolution of urinary tract dilatation. The problem inherent in use of animal models to study the pathogenesis of pulmonary hypoplasia in humans is that surgery in the fetal animal must be accomplished in the latter half of pregnancy to avoid abortion or pre-term delivery. Pulmonary hypoplasia in humans probably develops early in gestation, so
FIG. 2. Transverse sonogram of fetus shows 14.2 cm. cystic mass consistent with bladder (B). Adjacent cystic spaces represent dilated ureters (arrows).
Duodenal atresia with an enlarged stomach also has led to a presumptive diagnosis of ureteropelvic junction obstruction. 35 Conversely, bilateral ureteropelvic junction obstruction and polyhydramnios 7 • 25 • 18 may result in a misdiagnosis of duodenal atresia. 18 Patients with bladder outlet obstruction, such as those with posterior urethral valves or neuropathic disease, have dilatation of the bladder and 1 or both ureters. These findings should differentiate vesical outlet obstruction from obstruction at a higher level. Furthermore, some observers have reported a 20 per cent incidence of physiologic hydronephrosis in the third trimester of pregnancy, which can be responsible for additional false positive findings. Recently, we treated a child with rapidly progressive hydronephrosis detected in utero by ultrasonography. Our obstetricians performed 3 separate needle aspirations of the kidney for presumed obstruction of the ureteropelvic junction (fig. 3, A). Surgical exploration on the first day of life revealed a multicystic, nonfunctioning kidney with severe renal dysplasia (fig. 3, B). The diagnostic errors of in utero ultrasonography can be significant and all studies must be repeated with real-time techniques to confirm initial findings. PULMONARY HYPOPLASIA
What is the relationship between obstructive uropathy and pulmonary hypoplasia? Although the factors contributing to the development of pulmonary hypoplasia are understood poorly a minimum volume of amniotic fluid appears to be critical to normal pulmonary embryogenesis. 36• 37 A deficiency in amniotic fluid prevents normal chest compliance and affects
FIG. 3. A, real-time longitudinal sonogram shows large cystic mass in right renal fossa consistent with ureteropelvic junction obstruction. Percutaneous puncture demonstrates needle tip (small arrow) within 10 cm. cystic mass (curved arrows) between liver (L) and bladder (b). a, amniotic fluid. B, dysplastic renal parenchyma with dilated and small primitive ducts. Interlacing fibrous stroma and hyalinized collagen are prominent. H & E, reduced from Xl40.
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that comparisons between experimental and clinical studies are difficult to evaluate. To date no experimental or clinical studies have shown that unilateral congenital hydronephrosis produces pulmonary hypoplasia. Even with pulmonary compression in utero the human lung retains the ability to produce new alveoli postnatally. 42 Furthermore, in children with congenital diaphragmatic hernia early postnatal repair has been associated with resumption of alveolar development and normal pulmonary function. 49 RENAL DYSPLASIA
Is there experimental or clinical evidence to suggest that obstructive uropathy is responsible for renal dysplasia? Interestingly, in normal human embryogenesis urethral obstruction occurs before recanalization. 50 At 10 weeks of gestation the inner cortical nephrons produce urine, the ureter becomes patent and urine flows into the urogenital sinus. Shortly thereafter the cloaca! membrane ruptures and allows communication between the urinary tract and the amniotic cavity. Failure of the cloaca! membrane to rupture or failure of the ureters to recanalize results in bilateral obstructive uropathy. The allantois becomes obliterated at 16 weeks and the urachus closes at 32 weeks of gestation. Prolonged patency of either of these structures protects the fetal kidneys from increased pressure secondary to bladder outlet obstruction. Renal dysplasia is a histologic diagnosis characterized by poorly developed glomeruli, medullary cysts, fibrosis, islands of cartilage and primitive ducts. 5 1.5 2 Primitive ducts are the sine qua non of renal dysplasia and are necessary to establish the diagnosis. 58 Dysplasia may occur secondary to abnormalities of the ureteral bud or metanephrogenic blastema itself. 54 The potential contribution of vesicoureteral reflux in the genesis of renal dysplasia is unclear and studies to test this hypothesis are in progress. 55 The coexistence of urinary obstruction and renal dysplasia in humans has prompted studies of obstructive uropathy in experimental animal models. The extent and timing of ureter al obstruction in utero correlate with the severity of renal dysplasia. Early obstruction of the developing kidney results in dysplastic changes. 48 • 56 - 60 In fetal rabbits ligation of the ureters early in utero produces dilatation of the collecting ducts and cystic changes in the outer cortical nephrons. 57 Similarly, ureteral obstruction in fetal lambs during the first half of gestation produces contracted hydronephrotic kidneys and significant renal dysplasia. U reteral obstruction during the latter half of embryogenesis results in hydronephrosis without histologic changes of renal cystic dysplasia. 48 • 56 • 58- 60 Recent studies of chick embryos have shown that the primitive ducts associated with renal dysplasia may originate from branches of the ureteral bud that developed without condensed metanephrogenic mesenchyme. 61 These observations suggest that the most severe examples of renal dysplasia develop as a result of an abnormal location of the ureteral bud. These insults affect the kidney before nephrogenesis is complete. Clinical studies similarly have shown that the degree of obstructive uropathy and the interval during which obstruction occurs are the 2 most important factors responsible for the severity of abnormal renal development. 62 Bellinger reported death at 18 weeks of gestation in a fetus with posterior urethral valves and histologic studies of the kidneys demonstrated significant renal dysplasia. 38 In the human fetus significant urethral or ureteral obstruction is associated with increased intratubular pressure and cystic changes of renal dysplasia. 63 • 64 Maximal pressure exerted at the ampullary ends of the tubules causes shortening and straightening of the collecting ducts. 62 Mackie and Stephens reported a close association between the location of the ureteral bud on the wolffian duct and renal morphology. 65 These investigators postulated that ureteral buds originating from normal areas on the wolffian duct penetrate the metanephric blastema in the _proper position and produce
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normal renal differentiation. 66 Conversely, buds arising from an abnormal position on the duct attach to a peripheral portion of the metanephric blastema, and produce renal hypoplasia and dysplasia. The results of experimental animal studies and clinical observations of human pathogenesis have improved greatly our understanding of congenital hydronephrosis and renal dysplasia. The development of renal dysplasia early in gestation implies that in utero intervention designed to alter the course of obstructive uropathy must be accomplished early in the first trimester of gestation. Unfortunately, even these early efforts have not been successful in altering the course of abnormal renal embryogenesis. 67 ASSESSMENT OF RENAL FUNCTION
Currently, no reliable tests exist to assess accurately renal function in utero or the potential for recoverability of fetal kidneys with obstructive uropathy. Furthermore, early in gestation simple congenital hydronephrosis is extremely difficult to distinguish from cystic renal dysplasia secondary to obstructive uropathy. 33 Renal function in the fetus can be estimated by the volume of amniotic fluid detected by ultrasonography. Oligohydramnios is an accurate reflection of decreased urinary output and is the most important measure of renal impairment. A normal amniotic fluid volume indicates that at least 1 renal unit is functioning. It has been suggested that the intravenous administration of furosemide to the mother results in increased fetal urine output, which can be assessed by ultrasonic determination of bladder volume. 68 Failure to visualize the bladder after this stimulation test suggests that adequate functioning renal parenchyma is absent. 21 Although useful in patients with bilateral renal agenesis or severe bilateral renal dysplasia this technique has not been helpful in those with partial urinary obstruction. 69 The analysis of fetal urine by aspiration of the bladder or kidneys has not been of prognostic value. The ability of the bladder to refill after aspiration in utero similarly has not proved to be an effective predictor of renal function. 70 TECHNIQUES FOR FETAL INTERVENTION
Needle aspiration of bladder or kidney. Percutaneous decompression of the bladder has been performed in patients with prune belly syndrome and megacystitis. 34 Although successful technically this technique has not produced resolution of hydronephrosis or arrested the development of renal dysplasia. Furthermore, the hydronephrotic kidney may be secondary to multicystic renal dysplasia and would not benefit from in utero decompression. 71 Diversion of urine into the amniotic fluid by internal shunt drainage, Golbus and associates developed a technique for percutaneous placement of a catheter shunt from the bladder to the amniotic cavity. 72 This procedure has been successful in decompressing adequately the upper tracts but has noit arrested the associated renal dysplasia or altered the course of abnormal renal development. 69 Open surgical diversion. The feasibility of open surgical diversion for the fetus with congenital hydronephrosis has been well documented. Harrison and associates performed extensive studies on the pathophysiology of congenital hydronephrosis in the fetal lamb model. 41 • 48 These investigators developed successful anesthetic, surgical and tocolytic techniques for fetal surgery in nonhuman primates and in the human fetus. 67 • 70 Harrison and associates recently reported their cumulative e'xperience in 26 fetuses with dilated urinary tracts in utero, including 1 fetus who underwent bilateral cutaneous ureterostomy at 21 weeks of gestation because of obstructive uropathy secondary to posterior urethral valves. 67 • 69 Although surgery technically was successful the newborn died on the first day of life, and postmortem examination revealed renal dysplasia and pulmonary hypoplasia.
