Unilateral ureteral obstruction: beyond obstruction

Unilateral ureteral obstruction is a popular experimental model of renal injury. However, the study of the kidney response to urinary tract obstruction is only one of several advantages of this model. Unilateral ureteral obstruction causes subacute renal injury characterized by tubular cell injury, interstitial inflammation and fibrosis. For this reason, it serves as a model both of irreversible acute kidney injury and of events taking place during human chronic kidney disease. Being a unilateral disease, it is not useful to study changes in global kidney function, but has the advantage of a low mortality and the availability of an internal control (the non-obstructed kidney). Experimental unilateral ureteral obstruction has illustrated the molecular mechanisms of apoptosis, inflammation and fibrosis, all three key processes in kidney injury of any cause, thus providing information beyond obstruction. Recently this model has supported key concepts on the role in kidney fibrosis of epithelial–mesenchymal transition, tubular epithelial cell G2/M arrest, the anti-aging hormone Klotho and renal innervation. We now review the experimental model and its contribution to identifying novel therapeutic targets in kidney injury and fibrosis, independently of the noxa.     

Unilateral ureteral obstruction secondary to sarcoidosis

An episode of unilateral ureteral obstruction secondary to sarcoidosis is described. Corticosteroid treatment resulted in prompt and complete resolution of the obstruction and associated lymphadenopathy. We believe this represents the first reported case of ureteral obstruction secondary to sarcoidosis.     

Unilateral ureteral obstruction in neonatal rats leads to renal insufficiency in adulthood

BACKGROUND: Although unilateral ureteropelvic junction obstruction is the most common cause of congenital obstructive nephropathy in infants and children, management remains controversial, and follow-up after pyeloplasty is generally limited to the pediatric ages. We have developed a model of temporary unilateral ureteral obstruction (UUO) in the neonatal rat: One month following the relief of five-day UUO, the glomerular filtration rate (GFR) of the postobstructed kidney was normal despite a 40% reduction in the number of glomeruli and residual vascular, glomerular, tubular, and interstitial injury. METHODS: To determine whether hyperfiltration and residual injury of remaining nephrons leads to progression of renal insufficiency in later life, 31 rats were sham operated or subjected to left UUO at one day of age, with relief of UUO five days later, and were studied at one year of age. GFR was measured by inulin clearance, and the number of glomeruli, tubular atrophy, glomerular sclerosis, and interstitial fibrosis were measured by histomorphometry in sham, obstructed (UUO), and intact opposite kidneys. Intrarenal macrophages and alpha-smooth muscle actin were identified by immunohistochemistry. RESULTS: Despite relief of UUO, ultimate growth of the postobstructed kidney was impaired. The number of glomeruli was reduced by 40%, and GFR was decreased by 80%. However, despite significant compensatory growth of the opposite kidney, there was no compensatory increase in GFR, and proteinuria was increased. Moreover, glomerular sclerosis, tubular atrophy, macrophage infiltration, and interstitial fibrosis were significantly increased not only in the postobstructed kidney, but also in the opposite kidney. CONCLUSIONS: Although GFR is initially maintained following relief of five-day UUO in the neonatal rat, there is eventual profound loss of function of the postobstructed and opposite kidneys because of progressive tubulointerstitial and glomerular damage. These findings suggest that despite normal postoperative GFR in infancy, children undergoing pyeloplasty for ureteropelvic junction obstruction should be followed into adulthood. Elucidation of the cellular response to temporary UUO may lead to improved methods to assess renal growth, injury, and functional reserve in patients with congenital obstructive nephropathy.     

