Brenner and Rector's The Kidney, 8th ed.

CHAPTER 35. Urinary Tract Obstruction

Jørgen Frøkiaer   Mark L. Zeidel



Prevalence and Incidence, 1239



Classification, 1239



Etiology, 1239



Congenital Causes of Obstruction, 1240



Acquired Causes of Obstruction, 1241



Clinical Aspects, 1244



Diagnosis, 1244



History and Physical Examination, 1244



Biochemical Evaluation, 1244



Radiologic Evaluation, 1244



Pathophysiology of Obstructive Nephropathy, 1249



Effects of Obstruction on Glomerular Filtration, 1249



Effects of Obstruction on Tubule Function, 1252



Effects of Obstruction on Metabolic Pathways and Gene Expression, 1257



Pathophysiology of Recovery of Tubular Epithelial Cells From Obstruction or of Tubulointerstitial Fibrosis, 1257



Fetal Urinary Tract Obstruction, 1258



Treatment of Urinary Tract Obstruction and Recovery of Renal Function, 1258



Estimating Renal Damage and Potential for Recovery, 1259



Recovery of Renal Function after Prolonged Obstruction, 1259



Postobstructive Diuresis, 1259

In adults, 1.5 L to 2.0 L of urine flows daily from the renal papillae through the ureter, bladder, and urethra in an uninterrupted, unidirectional flow. Any obstruction of urinary flow at any point along the urinary tract may cause retention of urine and increased retrograde hydrostatic pressure, leading to kidney damage and interference with waste and water excretion, as well as fluid and electrolyte homeostasis. Because the extent of recovery of renal function in obstructive nephropathy related inversely to the extent and duration of obstruction, prompt diagnosis and relief of obstruction are essential for effective management. Fortunately, urinary tract obstruction is a highly manageable form of kidney disease.

Several terms describe urinary tract obstruction, and definitions may vary. [1] [2] In the following discussion we define hydronephrosis as a dilation of the renal pelvis and calices proximal to the point of obstruction. Obstructive uropathy refers to blockage of urine flow due to a functional or structural derangement anywhere from the tip of the urethra back to the renal pelvis that increases pressure proximal to the site of obstruction. Obstructive uropathy may or may not result in renal parenchymal damage. Such functional or pathologic damage is referred to as obstructive nephropathy. It should be noted that hydronephrosis and obstructive uropathy are not interchangeable terms—dilation of the renal pelvis and calices can occur without obstruction, and urinary obstruction may occur in the absence of hydronephrosis.


The incidence of urinary tract obstruction varies widely among different populations, and depends on concurrent medical conditions, sex, and age. Unfortunately, epidemiological reports have been based on the studies of selected “populations,” such as women with high-risk pregnancies and data from autopsy series. No data are available for any unselected populations.

A review of 59,064 autopsies of subjects varying in age from neonate to 80 years, noted hydronephrosis as a finding in 3.1% (3.3% in males and 2.9% in females).[3] In subjects under age 10, representing 1.5% of all autopsies, the principal causes of urinary tract obstruction were ureteral or urethral strictures, or neurologic abnormalities. It is unclear how frequently these abnormalities represented incidental findings, as opposed to being recognized clinically. Until the age of 20, there was no substantial sex difference in frequency of abnormalities. Between the ages of 20 and 60, urinary tract obstruction was more frequent among women than among men, mainly due to the effects of uterine cancer and pregnancy. Above the age of 60, prostatic disease raised the frequency of urinary tract obstruction among men above that among women.

In children under age 15, obstruction occurred in 2% of autopsies. Hydronephrosis was found in 2.2% of the boys and 1.5% of the girls; 80% of the hydronephrosis that did occur was found in subjects under 1 year of age.[4] A more recent autopsy series of 3172 children identified urinary tract abnormalities in 2.5%. Hydroureter and hydronephrosis were the most common findings, representing 35.9% of all cases.[5] In neither study was it clear what proportion of cases was diagnosed clinically before death.

Because a high proportion of these autopsy-detected cases of obstruction likely went undetected during life, the overall prevalence of urinary tract obstruction is very likely far greater than reports suggest. This conclusion is reinforced by the fact that there are several common but temporary causes of obstruction, such as pregnancy and renal calculi.


Classification of urinary tract obstruction can be by duration—acute or chronic,[6] by whether it is congenital or acquired, and by its location (upper or lower urinary tract, supravesical or subvesical, and so on). Acute obstruction may be associated with sudden onset of symptoms. Upper urinary tract (ureter or ureteropelvic junction) obstruction may present with renal colic. Lower tract (bladder or urethra) obstruction may present with disorders of micturition. By contrast, chronic urinary tract obstruction may develop insidiously, and present with few or only minor symptoms, and with more general manifestations. For example, recurrent urinary tract infections, bladder calculi, and progressive renal insufficiency may all result from chronic obstruction. Congenital causes of obstruction arise from developmental abnormalities, whereas acquired lesions develop after birth, either due to disease processes or as a result of medical interventions.


Because congenital and acquired urinary tract obstructions differ to a great degree in cause and clinical course, they will be described separately.

Congenital Causes of Obstruction

Congenital anomalies may obstruct the urinary tract at any level from the ureteropelvic junction to the tip of urethra, and the obstruction may damage one or both kidneys ( Table 35-1 ). Although some lesions occur rarely, as a group they represent an important cause of urinary tract obstruction, because in younger patients they often lead to severe renal impairment and may result in catastrophic end-stage renal disease. [7] [8] The widespread use of fetal ultrasonography, and its increasing sensitivity, has led to early detection in an increasing number of cases. In cases of severe obstruction early detection may lead to termination of the pregnancy or attempts to ameliorate the obstruction in utero. [8] [9] [10] However, ultrasound may detect mild obstruction of unknown clinical significance. [8] [9]

TABLE 35-1   -- Congenital Causes of Urinary Tract Obstruction



Ureteropelvic junction



Ureteropelvic junction obstruction



Proximal and middle ureter



Ureteral folds



Ureteral valves






Benign fibroepithelial polyps



Retrocaval ureter



Distal ureter



Ureterovesical junction obstruction



Vesicoureteral reflux



Prune-belly syndrome









Bladder diverticula



Neurologic conditions (e.g., spina bifida)






Posterior urethral valves



Urethral diverticula



Anterior urethral valves



Urethral atresia



Labial fusion




Ureteropelvic junction (UPJ) obstruction is the most common cause of hydronephrosis in fetuses[11] and young children, [12] [13] with a reported incidence of 5 cases per 100,000 population per year,[14] and it may affect adults as well. [15] [16] In fact, in one series, over 50% of patients with congenital UPJ obstruction were older than 20 years.[14] Although most cases of UPJ obstruction appear to represent sporadic events, familial forms exist, indicating a role for genetic inheritance in some cases.[17] Sixty percent of cases occur on the left side, and two thirds occur in males. In patients diagnosed at an age of under 1 year, 20% of cases are bilateral.[18] There is considerable controversy as to whether all cases of obstruction early in life are clinically significant. The widespread use of fetal ultrasound has resulted in detection of many cases that remain asymptomatic and may resolve spontaneously with simple follow-up of the child. [19] [20] Although most cases of UPJ obstruction are diagnosed prenatally by ultrasound,[18] the most common neonatal clinical presentation is a flank or abdominal mass.[21] By contrast, adults generally present with flank pain. [15] [16] Because intermittent obstruction may produce symptoms that mimic those of gastrointestinal disease, diagnosis may be delayed. At any age, UPJ obstruction may be associated with kidney stones, hematuria, hypertension, or recurrent urinary tract infection. [14] [15] [16]

It is thought that UPJ obstruction may result from an aperistaltic segment of the ureter, which cannot pump urine away from the renal pelvis and down the ureter.[22] Less commonly, the obstruction may be due to an actual ureteral stricture.[22] Histopathologic studies reveal multiple abnormalities at the UPJ. Light microscopic findings may reveal no abnormality, decreased muscle bulk, infiltration of inflammatory cells, or malorientation of the muscle fibers.[23] Electron microscopy usually demonstrates an abundance of collagen. An association between abnormal angulation at the UPJ and the presence of aberrant renal vessels suggest the possibility that the aberrant vessels lead to the functional defect in the ureter, [18] [24] but this remains controversial.[25] In general, it appears that obstruction does not result from the aberrant vessel but rather from an intrinsic defect of the musculature with the secondary dilated pelvis wrapped around the aberrant vessel. Rarely, fibroepithelial polyps can cause UPJ obstruction.[26]

