Unobstructed Kidneys Research Articles

Increased expression of decorin in experimental hydronephrosis

Transforming growth factor (TGF)-beta1 is a potential mediator of tubulointerstitial (TI) fibrosis in the rat unilateral ureteral obstruction (UUO) model. Decorin is a protein composed of a core protein and a chondroitin sulfate side chain and is capable of inactivating TGF-beta. Since TGF-beta strongly induces the synthesis of decorin in experimental glomerulonephritis, it was our intent to investigate whether altered decorin expression is operant in the rat UUO model. Renal cortical decorin mRNA levels initially became elevated (2.5-fold) in obstructed kidney (OBK) versus contralateral unobstructed kidney (CUK) 24 hours post-UUO and remained greater in the OBK specimens at 48 (2.3-fold), 96 (2.2-fold), and 168 (1.9-fold) hours post-ureteral ligation. Whole-body X-irradiation 11 days prior to UUO significantly reduced decorin mRNA at 24 and 96 hours post-UUO. On immunolabeling, decorin was only evident in the adventitia of blood vessels in CUK specimens at any time point after UUO. In contrast, OBK specimens initially demonstrated periglomerular and peritubular interstitial localization of decorin at 96 hours post-ureteral ligation, which became even more intense and diffuse in the tubulointerstitium at 168 hours post-UUO. On Western analysis, there were highly significant increases in decorin protein expression in the OBK versus the CUK specimens at 96 and 168 hours post-UUO. Levels of active TGF-beta1 in the renal cortex of OBK were 1.9- and 3.6-fold higher than CUK at 48 and 96 hours post-UUO. In summary, we demonstrated that post-UUO, decorin mRNA and protein expression is up-regulated in the renal cortex of OBK, but not CUK, specimens in a temporal parallel with active TGF-beta1 levels and macrophage infiltration. We postulate that the development of TI fibrosis in this model may be related to only a physiologic induction of decorin by TGF-beta, and that pharmacologic levels may be required to retard or prevent scarring via TGF-beta inhibition.

Expression of adhesion molecules in rat renal cortex during experimental hydronephrosis

Unilateral ureteral obstruction (UUO) is associated with an early and steadily increasing infiltration of macrophages into the renal cortical interstitium. As adhesion molecules may play an important role in macrophage recruitment following the mechanical disturbance after UUO, we delineated the time course of intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 mRNA and protein expression. A significant 6.6- (P < 0.001), 2.6- (P < 0.025), 2.6- (P < 0.01), and 2.0-fold (P < 0.005) increase in ICAM-1 mRNA expression was observed at 12, 24, 48, and 96 hours after obstruction, respectively, in comparison to the contralateral unobstructed kidney (CUK). Despite an apparent relief of obstruction, four weeks following reversal of obstruction mRNA levels of ICAM-1 remained equivalent to the 96-hour obstructed kidney group. No significant difference in VCAM-1 mRNA expression was observed between the obstructed kidneys and CUK specimens. Immunohistochemistry revealed focal labeling of ICAM-1 on the apical and basolateral surface of the renal tubules, peritubular interstitium, and vessels of the renal cortex by 12 hours after UUO. In contrast, only faint staining for ICAM-1 protein was observed in the cortex from CUK specimens. The obstructed and CUK specimens exhibited diffuse immunolocalization of VCAM-1 in the cortical tubules and Bowman's capsular epithelium. In situ hybridization showed mRNA transcription for ICAM-1 localized in the peritubular interstitium and cortical tubules from obstructed kidneys. To lend mechanistic insight into the response of ICAM-1 to the mechanical disturbance after UUO, the expression of ICAM-1 mRNA was examined when freshly isolated proximal tubules were exposed to angiotensin II (1 to 100 microM) immediately after preparation. Levels of ICAM-1 mRNA were elevated 1.4-, 7.1-, and 3.7-fold when exposed to 10 microM, 100 microM, and 1000 microM of angiotensin II for one hour, respectively, when compared to control cultures. The addition of losartan to proximal tubules for one hour prior to angiotensin II stimulation decreased ICAM-1 levels to control values. In summary, this investigation demonstrates that ICAM-1 is important in the initiation of macrophage recruitment into the renal cortex of the obstructed kidney. These findings provide evidence that angiotensin II, produced after ureteral ligation as a result of tubular injury and dysfunction, may play a central role in the release of ICAM-1 from the proximal tubule epithelial cells.