Unilateral ureteral obstruction in early development alters renal growth: dependence on the duration of obstruction

PURPOSE: Over 90% of nephrogenesis in the rat takes place postnatally in the first 10 days, analogous to the midtrimester human fetus. We wished to determine the relationship between the duration of unilateral ureteral obstruction and growth and morphology of both kidneys following relief of the obstruction in the neonatal rat. MATERIALS AND METHODS: One ureter of 1 day-old rats was sham-operated or occluded and released 1, 2, 3, or 5 days later, or not released. Fourteen or 28 days later, renal mass, tubular atrophy, and interstitial fibrosis were determined in the obstructed and contralateral kidney of each group. RESULTS: At 28 days, there was a linear relationship between kidney/body weight ratio and duration of obstruction, such that the decrement in renal mass resulting from ipsilateral obstruction was precisely compensated by an equal increment in the mass of the contralateral kidney (both, p <0.0001). Tubular atrophy was increased 100-fold in kidneys of rats with 28 days continuous ipsilateral obstruction, while relief of obstruction after 2 to 5 days reduced tubular atrophy by 90% (p <0.01). Interstitial fibrosis was also markedly reduced by relief of obstruction, with the severity of fibrosis being proportional to the duration of obstruction. CONCLUSIONS: We conclude that ureteral obstruction during the critical period of nephrogenesis impairs growth of the obstructed kidney and stimulates growth of the contralateral kidney in direct proportion to the duration of obstruction. Moreover, counterbalance between the two kidneys is finely regulated. Even 2 days of ureteral obstruction (with subsequent relief) induces contralateral renal growth, and induces ipsilateral tubular atrophy. However, the time dependence of renal injury on duration of obstruction suggests that earlier relief of obstruction in the developing kidney may allow greater ultimate preservation of functional renal mass.     

Renal hemodynamic response to ureteral obstruction during converting enzyme inhibition

Acute unilateral obstruction (UUO) of the pig kidney is associated with an increased secretion of intrarenally generated angiotensin II (ANG II). In order to clarify the importance of this intrarenal ANG II generation during acute UUO, ipsilateral and contralateral renal blood flow and renal secretion rate of ANG II were determined in pigs during continuous infusion of an angiotensin I converting enzyme (ACE) inhibitor. Pigs were operatively equipped with electromagnetic flow probes and catheters in the renal veins and aorta. Intravenous administration of the ACE inhibitor SQ 14 225 (captopril), 1 mg/kg per hour, resulted in a significant increase in renal blood flow in the contralateral kidney from 340±28 ml/min to 435±36 ml/min (P<0.01), whereas renal blood flow in the ipsilateral kidney was significantly reduced from 388±23 ml/min to 248±24 ml/min, similar to the reduction in controls. Captopril reduced mean aortic blood pressure, renal vascular resistance consistently on both sides, and plasma concentrations of ANG II and aldosterone from all sample sites. Renal secretion rate of ANG II showed a clear tendency to be reduced from the ipsilateral kidney. The results suggest that in UUO a compensatory increase in renal blood flow may be inhibited in part due to an enhanced secretion of ANG II in the ipsilateral kidney. However, a captopril-mediated inhibition of bradykinin breadown may also explain some of the observed changes.     

Neonatal ureteral obstruction alters expression of renal sodium transporters and aquaporin water channels

