Histologic and molecular evidence of obstructive uropathy in rats with hereditary congenital hydronephrosis

Partial obstruction of the upper urinary tract, a frequent challenge for the pediatric urologist, leads to renal damage, if deobstruction is delayed. Several but sometimes unsatisfactory animal models have been developed to study this phenomenon. Obstruction created by surgical manipulation lacks adequate correlation with a developing congenital obstruction. In some animals with congenital hydronephrosis, evidence of renal obstruction is absent. A study of the renal morphology of rats with hereditary unilateral hydronephrosis has exhibited clear evidence of renal obstruction distinguishable from renal dilatation. The renal mRNA expression of renin and transforming-growth factor- β₁ (TGF-β₁) was measured by a semiquantitative RT-PCR technique. In hydronephrotic kidneys, a marked loss of parenchyma, atrophy and dilation of tubuli and collecting ducts and interstitial fibrosis was observed. The mRNA expression of renin was increased significantly in comparison to controls, whereas the contralateral kidneys showed renin activity below control levels. TGF-β₁ expression was markedly increased in hydronephrotic kidneys, whereas contralateral kidneys did not differ significantly from control values. These data suggest the presence of renal obstruction and not only renal dilatation in these rats with congenital hydronephrosis. This colony seems to be a representative animal model to study congenital renal obstruction even in the fetal period without the need of surgical manipulation. Received: 3 June 1999 / Accepted: 1 October 1999     

Increased transforming growth factor-β1 and tubulointerstitial fibrosis in rats with congenital hydronephrosis

OBJECTIVES: Most of our knowledge concerning renal obstruction has been derived from experimental animal models, and it is not yet well defined in spontaneous hydronephrosis. The aim of our study is to evaluate the roles of transforming growth factor-beta1 (TGF-beta1) and apoptosis in congenital hydronephrotic kidneys in comparison with experimental models. METHODS: We made histological studies on kidneys from 6-week-old Wistar-Imamichi rats with congenital unilateral hydronephrosis as well as surgical models of complete or partial unilateral ureteral obstruction. The severity of hydronephrotic kidneys was evaluated on routine hematoxylin and eosin (H&E) stained sections, and the tubulointerstitial fibrosis analyzed morphometrically on Masson's trichrome stained sections. Renal tubular atrophy was assessed on periodic acid Schiff (PAS) stained sections, and tubular cell apoptosis assessed with TUNEL technique. The renal TGF-beta1 level was determined by a sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: We observed a significant loss of kidney weight with profound compensatory growth of the contralateral kidney in rats with congenital hydronephrosis. Most of the hydronephrotic kidneys were markedly enlarged with dilatation of the collecting system, renal parenchymal thinning, tubular atrophy, interstitial infiltration and fibrosis. The renal TGF-beta1 level was markedly elevated in hydronephrotic kidneys as compared with normal controls (326.01 +/- 30.64 pg/mg protein vs 227.81 +/- 11.07 pg/mg protein, P < 0.01). The tubular apoptotic score in hydronephrotic kidneys was also significantly higher than normal controls (2.17 +/- 0.50/HPF [high power field]vs 0.14 +/- 0.04/HPF, P < 0.01). The increased TGF-beta1 and apoptotic status paralleled the histological changes of tubulointerstitial fibrosis and tubular atrophy. Similar findings were also obtained in experimental obstructive models. CONCLUSION: In comparison with surgical models of partial and complete ureteral obstruction, our data provide solid morphological and molecular evidences of renal obstruction in rats with congenital hydronephrosis.     

Studies on intraarenal prostaglandins. Influence of unilateral ureteral obstruction on prostaglandins E2 and F2 alpha in the rabbit kidney.

Prostaglandins (PGs) E2 and F2 alpha in the rabbit kidney were determined by radioimmunoassay to study the effects of unilateral ureteral obstruction on intrarenal PGs. An increase of PGE2 in the inner medulla was observed in the hydronephrotic kidney. When isotonic glucose solution was infused after the release of ureteral obstruction, an elevation of PGE2 in the outer medulla occurred in the hydronephrotic kidney. Under water diuresis immediately following the release of obstruction, PGE2 in the inner medulla showed significant correlations to urinary flow rate, urinary osmolar concentration and free water clearance. The present study indicates that PGE2 in the inner medulla is enhanced by ureteral obstruction and may have a close relation to renal functional damage in mild hydronephrosis.     