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Early delivery. The status of pulmonary maturity can be assessed through measurement of the lecithin-sphingo-myelin ratio in the amniotic fluid or by the presence of phosphatidylglycerol. It often is possible to induce production of pulmonary surfactant by administration of steroids to the mother. 69 However, pulmonary response to steroids in the presence of pulmonary dysplasia may not be predictable. This technique and recent advances in the respiratory care of premature newborns have permitted early elective delivery with an excellent chance of survival in selected patients at 32 weeks of gestation. RISKS VERSUS BENEFITS
Hemorrhage, sepsis, abortion and premature labor (risk of respiratory distress syndrome) are significant risks to the fetus and mother subjected to in utero intervention. A theoretical but serious consideration is the potential development of postobstructive diuresis in the fetus with long-standing outlet obstruction. Renal physiology and blood flow in the fetus are significantly different from hemodynamics in the neonate. Thus, the sequelae and treatment of such a problem remain speculative. It is unclear whether placental function could compensate adequately for alterations in fetal electrolytes and volume changes that occur during post-obstructive diuresis. Furthermore, depletion of intravascular volume from rapid fluid shifts could lead to volume depletion, shock and fetal death. The risks of hysterotomy for open surgical decompression have been enumerated by Harrison and associates, and include 1) fetal or maternal death, 2) hemorrhage or sepsis with resultant abortion, 3) cesarean section, 4) unsuccessful surgery and 5) the occurrence of renal dysplasia and pulmonary hypoplasia despite successful surgery. 70 These risks must be weighed against the benefits of potential salvage of nephrogenesis and arrest of pulmonary hypoplasia. TREATMENT GROUPS
How do we select which fetuses with dilated upper tracts may benefit from in utero intervention? Harrison and associates recently reviewed their indications and methods for intervention in the fetus with congenital hydronephrosis. 69 These investigators used prenatal ultrasonography and currently available methods of assessing renal function in utero to segregate patients into 4 treatment groups: 1) unilateral hydronephrosis, 2) bilateral hydronephrosis with good function, 3) bilateral hydronephrosis with poor function and 4) bilateral hydronephrosis with equivocal function. The fetus with unilateral hydronephrosis and a normal contralateral renal unit does not have oligohydramnios and will have normal renal function. Furthermore, there is no evidence to suggest that unilateral hydronephrosis causes pulmonary hypoplasia. These patients can be observed expectantly and in utero intervention is not necessary except occasionally to permit vaginal delivery. The fetus with bilateral hydronephrosis and adequate amniotic fluid volume has nearly normal renal and pulmonary function, and does not need fetal intervention. These patients should be followed expectantly with serial ultrasound examinations and observation. Bilateral hydronephrosis and oligohydramnios in the fetus have been associated uniformly with severe renal dysplasia and pulmonary hypoplasia. 67 •69 Although accomplished successfully in these patients early surgical intervention in utero has not yet altered the outcome beneficially. The approach to the fetus with bilateral hydronephrosis and equivocal renal function was the subject of a recent review of 5 patients with posterior urethral valves and 2 with prune belly syndrome. 69 All patients had urethral obstruction, a thickwalled bladder and bilateral hydronephrosis. Most patients were delivered at <34 weeks of gestation after prenatal treatment with steroids (betamethasone) to induce production of pulmonary surfactant. One child was delivered at 32 weeks of
FIG. 4. Longitudinal ultrasonogram demonstrates bilateral cystic masses (arrows) in renal fossa consistent with ureteropelvic junction obstruction. T, thorax. H, head.