Congenital obstruction can also occur distal to the UPJ, in the proximal or middle ureter. Ureteral folds, which are noncircumferential areas of redundant mucosa, may cause temporary obstruction. Folds are usually asymptomatic and disappear as the child matures.[27] Ureteral valves, which are transverse folds of redundant ureteral mucosa and smooth muscle, represent uncommon causes of urinary tract obstruction. Valves may be accompanied by other urinary tract abnormalities.[28] Benign fibroepithelial polyps and congenital strictures[29] of the ureter may also cause obstruction. Abnormal development of the venous system may result in a right ureter that is located behind the vena cava. In this position, the ureter is at risk for obstruction by the vena cava,[30] producing the classic “fishhook” or “reversed J” sign deformity on an intravenous urogram. This deformity is right-sided, partial, and asymptomatic in early life. It generally goes undetected until the patient reaches adulthood. These patients usually come to clinical attention in their fourth decade, presenting with chronic urinary tract infection and colicky intermittent abdominal pain. Because the lesion is three times more common in males than females, the appearance of urinary tract infection in a male should suggest the diagnosis.

Congenital anomalies of the distal ureter represent another important cause of obstruction. A functional defect that resembles that seen at the UPJ, ureterovesical junction obstruction, is the second most common site of congenital ureteral obstruction.[31] Because these patients may develop striking enlargement of the involved ureter, ureterovesical junction obstruction is a prominent cause of congenital megaureter.[32] Vesicoureteral reflux results from anatomic abnormalities of the ureterovesical junction and may cause a congenitally enlarged ureter. The reflux may be caused by one or more of several factors, including a dysmorphic ureter, an abnormally positioned ureteral orifice, or bladder outlet obstruction.[33] Megaureter may also occur in prune-belly syndrome, which includes absence of the abdominal musculature, ureteral dilation, and bilateral cryptorchidism.[34] Congenital cystic dilatations of the terminal ureter, referred to as uterocele, may also obstruct the ureteral orifice.[35] If the ureter empties into the bladder at a site other than the lateral angle of the trigone, the ureterocele is referred to as ectopic. If the ureter empties into the bladder at the trigone, it is orthotopic. Ectopic ureteroceles often occur in conjunction with a duplicated collecting system.[35] Orthotopic ureteroceles occur less frequently than ectopic ones; some may be large enough to result in obstruction of both ureters during childhood. They carry a worse prognosis in childhood than ureteroceles diagnosed in adults.[36] Large orthotopic ureteroceles may occasionally lead to bladder outlet obstruction as well.[37] Renal duplication with ureteral ectopia may also lead to obstruction and hydronephrosis.[38]

Congenital bladder outlet obstruction may be caused by mechanical or functional factors. Mechanical causes include bladder diverticula, posterior urethral valves, urethral diver ticula, labial fusion, or duplication of the colon. Congenital bladder diverticula may obstruct one or both ureters or the bladder outlet,[39] and may even provoke acute renal failure.[39] Posterior urethral valves, seen only in boys in the proximal urethra, are the most common congenital cause of obstruction.[40] Although posterior urethral valves are usually diagnosed during childhood,[41] they may remain clinically silent into adulthood.[42] Diagnosis is best made by voiding cystourethrography. Perineal ultrasonography may also be useful, and can visualize the valve itself.[43] In cases of severe obstruction, early surgical intervention may prevent the development of renal failure. Urethral diverticula occur more commonly in girls than in boys and may lead to urethral obstruction.[44] Very rarely, labial fusion may cause urinary obstruction in newborn girls.[45] Colonic duplication, also very rare, may also lead to ureteral obstruction.[46]

Congenital functional bladder disorders obstruct the normal flow of urine because the bladder fails to fill and empty normally. Such disorders are usually due to a neurologic abnormality that most often involves the innervation of the bladder. [47] [48] Myelodysplasia, typically myelomeningocele with or without hydrocephalus, may alter strikingly the innervation of the bladder, resulting in dysfunction, and is associated with a 10% frequency of hydronephrosis at birth.[47] Because hydronephrosis may develop in another 15% of these patients early in childhood,[48] it is important to maintain careful follow-up in this group of patients to prevent later development of renal damage.[47]

Because operative complications may be high,[49] the use of fetal [50] [51] or neonatal [51] [52] surgery for the relief of obstruction remains controversial. [8] [9] [53] Although bilateral obstruction requires intervention, patients with unilateral hydronephrosis are often followed without surgery. Indications for surgery in unilateral hydronephrosis include symptoms of obstruction or impaired function in a presumably salvageable hydronephrotic kidney.

Acquired Causes of Obstruction

Intrinsic Causes

Acquired causes of obstruction may be intrinsic to the urinary tract (i.e., resulting from intraluminal or intramural processes) or may arise from causes extrinsic to it ( Table 35-2 ). Intrinsic causes of obstruction these may be considered according to anatomic location.

TABLE 35-2   -- Acquired Causes of Urinary Tract Obstruction



Intrinsic processes









Uric acid nephropathy












Multiple myeloma









Papillary necrosis



Blood clots



Fungus balls












Diabetes mellitus



Multiple sclerosis



Cerebrovascular disease



Spinal cord injury



Parkinson disease






Anticholinergic agents



Levodopa (α-adrenergic properties)






Ureteral strictures









Drugs (e.g., nonsteroidal anti-inflammatory agents)



Ureteral instrumentation



Urethral strictures



Benign or malignant tumors of the renal pelvis, ureter, bladder



Extrinsic processes



Reproductive tract












Tumor (fibroids, endometrial or cervical cancer)






Uterine prolapse



Ureteral ligation (surgical)






Tubo-ovarian abscess












Benign prostatic hyperplasia



Prostate cancer



Malignant neoplasms



Genitourinary tract



Tumors of kidney, ureter, bladder, urethra



Other sites



Metastatic spread



Direct extension



Gastrointestinal system



Crohn disease









Chronic pancreatitis with pseudocyst formation



Acute pancreatitis



Vascular system



Arterial aneurysms



Abdominal aortic aneurysm



Iliac artery aneurysm






Ovarian vein thrombophlebitis






Systemic lupus erythematosus



Polyarteritis nodosa



Wegener granulomatosis



Henoch-Schönlein Purpura



Retroperitoneal processes















Ascending lymphangitis of the lower extremities



Chronic urinary tract infection









Iatrogenic (multiple abdominal surgical procedures)



Enlarged retroperitoneal nodes



Tumor invasion



Tumor mass









Biologic agents







Intrinsic intraluminal causes of obstruction may be intrarenal or extrarenal. Intrarenal causes arise from formation casts or crystals within the renal tubules. These include uric acid nephropathy[54]; deposition of crystals of drugs that precipitate in the urine, including sulfonamides,[55] acyclovir,[56] indinavir,[57] and ciprofloxacin[58]; and multiple myeloma.[59] Uric acid nephropathy usually results from the large uric acid load released when alkylating agents abruptly kill large numbers of tumor cells in the treatment of patients with malignant hematopoietic neoplasms. The risk of uric acid nephropathy relates directly to plasma uric acid concentrations.[54] Uric acid nephropathy may also occur in the setting of disseminated adenomatous carcinoma of the gastrointestinal tract.[60] Sulfonamide crystal deposition, once a common occurrence, became rare with the introduction of sulfonamides that are more soluble in acid urine than earlier drugs. However, sulfadiazine has enjoyed a resurgence in use, because it is relatively lipophilic and penetrates the brain well, making it an excellent treatment for toxoplasmosis in patients with acquired immunodeficiency syndrome (AIDS). However, the same lipophilicity makes the drug prone to the formation of intrarenal crystals, which can lead to acute renal injury when the drug is given in large doses. [55] [61] Ciprofloxacin may also precipitate in the tubular fluid, resulting in crystalluria with stone formation and urinary obstruction.[58] In patients with multiple myeloma, casts composed of Bence Jones protein obstruct tubules and exert toxic effects on tubular epithelium, often leading to renal failure. [59] [62] As a result of damage from Bence Jones protein and other abnormalities that frequently occur in patients with multiple myeloma (e.g., hypercalcemia and amyloidosis), renal failure is the second most common cause of death in this patient population. [59] [62] In rare cases multiple myeloma may also cause proteinaceous precipitates in the renal pelvis, leading to obstructive uropathy.[63]