Determinants of progression and equilibrium in hydronephrosis

Upper urinary tract urodynamic parameters were measured serially in 12 dogs subjected to partial ureteropelvic junction obstruction. Measurements of pressure-volume relationships (pelvimetrics) and the physiologic capacity of the renal pelvis were important predictors of hydronephrotic equilibrium which occurred only in kidneys whose pelvic urine volume remained lower than the renal pelvic capacity. Because of acquired changes in compliance and renal function, the same degree of obstruction caused progressive hydronephrosis at low pelvic volumes but not at high volumes in some kidneys. Hydronephrosis can thus be viewed as a compensatory mechanism which protects the kidney against further dilation and elevated intrapelvic pressure.     

A new test to predict reversibility of hydronephrotic atrophy after stable partial unilateral ureteral obstruction

In previous studies we showed that hydronephrotic atrophy develops only in the first weeks after stable partial ureteral obstruction, and does not progress thereafter. Relief of obstruction only in the "destructive phase" and not in the later "steady-state phase" seems to improve or prevent hydronephrotic atrophy. Since the duration of partial ureteral obstruction is often not known, we studied urinary enzymes of rat kidneys after stable partial unilateral ureteral obstruction to identify the destructive phase. We chose as an example of the tubular lysosomal enzyme N-acetyl glucosaminidase (NAG) and as an example of the brush border enzyme gamma-glutamyl-transferase (Gamma-GT). NAG concentration but not so much Gamma-GT concentration was higher in the urine of the obstructed kidneys than in the urine of the contralateral control kidney, in the first two weeks after operation, and then returned to normal. These observations lead to the conclusion that the "destructive phase" after ureteral obstruction can be identified by the appearance of high urinary tubular lysosomal enzyme content. The clinical implication is that the timing of relief of asymptomatic stable partial ureteral obstruction of unknown duration can be based on the concentrations of urinary lysosomal enzymes.     

An unusual cause of complete distal ureteral obstruction: giant fibroepithelial polyp

Fibroepithelial polyp of the ureter is a rare benign neoplasm of mesodermal origin. It is an extremely rare cause of hydronephrosis in children. It usually causes partial ureteral obstruction without loss of renal function. The preferred treatment is endoscopic or surgical resection of the polyp with preservation of the renal unit. The authors present an adolescent patient with a nonfunctioning left hydronephrotic kidney caused by complete ureteral obstruction caused by a giant fibroepithelial polyp of the distal ureter. This is an extremely rare presentation and outcome of this benign ureteral neoplasm with resultant loss of renal unit.     

Dynamic renal scintigraphy in children with vesicoureteral reflux and suspected coexisting ureteropelvic junction obstruction

PURPOSE: We evaluated whether findings on voiding cystourethrography suggesting ureteropelvic junction (UPJ) obstruction coexists with vesicoureteral reflux (VUR) are associated with parameters on dynamic renal scintigraphy that support significant obstruction. MATERIALS AND METHODS: We reviewed records of 44 patients referred for scintigraphy after voiding cystourethrography performed at age 1 day to 9.4 years (mean 7 months, median 1.7 months) showed VUR and findings suggestive of UPJ obstruction (blockage of contrast material at the UPJ, contrast dilution in the renal pelvis, slow renal pelvic drainage). Results were correlated with Society for Fetal Urology hydronephrosis grade and ureteral morphology. RESULTS: Halftime was in the obstructive range (20 minutes or greater) for 7 of 47 kidneys (15%). The prevalence of a post-furosemide pelvicaliceal drainage halftime in the obstructive range increased with hydronephrosis grade (0% grade 1, 17% grade 2, 50% grade 3 to 4, p = 0.002) but did not vary with ureteral morphology (p = 0.08). In 12 of 38 cases (31%) where suspected UPJ obstruction was unilateral and a contralateral kidney was present differential uptake of the affected kidney was less than 45%. The prevalence of differential uptake less than 45% was higher in patients with than without ureteral dilatation (48% vs 12%, p = 0.02) but did not vary with hydronephrosis grade (p = 0.93). CONCLUSIONS: In children with VUR and suspected coexisting UPJ obstruction dynamic renal scintigraphy may support significant obstruction when hydronephrosis is at least moderate in degree or ureteral dilatation is present but is unlikely to do so if neither is observed.     