BACKGROUND: Congenital urinary tract obstruction is a common cause of renal insufficiency in the neonate and during infancy. Recently, we demonstrated that ureteral obstruction in adult rats is associated with reduction in the abundance of renal aquaporins (AQPs) and renal sodium transporters, which paralleled an impaired urinary concentrating capacity. METHODS: In the present study, renal handling of sodium and water, together with the expression of renal aquaporins and major renal sodium transporters, was examined in rats with neonatally induced partial unilateral ureteral obstruction (PUUO) within the first 48 hours of life to clarify the molecular mechanisms involved in the tubular functional defects in response to congenital obstruction. Rats were then followed for 12 or 24 weeks. RESULTS: Neonatal PUUO caused a progressive reduction in single kidney glomerular filtration rate (SKGFR) on the obstructed side to 43% of controls at 12 weeks (115 +/- 28 vs. 267 +/- 36 microL/min/100g bw, P < 0.05), and 31% of controls at 24 weeks (106 +/- 24 vs. 343 +/- 41 microL/min/100g bw, P < 0.05). Na-K-ATPase abundance was decreased in the obstructed kidney compared with the nonobstructed kidney at 24 weeks (79 +/- 6%, P < 0.05), and the abundance of bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1) located to the medullary thick ascending limb (mTAL) of the obstructed kidney was significantly reduced both at 12 weeks (42 +/- 10%, P < 0.05) and 24 weeks (50 +/- 10%, P < 0.05). Immunohistochemistry confirmed down-regulation of BSC-1 both at 12 and 24 weeks after onset of obstruction. Consistent with this, sodium excretion from the obstructed kidney was increased at 12 weeks (0.13 +/- 0.03 vs. 0.04 +/- 0.01 micromol/min/100g bw, P < 0.05), and persisted 24 weeks after onset of PUUO (0.15 +/- 0.02 vs. 0.06 +/- 0.01 micromol/min/100g bw, P < 0.05). AQP2 abundance in the collecting duct was also reduced both at 12 weeks (68 +/- 5%, P < 0.05) and at 24 weeks (69 +/- 13%, P < 0.05). Consistent with this, solute-free water reabsorption was decreased in the obstructed kidney at 12 weeks (0.61 +/- 0.42 vs. 1.97 +/- 0.63 microL/min/100g bw, P < 0.05) and remained decreased after 24 weeks of PUUO (0.42 +/- 0.04 vs. 1.56 +/- 0.39 microL/min/100g bw, P < 0.05). CONCLUSION: Major sodium transporters and aquaporins in the obstructed kidney are down-regulated in response to neonatally induced PUUO, which indicates that these transporters may play a crucial role for the persistent reduction in renal handling of sodium and water in response to PUUO.     

Effect of renal fibrosis after macrophage depletion in C3-deficient unilateral ureteral obstruction mice

Objective To investigate the effect and mechanism of renal fibrosis after macrophage depletion in C3-deficient unilateral ureteral obstruction mice. Methods Renal interstitial fibrosis model was established by unilateral ureteral obstruction (UUO) in male C3-deficient mice and age-matched C57BL/6 WT mice (8-12 weeks of age). Mice were randomly divided into 4 groups, including sham operation in wild type group（WT/sham）(n=18), UUO operation in wild type group（WT/UUO）(n=18), sham operation in C3-deficient group（C3KO/sham）(n=18), and UUO operation in C3-deficient group（C3KO/UUO）(n=18). The expression of complement C3 was detected by immunohistochemical staining and renal interstitial macrophages were assessed by immunofluorescence staining. Tubulointerstitial fibrosis was observed by both HE staining and Masson staining after 14 days of UUO. Collagen accumulation and score of tubulointerstitial injury were obtained. Wild type and C3-deficient UUO mice were treated by liposome clodronate in early or late stage respectively and then interstitially infiltrated macrophages and renal fibrosis were analysed. Mice were sacrificed randomly at 3,7,14 days after UUO and obstructed kidneys were collected. Macrophage phenotype was detected by double-labeling immunofluorescence with F4/80 and iNOS for the M1, F4/80 and CD206 for the M2 macrophage subpopulation. iNOS, Arg-1 and CD206 were also detected by western blot. Results C3 deficient mice exhibited attenuated renal fibrosis, reduced collagen accumulation and tubulointerstitial injury score compared with WT mice (P＜0.01). Meanwhile, macrophage depletion in early or late stage of UUO reduced renal fibrosis in WT mice, but had no effect on C3-deficient UUO mice. Decreased accumulation of M1 macrophages and expression of iNOS, increased accumulation of M2 macrophages and expression of Arg-1, CD206 were found in C3 deficient mice compared with WT mice in early stage of UUO (P＜0.01). Conclusion Renal fibrosis is not reduced after depletion of macrophages in C3 deficient UUO mice due to the altered macrophage polarization.     