Nitric oxide generation ameliorates the tubulointerstitial fibrosis of obstructive nephropathy.

Angiotensin-converting enzyme (ACE) inhibitors have been shown to minimize fibrosis of the kidney tubulointerstitium in several diseases. In addition to lowering angiotensin II levels, ACE inhibitors can increase kinin levels and subsequently increase nitric oxide formation. To determine whether nitric oxide generation is a component of the beneficial effect of ACE inhibitors on renal fibrosis, enalapril, enalapril plus NG-nitro-L-arginine methyl ester (L-NAME) or L-arginine was administered to rats that had undergone unilateral ureteral obstruction (UUO). Ureteral obstruction caused significant increases in interstitial volume, monocyte macrophage infiltration, interstitial collagen IV and alpha-smooth muscle actin expression, transforming growth factor-beta 1 mRNA, collagen IV mRNA, and tissue inhibitor of metalloproteinase-1 mRNA. Enalapril treatment significantly blunted the increase in all parameters during UUO. Cotreatment of the animals with enalapril and L-NAME reversed the beneficial effect of enalapril in the obstructed kidney for all parameters. Treatment of animals with UUO with L-arginine significantly blunted the increase in all parameters except for transforming growth factor-beta 1 mRNA expression. In the enalapril- plus-L-NAME-treated animals, there were modest but significant increases in monocyte/macrophage infiltration of the interstitium and glomerulus, and collagen IV and alpha-smooth muscle actin expression in the interstitium of the contralateral unobstructed kidney. The urine nitrite concentration was significantly increased by either enalapril or L-arginine treatment, whereas L-NAME significantly reduced urine nitrite concentration. These results suggest that treatment modalities that increase nitric oxide formation have a beneficial effect on the progression of cellular and molecular parameters of tubulointerstitial fibrosis caused by obstruction of the ureter.

Experimental partial ureteric obstruction in newborn rats. VIII. Contralateral kidney weight after release of the obstruction.

In unilateral kidney disease, it has been suggested that the ipsilateral state could be estimated by measuring contralateral kidney size; thus, a contralateral increase should reflect an ipsilateral impairment and vice versa. This could easily be performed using ultrasound. In our experiments with partial obstruction of one ureter (created in 1- to 3-day-old rats), a consistent and stable contralateral kidney hypertrophy occurred. However, after unobstruction, the hypertrophy persisted for at least a 6-week observation period, despite the disappearance of hydronephrosis and presence of a normal weight of the ipsilateral kidney. This would undeniably hamper the diagnostic utility of kidney size determination. To find out whether or not the hypertrophy ever disappears, we have performed studies after 6, 9 and 15 weeks. (1) The weight of the unobstructed kidney was found normal except after 15 weeks. The microstructure was normal except for some minor changes. (2) The contralateral kidney was significantly heavier than controls at all checkpoints (+10, +13 and +6%). No significant regression occurred over the observation period. (3) Furthermore, the weights of both kidneys were interrelated, but the slopes were positive; thus, the contralateral hypertrophy was not greater the lesser the ipsilateral kidney weight. The reasons for the persistence of contralateral hypertrophy are discussed. The present findings do not support the idea of documenting improvement by measuring contralateral kidney size. However, repeat studies in the same individual may prove to be more sensitive and are therefore recommended until further notice.

Detection of obstructive uropathy in the fetus: predictive value of sonographic measurements of renal pelvic diameter at various gestational ages.