小儿肾积水术后短期肾盂内压力的恢复

【摘要】〓目的〓探讨先天性肾积水小儿行离断式肾盂输尿管成形术后肾盂内压力的恢复规律。方法〓回顾性分析30例单侧肾盂输尿管连接部狭窄行离断式肾盂输尿管成形术的患儿。术中放置肾造瘘管。手术后14天内,每天测量肾盂内压力、膀胱内压力、患侧尿量。结果〓术后第一天,患侧肾盂内压力即降低至和膀胱内压力无明显差异。术后7天左右,肾盂内压力短暂升高,之后再次降低并保持稳定。患肾尿量于术后7天左右短暂性增多。结论〓术后7天左右,吻合口存在“功能性”梗阻。肾造瘘管或者输尿管支架管至少应该放置1周。     

Influence of thromboxane A2 inhibition on the development of hydronephrotic atrophy

The development of hydronephrotic atrophy as measured by dry and wet weight in relation to wholebody weight, in rats after complete unilateral ureteral obstruction could be influenced by oral administration of OKY 1581, an inhibitor of thromboxane A2 synthesis. The data are consistent with the thesis that preglomerular thromboxane A2-mediated active vasoconstriction is involved, most likely by ischemia, in the development of hydronephrotic atrophy, at least in the renal cortex.     

Salutary role for angiotensin in partial urinary tract obstruction

BACKGROUND: In the neonatal period, angiotensin II (Ang II) is up-regulated and induces a timely development of the renal pelvis and ureteral peristalsis, thereby protecting the kidney from hydronephrosis. We tested the possibility that in adulthood, Ang II may act salutarily on the kidney structure during partial urinary tract obstruction by inducing adaptive changes in the peristaltic machinery. METHODS: Adult male Sprague-Dawley rats were subjected to partial unilateral ureteral obstruction (UUO) and divided into two groups, that is, those treated with (group L, N = 21) and those without (group C, N = 21) an angiotensin type 1 (AT1) receptor antagonist (losartan). Control animals were sham operated (N = 10). Rats were sacrificed either at day 7 or day 14. RESULTS: The degree of hydronephrosis determined morphometrically was significantly more severe in group L than group C at both day 7 and day 14, indicating that Ang II inhibition accentuated hydronephrosis. The measurement of upstream pressure within the partially ligated ureter in vivo revealed that losartan significantly attenuates the frequency of ureteral peristaltic activities. In in vitro studies using ureteral strips harvested from normal adult Sprague-Dawley rats (N = 10), Ang II (10(-8) mol/L) was shown to augment contraction, which was completely inhibited by losartan (10(-6) mol/L). CONCLUSIONS: Ang II has a salutary effect of protecting kidneys from hydronephrosis during partial ureteral obstruction through its ability to augment ureteral peristalsis.     

Pathophysiology of hydronephrotic atrophy: the cause and role of active preglomerular vasoconstriction

Unilateral complete ureteral occlusion is followed by a decreased blood flow in the ipsilateral kidney, which is established within 1 week, after which a steady state of whole renal blood flow is observed. Active preglomerular vasoconstriction is assumed to be the main factor causing renal flow reduction in the hydronephrotic kidney, resulting in rapid decrease of the initial elevated pelvic pressure within 24 h. The assumption of active preglomerular vasoconstriction also explains the observation that blood flow reduction clearly precedes renal atrophy after ureteral ligation. Neither alpha-receptor blocking agents nor angiotensin II blockage, nor denervation, reversed flow reduction in the first hours or weeks after ureteral ligation. A thromboxane synthesis inhibitor (imidazole) did reverse flow reduction completely without affecting the contralateral renal blood flow, indicating that active vasoconstrictive is present. In respect to renal hydronephrotic atrophy, compartment analysis of the blood flow of the obstructed kidney demonstrates that vasoconstriction contributes to ischemic atrophy at least in the cortex of the hydronephrotic kidney. Vasoconstriction cannot be reversed by prostaglandin synthesis inhibition after renal atrophy is established, although the renal blood flow is still sensitive to other vasodilating drugs like dopamine. From our data we conclude that prostaglandin-mediated active preglomerular vasoconstriction is a main factor causing renal atrophy by ischemia.     