gestation because of oligohydramnios and underwent bilateral ureterostomy as a neonate. Renal biopsies showed dysplastic changes bilaterally. This patient presently is 4 years old and has chronic renal failure. Two patients had prenatal shunting of urine from the bladder into the amniotic cavity: 1 underwent bilateral ureterostomy and 1 bilateral pyelostomy. Renal biopsies from both patients demonstrated bilateral renal dysplasia. Four neonates were delivered at <34 weeks of gestation after prenatal treatment with steroids: 1 died at 3 weeks of respiratory distress and multiple congenital anomalies, and the remaining 3 were treated with vesicostomy or ablation of posterior urethral valves in the neonatal period. Each of the latter 3 children has normal renal function but 1 also has a defect in tubular concentration. It is interesting to speculate whether respiratory or renal failure would have precluded survival in these patients without in utero intervention. However, these findings document clearly that fetal intervention early in gestation has not prevented renal dysplasia or pulmonary hypoplasia. No evidence exists that relief of obstructive uropathy in the fetus improves renal or pulmonary function more than pyeloplasty, vesicostomy or ablation of posterior urethral valves in the neonate. Recently, we treated a child with bilateral hydronephrosis detected in utero by ultrasonography (fig. 4). The mother was managed expectantly and delivery was at 36 weeks of gestation. Bilateral pyeloplasty was done in the neonatal period and histologic study of the kidneys demonstrated no evidence of renal dysplasia. The patient had normal renal and pulmonary function 1 year postoperatively. COMMENT
In any field of surgery initial attempts at innovative and, often, aggressive techniques are met with skepticism and criticism. It is noteworthy that in approximately 1881 Billroth stated that "any surgeon who tries to suture a heart wound deserves to lose the esteem of his colleagues". Cardiac surgery has progressed significantly despite this remark. Similar speculation and reservations in the field of urology have been surpassed only by the multitude of technologic advances achieved during the last several decades. The efforts of Harrison and associates are exemplary and are to be commended. Their continuing research into the risks and effectiveness of fetal intervention for a variety of congenital anomalies has furthered our understanding of congenital hydronephrosis. Although in utero intervention for diagnosis or treatment of congenital hydronephrosis. Experimental and clinical evidence suggests strongly that histologic changes of renal dysplasia occur early in gestation, long before in utero intervention technically is feasible. Currently, there are no reliable tests to assess fetal renal function or the potential recoverability of kidneys with obstructive uropathy. Prenatal ultrasonography has been associated with a significant number of false results. This is particularly true in attempts to distinguish the hydronephrotic type of
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multicystic kidney from ureteropelvic obstruction. Therefore, it is important to repeat the ultrasonogram after delivery to establish an accurate diagnosis and to evaluate the status of the contralateral kidney. However, prenatal ultrasonography is useful for identification of the high risk pregnancy and allows for early referral of these patients to medical centers where postnatal care can be instituted promptly. In the fetus with obstructive uropathy there is no evidence to suggest that relief of obstruction in utero will result in improvement in renal or pulmonary function beyond that achieved by pyeloplasty, vesicostomy or ablation of posterior urethral valves in the neonate. Most fetuses with hydronephrosis have dilated low pressure systems with adequate urinary output and amniotic fluid volume, and can be followed safely to term delivery. The accumulated experience to date indicates that the fetus with congenital hydronephrosis detected in utero should be managed expectantly with serial ultrasound and observation. The natural history of congenital urinary tract dilatation in the fetus requires more extensive experimental study before fetal intervention by either radiography or in utero surgery can be recommended in the clinical setting. REFERENCES 1. Barclay, W. R., McCormick, R. A., Sidbury, J. B., Michejda, M. and Hodgen, G. D.: The ethics of in utero surgery. J.A.M.A., 246: 1550, 1981. 2. Fletcher, J. C.: The fetus as patient: ethical issues. Editorial. J.A.M.A., 246: 772, 1981. 3. United States Department of Health, Education and Welfare: Antenatal Diagnosis: Report of a Consensus Development Conference. National Institutes of Health Publication No. 79-1973. Bethesda, Maryland: Public Health Service, National Institutes of Health, pp. 1-9, 1979. 4. Cromie, W. J., Bates, R. D. and Duckett, J. W., Jr.: Penetrating renal trauma in the neonate. J. Urol., 119: 259, 1978. 5. Hirschhorn, K.: The role and the hazards of amniocentesis. Ann. N.Y. Acad. Sci., 240: 117, 1975. 6. Ryan, G. T., Ivy, R., Jr. and Pearson, J. W.: Fetal bleeding as a major hazard of amniocentesis. Obst. Gynec., 40: 702, 1972. 7. Cass, A., Smith, S., Godec, C., Veeraraghavan, K., Tsai, S. and Bendel, R.: Prenatal diagnosis of fetal urinary tract abnormalities by ultrasound. Urology, 18: 197, 1981. 8. Hobbins, J. C., Grannum, P. A., Berkowitz, R. L., Silverman, R. and Mahoney, M. J.: Ultrasound in the diagnosis of congenital anomalies. Amer. J. Obst. Gynec., 134: 331, 1979. 9. Kurjak, A., Kirkinen, P., Latin, V. and Ivankovic, D.: Ultrasonic assessment of fetal kidney function in normal and complicated pregnancies. Amer. J. Obst. Gynec., 141: 266, 1981. 10. Nelson, L. H., Resnick, M. I. and Sumner, T. E.: Sonolucencies in fetal and infant abdomen: implications for management. Urology, 15: 528, 1980. 11. Matturri, M., Peters, B. E. and Kedziora, J. A.: Prenatal and postnatal sonographic demonstration of bilateral ureteropelvic junction obstruction. Med. Ultrasound, 4: 94, Aug. 1980. 12. Okulski, T. A.: The prenatal diagnosis of lower urinary tract obstruction using B scan ultrasound: a case report. J. Clin. Ultrasound, 5: 268, 1977. 13. Farrant, P.: Early ultrasound diagnosis of fetal bladder neck obstruction. Brit. J. Rad., 53: 506, 1980. 14. Walzer, A. and Koenigsberg, M.: Prenatal evaluation of partial obstruction of the urinary tract. Radiology, 135: 93, 1980. 15. Hately, W. and Nicholls, B.: The ultrasonic diagnosis of bilateral hydronephrosis in twins during pregnancy. Brit. J. Rad., 52: 989, 1979. 16. Kay, R., Lee, T. G. and Tank, E. S.: Ultrasonographic diagnosis of fetal hydronephrosis in utero. Urology, 13: 286, 1979. 17. Fourcroy, J. L., Blei, C. L., Glassman, L. M. and White, R.: Prenatal diagnosis by ultrasonography of genitourinary abnormalities. Urology, in press. 18. Sanders, R. and Graham, D.: Twelve cases of hydronephrosis in utero diagnosed by ultrasonography. J. Ultrasound Med., 1: 341, 1982. 19. Touloukian, R. J. and Hobbins, J. C.: Maternal ultrasonography in the antenatal diagnosis of surgically correctable fetal abnormalities. J. Ped. Surg., 15: 373, 1980.