The goal of our study was to analyze the fetal renal pelvic diameters measured sonographically at several gestational intervals in live-born neonates subsequently found to have either obstructive uropathy or normal kidneys. This information will improve the efficacy of sonography in the diagnosis of obstructive uropathy. From an ongoing prospective study assessing the significance of fetal renal pelvic diameters of 4 mm or more at obstetric sonography, the findings in 29 obstructed kidneys in 24 babies were compared with the findings in 380 kidneys from 233 infants who had no obstruction. Twenty-three infants had unilateral obstruction of the ureteropelvic junction, two had unilateral renal obstruction at the ureterovesical junction, one had posterior urethral valves and in addition had both kidneys obstructed because of obstruction at the ureterovesical junction, one kidney was obstructed because of megaloureter, and one kidney was obstructed because of obstruction in a duplex collecting system. Obstruction was identified on nephrostograms, excretory urograms, or radionuclide renograms. The sonographic findings were compared at three gestational age ranges: 16-23 weeks' gestation, 24-30 weeks' gestation, and 31-40 weeks' gestation. The progression of pelvic dilatation in both groups (12 obstructed and 86 unobstructed) was analyzed for the subset of kidneys examined in all three time periods. At 16-23 weeks' gestation, the difference in mean pelvic diameter between obstructed and unobstructed kidneys was not statistically significant, but the difference between obstructed and unobstructed groups at 24-30 weeks' and 31-40 weeks' gestation was significant (p < .001). Renal pelvic diameter showed a much greater rise in diameter through pregnancy in the obstructed group than in the unobstructed group (p < .0003). The sensitivity of the cutoff point of 4-mm renal pelvic diameter for detecting obstruction was 76% before 23 weeks' gestation, including kidneys with a marked decrease in function postnatally; the sensitivity of a 10-mm cutoff point at 16-23 weeks' gestation was 12%. The likelihood that a fetus had renal obstruction increased with increasing diameter of the fetal renal pelvis in all three time periods. Kidneys with significant obstruction postnatally may have no dilatation of the renal pelvis before 23 weeks' gestation. Most obstructed kidneys had pelvic diameters of less than 10 mm before 23 weeks' gestation. During pregnancy, renal pelvic diameter increases at a greater rate in kidneys that later are shown to be obstructed than in those that are not obstructed.

Differential mRNA expression of renal cortical tissue inhibitor of metalloproteinase-1, -2, and -3 in experimental hydronephrosis.

The pathophysiologic sequelae of both acute and chronic experimental unilateral ureteral obstruction (UUO) in the rat are the result of a variety of complex humoral and cellular interactions. The development of interstitial fibrosis is dependent on the tightly coupled regulation of synthesis and degradation of extracellular matrix proteins. This laboratory, among others, has shown an up-regulated expression of renal cortical transforming growth factor (TGF)-beta 1 within hours of the onset of UUO. Because a potential contribution of TGF-beta to fibrosis may be its ability to increase the expression of proteinase inhibitors such as members of the tissue inhibitor of metalloproteinase (TIMP) family, this laboratory now sought to delineate the kinetics of TIMP-1, TIMP-2, and TIMP-3 mRNA expression in the renal cortex after UUO. There was a marked elevation of TIMP-1 mRNA expression after UUO, which was first noted at 12 h after ureteral ligation. By 96 h after UUO; there was a 30-fold increment in TIMP-1 mRNA in the obstructed kidneys compared with the contralateral unobstructed kidney or sham-operated rat specimens. In contradistinction to TIMP-1, a decrease in TIMP-3 mRNA levels was noted at 12 h after ureteral obstruction and persisted at the 24-, 48-, and 96-h time intervals. TIMP-2 gene expression remained at a relatively constant level during the entire study. It is proposed that the increased expression of TGF-beta 1 post-UUO induces a profibrogenic state and initiates a cascade of dysregulatory events including the up-regulation of TIMP-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Macrophages, monocyte chemoattractant peptide-1, and TGF-beta 1 in experimental hydronephrosis.