Variable chronic partial ureteral obstruction in the neonatal rat: a new model of ureteropelvic junction obstruction

BACKGROUND: Congenital ureteropelvic junction (UPJ) obstruction is a common developmental anomaly. To elucidate the mechanisms underlying the renal consequences of congenital UPJ obstruction, we have developed a new model of variable partial unilateral ureteral obstruction (UUO) in the neonatal rat. METHODS: Rat pups were subjected to sham-operation, complete UUO, or variable partial UUO within the first day of life. After 14 or 28 days, the relative number of glomeruli, cell proliferation, tubular apoptosis, tubular atrophy, and interstitial fibrosis were quantitated in histologic sections. Glomerular filtration rate (GFR) was determined after 28 days of partial or complete UUO. RESULTS: Following 70% to 75% reduction in ureteral diameter, renal growth from 14 to 28 days was reduced by 60%, and the number of glomeruli decreased by 50%. Renal pelvic diameter increased in proportion to the severity of obstruction following 14 days of partial UUO, and by 28 days, was maximally dilated regardless of the luminal diameter. Renal proliferation was increased, while tubular apoptosis, tubular atrophy, and interstitial fibrosis were less severe 14 days following partial UUO than in complete UUO. GFR was reduced by 80%, and proteinuria developed following 28 days of partial UUO. CONCLUSION: Renal function is impaired by chronic ipsilateral partial UUO, which reduces the number of nephrons, and leads to progressive renal pelvic dilatation. Tubular atrophy and interstitial fibrosis develop prior to significant renal pelvic dilatation. Correlation of clinically measurable parameters with renal morphometry or imaging studies in this model may lead to new approaches to the management of congenital UPJ obstruction.     

Hydronephrotic atrophy after stable mild or severe partial ureteral obstruction: natural history and recovery after relief of obstruction

After stable mild or severe partial unilateral ureteral obstruction in rats, the ratio of renal dry weight to whole body weight changes in two phases. In a "destructive phase" of two to six weeks, slight weight reduction occurs in the kidneys with mild obstruction and pronounced weight reduction occurs in those with severe obstruction. Then, in a "steady-state phase", there is no further weight reduction in kidneys with either mild or severe obstruction. Relief of ureteral obstruction during the steady-state phase does not result in an increase in renal dry weight. We conclude that the development of hydronephrotic atrophy after stable mild or severe partial unilateral ureteral obstruction can not be influenced by relief of obstruction in the steady-state phase.     

MCP-1 gene activation marks acute kidney injury

Monocyte chemoattractant protein 1 (MCP-1) mediates acute ischemic and toxic kidney injury, but whether this can be used as a biomarker of acute kidney injury (AKI) is unknown. We obtained kidney and urine samples from mice with intrarenal (maleate), prerenal (endotoxemia), or postrenal (ureteral obstruction) injury. We also studied the independent effects of uremia without concomitant kidney injury by performing bilateral ureteral transection in mice. Additionally, we obtained urine samples from APACHE II-matched critically ill patients with or without advancing azotemia (n = 10 in each group). We assayed selected samples for MCP-1, MCP-1 mRNA, and for an activating histone mark (H3K4m3) at urinary fragments of the MCP-1 gene and contrasted the results with those obtained for neutrophil gelatinase-associated lipocalin (NGAL), a comparator "AKI biomarker" gene. Maleate increased urinary MCP-1 protein and mRNA more than the corresponding increases in NGAL. Endotoxemia and ureteral obstruction also increased NGAL and MCP-1 gene expression. Uremia, in the absence of renal injury, induced the NGAL gene, but not MCP-1, suggesting the possibility of better specificity of MCP-1 for AKI. Clinical assessments supported the utility of MCP-1 as a biomarker (e.g., nonoverlapping concentrations of urinary MCP-1 in patients with and without AKI). Elevated levels of urinary MCP-1 mRNA and levels of H3K4m3 at the MCP-1 gene supported MCP-1 gene activation in patients with renal injury. In conclusion, these data suggest that MCP-1 has potential as a biomarker of AKI and provide "proof of concept" that urinary histone assessments provide mechanistic insight among patients with kidney disease.     