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20. Mendoza, S. A., Griswold, W. R., Leopold, G. R. and Kaplan, G. W.: Intrauterine diagnosis of renal anomalies by ultrasonography. Amer. J. Dis. Child., 133: 1042, 1979. 21. Harrison, M. R., Golbus, M. S. and Filly, R. A.: Management of the fetus with a correctable congenital defect. J.A.M.A., 246: 774, 1981. 22. Dubbins, P.A., Kurtz, A. B., Wapner, R. J. and Goldberg, B. B.: Renal agenesis: spectrum of in utero findings. J. Clin. Ultrasound, 9: 189, 1981 23. Canty, T. G., Leopold, G. R. and Wolf, D. A.: Maternal ultrasonography for the antenatal diagnosis of surgically significant neonatal anomalies. Ann. Surg., 194: 353, 1981. 24. Hadlock, F. P., Deter, R. L., Carpenter, R., Gonzalez, E. T. and Park, S. K.: Sonography of fetal urinary tract anomalies. Amer. J. Roentgen., 137: 261, 1981. 25. Martin, J. J. and Taylor, E. S., Jr.: Diagnosis of bilateral hydronephrosis in utero by ultrasonography. Urology, 17: 272, 1981. 26. Pope, T. L., Jr., Alford, B. A., Buschi, A. J., Brenbridge, A. N. A. G. and Bergman, S.: Nuclear scintigraphy and ultrasound in the diagnosis of congenital ureteropelvic junction obstruction. J. Urol., 124: 917, 1980. 27. Badlani, G., Abrams, H. J. and Kumari, S.: Diagnosis of fetal hydronephrosis in utero using ultrasound. Urology, 16: 315, 1980. 28. Garrett, W. J., Kossoff, G. and Osborn, R. A.: The diagnosis of fetal hydronephrosis, megaureter and urethral obstruction by ultrasonic echography. Brit. J. Obst. Gynaec., 82: 115, 1975. 29. Mahan, J., Gonzales, R., Godec, C. J. and Vernier, R. L.: Intrauterine obstructive uropathy: is early detection and intervention beneficial? Read at annual meeting of Northwestern Pediatric Society, Chanhassan, Minnesota, September 24, 1982. 30. Stuck, K. J., Koff, S. A. and Silver, T. M.: Ultrasonic features of multicystic dysplastic kidney: expanded diagnostic criteria. Radiology, 143: 217, 1982. 31. Bearman, S. B., Hine, P. L. and Sanders, R. C.: Multicystic kidney: a sonographic pattern. Radiology, 118: 685, 1976. 32. Griscom, N. T., Vawter, G. F. and Fellers, F. X.: Pelvoinfundibular atresia: the usual form of multicystic kidney: 44 unilateral and two bilateral cases. Semin. Roentgen., 10: 125, 1975. 33. Felson, B. and Cussen, L. J.: The hydronephrotic type of unilateral congenital multicystic disease of the kidney. Semin. Roentgen., 10: 113, 1975. 34. Oesch, I., Jann, X. and Bettex, M.: Ultrasonographic antenatal detection of obstructed bladder. Diagnosis and management. Eur. Urol., 8: 78, 1982. 35. Hodgson, N. B.: Personal communication, 1982. 36. Wigglesworth, J. S., Desai, R. and Guerrini, P.: Fetal lung hypoplasia: biochemical and structural variations and their possible significance. Arch. Dis. Child., 56: 606, 1981. 37. Cooney, T. P. and Thurlbeck, W. M.: Pulmonary hypoplasia in Down's syndrome. New Engl. J. Med., 307: 1170, 1982. 38. Bellinger, M. F.: Fetal intervention for obstructive uropathy. Dial. Ped. Urol., 5: 6, May 1982. 39. Wigglesworth, J. S. and Desai, R.: Is fetal respiratory function a major determinant of perinatal survival? Lancet, 1: 264, 1982. 40. DeLorimier, A. A., Tierney, D. F. and Parker, H. R.: Hypoplastic lungs in fetal lambs with surgically produced congenital diaphragmatic hernia. Surgery, 62: 12, 1967. 41. Harrison, M. R., Ross, N., Noall, R. and de Lorimier, A. A.: Correction of congenital hydronephrosis in utero I. The model: fetal urethral obstruction produces hydronephrosis and pulmonary hypoplasia in fetal lambs. J. Ped. Surg., 18: 247, 1983. 42. Inselman, L. S. and Mellins, R. B.: Growth and development of the lung. J. Ped., 98: 1, 1981. 43. Swischuk, L. E., Richardson, C. J., Nichols, M. M. and Ingman, M. J.: Bilateral pulmonary hypoplasia in the neonate. Amer. J. Roentgen., 133: 1057, 1979. 44. Warden, S.S., Hoover, D. L., Winslow, B. H. and Devine, P. C.: Pulmonary hypoplasia in obstructive uropathy. Soc. Ped. Newsletter, pp. 31-32, March 22, 1982. 45. Sundell, H., Serenius, F. S., Barthe, P., Friedman, Z., Kanarek, K. S., Escabedo, M. B., Orth, D. N. and Stahlman, M. T.: The effect of EGF on fetal lamb lung maturation. Ped. Res., abstract 687, 9: 371, 1975. 46. Catterton, W. Z., Escobedo, M. B., Sexson, W. R., Gray, M. E., Sundell, H. W. and Stahlman, M. T.: Effect of epidermal growth factor on lung maturation in fetal rabbits. Ped. Res., 13: 104, 1979.
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4 7. Gregory, H.: Isolation and structure of urogastrone and its relationship to epidermal growth factor. Nature, 257: 325, 1975. 48. Harrison, M. R., Nakayama, D. K., Noall, R. and de Lorimier, A. A.: Correction of congenital hydronephrosis in utero. IL Decompression reverses the effects of obstruction on the fetal lung and urinary tract. J. Ped. Surg., 1 7: 965, 1982. 49. Wohl, M. E. B., Griscom, N. T., Schuster, S. R., Zwerdling, R. G. and Strieder, D.: Lung growth and function following repair of congenital diaphragmatic hernia. Ped. Res., 7: 424, 1973. 50. Ruano-Gil, D., Coca-Payeras, A. and Tejedo-Mateu, A.: Obstruction and normal recanalization of the ureter in the human embryo: its relation to congenital ureteric obstruction. Eur. Urol., 1: 287, 1975. 51. Ericsson, N. 0. and Ivemark, B. I.: Renal dysplasia and pyelonephritis in infants and children. Part I. Arch. Path., 66: 255, 1958. 52. Bernstein, J.: The morphogenesis of renal parenchymal malformation. Ped. Res., abstract 122, 2: 319, 1968. 53. Bernstein, J.: The morphogenesis of renal parenchymal maldevelopment (renal dysplasia). Ped. Clin. N. Amer., 18: 395, 1971. 54. Winick, M. and McCrory, W. W.: Renal differentiation: a model for the study of development. Birth Defects, 4: 1, 1968. 55. Kramer, S. A. and Torres, V. E.: Unpublished data. 56. Beck, A. D.: The effect of intra-uterine urinary obstruction upon the development of the fetal kidney. J. Urol., 105: 784, 1971. 57. Fetterman, G. H., Ravitch, M. M. and Sherman, F. E.: Cystic changes in fetal kidneys following ureteral ligation: studies by microdissection. Kidney Int., 5: 111, 1974. 58. Tanagho, E. A.: Surgically induced partial urinary obstruction in the fetal lamb. I. Technique. Invest. Urol., 10: 19, 1972. 59. Tanagho, E. A.: Surgically induced partial urinary obstruction in the fetal lamb. II. Urethral obstruction. Invest. Urol., 10: 25, 1972. 60. Tanagho, E. A.: Surgically induced partial urinary obstruction in the fetal lamb. Ill. Ureteral obstruction. Invest. Urol., 10: 35, 1972.
nl. Maizels, M., Simpson, S. B. and Firlit, C. F.: Understanding the
62. 63. 64. 65. 66. 67.
68. 69.
70.