Early cellular and molecular derangements have been evaluated as potential pivotal factors for the late development of interstitial fibrosis after experimental hydronephrosis. In this study, we delineated the kinetics of renal cortical macrophage infiltration as well as the cortical expression of transforming growth factor-beta 1 (TGF-beta 1) and monocyte chemoattractant peptide-1 (MCP-1) at 12, 48, and 96 h after unilateral ureteral obstruction (UUO). Interstitial macrophage number in the obstructed kidney versus the contralateral unobstructed kidney (CUK) significantly increased by 12 (11.1 +/- 0.9 vs. 4.5 +/- 0.6), 48 (27.5 +/- 0.9 vs. 4.0 +/- 0.8), and 96 h (71.4 +/- 4.6 vs. 3.2 +/- 0.4) after UUO. MCP-1 mRNA was detected from 12 to 96 h in the obstructed kidney but was absent in the CUK specimens at all time points. Apical tubular MCP-1 expression, on immunolabeling, was present from 12 through 96 h after UUO in the obstructed kidney but not the CUK specimen. On Northern analysis, there were highly significant 2.6-, 5.8-, and 7.0-fold increments in renal cortical TGF-beta 1 mRNA levels at 12, 48, and 96 h, respectively, in the obstructed kidney versus the CUK specimen. Intracellular TGF-beta 1, on immunolabeling, was detected only in the obstructed kidneys of UUO rats at all three time points and was confined to peritubular cells of the renal interstitium. A significant (P < 0.005) correlation (r = 0.95) between interstitial macrophage number and cortical TGF-beta 1 mRNA levels was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Reflex Anuria and Uremia From Unilateral Ureteral Obstruction

A 59-year-old man had anuria of 32 hours’ duration that was associated with unilateral calculous ureteral obstruction. Retrograde pyelography showed a normal contralateral collecting system. Initial technetium pentetate (DTPA) scanning showed diminished uptake of radioactivity by the unobstructed kidney compared with the obstructed kidney, whereas a follow-up study, after relief of ureteral obstruction, showed a reversal of this pattern. Previously reported cases of “reflex anuria” are reviewed along with the relevant experimental literature. Vascular or ureteral spasm related in part to an abnormality of the autonomic nervous system may underlie this rare entity.

DIAGNOSIS OF URINARY TRACT OBSTRUCTION IN DOGS USING DUPLEX DOPPLER ULTRASONOGRAPHY

The ability of duplex Doppler ultrasonography to assist with the diagnosis of urinary tract obstruction was investigated in a study of 5 dogs with surgically induced, unilateral ureteral obstruction. The resistive index (RI) of obstructed kidneys was compared to that of controls and to the contralateral unobstructed kidneys. The RI was also evaluated following relief of obstruction. On the basis of an RI measurement ≥0.70 indicating obstruction, a sensitivity of 73% and a specificity of 77% was determined for the diagnosis of obstruction with Doppler ultrasonography. Although mean RI was elevated in obstructed kidneys compared to controls, it was concluded that a high false‐negative rate (27%) limits the clinical usefulness of Doppler ultrasonography for the detection of urinary obstruction in dogs. The RI difference between obstructed and nonobstructed kidneys was also evaluated within individual animals, but the magnitude of difference between kidneys did not significantly improve the detection rate for obstruction.

Motor neuron syndrome in the arms after radiation treatment.

The pathophysiologic sequelae of both acute and chronic experimental unilateral ureteral obstruction (UUO) in the rat are the result of a variety of complex humoral and cellular interactions. The development of interstitial fibrosis is dependent on the tightly coupled regulation of synthesis and degradation of extracellular matrix proteins. This laboratory, among others, has shown an up-regulated expression of renal cortical transforming growth factor (TGF)-beta 1 within hours of the onset of UUO. Because a potential contribution of TGF-beta to fibrosis may be its ability to increase the expression of proteinase inhibitors such as members of the tissue inhibitor of metalloproteinase (TIMP) family, this laboratory now sought to delineate the kinetics of TIMP-1, TIMP-2, and TIMP-3 mRNA expression in the renal cortex after UUO. There was a marked elevation of TIMP-1 mRNA expression after UUO, which was first noted at 12 h after ureteral ligation. By 96 h after UUO; there was a 30-fold increment in TIMP-1 mRNA in the obstructed kidneys compared with the contralateral unobstructed kidney or sham-operated rat specimens. In contradistinction to TIMP-1, a decrease in TIMP-3 mRNA levels was noted at 12 h after ureteral obstruction and persisted at the 24-, 48-, and 96-h time intervals. TIMP-2 gene expression remained at a relatively constant level during the entire study. It is proposed that the increased expression of TGF-beta 1 post-UUO induces a profibrogenic state and initiates a cascade of dysregulatory events including the up-regulation of TIMP-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary PGE 2 in rats with chronic partial unilateral ureteral obstruction