Renal pelvis volume during diuresis in children with hydronephrosis: implications for diagnosing obstruction with diuretic renography

PURPOSE: We measured the volume of the renal pelvis during diuretic renography (DR) in children with normal and hydronephrotic kidneys to determine if changes in pelvic volume could affect the accuracy of DR in diagnosing obstruction. MATERIALS AND METHODS: We studied 18 patients 1 month to 10 years old with unilateral hydronephrosis ultimately proved to be either obstructive or nonobstructive. Simultaneous DR and ultrasound were performed with patients supine using the gamma camera. Ultrasound measurements of the renal pelvis in 3 dimensions, obtained before and at intervals after diuretic injection, were used to calculate renal pelvic volume. The contralateral normal kidneys were used as controls. RESULTS: Between 15 and 60 minutes after diuretic injection the renal pelvis enlarged to a maximum volume in all hydronephrotic and normal kidneys and then gradually decreased in size. Mean average increase in volume for hydronephrotic kidneys ranged from 46% in obstructed kidneys to 88% in nonobstructed kidneys. Volume expansion caused dilution of isotope within the renal pelvis, which resulted in prolongation of elimination half-time (T1/2) in 42% of nonobstructed hydronephrotic kidneys sufficient to register an obstructed washout pattern. However, there were no differences in the initial pelvic volume or the rate or extent of increases or decreases in pelvic volume that would permit nonobstructed hydronephrotic kidneys to be distinguished from obstructed ones. CONCLUSIONS: The renal pelvis enlarges during diuresis in children with hydronephrosis. This enlargement causes dilution of isotope within the renal pelvis during DR, which prolonged the isotope washout rate or T1/2 sufficiently to produce an obstructed washout pattern in more than 40% of hydronephrotic kidneys that were ultimately proved to be nonobstructed. This misdiagnosis of obstruction is particularly likely to occur in children younger than 2 years because pelvic volume expansion is so exaggerated. Consequently, T1/2 appears to be particularly vulnerable to inaccuracy in diagnosing obstruction in this age group, and, therefore, it should not be relied on as an operative determinant.     

Renal excretion of prostanoids and cyclic AMP in chronic partial ureteral obstruction of the rabbit

The renal excretion of prostaglandins E2 and 6-keto-F1 alpha, thromboxane B2 and cyclic adenosine 3', 5'-monophosphate was measured in a solitary kidney model of chronic ureteral obstruction in rabbits. The presence of obstruction was confirmed by intravenous pyelography. Growth rate of the animals and furosemide-stimulated diethylenetriaminepentaacetic acid renography were used to grade the obstruction. As correlated to urinary creatinine concentration the excretion of 6-keto-PGF1 alpha dominated in nephrectomized, unobstructed control animals. With the degree of ureteral obstruction becoming more severe, the output of PGE2 increased, while that of 6-keto-PGF1 alpha and TxB2 decreased. As a result the ratios PGE2/6-keto-PGF1 alpha and PGE2/TxB2 were three times as high in severely obstructed rabbits as in control animals. The renal output of cyclic AMP was unaffected by chronic obstruction. We conclude that the renal metabolism of prostanoids is affected in a unique way in chronic partial obstruction of the ureter.     

