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.     

Bilateral complete ureteral obstruction and renal insufficiency secondary to granulomatous disease

Chronic granulomatous disease is a rare disorder of neutrophil function that impairs the ability of phagocytes to react to infection and produces inflammatory lesions that may involve many organ systems. A young man recently presented with bilateral mid ureteral obstruction and renal insufficiency secondary to inflammation due to chronic granulomatous disease. To our knowledge, we believe this to be the only case of complete bilateral ureteral obstruction due to chronic granulomatous disease reported to date. A review of the disease, its pathogenesis and potential involvement of the urinary tract is presented.     

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 impairs renal antioxidant enzyme activation during sodium depletion

BACKGROUND: Obstructive nephropathy leads to progressive renal tubular atrophy and interstitial fibrosis and is associated with sodium wasting and sodium depletion. Renal damage resulting from unilateral ureteral obstruction (UUO) may be aggravated by reactive oxygen species (ROS), which are produced by a variety of processes. Ideally, deleterious effects of ROS are attenuated by antioxidant enzymes, including the superoxide dismutases, glutathione peroxidases, catalase, and glutathione-S-transferases. The general paradigm is that tissue damage occurs when ROS production is greater than the protective capacity of the antioxidant enzymes. METHODS: This study was designed to investigate the response of renal antioxidant enzymes to UUO and sodium depletion. Adult, male Sprague-Dawley rats received normal-sodium or sodium-depleted siets and were subjected to UUO or sham operation. Obstructed (UUO), intact opposite, or sham-operated kidneys were harvested after 14 days, and antioxidant enzyme activities were measured in kidney homogenates. Thiobarbituric acid reactive substances were measured in these homogenates at 3 and 14 days after UUO or sham operation as an index of ROS production. RESULTS: Renal interstitial area, a measure of fibrosis, was increased by UUO and was doubled in sodium-depleted animals. Sodium depletion increased manganese superoxide dismutase, glutathione peroxidases, and glutathione-S-transferase activities in sham-operated kidneys but not in UUO kidneys. Relative to intact opposite kidneys, UUO kidneys had reduced activities of catalase, manganese superoxide dismutase, and glutathione-S-transferase in normal-sodium animals and all antioxidant enzymes tested in sodium-depleted animals. Renal thiobarbituric acid reactive substances were increased by three days of UUO and were increased further by 14 days of sodium depletion. CONCLUSION: In summary, sodium depletion increased several renal antioxidant enzymes, consistent with a stress response to increased ROS production. Further, UUO not only reduced antioxidant enzyme activities but also inhibited increases seen with sodium depletion. We conclude that suppression of renal antioxidant enzyme activities by UUO contributes to the progression of renal injury in obstructive nephropathy, a process exacerbated by sodium depletion.     

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.     

Compensatory renal growth due to neonatal ureteral obstruction: implications for clinical studies

In response to unilateral ureteral obstruction (UUO), the contralateral kidney undergoes compensatory renal growth, which is enhanced in early development. We investigated the renal growth response to UUO in the neonatal rat. Within 2 days of birth, animals were subjected to sham-operation, complete UUO, or variable partial UUO, and kidneys were harvested 3–60 days later. Contralateral kidney weight increased after only 7 days of complete UUO. Increase in contralateral kidney weight was not significant for partial UUO until 45 days, but kidney/body weight ratio increased after only 14 days of 0.3 mm partial UUO. The rate of contralateral renal growth increased with age and with increasing severity of UUO. In rats subjected to 45 days UUO, glomerular area was proportional to kidney/body weight ratio (r =0.61, p <0.01). We conclude that the rate of compensatory renal growth is dependent on the severity and duration of obstruction, and takes place at the single nephron level. The results suggest that biologic variability limits the early detection of compensatory renal growth, which is compounded by limitations in measuring renal size by clinical imaging. Factoring kidney length (or volume) by intervertebral length (or body surface area) should improve the precision of tracking renal growth.     

Contribution of endogenous vasoactive compounds to renal vascular resistance in neonatal chronic partial ureteral obstruction

To evaluate the relative contribution of endogenous vasoactive compounds to maintenance of increased renal vascular resistance in neonatal obstructive nephropathy, cardiac output and renal blood flow were measured using radioactive microspheres in 25 +/- 3 day-old guinea pigs subjected to unilateral partial ureteral constriction within the first two days of life. Mass and renal blood flow of the obstructed kidney were significantly lower than those of the contralateral kidney. Following a control period, thromboxane synthesis was blocked by infusion of OKY-046, after which prostaglandin synthesis was inhibited by indomethacin. In a separate group of animals, angiotensin converting enzyme inhibitor, MK-422, was infused before or after administration of OKY-046. While neither OKY-046 nor indomethacin had a consistent effect on vascular resistance, infusion of MK-422 resulted in selective reduction of renal vascular resistance of the obstructed kidney compared to resistance in the intact kidney and other vascular beds. Removal of the contralateral kidney at the time of ureteral constriction in an additional group of animals resulted in hypertrophy and vasodilation of the obstructed kidney which was not altered by thromboxane or cyclooxygenase inhibition. We conclude that in the neonatal kidney subjected to ipsilateral chronic partial ureteral obstruction, vasoconstriction is mediated at least in part by angiotensin II, but not by thromboxane. Furthermore, vasodilation of the obstructed kidney resulting from contralateral nephrectomy is not dependent on prostaglandin synthesis. Renal vascular resistance of the kidney with prolonged partial ureteral constriction in early development thus appears to be inversely related to renal growth and is not significantly mediated by endogenous prostanoids.     