Several intrinsic intraluminal, extrarenal, or intraureteral processes may also cause obstruction. Nephrolithiasis represents the most common cause of ureteral obstruction in younger men.[64] Twelve percent of the U.S. population form a symptomatic stone at some time in their lives, with a male-to-female predominance of 3:1.[65] Calcium oxalate stones occur most commonly. Obstruction caused by such stones occurs sporadically, and tends to be acute and unilateral, and usually without a long-term impact on renal function. Of course, when a stone obstructs a solitary kidney, the result can be anuric or oliguric acute renal failure. Less common types of stones, such as struvite (ammonium-magnesium-sulfate) and cysteine stones, more frequently cause significant renal damage because these substances accumulate over time, and often form staghorn calculi. Stones tend to lodge and to obstruct urine flow at narrowings along the ureter, including the ureteropelvic junction, the pelvic brim (where the ureter arches over the iliac vessels), and the ureterovesical junction.

Other processes that cause ureteral obstruction include papillary necrosis, blood clots, and cystic inflammation. Papillary necrosis[65] may result from sickle cell disease or trait[66] amyloidosis, analgesic abuse, acute pyelonephritis, or diabetes mellitus. Renal allografts may develop papillary necrosis as well. [67] [68] Acute obstruction may even require surgical intervention.[69] Blood clots secondary to a benign or malignant lesion of the urinary tract or cystic inflammation of the ureter (ureteritis cystica) can also lead to obstruction and hydronephrosis.[70]

Intrinsic intramural processes that cause obstruction include failure of micturition or more rarely of ureteral peristalsis. Bladder storage of urine and micturition require complex interplay of spinal reflexes, midbrain and cortical function.[71] Neurologic dysfunction[72] occurring in diabetes mellitus, multiple sclerosis, spinal cord injury, cerebrovascular disease, and Parkinson disease, can result from upper motor neuron damage. These can produce a variety of forms of bladder dysfunction. If the bladder fails to empty properly, it can remain filled most of the time, resulting in chronic increased intravesical pressure, which is transmitted retrograde into the ureters and to the renal pelvis and kidney. In addition, failure of coordination of bladder contraction with the opening of the urethral sphincter may lead to bladder hypertrophy. In this setting, bladder filling requires increased hydrostatic pressures to stretch the hypertrophic detrusor muscle. Again the increased pressure in the bladder is transmitted up the urinary tract to the ureters and renal pelvis. Lower spinal tract injury may result in a flaccid, atonic bladder and failure of micturition, as well as recurrent urinary tract infections.

Various drugs may cause intrinsic intramural obstruc-tion by disrupting the normal function of the smooth muscle of the urinary tract. Anticholinergic agents[73] may interfere with bladder contraction, while levodopa[74] may mediate an α-adrenergic increase in urethral sphincter tone, resulting in increased bladder outlet resistance. Chronic use of tiaprofenic acid (Surgam) can cause severe cystitis with subsequent ureteral obstruction.[75] In all circumstances when the bladder does not void normally, renal damage may develop as a consequence of recurrent urinary tract infections and back-pressure produced by the accumulation of residual urine.

Acquired anatomic abnormalities of the wall of the urinary tract include ureteral strictures, and benign as well as malignant tumors of the urethra, bladder, ureter, or renal pelvis.[76] Ureteral strictures may result from radiation therapy for pelvic or lower abdominal cancers, such as cervical cancer,[77] or as a result of analgesic abuse.[78] Strictures may also develop as a complication of ureteral instrumentation or surgery.

Infectious organisms may also produce intrinsic obstruction of the urinary tract. Schistosoma haematobium afflicts nearly 100 million people worldwide. Though active infection can be treated and obstructive uropathy may resolve, chronic schistosomiasis (bilharziasis) may develop in untreated cases, leading to irreversible ureteral or bladder fibrosis and obstruction.[79] Of other infections, 5% of patients with tuberculosis have genitourinary involvement,[80]predominantly unilateral tuberculous stricture of the ureter.[80] Mycoses such as Candida albicans or Candida tropicalis infection may also result in obstruction due to intraluminal obstruction (fungus ball) or invasion of the ureteral wall.[81]

Extrinsic Causes

Acquired extrinsic urinary tract obstruction occurs in a wide variety of settings. The relatively high frequency of obstructive uropathy from processes in the female reproductive tract such as pregnancy and pelvic neoplasms results in higher rates of urinary tract obstruction in younger women than in younger men.[2] The advent of routine abdominal and fetal ultrasonography in pregnant women has revealed that more than two thirds of women entering their third trimester demonstrate some degree of dilation of the collecting system,[82] most often resulting from mechanical ureteral obstruction.[82] This temporary form of obstruction is usually observed above the point at which the ureter crosses the pelvic brim, and affects the right ureter more often than the left.[82] The vast majority of these cases are subclinical and appear to resolve completely soon after delivery.[83] Clinically significant obstructive uropathy in pregnancy almost always presents with flank pain.[84] In these cases, ultrasonography serves as a useful initial screening test,[21] and magnetic resonance imaging (MRI) can be used if the ultrasound is not conclusive.[84] Of course, the diagnostic evaluation must be tailored to minimize fetal radiation exposure. If the obstruction is significant, a ureteral stent can be placed cystoscopically, and its efficacy can be monitored with repeated follow-up ultrasonography.[85] The stent can be left in place for the duration of pregnancy, if needed. Clinically significant ureteral obstruction is rare in pregnancy and bilateral obstruction leading to acute renal failure is exceptionally rare. [64] [84] Conditions in pregnancy that may predispose to obstructive uropathy and acute renal injury include multiple fetuses, polyhydramnios, an incarcerated gravid uterus, or a solitary kidney.[83]

Pelvic malignancies, especially cervical adenocarcinomas, represent the second most common cause of extrinsic obstructive uropathy in women.[84] In older women, uterine prolapse and other failures of normal pelvic floor tone may cause obstruction, with hydronephrosis developing in 5% of patients.[85] In this setting prolapse may lead to compression of the ureter by uterine blood vessels. In addition, prolapse has been associated with urinary tract infection, sepsis, pyonephrosis, and renal insufficiency. Prolapse of other pelvic organs due to weakening of the pelvic floor may also result in obstruction.[85] Benign uterine tumors or cystic ovary have been reported to cause obstruction, especially in patients with particularly bulky masses.[86] Pelvic inflammatory disease, particularly a tubo-ovarian abscess, can also cause obstruction.[87] Pelvic lipomatosis, a disease with an unclear etiology, seen more often in men, is another rare reason for compressive urinary tract obstruction.[88]

Although endometriosis only rarely results in ureteral obstruction, [91] [92] it should be included in the differential diagnosis any time a premenopausal woman presents with unilateral obstruction. The onset of obstruction may be insidious, and the process is usually confined to the pelvic portion of the ureter. [91] [92] Ureteral involvement may be intrinsic or extrinsic, with extrinsic compression arising principally from adhesions associated with the endometriosis. Because ureteral involvement may come on slowly and may be unilateral, it is important to screen for obstructive uropathy in advanced cases of endometriosis using excretory urography [91] [92] or computed tomography (CT); these are chosen because ultrasound may not reveal hydronephrosis if adhesions are preventing dilatation of the ureter above the site of obstruction.[91] When surgery of any kind is contemplated in patients with endometriosis, it is all the more important to image the ureters, because they cross the anticipated surgical field and may well be near, or attached to, adhesions. [91] [92] [93] It is important to note that 52% of inadvertent ligations of the ureter in abdominal and retroperitoneal operations occur in gynecologic procedures.[92]