Interleukin-1 accounts for intrarenal Th17 cell activation during ureteral obstruction

Interleukin 17A-secreting T-helper 17 (Th17) cells are pathogenic in inflammatory kidney diseases, but their intrarenal regulation is poorly understood. In order to better define Th17 cell dynamics during interstitial inflammation, we utilized the mouse unilateral ureteral obstruction model to analyze inflammatory cell subtypes by multicolor flow cytometry and cell sorting and by effects on in vitro-generated Th17 cells. Interleukin 17A expression localized to CCR6(+)CCR4(+/-)CD4(+) T-cells and progressively increased in obstructed kidneys. The number of CCR6(+)CD4(+) T-cells increased over 10-fold by 72?h, were enriched for interleukin 17A production, and were highly proliferative based on in vivo bromodeoxyuridine incorporation. Secreted products of leukocytes isolated from obstructed kidneys enhanced the interleukin 17A production of in vitro-generated Th17 cells. This Th17-enhancing activity was identified as interleukin-1 produced by renal dendritic cells and monocytes. The in vivo validity of these findings was confirmed in mice lacking the interleulin-1 receptor and in mice treated with a recombinant interleukin-1 receptor antagonist, each of which exhibited reduced intrarenal Th17 activity compared with control mice. Thus, the inflamed kidney accumulates CCR6(+) Th17 cells that undergo activation and proliferation. Production of interleukin 1 family cytokines by resident dendritic cells and infiltrating monocytes enhances intrarenal Th17 activation in acute kidney injury.     

EDRF modulates renal hemodynamics during unilateral ureteral obstruction in the rat.

Unilateral ureteral obstruction (UUO) results in vasoconstriction of the ipsilateral kidney, and vasodilatation of the intact opposite kidney. To investigate the role of endogenous nitric oxide, an endothelial-derived relaxing factor (EDRF), in the regulation of renal hemodynamics during UUO, Sprague-Dawley rats were anesthetized for study 24 hours after left UUO or sham-operation. Total vascular resistance (TVR) and renal vascular resistance (RVR) were measured using radioactive microspheres during control periods and following infusion of the nitric oxide synthase inhibitor, L-NAME (2.5 mg/kg). Blood pressure and RVR were increased by L-NAME, with a greater increment in the RVR/TVR ratio of the kidney with ipsilateral UUO than in the intact opposite kidney or sham-operated kidneys. Infusion of L-arginine (L-Arg), a substrate for nitric oxide synthase, did not alter the RVR/TVR ratio of either kidney of rats with UUO, but reduced the ratio in sham-operated animals. L-NAME tended to reduce urine flow and urinary sodium and cyclic GMP excretion, whereas L-Arg resulted in a marked diuresis, natriuresis, and increased excretion of cyclic GMP in both operative groups. We conclude that EDRF activity is increased in the kidney with ipsilateral UUO, which serves to counteract renal vasoconstriction. This response is not limited by availability of substrate (L-Arg). Vasodilatation of the intact opposite kidney appears to be mediated by factors other than EDRF.     

Unilateral ureteral obstruction secondary to rupture of liver echinococcal cyst.

We report a case of ureteral obstruction by reactive retroperitoneal fibrosis secondary to rupture of a liver echinococcal cyst after minimal blunt flank trauma. The patient presented initially with a cyst-cutaneous fistula and was treated with mebendazole, since surgery was refused. Unilateral ureteral obstruction due to reactive dense retroperitoneal fibrosis developed 2 years later, which presumably was initiated by intense inflammatory reaction to the cyst content. Diagnosis was established by excretory urography, ultrasonography and computerized tomography, and was histologically confirmed. Hydronephrosis and hydroureter resolved following ureterolysis. This complication is anticipated to be encountered more frequently with the use of the new potent anthelmintic agents, which may successfully prevent daughter cyst formation but fail to abolish reactive retroperitonitis.     