71. 72.
morphogenesis of renal dysplasia. Read at annual meeting of North Central Section, American Urological Association, Marco Island, Florida, October 17-23, 1982. Osathanondh, V. and Potter, E. L.: Pathogenesis of polycystic kidneys. Type 4 due to urethral obstruction. Arch. Path., 77: 502, 1964. Milliken, L. D., Jr. and Hodgson, N. B.: Renal dysplasia and urethral valves. J. Urol., 108: 960, 1972. Filmer, R. B., Taxy, J. B. and King, L. R.: Renal dysplasia: clinicopathological study. Trans. Amer. Ass. Genito-Orin. Surg., 66: 18, 1974. Mackie, G. G. and Stephens, F. D.: Duplex kidneys: a correlation of renal dysplasia with position of the ureteral orifice. J. Urol., 114: 274, 1975. Mackie, G. G., Awang, H. and Stephens, F. D.: The ureteric orifice: the embryologic key to radiologic status of duplex kidneys. J. Ped. Surg., 10: 473, 1975. Harrison, M. R., Golbus, M. S., Filly, R. A., Callen, P. W., Katz, M., de Lorimier, A. A., Rosen, M. and Jonsen, A. R.: Fetal surgery for congenital hydronephrosis. New Engl. J. Med., 306: 591, 1982. Wladimiroff, J. W.: Effect of frusemide on fetal urine production. Brit. J. Obst. Gynaec., 82: 221, 1975. Harrison, M. R., Golbus, M. S., Filly, R. A., Nakayama, D. K., Callen, P. W., DeLorimier, A. A. and Hricak, H.: Management of the fetus with congenital hydronephrosis. J. Ped. Surg., 17: 728, 1982. Harrison, M. R., Anderson, J., Rosen, M. A., Ross, N. A. and Hendrickx, A. G.: Fetal surgery in the primate. I. Anesthetic, surgical, and tocolytic management to maximize fetal-neonatal survival. J. Ped. Surg., 17: 115, 1982. Kramer, S. A. and Kelalis, P. P.: Unpublished data. Golbus, M. S., Harrison, M. R., Filly, R. A., Callen, P. W. and Katz, M.: In utero treatment of urinary tract obstruction. Amer. J. Obst. Gynec., 142: 383, 1982.
Vol. 130, October Printed in U.S.A.
Review Article CURRENT STATUS OF FETAL INTERVENTION FOR CONGENITAL HYDRONEPHROSIS STEPHEN A. KRAMER* From the Department of Urology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
The rationale for antenatal intervention in the fetus with congenital hydronephrosis is that unrelieved, high grade urinary obstruction in utero may produce progressive renal damage. A review is presented of the current status of fetal intervention for congenital hydronephrosis and an attempt is made to answer several pertinent medical questions that urologists must address, that is 1) how accurate is prenatal ultrasonography in the diagnosis of obstructive hydronephrosis, 2) how do we differentiate dilated, low pressure hydronephrosis from obstructive uropathy, 3) what is the relationship between obstructive uropathy and pulmonary hypoplasia, 4) is there experimental or clinical evidence to suggest that obstructive uropathy is responsible for renal dysplasia, 5) what techniques currently are available to assess fetal renal function, 6) how do we assess the extent of renal dysplasia and the potential recoverability of obstructive uropathy in the fetus, 7) how long can fetal kidneys remain obstructed before loss of function becomes irreversible, 8) what techniques currently are available for in utero intervention, and what are the risks and potential benefits of these procedures, 9) will decompression of the obstructed urinary tract early in gestation alter the outcome beneficially and 10) how do we select which fetuses with dilated upper tracts need in utero intervention? A discussion of the ethical aspects of in utero intervention is provided elsewhere. 1·2 PRENATAL EVALUATION
Recent technological advances in perinatology have been responsible for a marked decrease in prenatal morbidity and mortality. Improvements in obstetric surveillance include prenatal ultrasonography, amniocentesis and fetoscopy in selected patients. Amniocentesis can be used to detect genetic and biochemical abnormalities. Fetoscopy provides a method of direct visualization of the fetus and intrauterine contents. Although these procedures supply meaningful information they are invasive and have been associated with significant complications. 3-6 Prenatal ultrasonography is a safe and noninvasive technique that can detect a variety of congenital abnormalities in utero. 7- 18 Antenatal sonography is of proved benefit in the detection and followup of patients with oligohydramnios. 19-21 Advances in the development of high resolution, gray scale, real-time ultrasonography have permitted improved visualization of fetal anatomy, and the potential exists for detection of congenital anomalies as early as 12 to 15 weeks of gestation.22-24 Ultrasonography may identify accurately up to 90 per cent-of fetal kidneys by 17 to 20 weeks of gestation and 95 per cent by 22 weeks of gestation. The widespread use of this study during pregnancy· has led to an increased recognition of fetal hydronephrosis. 25 -28 Not all large sonolucent retroperitoneal masses in the fetal * Requests for reprints: Department of Urology, Mayo Clinic, Rochester, Minnesota 55905.
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abdomen are the result of obstructive uropathy. 29 The fetus with presumed hydronephrosis detected by prenatal ultrasonography must undergo repeated studies with real-time techniques for initial findings to be confirmed. Dilatation of the collection system may be transient and may resolve before delivery. Overdistension of the bladder may produce intermittent hydronephrosis that disappears after the fetus voids. 18 Thus, it is important to obtain ultrasonograms at several phases of bladder filling. In patients undergoing fetal ultrasonography several errors in the diagnosis of presumed obstructive uropathy have occurred, including multicystic kidney, vesicoureteral reflux, megacalycosis, ureterocele, congenital nonobstructive megaureter, prune belly syndrome, simple renal cyst, duodenal atresia, bladder outlet obstruction and physiologic hydronephrosis. In a recent study 8 of 13 patients (60 per cent) with proved obstructive uropathy at birth had an incorrect diagnosis by prenatal ultrasonography. 29 CAUSES OF COLLECTING SYSTEM DILATATION
Multicystic kidney probably is the most common entity confused with congenital ureteropelvic junction obstruction. 30 Ultrasonography in neonates and infants can often differentiate the classic multicystic kidney from obstruction at the ureteropelvic junction. 31 The morphologic appearance of ureteropelvic junction obstruction is discernible readily from the usual type of multicystic kidney secondary to pelvioinfundibular atresia (fig. 1). 32 Stuck and associates recently outlined ultrasonographic criteria for identifying multicystic kidneys: 1) presence of interfaces between cyst, 2) nonmedial location oflargest cyst, 3) absence of an identifiable renal sinus, 4) multiplicity of oval or round cysts that do not communicate and 5) absence of parenchymal tissue. 30 However, it is noteworthy that atresia of the ureter or pelvis during intrauterine development may produce the hydronephrotic type of multicystic kidney that simulates ureteropelvic junction obstruction. 33 In these selected patients the distinction between multicystic kidney and ureteropelvic junction obstruction in utero can be extremely difficult, and misdiagnosis may result in inappropriate fetal or obstetric intervention. Several children with significant vesicoureteral reflux have been presumed to have obstructive uropathy on the basis of results of prenatal ultrasonography. Children with dilatation of the renal pelvis secondary to reflux usually have ureteral dilatation, which is not present in patients with congenital ureteropelvic junction obstruction. Prune belly syndrome and nonobstructive dilatation of the collecting system have been diagnosed incorrectly as obstructive uropathy in utero (fig. 2). 34 Ultrasonographic findings in children with prune belly syndrome include an enlarged bladder, bilateral ureteral dilatation, small kidneys and oligohydramnios. Infrequently, these children have hydronephrotic kidneys. However, megaureters and megacystis should allow differentiation from ureteropelvic junction obstruction.