Above age 60 obstructive uropathy occurs more commonly in men than in women. Benign prostatic hyperplasia, which is by far the most common cause of urinary tract obstruction in men, produces some symptoms of bladder outlet obstruction in 75% of men aged 50 years and older. [95] [96] It is likely that the proportion of affected older men would be higher if physicians routinely took a detailed history for symptoms. [95] [96] Presenting symptoms of bladder outlet obstruction include difficulty initiating micturition, weakened urinary stream, dribbling at the end of micturition, incomplete bladder emptying, and nocturia. The diagnosis may be established by history and urodynamic studies, as well as imaging in some cases. [95] [96] [97]

Malignant genitourinary tumors occasionally cause urinary tract obstruction. Bladder cancer is the second most common cause (after cervical cancer) of malignant obstruction of the ureter.[2] Prostate cancer may cause obstruction[96] by compressing the bladder neck, invading the ureteral orifices, or by metastatic involvement of the ureter or pelvic nodes.[96] Although urothelial tumors of the renal pelvis, ureter, and urethra are very rare, they also may lead to urinary obstruction.[97]

Several gastrointestinal processes may rarely cause obstructive uropathy. Inflammation in Crohn disease may extend into the retroperitoneum, leading to obstruction of the ureters, [100] [101] usually on the right side.[100] In addition, several gastrointestinal diseases may cause oxalosis, leading to nephrolithiasis.[101] Appendicitis may lead to retroperitoneal scarring or abscess formation in children and young adults,[102] leading to obstruction of the right ureter. Diverticulitis in older patients[103] may rarely cause obstruction of the left ureter. Fecaloma is another rare cause of bilateral ureteral obstruction.[104] Chronic pancreatitis with pseudocyst formation sometimes causes left ureteral obstruction,[105] and may very rarely cause bilateral obstruction.[106] Acute pancreatitis may result in right-sided obstruction.[107]

Vascular abnormalities or diseases may also lead to obstruction. Abdominal aortic aneurysm is the most common vascular cause of urinary obstruction,[108] which may be caused by direct pressure of the aneurysm on the ureter or associated retroperitoneal fibrosis. Aneurysms of the iliac vessels may also cause obstruction of the ureters as they cross over the vessels.[108] Rarely, the ovarian venous system may cause right ureteral obstruction.[109] In addition, and also rarely, vasculitis caused by systemic lupus erythematosus,[110] polyarteritis nodosa,[111] Wegener granulomatosis,[112] and Henoch-Schönlein purpura [115] [116] have been reported to cause obstruction.

Retroperitoneal processes, such as tumor invasion leading to compression, as well as retroperitoneal fibrosis, can result in obstruction. The major extrinsic causes of retroperitoneal obstruction, accounting for 70% of all cases, are due to tumors of the colon, bladder, prostate, ovary, uterus, or cervix. [2] [117] [118] When idiopathic, retroperitoneal fibrosis [117] [118] usually involves the middle third of the ureter, and affects men and women equally, predominantly those in the fifth and sixth decades of life.[116] Retroperitoneal fibrosis may also be drug-induced (e.g., methysergide), or it may occur as a consequence of scarring from multiple abdominal surgical procedures.[116] It may also be associated with conditions as varied as gonorrhea, sarcoidosis, chronic urinary tract infections, Henoch-Schouml;nlein purpura, tuberculosis, biliary tract disease, and inflammatory processes of the lower extremities with ascending lymphangitis.[116]

Malignant neoplasms can obstruct the urinary tract by direct extension or by metastasis (overall frequency of 1% in one autopsy series).[117] As noted previously, cervical cancer is the most common obstructing malignant neoplasm, followed by bladder cancer. [2] [120] [121] Rare childhood tumors such as pelvic neurofibromas can induce upper urinary tract obstruction in up to 60% of patients.[120] Wilms tumor may obstruct via local compression of the renal pelvis.[121] Miscellaneous inflammatory processes can also result in obstruction. These include granulomatous causes such as sarcoidosis[122] and chronic granulomatous disease of childhood.[123] Amyloid deposits may produce isolated involvement of the ureter. Furthermore, a pelvic mass or inflammatory process associated with actinomycosis may cause external ureteral compression. [126] [127] Retrovesical echinococcal cyst can also impede urine flow.[126] Retroperitoneal malacoplakia can also be a rare cause of urinary obstruction.[127] Polyarteritis nodosa associated with Hepatitis B has also been reported to result in bilateral hydronephrosis.[128]

Hematologic abnormalities induce obstruction of the urinary tract by a variety of mechanisms. In the retroperitoneum, enlarged lymph nodes or a tumor mass may compress the ureter.[129] Alternatively, precipitation of cellular breakdown products such as uric acid (see earlier) and paraproteins, as in multiple myeloma, may cause intrinsic obstruction. In patients with clotting abnormalities, blood clots or hematomas may obstruct the urinary tract, as can sloughed papillae in patients with sickle cell disease or analgesic nephropathy (see earlier). Although leukemic infiltrates rarely cause obstruction in adults, in children they cause obstruction in 5% of patients.[130] Lymphomatous infiltration of the kidney occurs relatively commonly, but obstruction related to ureteral involvement in lymphoma is rarer.[131]


Urinary tract obstruction may cause symptoms referable to the urinary tract. However, even patients with severe obstruction may be asymptomatic, especially in settings where the obstruction develops gradually, or in patients with spinal cord injury.[132] The clinical presentation often depends on the rate of onset of the obstruction (acute or chronic), the degree of obstruction (partial or complete), whether the obstruction is unilateral or bilateral, and whether the obstruction is intrinsic or extrinsic. Pain in obstructive uropathy is usually associated with obstruction of sudden onset, as from a kidney stone, blood clot, or sloughed papilla, and appears to result from abrupt stretching of the renal capsule or the wall of the collecting system, where C-type sensory fibers are located. The severity of the pain appears to correlate with the rate, rather than the degree, of distention. The pain may present as typical renal colic (sharp pain that may radiate toward the urethral orifice), or, in patients with reflux, the pain may radiate to the flank only during micturition. With ureteropelvic junction obstruction, flank pain may develop or worsen when the patient ingests large quantities of fluids or receives diuretics.[133] Early satiety and weight loss may be another symptom.[134] Ileus or other gastrointestinal symptoms may be associated with the pain, especially in cases of renal colic, so that it can be difficult to differentiate obstruction for gastrointestinal disease.

Sometimes, patients notice changes in urine output as obstruction sets in. Urinary tract obstruction is one of the few conditions that can result in anuria, usually because of bladder outlet obstruction, or obstruction of a solitary kidney at any level. Obstruction may also occur with no change in urine output. Alternatively, episodes of polyuria may alternate with periods of oliguria. Recurrent urinary tract infections may be the only sign of obstruction, particularly in children. As mentioned earlier, prostatic disease with significant bladder outlet obstruction often presents with difficulty initiating urination, decreased size or force of the urine stream, postvoiding dribbling, and incomplete emptying.[135] Spastic bladder or irritative symptoms such as frequency, urgency, and dysuria may result from urinary tract infection. The appearance of obstructive symptoms synchronous with the menstrual cycle may also be a sign of endometriosis.[136]

On physical examination, several signs may suggest urinary obstruction. A palpable abdominal mass, especially in neonates, may represent hydronephrosis, or, in all age groups, a palpable suprapubic mass may represent a distended bladder. On laboratory examination, proteinuria, if present, is generally less than 2 g/day. Microscopic hematuria is a common finding, but gross hematuria may develop occasionally as well.[137] The urine sediment is often unremarkable. Less common manifestations of urinary tract obstruction include deterioration of renal function without apparent cause, hypertension,[138] polycythemia, and abnormal urine acidification and concentration.


Careful history and physical examination represent the cornerstone of diagnosis, often leading to detection of urinary tract obstruction, and suggesting the reason for it. History and physical focus the evaluation, so that the minimal amount of time and expense are incurred in determining the cause of the obstruction.