Urinary prostaglandin E 2 (PGE 2) was measured in Munich-Wistar rats with surgically created chronic partial unilateral ureteral obstruction (UUO). Mean values of bladder urine PGE 2 were higher in sham than in UUO (24.5 ± 14.4 vs 12.9 ± 8.2 ng/mg creatinine, respectively, P < 0.05). Following diuresis, both ureters were cannulated and urine was collected. PGE 2 excretion was increased in sham (66.5 ± 34.4 and 70.1 ± 44.5 ng/mg creatinine, left and right, respectively). But in UUO, the obstructed kidney excreted less PGE 2 than the contralateral kidney (32.1 ± 6.0 vs 62.3 ± 40.4 ng/mg creatinine, obstructed vs contralateral, respectively, P = 0.08). PGE 2 synthesis was then determined in separated renal medullary and cortical slices. Renal medullary slices from kidneys with severe obstruction synthesized less PGE 2 than the contralateral unobstructed side (3.30 ± 1.22 vs 10.52 ± 3.23 ng/mg wet wt-30 min, respectively, P < 0.05) and failed to respond to arachidonic acid stimulation with any significant increase in PGE 2 synthesis (3.30 ± 1.22 vs 4.47 ± 1.04 ng/mg wet wt-30 min, baseline vs stimulated). In contrast, contralateral unobstructed kidney slices responded with a significant increase in PGE 2 synthesis (10.52 ± 3.23 vs 21.10 ± 2.50 ng/mg wet wt-30 min, baseline vs stimulated, P < 0.05). We conclude that chronic partial UUO in the Munich-Wistar rats resulted in significantly less PGE 2 elaboration.

Experimental evaluation of furosemiderenography in unobstructed and partially obstructed upper urinary tracts in pigs

To evaluate the reliability and the constancy of the furosemide renography an experimental evaluation of the test has been performed. A standardized unilateral partial proximal ureteral obstruction was applied to 11 pigs. Preoperatively and again weekly in the three weeks following obstruction a furosemide renogram (FR) was done. The furosemide renography was a very constant parameter in the unobstructed kidney (85%) and in the partly obstructed kidney (85%). A type I FR pattern (O'Reilly classification) was an exact indicator of an unobstructed pelvis. After partial ureteral obstruction, an immediate change in the FR pattern was seen either into type II or type IIIa renography. In this experimental study furosemide renography was found to be a reliable tool in the differentiation between the unobstructed normal renal pelves and the partly obstructed dilated renal pelves.

Measurement of Renal Parenchymal Transit Time of 99mTc-MAG3 Using Factor Analysis

Renal parenchymal transit time of the recently introduced radiopharmaceutical 99mTc-MAG3 (mercaptoacetylglycylglycinel) was measured in 37 kidneys, using factor analysis to separate parenchymal activity from that in the collecting system. A new factor algorithm was employed, based on prior interpolative background subtraction and use of the fact that the initial slope of the collecting system factor time-activity curve must be zero. The only operator intervention required was selection of a rectangular region enclosing the kidney (by identifying two points at opposite corners). Transit time was calculated from the factor time-activity curves both by deconvolution of the parenchymal factor curve and also by measuring the appearance time for collecting system activity from the collecting system factor curve. There was substantial agreement between the two methods. Factor analysis led to a narrower range of normal values than a conventional cortical region-of-interest method, presumably by decreasing crosstalk from the collecting system. In preliminary trials, the parenchymal transit time did not well separate four obstructed from seventeen unobstructed kidneys, but it successfully (p less than 0.05) separated six transplanted kidneys with acute rejection or acute tubular necrosis from 10 normal transplants.