Alterations of renal hemodynamics in unilateral ureteral obstruction mediated by activation of endothelin receptor subtypes

PURPOSE: Unilateral ureteral obstruction (UUO) for 21 hours causes severe renal vasoconstriction. We examined the role of endothelin (ET)-A receptor in renal hemodynamic alterations induced by UUO. MATERIALS AND METHODS: Hemodynamic and clearance experiments were performed in 3 groups of anesthetized dogs. In group 1, 6 sham operated dogs received intrarenal infusion of the specific ET-A receptor antagonist BQ-610 (Peninsula Laboratories, Inc., Belmont, California), followed by infusion of the nitric oxide synthase substrate L-arginine. In the 7 group 2 dogs release of 21-hour UUO was followed by intrarenal infusion of BQ-610 and L-arginine. In the 5 group 3 dogs release of 21-hour UUO was followed by L-arginine infusion. RESULTS: UUO caused marked decreases in renal blood flow (RBF) and glomerular filtration rate (GFR) in groups 2 and 3 compared with group 1. In group 1 BQ-610 and L-arginine infusion did not alter RBF or GFR. In contrast, BQ-610 infusion in group 2 after UUO release led to a significant increase in RBF and GFR as well as additional increases after L-arginine infusion. After UUO release in group 3 L-arginine infusion alone did not change RBF or GFR. CONCLUSIONS: After UUO release blockade of the ET-A receptor ameliorates renal vasoconstriction. The addition of L-arginine, which is a substrate for nitric oxide synthase, superimposed on ET-A receptor blockade confers a further decrease in renal vascular resistance, suggesting that the ET and L-arginine-nitric oxide systems are involved in renal hemodynamic alterations caused by UUO.     

移植肾输尿管梗阻的外科处理

目的：提高对移植肾输尿管梗阻的治疗水平。方法：回顾性分析16例移植肾输尿管梗阻的临床资料。6例急性梗阻患者中，2例因髂窝血肿压迫者行血肿清除术；2例血凝块堵塞者，1例逆行留置输尿管导管，另1例行输尿管再植术；2例结石者行体外冲击波碎石治疗。10例慢性梗阻患者中，7例输尿管远端狭窄，行输尿管再植术；3例输尿管中、远段狭窄，行自身输尿管与移植肾肾盂吻合术。结果：16例经外科处理后，移植肾功能明显改善，随访观察半年无复发。结论：移植肾输尿管梗阻经及时恰当的外科处理，疗效满意，对慢性梗阻患者，应根据术中输尿管探查情况，选用输尿管再植术或自身输尿管与移植肾肾盂吻合术。     

移植肾并发输尿管梗阻的治疗

目的 探讨肾移植术后并发输尿管梗阻的治疗策略.方法 同种异体肾移植术后7 d～10年并发输尿管梗阻患者34例,其中3例移植输尿管部分坏死患者以开放手术治疗,其余31例采用经尿道逆行输尿管镜技术及经皮肾穿刺顺行输尿管镜技术进行碎石、内切开或扩张等方法解除梗阻,放置双J管内引流,观察患者肾功能改善情况.结果 3例开放手术清除坏死段输尿管后移植输尿管再吻合成功;1例输尿管内血凝块堵塞者成功清除血凝块;2例输尿管膀胱吻合口水肿、11例输尿管膀胱吻合口狭窄及6例吻合口上方狭窄患者行狭窄段扩张或内切开;6例输尿管结石及1例体外冲击波碎石术后石街患者行输尿管镜碎石、取石治疗;2例输尿管迂曲及2例尿漏患者行输尿管镜下置管术.术后随访18～50个月,29例引流通畅,肾功能恢复正常,血肌酐45～120μmol/L;5例肾功能恢复较差,血肌酐170～360 μmol/L;1例吻合口上方狭窄患者需定期更换支架管.结论微创技术治疗移植肾输尿管梗阻疗效好、安全.     

Calycovesicostomy for total ureteral obstruction after renal transplantation

Surgical reconstruction for ureteral obstruction is necessary in 1 to 10 per cent of renal transplants. On an acute basis edema, ischemia, lymphocele and hematoma formation cause ureteral obstruction. Chronic etiologies include ureterovesical obstruction and retroperitoneal or ureteral fibrosis. Options for repair are myriad and include repeat ureteral reimplantation, pyeloureterostomy, ureteroureterostomy, pyelocystostomy and calycovesicostomy. We report on the desirability of calycovesicostomy as a last resort option for total ureteral obstruction after renal transplantation.