单侧输尿管梗阻大鼠肾间质纤维化的发生机制

目的 探讨单侧输尿管梗阻后肾间质纤维化的形成机制.方法 采用单侧输尿管梗阻(uniliteral ureteral obstruction UUO)致肾间质纤维化大鼠模型,将54只大鼠随机分假手术组、梗阻组.术后7天、14天、21天观察肾组织病理改变,并应用免疫组织化学方法检测肾间质核转录因子-κB(Nuclear factor-κB NF-κB)、纤溶酶原激活物抑制剂-1(plasminogen activator inhibitor-1 PAI-1)的表达.结果 随着梗阻时间延长,梗阻组肾间质PAI-1和NF-κB的表达增加,假手术组无明显变化,两组相比有显著差异(p＜0.01).结论 单侧输尿管梗阻肾间质NF-κB、PAI-1的过度表达,是形成间质纤维化的重要原因之一.     

Triptolide attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction

Aim: Extracts of Tripterygium wilfordii Hook F. have been used to treat glomerulonephritis for more than 30 years in China. Most of the anti‐inflammatory and immunosuppressive activities of these extracts can be attributed to triptolide (Trip). The present study was to investigate the effect of Trip on renal interstitial fibrosis in a model of unilateral ureteral obstruction (UUO). Methods: UUO or sham‐operated rats were randomly assigned to receive mycophenolate mofetil (MMF), Trip or vehicle and were killed on days 7 and 14 after UUO or sham operation. Kidney specimens were fixed for immunohistochemistry for myofibroblasts (α‐smooth muscle actin, α‐SMA), macrophages (ED‐1), monocyte chemoattractant protein‐1 (MCP‐1) and osteopontin. Interstitial collagen deposition and amounts of transforming growth factor‐β1 (TGF‐β1) were determined by Sirius red staining and enzyme‐linked immunosorbent assay, respectively. The mRNA expression of TGF‐β1, connective tissue growth factor (CTGF), MCP‐1 and osteopontin were measured by real‐time polymerase chain reaction analysis. Results: The scores for the density of α‐SMA‐ and ED‐1‐positive cells, the staining of MCP‐1 and osteopontin, interstitial collagen deposition and amounts of TGF‐β1 were significantly reduced by MMF or Trip. MMF or Trip significantly reduced the mRNA expression of TGF‐β1, CTGF, MCP‐1 and osteopontin. Conclusion: Trip significantly attenuated tubulointerstitial fibrosis in a rat UUO model and the effect of Trip on renal fibrosis was similar to that of MMF. Trip may be useful as a potential candidate in the treatment of renal fibrosis.     

Osteopontin regulates renal apoptosis and interstitial fibrosis in neonatal chronic unilateral ureteral obstruction

Congenital obstructive nephropathy is a major cause of renal insufficiency in children. Osteopontin (OPN) is a phosphoprotein produced by the kidney that mediates cell adhesion and migration. We investigated the role of OPN in the renal response to unilateral ureteral obstruction (UUO) in neonatal mice. OPN null mutant (-/-) and wild-type (+/+) mice were subjected to sham operation or UUO within the first 2 days of life. At 7 and 21 days of age, fibroblasts (fibroblast-specific protein (FSP)-1), myofibroblasts (alpha-smooth muscle actin (SMA)), and macrophages (F4/80) were identified by immunohistochemical staining. Apoptotic cells were detected by terminal deoxy transferase uridine triphosphate nick end-labeling technique and interstitial collagen by Masson trichrome or picrosirius red stain. Compared to sham-operated or contralateral kidneys, obstructed kidneys showed increases in all parameters by 7 days, with further increases by 21 days. After 21 days UUO, there was an increase in tubular and interstitial apoptosis in OPN -/- mice as compared to +/+ animals (P<0.05). However, FSP-1- and alpha-SMA-positive cells and collagen in the obstructed kidney were decreased in OPN -/- compared to +/+ mice (P<0.05), whereas the interstitial macrophage population did not differ between groups. We conclude that OPN plays a significant role in the recruitment and activation of interstitial fibroblasts to myofibroblasts in the progression of interstitial fibrosis in the developing hydronephrotic kidney. However, OPN also suppresses apoptosis. Future approaches to limit the progression of obstructive nephropathy in the developing kidney will require targeting of specific renal compartments.     

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.     