Distal Ureteral Atresia Associated with Crossed Renal Ectopia with Fusion: Recovery of Renal Function after Release of a 10-Year Ureteral Obstruction

We report on a 10-year-old boy with distal ureteral atresia associated with crossed renal ectopia with fusion. He was admitted with a high fever associated with a urinary tract infection. The diagnosis was established by antegrade and retrograde pyelography. The upper hydronephrotic portion of the kidney, obstructed for 10 years, recovered its function after nephrostomy placement. To our knowledge, this is the first patient whose renal function has recovered despite an ureteral obstruction of 10-years' duration. Therefore, we recommend a transient nephrostomy placement even for far advanced pediatric hydronephrosis, to test for the possibility of functional recovery.     

Bilateral ureteral obstruction secondary to endometriosis

Endometriotic ureteral obstruction is an uncommon but serious event often unrecognized until hydronephrotic renal atrophy has occurred. A case of bilateral endometriotic ureteral obstruction treated with danazol (Danocrine) is reported, and the literature is reviewed.     

Obstructive nephropathy in the mouse: progressive fibrosis correlates with tubulointerstitial chemokine expression and accumulation of CC chemokine receptor 2- and 5-positive leukocytes

The infiltration of leukocytes plays a major role in mediating tubulointerstitial inflammation and fibrosis in chronic renal disease. CC chemokines participate in leukocyte migration and infiltration into inflamed renal tissue. Because CC chemokine-directed leukocyte migration is mediated by target cell expression of a group of CC chemokine receptors, this study examined the expression of CC chemokines and their receptors during initiation of tubulointerstitial fibrosis after unilateral ureteral obstruction in C57BL/6 mice. Obstructed kidneys developed hydronephrosis, tubular cell damage, interstitial inflammation, and fibrosis. From days 2 to 10, a progressive interstitial influx of F4/80+ macrophages and CD3+ lymphocytes occurred (macrophages, 4-fold; lymphocytes, 20-fold at day 10, compared with contralateral control kidneys). In parallel, the number of activated fibroblast-specific protein 1+ fibroblasts and interstitial collagen IV accumulation increased from days 2 to 10. The mRNA expression of CC chemokines (predominantly monocyte chemoattractant protein-1 [MCP-1]/CCL2, RANTES/CCL5) and their receptors CCR1, CCR2, CCR5 increased progressively from days 2 to 10. By in situ hybridization, a prominent interstitial mRNA expression of MCP-1 and RANTES and their receptors CCR2 and CCR5 localized to interstitial mononuclear cell infiltrates. MCP-1 and RANTES expression was also seen in tubular epithelial cells. Fluorescence-activated cell sorter analysis of single-cell suspensions from obstructed kidneys revealed a prominent expression of CCR2 and CCR5 by infiltrating macrophages, whereas most lymphocytes expressed CCR5 only. These data demonstrate an increased expression of MCP-1/CCL2 and RANTES/CCL5 at sites of tubulointerstitial damage and progressive fibrosis during unilateral ureteral obstruction that correlates with simultaneous accumulation of interstitial macrophages and T lymphocytes expressing the respective surface receptors CCR2 and CCR5. The chemokine receptor-mediated leukocyte influx into the tubulointerstitium could offer a new potential target for therapeutic intervention in progressive renal tubulointerstitial fibrosis.     

Maximum urinary concentration ability in patients with idiopathic hydronephrosis

The maximum urinary concentration ability and renal parenchymal function of each kidney were investigated in 34 patients with unilateral hydronephrosis. The ability to concentrate urine was not reduced in 10 hydronephrotic and 24 contralateral kidneys. The concentration ability was moderately reduced in 14 hydronephrotic and 10 non-hydronephrotic kidneys and severely impaired in 10 hydronephrotic kidneys. A reduced concentration ability was found almost entirely in hydronephrosis complicated with upper urinary tract infection or renal calculi. Hydronephrotic kidneys without these complications showed a normal concentration ability in 10 of 11 cases. Parenchymal function was reduced in only 10 hydronephrotic kidneys, 7 of which had had upper urinary tract infections and 3 of which had renal stones. It is our opinion that uncomplicated cases of unilateral hydronephrosis should not be operated upon unless necessitated by signs and symptoms. Measurement of the maximum urinary concentration ability might be helpful in setting the correct indication for surgery in borderline cases.