History and Physical Examination

Important information in the history includes the type and duration of symptoms (voiding difficulties, flank pain, decreased urine output), presence or absence of urinary tract infections and their number and frequency (especially in children), pattern of fluid intake and urine output, as well as any symptoms of chronic renal failure (such as fatigue, sleep disturbance, loss of appetite, pruritus). In addition, relevant past medical history should be reviewed in detail, looking for predisposing causes, including stone disease, malignancies, gynecologic diseases, history of recent surgery, AIDS, and drug use.

The physical examination should focus first on vital signs, which may provide evidence of infection (fever, tachycardia), or of frank volume overload (hypertension). Evaluation of the patient's volume status will guide fluid therapy. The abdominal examination may reveal a flank mass that may represent hydronephrosis (especially in children), or a suprapubic mass, which may represent a distended bladder. Features of chronic renal failure, such as pallor (anemia), drowsiness (uremia), neuromuscular irritability (metabolic abnormalities), or pericardial friction rub (uremic pericarditis), may also be noted. A thorough pelvic examination in women and a rectal examination for all patients are mandatory. A careful history and a well directed and complete physical examination often reveal the specific cause of urinary obstruction. Coexistence of obstruction and infection is a urologic emergency and appropriate studies (ultrasound, intravenous pyelography, CT) must be performed immediately, so that the obstruction can be relieved promptly.

Biochemical Evaluation

The laboratory evaluation includes urinalysis and examination of the sediment on a fresh specimen by an experienced observer. Unexplained renal failure with benign urinary sediment should suggest urinary tract obstruction. Microscopic hematuria without proteinuria may suggest calculus or tumor. Pyuria and bacteriuria may indicate pyelonephritis; bacteriuria alone may suggest stasis. Crystals in a freshly voided specimen should lead to consideration of nephrolithiasis or intrarenal crystal deposition.

Hematologic evaluation includes the hemoglobin/hematocrit and mean corpuscular volume (to identify anemia of chronic renal disease), and white blood cell count (to identify possible hematopoietic system neoplasm or infection). Serum electrolytes (Na, Cl K, and HCO3), blood urea nitrogen concentration, creatinine, Ca2+, phosphorus, Mg2+, uric acid, and albumin levels should be measured. These will help identify disorders of distal nephron function (impaired acid excretion or osmoregulation) and uremia. Urinary chemistries may also suggest distal tubular dysfunction (high urine pH, isosthenuric urine) and inability to reabsorb sodium normally (urinary Na > 20 mEq/L, fractional excretion of Na [FENa] >1%, and osmolality <350 mOsm). Alternatively, in acute obstruction urinary chemistry values may be consistent with prerenal azotemia (urinary Na < 20 mEq/L, FENa < 1%, and osmolality <500 mOsm).[6]

Novel biomarkers relevant for the functional as well as cellular and molecular changes are being developed as an index of renal injury and to predict renal reserve or recovery after reconstruction. Attempts to predict the clinical outcome of congenital unilateral ureteropelvic junction obstruction in newborn by urine proteome analysis reveals an example of this powerful new technology. Polypeptides in the urine were identified and enabled diagnosis of the severity of obstruction, and using this technique the clinical evolution was predicted with 94% precision in neonates with ureteropelvic junction obstruction.[139]

Radiologic Evaluation (see also Chapter 27 )

The history, physical examination, and initial laboratory studies should guide the radiologic evaluation. Pain, degree of renal dysfunction, and the presence of infection dictate the speed and nature of the evaluation. Numerous radiologic techniques are available; each has advantages and disadvantages, including the ability to identify the site and cause of the obstruction and to separate functional obstruction from mere dilation of the urinary tract. [163] [164]Patient-specific factors, such as the risk of radiocontrast in the setting of renal insufficiency, or the risk of exposure to radiation in pregnant women, must also be weighed.[21]

Plain Film Imaging of the Abdomen

As noted earlier, acute abdominal or flank pain with normal or mildly impaired renal function suggests a renal calculus. In this setting, plain films of the abdomen (kidney, ureter, and bladder) can provide information on the size and overall contour of the kidneys. Because 90% of calculi are radiopaque, they may be detected along the course of ureter, or even in the bladder ( Fig. 35-1 ). If necessary, plain films can be performed in pregnant patients with appropriate shielding. In addition to calculi, the plain film may detect radiopaque foreign bodies such as stents (see Fig. 35-1 ).



FIGURE 35-1  Plain film of abdomen. Calcifications are seen overlapping left ureter (arrowhead). Small arrows demonstrate a stent inserted into the kidney to relieve the obstruction.




Ultrasonography (US) is the preferred screening modality when obstruction is suspected, [141] [143] because it is highly sensitive for hydronephrosis, [141] [143] it is safe and can be repeated frequently, it is low in cost, and avoids ionizing radiation, making it ideal for pregnant patients.[21] Moreover, because US requires no radiographic contrast, it is well suited to patients in whom contrast is contraindicated, including those with an elevated or rising serum creatinine level [141] [143] to rule out obstruction as a cause of renal insufficiency, as well as in patients allergic to contrast material, and in pediatric patients. In addition to detecting hydronephrosis, US can reveal dilatation of the renal pelvis and calices. It may also determine the size and shape of the kidney, and may demonstrate thinned cortex in case of severe long-standing hydronephrosis( Fig. 35-2 ). Finally, US may detect perinephric abscesses, which may complicate some forms of obstructive nephropathy.



FIGURE 35-2  Renal ultrasound. A, Normal kidney. B, Hydronephrotic kidney: dilated calices and pelvis (arrows).



Ultrasonography is both highly sensitive and highly specific in detecting hydronephrosis, with the rates approaching 90%. [141] [143] [144] [145] Importantly, US works equally well in patients with azotemia, in whom radiocontrast studies are contraindicated.[142] Hydronephrosis is detected as a dilated collecting system—an anechoic central area surrounded by echogenic parenchyma.

However, in some cases of acute urinary obstruction, US may fail to detect pathology. During the first 48 hours of obstruction, [141] [143] [144] [145] or when hydronephrosis is absent despite obstruction,[143] the US may reveal no abnormality. False-negative results also occur in cases of dehydration, staghorn calculi, nephrocalcinosis,[142] retroperitoneal fibrosis,[144] and misinterpretation of caliectasis as cortical cysts.[145] A dilated collecting system without obstruction may be observed in up to 50% of patients with urinary diversion through ileal conduits.[146] To enhance the sensitivity and specificity of US, some investigators have developed special obstructive scoring systems, which grade increased echogenicity, parenchymal rims > 5 mm, contralateral hypertrophy, resistive index ratio ≥1.10, and other features to differentiate between obstructing and nonobstructing hydronephrosis.[147] False-positive studies may result from a large extrarenal pelvis, parapelvic cysts,[148] vesicoureteral reflux, or high urine flow rate.[142] In addition, US may only suggest, but not reveal, the presence, or cause of the obstruction.

