Development of a Fetal Renal Function Test Using Endogenous Creatinine Clearance By N. Scott Adzick, Michael R. Harrison, Alan W. Flake, and Jean-Martin Laberge San Francisco, California 9 Selecting appropriate management for the fetus with obstructive uropathy depends on our ability to accurately assess the severity of existing renal damage and to predict the potential for recovery of renal function if the obstruc- tion is relieved. Diagnosis and treatment would be mark- edly enhanced by a simple, safe. quantitative fetal renal function test. To answer the question of whether endoge- nous fetal creatinine clearance (CrC) is an accurate mea- sure of glomerular filtration rate (GFR} in the obstructed fetal kidney, we compared fetal CrC to a standard test for GFR--iothalamate clearance (IC). Six fetal lambs under- went unilateral ureteral ligation at 60 to 63 days gestation (term = 145 days). The contralateral unobstructed kidneys served as a control, At a second operation at 113 to 120 days, renal function was measured by hourly split urine collections for determination of CrC, IC, and fractional sodium excretion on each side over a 4-hr study period. There was excellent correlation of CrC with IC in all kidneys (r = 0.997, P < 0.001, y = 1,14x). Compared to the control side, the obstructed fetal kidneys had signifi- cantly decreased GFR and abnormal tubular function with marked sodium loss, This study indicates that (1) fetal kidneys with long-standing obstruction are "salt-wasters" which may explain the nearly isotonic urine produced by human fetuses with renal dysplasia as opposed to the hypotonic urine produced by normal fetuses; (2) fetal CrC correlates well with fetal GFR measured in either normal or obstructed fetal kidneys; (3) since maternal and fetal serum creatinine levels are equal, fetal CrC can be deter- mined by fetal urine collection and maternal blood sampling alone, which obviates the need for simultaneous fetal blood sampling. This test should be useful in assessment of human fetuses with urinary tract obstruction. 9 1985 by Grune & Stratton. Inc. INDEX WORDS: Fetal renal function; congenital hydro- nephrosis; fetal urinary tract obstruction; fetal surgery; prenatal diagnosis. C URRENTLY, there is no reliable test to accu- rately assess renal function in utero or to predict From the Fetal Treatment Program and Departments of Surgery (Division of Pediatric Surgery), University of California, San Francisco. Supported in part by NIH Research Grant No. AM 29890 and Basic Research Grant No. 1~803 from the March of Dimes Birth Defects Foundation. Presented before the 16th Annual Meeting of the American Pediatric Surgical Association, Kohala Coast, Hawaii, May 1-4, 1985. Address reprint requests to Michael R. Harrison, MD, University of California, Room 585 HSE, San Francisco, CA 94143. 9 1985 by Grune & Stratton, Inc. 0022-3468/85/2006-0006503.00/0 the potential for recovery of fetal kidneys with obstruc- tive uropathy. Diagnosis and treatment would be markedly enhanced by a simple, safe, and quantitative fetal renal function test to predict which fetuses with obstructive uropathy would benefit from urinary tract decompression. Is endogenous fetal creatinine clearance an accurate measure of glomerular filtration rate in obstructed fetal kidneys? To answer this question, we used a fetal lamb model and compared fetal creatinine clearance to a standard test for glomerular filtration rate--iothala- mate clearance. 1 We also determined the etiology of the nearly isotonic urine produced by dysplastic kid- neys with long-standing obstruction. MATERIALS AND METHODS Surgical Technique Six fetal Iambs underwent unilateral left ureteral ligation at 60 to 63 days gestation. This procedure results in progressive renal paren- chymal injury with unilateral renal dysplasia at term (145 days).2 At a second operation at 113 to 120 days gestation, the ewe was placed under general endotraeheal halothane anesthesia, and the maternal respiratory rate and volume were adjusted to maintain normal maternal arterial pH, pCO2, and a high PO2. The hindquarters of the fetus were then delivered through a maternal hysterotomy, a fetal flank incision was made, and the obstructed ureter was identified. Initial aspirates of fetal urine from each kidney were analyzed for sodium, chloride, and creatinine concentration. Each fetus under- went placement of (1) a ureterostomy catheter to drain the obstructed kidney, (2) a suprapubic bladder catheter to drain the contralateral unobstructed control kidney, (3) a femoral arterial catheter for blood pressure monitoring and blood sampling, and (4) a femoral venous catheter for iothalamate (Conray 60) infusion (Fig 1). Iothalamate clearance is a standard measurement for glomerular filtration rate (GFR). 3 Renal Function Studies Renal function was measured by hourly split urine collections for determination of creatinine clearance (CrC), iothalamate clearance (IC), and fractional sodium excretion from each kidney over a 4-hour period. A 4-hour collection period was chosen since this simulates our clinical diagnostic urinary catheter experience in human fetuses with obstructive uropathy. 4 IC was measured using a constant infusion of iothalamate (150 mg/hr) after giving an initial intravenous bolus of 600 mg. An equilibration time of at least 30 minutes was allowed before beginning the first clearance period. Blood was sampled at the midpoint of each hourly clearance period for determination of blood gases, iothalamate concentration, and plasma sodium, chloride, and creatinine concentrations. All fetuses 9 had four clearance determinations for each kidney. Creatinine and iothalamate clearances were calculated by the conventional formula U x V/P, and were expressed as mL/hr/kg body weight. Fractional sodium (Na) excretion was calculated as UNA x V x 100/PNA x 602 Journal of Pediatric Surgery, Vo120, No 6 (December),1985: pp 602-607