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FIG. 1. Parasagittal scan of left kidney demonstrates 8 cm. mass composed of multiple cystic spaces of different sizes consistent with multicystic dysplastic kidney.
adversely normal lung development. However, oligohydramnios has not been associated universally with pulmonary hypoplasia. Bellinger reported 2 fetuses with oligohydramnios who did not have postnatal pulmonary insufficiency. 38 Abnormal fetal respirations, 39 chest wall abnormalities 40 and mechanical factors 36• 41 - 43 all have been implicated in the genesis of pulmonary hypoplasia. DeLorimier and associates produced pulmonary hypoplasia in fetal lambs by creating a diaphragmatic hernia in utero. 40 Recent evidence suggests that pulmonary hypoplasia may be related to diminished epithelial growth factor in utero. 44 This polypeptide hormone is responsible for pulmonary growth and differentiation in fetal rabbits and lambs, and it appears to afford protection against the development ofhyaline membrane disease in these animals. 45 •46 Human ,6-urogastrone, 47 a peptide isolated from human urine and similar in structure and action to epithelial growth factor, may be deficient in the amniotic fluid of patients with oligohydramnios and this deficiency may contribute to pulmonary hypoplasia. Bilateral congenital hydronephrosis may produce urinary ascites with elevation of the diaphragms and cause secondary mechanical compression of the fetal thorax. Harrison and associates produced congenital hydronephrosis in fetal lambs by obstruction of the urethra and ligation of the urachus. 41 These investigators found that lambs that underwent obstruction during the third trimester were born with hypoplastic lungs and had a higher incidence of fetal mortality. 48 Conversely, lambs that underwent in utero decompression of urinary tract obstruction during the middle of the last trimester had less respiratory difficulty, increased lung weight at birth and resolution of urinary tract dilatation. The problem inherent in use of animal models to study the pathogenesis of pulmonary hypoplasia in humans is that surgery in the fetal animal must be accomplished in the latter half of pregnancy to avoid abortion or pre-term delivery. Pulmonary hypoplasia in humans probably develops early in gestation, so
FIG. 2. Transverse sonogram of fetus shows 14.2 cm. cystic mass consistent with bladder (B). Adjacent cystic spaces represent dilated ureters (arrows).
Duodenal atresia with an enlarged stomach also has led to a presumptive diagnosis of ureteropelvic junction obstruction. 35 Conversely, bilateral ureteropelvic junction obstruction and polyhydramnios 7 • 25 • 18 may result in a misdiagnosis of duodenal atresia. 18 Patients with bladder outlet obstruction, such as those with posterior urethral valves or neuropathic disease, have dilatation of the bladder and 1 or both ureters. These findings should differentiate vesical outlet obstruction from obstruction at a higher level. Furthermore, some observers have reported a 20 per cent incidence of physiologic hydronephrosis in the third trimester of pregnancy, which can be responsible for additional false positive findings. Recently, we treated a child with rapidly progressive hydronephrosis detected in utero by ultrasonography. Our obstetricians performed 3 separate needle aspirations of the kidney for presumed obstruction of the ureteropelvic junction (fig. 3, A). Surgical exploration on the first day of life revealed a multicystic, nonfunctioning kidney with severe renal dysplasia (fig. 3, B). The diagnostic errors of in utero ultrasonography can be significant and all studies must be repeated with real-time techniques to confirm initial findings. PULMONARY HYPOPLASIA
What is the relationship between obstructive uropathy and pulmonary hypoplasia? Although the factors contributing to the development of pulmonary hypoplasia are understood poorly a minimum volume of amniotic fluid appears to be critical to normal pulmonary embryogenesis. 36• 37 A deficiency in amniotic fluid prevents normal chest compliance and affects
FIG. 3. A, real-time longitudinal sonogram shows large cystic mass in right renal fossa consistent with ureteropelvic junction obstruction. Percutaneous puncture demonstrates needle tip (small arrow) within 10 cm. cystic mass (curved arrows) between liver (L) and bladder (b). a, amniotic fluid. B, dysplastic renal parenchyma with dilated and small primitive ducts. Interlacing fibrous stroma and hyalinized collagen are prominent. H & E, reduced from Xl40.
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that comparisons between experimental and clinical studies are difficult to evaluate. To date no experimental or clinical studies have shown that unilateral congenital hydronephrosis produces pulmonary hypoplasia. Even with pulmonary compression in utero the human lung retains the ability to produce new alveoli postnatally. 42 Furthermore, in children with congenital diaphragmatic hernia early postnatal repair has been associated with resumption of alveolar development and normal pulmonary function. 49 RENAL DYSPLASIA
Is there experimental or clinical evidence to suggest that obstructive uropathy is responsible for renal dysplasia? Interestingly, in normal human embryogenesis urethral obstruction occurs before recanalization. 50 At 10 weeks of gestation the inner cortical nephrons produce urine, the ureter becomes patent and urine flows into the urogenital sinus. Shortly thereafter the cloaca! membrane ruptures and allows communication between the urinary tract and the amniotic cavity. Failure of the cloaca! membrane to rupture or failure of the ureters to recanalize results in bilateral obstructive uropathy. The allantois becomes obliterated at 16 weeks and the urachus closes at 32 weeks of gestation. Prolonged patency of either of these structures protects the fetal kidneys from increased pressure secondary to bladder outlet obstruction. Renal dysplasia is a histologic diagnosis characterized by poorly developed glomeruli, medullary cysts, fibrosis, islands of cartilage and primitive ducts. 5 1.5 2 Primitive ducts are the sine qua non of renal dysplasia and are necessary to establish the diagnosis. 58 Dysplasia may occur secondary to abnormalities of the ureteral bud or metanephrogenic blastema itself. 54 The potential contribution of vesicoureteral reflux in the genesis of renal dysplasia is unclear and studies to test this hypothesis are in progress. 55 The coexistence of urinary obstruction and renal dysplasia in humans has prompted studies of obstructive uropathy in experimental animal models. The extent and timing of ureter al obstruction in utero correlate with the severity of renal dysplasia. Early obstruction of the developing kidney results in dysplastic changes. 48 • 56 - 60 In fetal rabbits ligation of the ureters early in utero produces dilatation of the collecting ducts and cystic changes in the outer cortical nephrons. 57 Similarly, ureteral obstruction in fetal lambs during the first half of gestation produces contracted hydronephrotic kidneys and significant renal dysplasia. U reteral obstruction during the latter half of embryogenesis results in hydronephrosis without histologic changes of renal cystic dysplasia. 48 • 56 • 58- 60 Recent studies of chick embryos have shown that the primitive ducts associated with renal dysplasia may originate from branches of the ureteral bud that developed without condensed metanephrogenic mesenchyme. 61 These observations suggest that the most severe examples of renal dysplasia develop as a result of an abnormal location of the ureteral bud. These insults affect the kidney before nephrogenesis is complete. Clinical studies similarly have shown that the degree of obstructive uropathy and the interval during which obstruction occurs are the 2 most important factors responsible for the severity of abnormal renal development. 62 Bellinger reported death at 18 weeks of gestation in a fetus with posterior urethral valves and histologic studies of the kidneys demonstrated significant renal dysplasia. 38 In the human fetus significant urethral or ureteral obstruction is associated with increased intratubular pressure and cystic changes of renal dysplasia. 63 • 64 Maximal pressure exerted at the ampullary ends of the tubules causes shortening and straightening of the collecting ducts. 62 Mackie and Stephens reported a close association between the location of the ureteral bud on the wolffian duct and renal morphology. 65 These investigators postulated that ureteral buds originating from normal areas on the wolffian duct penetrate the metanephric blastema in the _proper position and produce