Importantly, although US is a useful screening test, it does not define renal function and cannot completely rule out obstruction, especially when prior clinical suspicion is high. Every experienced nephrologist has seen cases of obstruction with negative US studies. Therefore, the diagnosis of obstruction must still be considered in patients with worsening renal function, chronic azotemia, or acute changes in renal function or urine output, even in the absence of hydronephrosis on the US.[149]

Antenatal Ultrasonography

Prenatal diagnosis of renal pathology was first described in the 1970s.[150] After that, routine maternal ultrasonography devices of ever-increasing resolution resulted in a fourfold increase in antenatal detection of congenital urinary tract obstruction.[31] Prenatal hydronephrosis is diagnosed with an incidence of between 1 in 100 and 1 in 500 maternal-fetal US studies. [8] [9] [154] Either obstructive or nonobstructive processes can cause dilation of the urinary tract. Obstructive causes include blockage at the ureteropelvic junction (UPJ; 44%), or the ureterovesical junction (21%), as well as multicystic dysplastic kidney, ureterocele or ureteral ectopia, duplex kidney (12%), posterior urethral valves (PUVs, 9%), urethral atresia, sacrococcygeal teratoma, and hydrometrocolpos (fluid distention of the uterus). Nonobstructive causes include vesicoureteral reflux (VUR, 14%), physiologic dilation, prune-belly syndrome, renal cystic disease, and megacalycosis (massive dilatation of the renal calyces). [155] [156] [157] [158] Increased renal echogenicity and oligohydramnios (inadequate quantities of amniotic fluid) in the setting of bladder distention are highly predictive (87%) of an obstructive etiology. This finding is important in the prenatal counseling and treatment of boys with bilateral hydronephrosis and marked bladder dilation.[156]

Determining which cases require intervention and which can be treated conservatively remains a major issue in prenatal US diagnosis of urinary tract obstruction. Persistent postnatal renal abnormalities appear likely when the anteroposterior diameter of the fetal renal pelvis measures more than 6 mm at less than 20 weeks, more than 8 mm at 20 to 30 weeks, and more than 10 mm at more than 30 weeks of gestation.[157] The long-term morbidity of mild hydronephrosis (pelviectasis without caliceal dilation) is low. [8] [9] Moderate hydronephrosis (dilated pelvis and calices without parenchymal thinning) may be associated with gradual improvement in severity of dilation, without loss of anticipated relative renal function. Cases of severe hydronephrosis (pelvicaliceal dilation with parenchymal thinning) may require surgical intervention for declining renal function, infection, or symptoms. Overall, because approximately 5% to 25% of patients with antenatal hydronephrosis will ultimately require surgical intervention, [154] [161] careful long-term follow-up of these patients is required throughout childhood and into adulthood. Almost all patients with antenatal hydronephrosis will have postnatal ultrasonography performed in the first days of life, keeping in mind that most cases of the mild hydronephrosis will resolve without intervention.[159] Functional imaging is required to define residual renal function of patients with hydronephrosis, and to monitor its course over postnatal life. However, in the absence of bilateral hydronephrosis, a solitary kidney, or suspected posterior urethral valve, functional imaging can be deferred until the first 4 to 6 weeks of life.[151] Otherwise, nuclear medicine renal scans should be performed.

All infants with prenatally detected hydronephrosis that is confirmed with postnatal studies should be placed on antibiotic prophylaxis pending the outcome of further evaluation. An infection in the setting of ureteral obstruction can cause significant morbidity, resulting in an infant with sepsis, and renal damage is a potential comorbidity. Oral amoxicillin (10 mg/kg/day) is the most commonly used prophylactic antibiotic.[151]

Duplex Doppler Ultrasonography

Ultrasound has emerged as the primary imaging modality in conditions in which either renal obstruction or renal medical disease is suspected on the basis of clinical and laboratory findings. In urinary tract obstruction, pathophysiologic changes affecting the pressure in the collecting system and kidney perfusion are well imaged and form the basis for the correct interpretation of real-time ultrasonography and color duplex Doppler sonography. As detailed earlier, ultrasound is very sensitive for the detection of collecting system dilatation (“hydronephrosis”); however, obstruction is not synonymous with dilatation, as either obstructive or nonobstructive dilatation may be present. To differentiate these conditions, color duplex Doppler with measurement of the resistive index (RI) in the intrarenal arteries may be helpful, as obstruction (except in the acute and subacute stages) leads to intrarenal vasoconstriction with a consecutive increase of the RI above the upper limit of 0.7, whereas nonobstructive dilatation does not. [155] [156] Diuretic challenge to the kidney may further enhance these differences in RI between obstruction and dilatation.[154]

Intravenous Urography

Intravenous urography (IVU; also known as intravenous pyelography, or IVP) may be useful when history, physical examination, or US findings suggest upper urinary tract obstruction in nonpregnant patients with normal renal function and no allergies to contrast material ( Fig. 35-3 ). Urography may provide data on the relative function of each kidney, and anatomic information, particularly on the ureter, as well as the location of the obstruction. Until recently it was the gold standard for imaging in acute renal colic,[160] though recent data have questioned the diagnostic efficacy of IVU.[160] However, the procedure has drawbacks. Contrast nephrotoxicity may be significant in any patient with obstruction and impaired renal function, but especially in high-risk patients such as those with diabetes and prior chronic renal insufficiency.[161] Kidneys may not be well visualized in patients with low GFR because of delayed excretion of the contrast agent, or, in cases of severe obstruction, too little contrast material may be excreted on the affected side to allow adequate identification of the site of obstruction. All these concerns have led to replacement of IVU with CT, US, and MRI in many cases. Nevertheless, because it is readily available, well known to most physicians, capable of identifying the site of obstruction in a significant portion of cases (especially in cases of intraluminal noncalculous obstruction), and able to depict the anatomy of the urinary tract, IVU may be a useful and informative diagnostic tool.[162] In children, MR urography and ultrasonography may replace IVU in many cases (see later).



FIGURE 35-3  Intravenous pyelography. Normal right kidney and dilated collecting system on the left. The obstruction was relieved with a stent.



Computed Tomography

Computed tomography was initially used mainly in cases with a high index of clinical suspicion, in which US or IVU had failed to identify obstruction.[163] With the higher resolution of multidetector row CT scanners, this approach is rapidly supplanting intravenous urography for evaluation of the upper urinary tract. [166] [167] CT has a particular advantage in that it can visualize a dilated collecting system, even without contrast enhancement. It can also be performed much more quickly than IVU, especially when renal impairment or obstruction would delay contrast excretion by the affected kidney in an IVU ( Fig. 35-4 ). Non-contrast-enhanced CT identifies ureteral stones more effectively than IVU and detects the presence or absence of ureteral obstruction as effectively IVU. [168] [169] Because of its exquisite sensitivity to density, CT can identify even radiolucent stones, because even uric acid stone density is at least 100 HU, which is higher than soft tissue density on CT (usually 10-70 HU). CT is especially effective in identifying extrinsic causes of obstruction (e.g., retroperitoneal fibrosis, lymphadenopathy, hematoma). Helical CT has also proven to be an accurate and noninvasive method of demonstrating crossing vessels in UPJ obstruction. [170] [171] CT can detect extraurinary pathology and can establish nonurogenital causes of pain. All of these advantages establish non-contrast-enhanced helical CT as the diagnostic study of choice for the evaluation of the patient with acute flank pain. CT is very useful in delineating the pelvic organs, such as the bladder and prostate, and may demonstrate abnormalities such as an obstructed and distended bladder ( Fig. 35-5 ), secondary to an enlarged prostate. US may be the first method of diagnosis in this setting ( Fig. 35-6 ), but CT resolution and depiction of details are usually superior to those of US.[163]



FIGURE 35-4  Computed tomography, noncontrast study. A, Left hydronephrosis: dilated renal pelvis (arrows), with normal kidney on right. B, Reason for obstruction: left midureteral stone (arrow).





FIGURE 35-5  Computed tomography of the pelvis. A, Large postvoiding residual urine in the bladder. B, Enlarged prostate (arrows), leading to urinary retention.





FIGURE 35-6  Pelvic ultrasound. A, Distended bladder (arrowheads). B, Enlarged prostate (arrows), causing infravesical urinary obstruction.



Isotopic Renography

Isotopic renography, or renal scintigraphy, can diagnose upper urinary tract obstruction and provide information on the relative function of both kidneys, while avoiding the risk of radiocontrast agents. [172] [173] Radioisotope is injected intravenously, and its excretion by the kidneys is followed using imaging with a gamma scintillation camera. Although this method gives a functional assessment of the obstructed kidney, anatomic definition is poor. Isotopic renography is typically used to estimate the fractional contribution of each kidney to overall renal function. Its most frequent use is to help the urologist to decide whether it is worthwhile to repair the obstruction to a kidney or resect it. In addition, the test can be repeated after the relief of obstruction to gauge the extent to which relief of the obstruction has restored renal function.