Effects of probucol on renal function in rats with bilateral ureteral obstruction

To ascertain the potential role of reactive oxygen metabolites in the pathophysiology of obstructive uropathy, we examined the effect of probucol, an antioxidant agent, on renal function in normal rats and rats with unilateral release of bilateral ureteral obstruction (BUO) of 24 hours duration. Rats were fed either a standard diet or a standard diet containing one percent probucol for two weeks prior to study. Probucol lowered serum cholesterol in both normal and BUO rats. Probucol did not significantly affect renal function in normal rats. BUO rats given probucol had greater inulin and PAH clearances at three to five hours and three days following release of BUO than rats with BUO not given probucol. Kidneys from obstructed rats had higher levels of malondialdehyde, an index of lipid peroxidation, a greater number of leukocytes in the cortex, decreased levels of reduced glutathione and increased levels of oxidized glutathione. Renal cortex from obstructed rats treated with probucol had significantly higher levels of reduced glutathione than kidneys of obstructed rats not given probucol. A decrease in cholesterol, using another lipid-lowering agent, lovastatin, did not modify renal function in rats with BUO. The data can be interpreted to indicate a role for reactive oxygen species in the pathophysiology of obstructive nephropathy. The improved renal function seen in probucol-treated rats with BUO may be due to an effect of this agent in affecting accumulation of reactive oxygen metabolites and/or decreasing the number of leukocytes infiltrating the renal cortex.     

双环醇对单侧输尿管梗阻大鼠肾间质纤维化的影响及作用机制

肾间质纤维化是反映肾功能下降严重程度和判断预 后最重要的指标[1],寻求抗肾间质纤维化的新药物已成为当前肾脏病研究的热点之一.双环醇是在联苯双酯的基础上,经结构改造和筛选得到的国家Ⅰ类抗肝炎新药.近来研究发现,双环醇对肝纤维化具有明显的抑制作用[2].本研究应用双环醇动态观察单侧输尿管梗阻(UUO)术后肾组织NF-κB的表达水平,探讨双环醇对UUO大鼠肾间质纤维化的影响及其可能机制.     

Partial unilateral ureteral obstruction in rats

This review comprises an overview of the current knowledge on experimental partial unilateral ureteral obstruction (PUUO) and a summary of our latest original experimental PUUO studies in rats. Neonatal PUUO is the type of obstruction that is most often encountered in pediatric clinical practice. However, the pathogenesis of PUUO is still incompletely understood. Most of our knowledge on PUUO has been derived from experimental studies in a variety of animal models. Although progress has been made, the natural history of congenital hydronephrosis is still incompletely described. The effects on kidney functions of long-term urinary tract obstruction, especially PUUO, have been less intensively studied. Recently, we created models with mild and severe PUUO in young rats by embedding the upper one fourth or the upper two thirds of the left ureter into the psoas muscle, respectively. Thereafter, the technique was used to create mild and severe PUUO in newborn rats and magnetic resonance imaging studies showed that both mild and severe obstruction caused a time-dependent decrease in renal blood flow. Compensatory increase in total kidney volume and renal vein blood flow in contralateral non-obstructed kidneys was not detectable when functional deterioration in the partially obstructed kidneys was present. Finally, we investigated the dynamic changes in renal relative signal intensity (RSI) of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) using magnetic resonance imaging in rats with partial, complete unilateral ureteral obstruction and sham-operated controls. The results showed that changes in Gd-DTPA RSI are compatible with the known physiological and anatomical changes in kidneys in response to ureteral obstruction and useful for distinguishing an obstructed from a non-obstructed collecting system and also for differentiating a partially obstructed from a completely obstructed collecting system.     

Effects of renal sympathetic denervation on renal interstitial fibrosis in rats with unilateral ureteral obstruction

Objective To observe the influence of renal sympathetic denervation (RSD) on renal interstitial fibrosis and transforming growth factor beta 1(TGF-β1) and microRNA-21 (miR-21) in rats with unilateral ureteral obstruction(UUO). Methods 40 male Wistar rats were randomly divided into UUO group (A group, n=10), sham UUO group (B group, n=10), RSD+UUO group (C group, n=10) and RSD+sham UUO group (D group, n=10). Rats in A group and C group underwent unilateral ureteral ligation, while those in B group and D group underwent sham operation. Rats in C group and D group were followed by RSD. Rats were sacrificed at 21 days after the operation to evaluate the fibrosis by Masson staining. Immunohistochemical staining and Western blotting were used to detect the expressions of collagen I (COL-I), collagen Ⅲ(COL-Ⅲ) and TGF-β1 in four groups. The expression of miR-21 was detected by fluorescence in situ hybridization (FISH) and quantitative real-time PCR (RT-qPCR). Results A large amount of collagen deposition was observed in the renal interstitial area in A and C group compared to either B or D group (P＜0.05), but the change in C group was decreased significantly than that in A group (P＜0.05). Similarly, the expressions of COL-I, COL-Ⅲ, TGF-β1 and miR-21 were obviously higher in A and C group compared to either B or D group (P＜0.05), but those change in C group were decreased significantly than those in A group (P＜0.05). The above indexes were not significantly different between B group and D group (P＞0.05). Conclusion RSD may relieve the renal interstitial fibrosis in UUO rats, and down-regulate the expression of TGF-β1 and miR-21.