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normal renal differentiation. 66 Conversely, buds arising from an abnormal position on the duct attach to a peripheral portion of the metanephric blastema, and produce renal hypoplasia and dysplasia. The results of experimental animal studies and clinical observations of human pathogenesis have improved greatly our understanding of congenital hydronephrosis and renal dysplasia. The development of renal dysplasia early in gestation implies that in utero intervention designed to alter the course of obstructive uropathy must be accomplished early in the first trimester of gestation. Unfortunately, even these early efforts have not been successful in altering the course of abnormal renal embryogenesis. 67 ASSESSMENT OF RENAL FUNCTION
Currently, no reliable tests exist to assess accurately renal function in utero or the potential for recoverability of fetal kidneys with obstructive uropathy. Furthermore, early in gestation simple congenital hydronephrosis is extremely difficult to distinguish from cystic renal dysplasia secondary to obstructive uropathy. 33 Renal function in the fetus can be estimated by the volume of amniotic fluid detected by ultrasonography. Oligohydramnios is an accurate reflection of decreased urinary output and is the most important measure of renal impairment. A normal amniotic fluid volume indicates that at least 1 renal unit is functioning. It has been suggested that the intravenous administration of furosemide to the mother results in increased fetal urine output, which can be assessed by ultrasonic determination of bladder volume. 68 Failure to visualize the bladder after this stimulation test suggests that adequate functioning renal parenchyma is absent. 21 Although useful in patients with bilateral renal agenesis or severe bilateral renal dysplasia this technique has not been helpful in those with partial urinary obstruction. 69 The analysis of fetal urine by aspiration of the bladder or kidneys has not been of prognostic value. The ability of the bladder to refill after aspiration in utero similarly has not proved to be an effective predictor of renal function. 70 TECHNIQUES FOR FETAL INTERVENTION
Needle aspiration of bladder or kidney. Percutaneous decompression of the bladder has been performed in patients with prune belly syndrome and megacystitis. 34 Although successful technically this technique has not produced resolution of hydronephrosis or arrested the development of renal dysplasia. Furthermore, the hydronephrotic kidney may be secondary to multicystic renal dysplasia and would not benefit from in utero decompression. 71 Diversion of urine into the amniotic fluid by internal shunt drainage, Golbus and associates developed a technique for percutaneous placement of a catheter shunt from the bladder to the amniotic cavity. 72 This procedure has been successful in decompressing adequately the upper tracts but has noit arrested the associated renal dysplasia or altered the course of abnormal renal development. 69 Open surgical diversion. The feasibility of open surgical diversion for the fetus with congenital hydronephrosis has been well documented. Harrison and associates performed extensive studies on the pathophysiology of congenital hydronephrosis in the fetal lamb model. 41 • 48 These investigators developed successful anesthetic, surgical and tocolytic techniques for fetal surgery in nonhuman primates and in the human fetus. 67 • 70 Harrison and associates recently reported their cumulative e'xperience in 26 fetuses with dilated urinary tracts in utero, including 1 fetus who underwent bilateral cutaneous ureterostomy at 21 weeks of gestation because of obstructive uropathy secondary to posterior urethral valves. 67 • 69 Although surgery technically was successful the newborn died on the first day of life, and postmortem examination revealed renal dysplasia and pulmonary hypoplasia.
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Early delivery. The status of pulmonary maturity can be assessed through measurement of the lecithin-sphingo-myelin ratio in the amniotic fluid or by the presence of phosphatidylglycerol. It often is possible to induce production of pulmonary surfactant by administration of steroids to the mother. 69 However, pulmonary response to steroids in the presence of pulmonary dysplasia may not be predictable. This technique and recent advances in the respiratory care of premature newborns have permitted early elective delivery with an excellent chance of survival in selected patients at 32 weeks of gestation. RISKS VERSUS BENEFITS
Hemorrhage, sepsis, abortion and premature labor (risk of respiratory distress syndrome) are significant risks to the fetus and mother subjected to in utero intervention. A theoretical but serious consideration is the potential development of postobstructive diuresis in the fetus with long-standing outlet obstruction. Renal physiology and blood flow in the fetus are significantly different from hemodynamics in the neonate. Thus, the sequelae and treatment of such a problem remain speculative. It is unclear whether placental function could compensate adequately for alterations in fetal electrolytes and volume changes that occur during post-obstructive diuresis. Furthermore, depletion of intravascular volume from rapid fluid shifts could lead to volume depletion, shock and fetal death. The risks of hysterotomy for open surgical decompression have been enumerated by Harrison and associates, and include 1) fetal or maternal death, 2) hemorrhage or sepsis with resultant abortion, 3) cesarean section, 4) unsuccessful surgery and 5) the occurrence of renal dysplasia and pulmonary hypoplasia despite successful surgery. 70 These risks must be weighed against the benefits of potential salvage of nephrogenesis and arrest of pulmonary hypoplasia. TREATMENT GROUPS
How do we select which fetuses with dilated upper tracts may benefit from in utero intervention? Harrison and associates recently reviewed their indications and methods for intervention in the fetus with congenital hydronephrosis. 69 These investigators used prenatal ultrasonography and currently available methods of assessing renal function in utero to segregate patients into 4 treatment groups: 1) unilateral hydronephrosis, 2) bilateral hydronephrosis with good function, 3) bilateral hydronephrosis with poor function and 4) bilateral hydronephrosis with equivocal function. The fetus with unilateral hydronephrosis and a normal contralateral renal unit does not have oligohydramnios and will have normal renal function. Furthermore, there is no evidence to suggest that unilateral hydronephrosis causes pulmonary hypoplasia. These patients can be observed expectantly and in utero intervention is not necessary except occasionally to permit vaginal delivery. The fetus with bilateral hydronephrosis and adequate amniotic fluid volume has nearly normal renal and pulmonary function, and does not need fetal intervention. These patients should be followed expectantly with serial ultrasound examinations and observation. Bilateral hydronephrosis and oligohydramnios in the fetus have been associated uniformly with severe renal dysplasia and pulmonary hypoplasia. 67 •69 Although accomplished successfully in these patients early surgical intervention in utero has not yet altered the outcome beneficially. The approach to the fetus with bilateral hydronephrosis and equivocal renal function was the subject of a recent review of 5 patients with posterior urethral valves and 2 with prune belly syndrome. 69 All patients had urethral obstruction, a thickwalled bladder and bilateral hydronephrosis. Most patients were delivered at <34 weeks of gestation after prenatal treatment with steroids (betamethasone) to induce production of pulmonary surfactant. One child was delivered at 32 weeks of
FIG. 4. Longitudinal ultrasonogram demonstrates bilateral cystic masses (arrows) in renal fossa consistent with ureteropelvic junction obstruction. T, thorax. H, head.