Diuretic renography was introduced into clinical practice in 1978,[171] and can be used to distinguish between dilation with obstruction and dilation without obstruction. The method was developed, applied, and validated in adults,[171] but is of particular use in infants and children, where it is not always easy to distinguish between dilatation and frank obstruction. Following administration of radioisotope, when the isotope appears in the renal pelvis, a loop diuretic such as furosemide is given intravenously. If stasis is causing the dilation, the induced diuresis results in prompt washout of the tracer from the renal pelvis. By contrast, when dilation is caused by obstruction, the washout does not occur.[172] Data can be interpreted visually or by quantitative measurement of the half-life (t1/2) for the clearance of the tracer from the collecting system.[173] It is generally accepted that the clearance of the isotope from the collecting system with t½ less than 15 minutes is normal, and a t½ of more than 20 minutes usually depicts obstruction in adults. Clearance of the tracer with a t½ between 15 and 20 minutes is considered equivocal. An absent or blunted response to the diuretic resulting from decreased renal function makes interpretation of the test difficult and limits its usefulness.[174] Moreover, in children diuretic renography is also a very important method for guiding the management of asymptomatic congenital hydronephrosis. From this examination the differential renal function (DRF) can be obtained, which is a robust measure provided there is adequate background subtraction. Pitfalls are related to the drawing of regions of interest, particularly in infants, to estimating the interval during which DRF is calculated, and to an adequate signal-to-noise ratio. There is no definition of a “significant” reduction in DRF. The classical variables of the diuretic renogram may not allow an estimate of the best drainage. Poor pelvic emptying may be apparent because the bladder is full and because the effect of gravity on drainage is incomplete. Estimating the drainage as residual activity rather than any parameter on the slope might be more adequate, especially if the time of furosemide administration is changed. Renal function and pelvic volume can influence the quality of drainage. Drainage may be better estimated using new tools.[175]

Magnetic Resonance Imaging

New MR imaging systems and specific MR contrast agents provide significant developments in the evaluation of renal performance (glomerular filtration rate measurement), in the search for prognostic factors (hypoxia, inflammation, cell viability, degree of tubular function, and interstitial fibrosis), and for monitoring new therapies. [167] [179] New developments that have provided higher signal-to-noise ratio and higher spatial and/or temporal resolutions have the potential to direct new opportunities for obtaining morphologic and functional information on tissue characteristics that are relevant for various renal diseases including urinary tract obstruction with respect to diagnosis, prognosis, and treatment follow-up. [167] [179] MRI can be used to explore the urinary tract when obstruction is suspected. Because MRI does not use ionizing radiation and because gadolinium contrast agents are essentially non-nephrotoxic, MRI is especially useful in children, women of childbearing age, and patients with renal insufficiency or renal allografts. [180] [181] However, recent evidence that the use of certain gadolinium agents (most notably gadodiamide) in patients with renal insufficiency may lead to nephrogenic systemic fibrosis, a sometimes fatal and untreatable condition featuring fibrosis of skin and other organs, requires that gadolinium be used with caution when obstruction is accompanied by renal insufficiency. [181] [182] It provides improved spatial resolution,[179] and it is superior to IVU in detecting obstruction in the presence of severe renal failure. However, MRI today is not clearly superior to other imaging methods,[180] and provides no substantial diagnostic advantages in comparison to combined US and CT. In addition, it cannot demonstrate urinary calculi.[179] Depending on local conditions, it may be more expensive than other modalities. In children, MR urography may replace conventional uroradiological methods, and a recent study suggests that functional MRI in the future may replace isotope renography for evaluation of delayed renal function.[181] Promising experimental studies have recently demonstrated that MRI may provide valuable information regarding renal function, including energy consumption from so-called BOLD (blood oxygenation level dependent) imaging; this kind of data may be helpful in the future in predicting the level of return of renal function following obstruction. [185] [186]

Whitaker Test

The Whitaker test defines the functional effect of upper urinary tract dilatation by measuring the hydrostatic pressures in the renal pelvis and bladder during infusion of a saline and contrast mixture into the renal pelvis, via a catheter.[187] [188] With a bladder catheter in place, the patient is placed in the prone position on the fluoroscopic table and a cannula is inserted percutaneously into the renal pelvis, and connected to a pressure transducer. A mixture of saline and contrast material is infused through the renal cannula at a rate of 10 mL/minute, and pressures are monitored. The presence of contrast material allows fluorographic monitoring of the procedure as well, to define the site of the possible obstruction.[184] The urinary tract is considered nonobstructed if renal pelvic pressure is less than 15 cm H2O, equivocal at a pressure between 15 and 22 cm H2O, and obstructed if pressure exceeds 22 cm H2O.[186] With the advent of imaging techniques, and because of its invasiveness, pressure-flow studies are not often used today, and have been replaced to some degree by diuretic renography. However, in cases of extreme upper tract dilation or poor renal function, precluding the adequate diuretic response, the Whitaker test may be considered.

Retrograde and Antegrade Pyelography

When other tests do not provide adequate anatomic detail, or when obstruction must be relieved (e.g., obstruction of a solitary kidney, bilateral obstruction, or symptomatic infection in the obstructed system), more invasive investigation, with a combination of treatments, may be necessary. Retrograde pyelography is performed during cystoscopy, by cannulating the ureteral orifice and injecting contrast. [190] [191] [192] [193] In some cases of complete obstruction, contrast may not reach the kidney, but the procedure will define the lower level of the obstruction. Retrograde pyelography can be combined with placement of a ureteral stent to relieve an obstruction, or with possible stone extraction. Because the procedure passes through the bladder to reach the upper urinary tract, the risk of introducing infection proximal to the obstruction must be kept in mind, and the obstruction should be relieved immediately after retrograde pyelography. Antegrade pyelography is performed by percutaneous cannulation of the renal pelvis, and injection of the contrast material into the kidney and ureter. [190] [191] [192] [193] This procedure should establish the proximal level of obstruction, and may also serve as a first step in relieving obstruction by means of percutaneous nephrostomy (Figs. 35-7 and 35-8 [7] [8]).



FIGURE 35-7  Antegrade pyelography. A, Dilated renal pelvis and calices on left. B, Stones (arrowheads) as filling defects in the distal ureter (not seen on plain film). Intravenous pyelography was unsuccessful owing to the obstructed and malfunctioning kidney.





FIGURE 35-8  Antegrade pyelography. No contrast is entering the ureter because of the obstructed and dilated right renal pelvis. (The patient has retroperitoneal fibrosis.)




Despite the fact that acquired obstructive nephropathy in humans usually results from partial urinary tract obstruction and is generally prolonged in its time course, most mechanistic studies of renal dysfunction in acquired obstruction use models of acute complete obstruction, usually for 24 hours. In these animal models, the extent of obstruction is clear and reproducible, and, if the kidneys are studied soon after the obstruction is performed or released the results are not confounded by changes in renal structure brought on by inflammation or fibrosis. Complete obstruction of short duration strikingly alters renal blood flow, glomerular filtration, and tubular function, while producing minimal anatomic changes in blood vessels, glomeruli, and tubules. [2] [24]

Effects of Obstruction on Glomerular Filtration

Obstruction profoundly alters all components of glomerular function. The extent of the disturbance in GFR depends on the severity and duration of the obstruction, whether it is unilateral or bilateral, and the extent to which the obstruction has been relieved or persists. [2] [24] To describe the effects of obstruction on glomerular filtration, we must review aspects of normal GFR. Whole-kidney GFR depends on the filtration rate of all functioning glomeruli and the proportion of glomeruli actually filtering. Single-nephron GFR (SNGFR) is determined by the blood flow in the glomerulus, the net ultrafiltration pressure across the glomerular capillary, and the ultrafiltration coefficient (Kf). Glomerular blood flow and the hydraulic pressure in the glomerular capillary (PGC) are determined by the resistances of the afferent (RA) and efferent (RE) arterioles. Net ultrafiltration pressure is determined by PGC, the hydraulic pressure of the Bowman space (which equals the proximal tubule hydraulic pressure, PT), and the differences in oncotic pressure between the glomerular capillary and Bowman space. Kf is determined by the permeability properties of the filtering surface and the surface area available for filtration. Obstruction can alter one or all of these determinants of GFR.