Duplex ultrasound evaluation of normal native kidneys and native kidneys with urinary tract obstruction.

The average resistive indices of 15 native kidneys from 8 patients with no known renal dysfunction were determined with the Doppler waveform obtained from the interlobar arteries. The average resistive index for this group was .58; the highest value was .66. The interlobar arteries of four native kidneys with urinary tract obstruction as well as those of the contralateral unobstructed kidneys were evaluated by Duplex ultrasound. Unilateral urinary tract obstruction was due to a congenital ureteropelvic junction obstruction in one patient or an acutely obstructing calculus at the ureterovesical junction in three patients. The average resistive index of the four obstructed kidneys was .75 and the lowest value was .71. The average resistive index of the four contralateral unobstructed kidneys in these patients and the 15 kidneys from patients with no known renal abnormalities was .58, which was significantly different from the value for the obstructed kidneys (p less than .005). The resistive index from the interlobar arteries of normal native kidneys is reproducible as previously reported in renal transplants. Pathologic renal processes, such as urinary tract obstruction, may be characterized by abnormally high resistive indices.

Serial Renal Function in an Ovine Model of Unilateral Fetal Urinary Tract Obstruction

Renal tubular and glomerular function following ovine fetal urinary tract obstruction has been studied predominantly in anesthetized, exteriorized fetuses immediately after relief of obstruction. Since surgery and anesthesia may alter fetal cardiovascular and renal physiology, we developed a chronically catheterized, ovine model of unilateral fetal urinary tract obstruction to compare function of the unobstructed and obstructed kidneys repeatedly after relief of obstruction. Split renal function of the previously obstructed kidneys and unobstructed kidneys was measured serially in 7 fetal sheep after obstruction at 55 to 85 days per 147 days of gestation for 30 to 49 days. Seventy-five split clearances were determined on days 1, 2, 3 to 4 and 5 to 6 postoperatively. Not every fetus was studied each day. By 2-way ANOVA, renal function was stable on day 1 after surgery and did not change with time. Previously obstructed kidneys had lower creatinine clearance (0.16 versus 0.71ml. per minute, p equals 0.0001), higher fractional sodium excretion (33.04 versus 6.02 per cent, p equals 0.0001) and higher urine sodium/creatinine ratio (4.80 versus 0.90mEq. per mg., p equals 0.0001). Urine flow in the unobstructed kidneys did not differ significantly from that of the obstructed kidneys (0.122 versus 0.083ml. per minute, p equals 0.35). Obstruction reduced kidney weight (4.7 versus 9.7gm., p equals 0.0006), cortical thickness (—39 per cent) and nephrogenic zone (—59 per cent), and it increased collecting duct dilatation and medullary fibrosis. No cysts or dysplasia was noted. Fetal urinary tract obstruction for 39.7 days alters renal histology, glomerular function and tubular function. Renal function is stable by 1 day after catheterization and does not change from days 1 to 6 following relief of obstruction.

Brush border enzymes as markers for ascending pyelonephritis: active immunization with pili

Activities of renal brush border membrane (BBM) enzymes, alkaline phosphatase, maltase and leucine aminopeptidase, were determined in control, pyelonephritic and immunized-infected rats. The activities of all enzymes decreased significantly (P < 0.05) in obstructed kidney while activities of alkaline phosphatase and leucine aminopeptidase increased significantly (P < 0.05) in unobstructed kidney in early stages of infection. The affinity constant (Km) of all enzymes remained unaltered in control and experimental groups. Significant differences (P < 0.05) in the activities of BBM enzymes of infected and immunized-infected animals suggested a protective role of active immunization with pili.