gestation because of oligohydramnios and underwent bilateral ureterostomy as a neonate. Renal biopsies showed dysplastic changes bilaterally. This patient presently is 4 years old and has chronic renal failure. Two patients had prenatal shunting of urine from the bladder into the amniotic cavity: 1 underwent bilateral ureterostomy and 1 bilateral pyelostomy. Renal biopsies from both patients demonstrated bilateral renal dysplasia. Four neonates were delivered at <34 weeks of gestation after prenatal treatment with steroids: 1 died at 3 weeks of respiratory distress and multiple congenital anomalies, and the remaining 3 were treated with vesicostomy or ablation of posterior urethral valves in the neonatal period. Each of the latter 3 children has normal renal function but 1 also has a defect in tubular concentration. It is interesting to speculate whether respiratory or renal failure would have precluded survival in these patients without in utero intervention. However, these findings document clearly that fetal intervention early in gestation has not prevented renal dysplasia or pulmonary hypoplasia. No evidence exists that relief of obstructive uropathy in the fetus improves renal or pulmonary function more than pyeloplasty, vesicostomy or ablation of posterior urethral valves in the neonate. Recently, we treated a child with bilateral hydronephrosis detected in utero by ultrasonography (fig. 4). The mother was managed expectantly and delivery was at 36 weeks of gestation. Bilateral pyeloplasty was done in the neonatal period and histologic study of the kidneys demonstrated no evidence of renal dysplasia. The patient had normal renal and pulmonary function 1 year postoperatively. COMMENT
In any field of surgery initial attempts at innovative and, often, aggressive techniques are met with skepticism and criticism. It is noteworthy that in approximately 1881 Billroth stated that "any surgeon who tries to suture a heart wound deserves to lose the esteem of his colleagues". Cardiac surgery has progressed significantly despite this remark. Similar speculation and reservations in the field of urology have been surpassed only by the multitude of technologic advances achieved during the last several decades. The efforts of Harrison and associates are exemplary and are to be commended. Their continuing research into the risks and effectiveness of fetal intervention for a variety of congenital anomalies has furthered our understanding of congenital hydronephrosis. Although in utero intervention for diagnosis or treatment of congenital hydronephrosis. Experimental and clinical evidence suggests strongly that histologic changes of renal dysplasia occur early in gestation, long before in utero intervention technically is feasible. Currently, there are no reliable tests to assess fetal renal function or the potential recoverability of kidneys with obstructive uropathy. Prenatal ultrasonography has been associated with a significant number of false results. This is particularly true in attempts to distinguish the hydronephrotic type of
FETAL INTERVENTION FOR CONGENITAL HYDRONEPHROSIS
multicystic kidney from ureteropelvic obstruction. Therefore, it is important to repeat the ultrasonogram after delivery to establish an accurate diagnosis and to evaluate the status of the contralateral kidney. However, prenatal ultrasonography is useful for identification of the high risk pregnancy and allows for early referral of these patients to medical centers where postnatal care can be instituted promptly. In the fetus with obstructive uropathy there is no evidence to suggest that relief of obstruction in utero will result in improvement in renal or pulmonary function beyond that achieved by pyeloplasty, vesicostomy or ablation of posterior urethral valves in the neonate. Most fetuses with hydronephrosis have dilated low pressure systems with adequate urinary output and amniotic fluid volume, and can be followed safely to term delivery. The accumulated experience to date indicates that the fetus with congenital hydronephrosis detected in utero should be managed expectantly with serial ultrasound and observation. The natural history of congenital urinary tract dilatation in the fetus requires more extensive experimental study before fetal intervention by either radiography or in utero surgery can be recommended in the clinical setting. REFERENCES 1. Barclay, W. R., McCormick, R. A., Sidbury, J. B., Michejda, M. and Hodgen, G. D.: The ethics of in utero surgery. J.A.M.A., 246: 1550, 1981. 2. Fletcher, J. C.: The fetus as patient: ethical issues. Editorial. J.A.M.A., 246: 772, 1981. 3. United States Department of Health, Education and Welfare: Antenatal Diagnosis: Report of a Consensus Development Conference. National Institutes of Health Publication No. 79-1973. Bethesda, Maryland: Public Health Service, National Institutes of Health, pp. 1-9, 1979. 4. Cromie, W. J., Bates, R. D. and Duckett, J. W., Jr.: Penetrating renal trauma in the neonate. J. Urol., 119: 259, 1978. 5. Hirschhorn, K.: The role and the hazards of amniocentesis. Ann. N.Y. Acad. Sci., 240: 117, 1975. 6. Ryan, G. T., Ivy, R., Jr. and Pearson, J. W.: Fetal bleeding as a major hazard of amniocentesis. Obst. Gynec., 40: 702, 1972. 7. Cass, A., Smith, S., Godec, C., Veeraraghavan, K., Tsai, S. and Bendel, R.: Prenatal diagnosis of fetal urinary tract abnormalities by ultrasound. Urology, 18: 197, 1981. 8. Hobbins, J. C., Grannum, P. A., Berkowitz, R. L., Silverman, R. and Mahoney, M. J.: Ultrasound in the diagnosis of congenital anomalies. Amer. J. Obst. Gynec., 134: 331, 1979. 9. Kurjak, A., Kirkinen, P., Latin, V. and Ivankovic, D.: Ultrasonic assessment of fetal kidney function in normal and complicated pregnancies. Amer. J. Obst. Gynec., 141: 266, 1981. 10. Nelson, L. H., Resnick, M. I. and Sumner, T. E.: Sonolucencies in fetal and infant abdomen: implications for management. Urology, 15: 528, 1980. 11. Matturri, M., Peters, B. E. and Kedziora, J. A.: Prenatal and postnatal sonographic demonstration of bilateral ureteropelvic junction obstruction. Med. Ultrasound, 4: 94, Aug. 1980. 12. Okulski, T. A.: The prenatal diagnosis of lower urinary tract obstruction using B scan ultrasound: a case report. J. Clin. Ultrasound, 5: 268, 1977. 13. Farrant, P.: Early ultrasound diagnosis of fetal bladder neck obstruction. Brit. J. Rad., 53: 506, 1980. 14. Walzer, A. and Koenigsberg, M.: Prenatal evaluation of partial obstruction of the urinary tract. Radiology, 135: 93, 1980. 15. Hately, W. and Nicholls, B.: The ultrasonic diagnosis of bilateral hydronephrosis in twins during pregnancy. Brit. J. Rad., 52: 989, 1979. 16. Kay, R., Lee, T. G. and Tank, E. S.: Ultrasonographic diagnosis of fetal hydronephrosis in utero. Urology, 13: 286, 1979. 17. Fourcroy, J. L., Blei, C. L., Glassman, L. M. and White, R.: Prenatal diagnosis by ultrasonography of genitourinary abnormalities. Urology, in press. 18. Sanders, R. and Graham, D.: Twelve cases of hydronephrosis in utero diagnosed by ultrasonography. J. Ultrasound Med., 1: 341, 1982. 19. Touloukian, R. J. and Hobbins, J. C.: Maternal ultrasonography in the antenatal diagnosis of surgically correctable fetal abnormalities. J. Ped. Surg., 15: 373, 1980.
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