New sensitive markers for the detection of experimental ascending pyelonephritis

Kinetic parameters (Km and Vmax) of renal brush border membrane (BBM) enzymes alkaline phosphatase, maltase, leucine-aminopeptidase and γ-glutamyltranspeptidase were used as markers for the early detection of pyelonephritis. Km of all the enzymes studied remained unaltered. The Vmax of all the enzymes studied were found to be significantly decreased (p<0.05) 3 or 4 days postinfection and onwards in the left obstructed kidney. The Vmax of alkaline phosphatase and leucine-aminopeptidase was found to be significantly increased (p<0.05) in early stages and decreased(p<0.05) in later stages of infection in the right unobstructed kidney. No histopathological lesions conforming pyelonephritis could be seen 7 days postinfection in the left kidney and right kidney remained histopathologically unaltered. This demonstrated that BBM enzymes are much earlier disturbed as compared to histopathological changes.

CEFTAZIDIME (CTZ) CLEARANCE (CL) WITH CONGENITAL URINARY TRACT OBSTRUCTION (UTO)

Congenital UTO is the leading cause of childhood renal failure. Although these children receive complex drug therapy, the effects of UTO upon pharmacokinetics have not been adequately studied in immature humans or animals. Pseudomonas infections often complicate congenital UTO and may be treated with CTZ. To study the effects of UTO upon CTZ kinetics, we produced unilateral UTO in 3 fetal sheep at 75d/146d gestation. After spontaneous term birth, catheters were inserted to: drain the obstructed kidney; separately collect urine from the unobstructed kidney; and infuse drug and sample blood separately. Obstructed kidney glomerular filtration rates ranged from 0 to 28% of total by DTPA renal scans. CTZ was infused into 3 lambs for 3 hrs before 3 one hr urine collections to determine each kidney's: CTZ CL, creatinine CL (CR CL), and fractional sodium excretion (FENa). UTO decreased urine flow (0.05 to 0.01 ml/min-kg, p<.05); CR CL (2.16 to 0.44 ml/min-kg, p=.002); and increased FENa (0.35 to 7.94%, p<.05). UTO reduced urine [CTZ] to a low of 74.3±8.6 μg/ml. CTZ CL (y) correlated with CR CL (x) such that y=1.60 x −0.10 (r=.80, p<.001). UTO severely impairs renal function as well as CTZ excretion. Pseudomonas kidney infections in infants with bilateral UTO may require higher CTZ doses to reach therapeutic urine [CTZ] and longer dosing intervals which may be estimated from CR CL.

Development of a fetal renal function test using endogenous creatinine clearance

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 obstruction is relieved. Diagnosis and treatment would be markedly enhanced by a simple, safe, quantitative fetal renal function test. To answer the question of whether endogenous fetal creatinine clearance (CrC) is an accurate measure 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 underwent 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 less than 0.001, y = 1.14 x). Compared to the control side, the obstructed fetal kidneys had significantly decreased GFR and abnormal tubular function with marked sodium loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Correction of congenital hydronephrosis in utero IV: In utero decompression prevents renal dysplasia

Renal dysplasia (RD) is commonly seen in babies with urinary tract obstruction (UTO). Recent experimental evidence suggests that early fetal UTO leads to the development of RD. The RD seen in children with congenital UTO is usually not reversible, even when the obstruction is relieved soon after birth. Is the RD associated with congenital UTO preventable or reversible by decompression of the urinary tract early in gestation? If so, at what stage of development must this decompression be performed? We produced complete unilateral ureteral obstruction in 25 early second trimester (62 to 65 days) lamb fetuses, a procedure that results in ipsilateral RD at term (140 days). At a second operation, 20, 40, or 60 days after the initial procedure, we decompressed the obstructed kidney by a cutaneous end-ureterostomy. The contralateral unobstructed kidneys served as controls. Renal function (urine output and iothalamate clearance) and histopathology were evaluated after delivery at term. Recovery of renal function was directly proportional to the duration of in utero decompression and inversely proportional to duration of obstruction. In addition, in utero decompression prevented or greatly ameliorated the development of RD. However, some postobstructive changes persisted; these were proportional to the length of in utero obstruction. These results substantiate the clinical impression that some human fetuses with congenital UTO may benefit from early in utero decompression.