The Early, Hyperemic Phase

In the immediate 2 to 3 hours following the onset of unilateral ureteral obstruction, blockade of antegrade urine flow markedly increased PT. This increase in pressure in Bowman space would be expected to halt GFR immediately.[194] [195] [196] However, during this early phase of obstruction, the afferent arterioles dilate, decreasing RA, increasing PGC, and counteracting the increase in PT. [194] [195] Because this vasodilator or “hyperemic response” occurs in denervated kidneys in situ and in isolated perfused kidneys, [197] [198] it must result from intrarenal mechanisms. In fact, glomeruli of individual nephrons exhibit the same response in in vivo micropuncture experiments when antegrade urine flow is blocked by placement of a wax block in the tubule of the nephron.[196]

Many mechanisms may mediate this afferent vasodilation, including increases in vasodilator hormones such as prostaglandins, regulation by the macula densa, and a direct myogenic reflex. This hyperemic response is not attenuated by renal nerve stimulation or infusion of catecholamines.[197] This response may be linked to changes in interstitial pressure. [197] [201]

In the tubuloglomerular feedback response, reduced distal tubular flow past the macula densa induces reductions in RA and increases in PGC, so that SNGFR rises. Similarly, because obstruction reduces urine flow past the macula densa, this structure induces afferent vasodilation.[196] However, micropuncture studies have separated the stoppage in flow from increases in PT by placing an additional puncture in the tubule that was proximal to the blockage of flow to the macula densa. In this setting, flow past the macula densa was halted, but PT remained normal, because accumulating tubular fluid was permitted to leak out.[192] In such nephrons the increase in PGC observed in obstructed tubules did not occur, indicating that the obstruction itself and not the macula densa stimulates afferent vasodilation.[192]

Renal prostaglandins and renal nerves play important roles in the hyperemic response. Indomethacin blocks the hyperemic response, indicating that vasodilator prostaglandins are critical to afferent vasodilation. [196] [202] [203] A role for renal nerves in the hemodynamic response to obstruction can be discerned from studies in bilateral obstruction, where the afferent vasodilation response is absent or markedly attenuated. [2] [24] [201] Obstruction of the left kidney augments afferent renal nerve activity from the left kidney and efferent nerve activity to the right kidney. Increased efferent nerve activity to the right kidney was accompanied by reduced blood flow to that kidney. This vasoconstrictor response was ablated by denervation of either the left or right kidney before induction of left ureteral obstruction. These results suggest that, in the setting of bilateral ureteral obstruction, increased afferent renal nerve traffic triggers vasoconstrictive renorenal reflex activity that counteracts the early intrinsic renal vasodilator effects of obstruction.[198]

The Late, Vasoconstrictive Phase

Because established obstruction results in cessation of glomerular filtration, efforts to study the regulation of SNGFR later in obstruction have measured determinants of GFR immediately after release of obstruction. [2] [204] Using this approach, investigators have shown that renal blood flow declines progressively after 3 hours of unilateral obstruction, and through 12 to 24 hours of obstruction. [205] [206] [207] Interestingly, although tubular pressures rise initially after obstruction, they then decline, so that by 24 hours renal plasma flow, GFR, and intratubular pressures have all dropped below normal values. [194] [196] [206] [207] [208] [209] At 24 hours into the obstruction, examination of regional blood flow in the kidney by injections of silicone rubber reveal large areas of the cortical vascular bed that are either underperfused or not perfused at all. [2] [196] [206] [207] [210] Depending on the species, the different vascular beds in the outer and juxtamedullary cortex receive differing proportions of the renal blood flow under basal conditions and following obstruction. However, it is clear that at 24 hours of obstruction, reduced whole-kidney GFR is due, in large part, to nonperfusion of many glomeruli.

Beyond 24 hours of obstruction, SNGFR of glomeruli that remain perfused is decreased markedly, both because of reduced blood flow to the afferent arteriole, and also because of afferent vasoconstriction, which, in turn, reduces PGC. [208] [211] Because PGC responds in the same manner when the individual nephron is blocked with oil for 24 hours before micropuncture measurements are performed, it is clear that afferent arteriolar vasoconstriction plays an important role in attenuating SNGFR during the established phase of obstruction.[209] These results indicate that, like the early hyperemic response, intrarenal mechanisms play the major role in the late vasoconstrictive response to unilateral obstruction. In bilateral obstruction, renal blood flow is reduced to levels 30% to 60% below normal ( Table 35-3 ). [208] [211] [213] In both unilateral and bilateral obstruction, SNGFR falls to a similar degree. However, the mechanisms involved are different in the two conditions. In unilateral obstruction, reduced PGC lowers the driving pressure for filtration when set against a nearly normal PT. By contrast, in bilateral obstruction, PGC remains normal and GFR is halted by a highly elevated PT.[205] These results suggest that systemic factors, such as accumulation of extracellular fluid volume and urea, increases in natriuretic substances and alterations in renal nerve activity modulate the vasoconstrictive effect of obstruction on the affected kidney.[210]

TABLE 35-3   -- Glomerular Hemodynamics in Ureteral Obstruction

Stage of Obstruction





1–2 hr unilateral



24 hr unilateral




24 hr bilateral





After release: 24 hr unilateral




After release: 24 hr bilateral





See text for discussion and references.

PT, proximal tubule hydraulic pressure; RA, afferent arteriole resistance; PGC, hydraulic pressure of Bowman space; =, unchanged; ↑, increased; ↑↑, markedly increased; ↓, reduced; ↓↓, markedly reduced; SNGFR, single nephron glomerular filtration rate.




Regulation of the Glomerular Filtration Rate in the Postobstructive Period

The level to which renal blood flow and GFR are reduced after release of obstruction varies with the species studied and the duration of obstruction. [196] [207] [214] [215] Following release of a 24-hour complete unilateral obstruction the GFR remains below 50% of normal in dogs and 25% of normal in rats; renal blood flow remains markedly reduced in both species.[2] After release of bilateral ureteral obstruction, renal blood flow reaches levels higher than that observed following unilateral obstruction, likely due to systemic natriuretic influences such as volume accumulation, reduced sympathetic tone, or increased circulating atrial natriuretic peptide, but the GFR remains markedly attenuated. Despite the fact that renal blood flow is increased, GFR remains low in part because of nonperfusion or underperfusion of many glomeruli as shown in silicone rubber injections. [196] [206] [207] Where glomeruli remain perfused, intense afferent vasoconstriction reduces PGC, so that even though PT also falls with release of the obstruction, the driving force for glomerular filtration remains low. [208] [211] In addition, a sharp reduction in Kf also augments the fall in GFR at this point following release of unilateral and bilateral obstruction. [208] [211] [216]

Several mechanisms contribute to afferent vasoconstriction and a reduced Kf. First, release of obstruction strikingly augments the flow of tubular fluid past the macula densa. Although the absolute rate of flow is still far below normal, the macula densa likely senses the dramatic change in the rate of flow, and this may lead to intense vasoconstriction.[2] In favor of this view, the sensitivity of the tubuloglomerular feedback mechanism is enhanced in unilateral, as compared with bilateral, obstruction, suggesting that the ability of the mechanism to regulate afferent arteriolar tone is modulated by the extrarenal hormonal milieu.[214]

It is also likely that increased secretion of angiotensin II participates actively in afferent vasoconstriction and reduced Kf following release of ureteral obstruction. Ureteral obstruction rapidly increases renal vein renin levels at a time when renal blood flow is normal or elevated, [218] [219] [220] [221] but at later time points, renal vein renin levels return to normal. [219] [220] [221] In addition, infusion of captopril attenuated the declines in renal blood flow and GFR observed in both unilateral and bilateral obstruction. [216] [219] [222] [223] Because inhibition of angiotensin-converting enzyme can also increase kinin activity, infusions of either carboxypeptidase B, which destroys kinins, or aproninin, which blocks kinin generation were used to eliminate the kinin effect. Captopril remained equally effective in the presence of either agent, indicating that captopril reduced RA primarily by blocking generation of angiotensin II. Although Kf was not measured in these studies, it appears likely that increased angiotensin II may also help decrease Kf following release of obstruction.[213] The significance of the renin-angiotensin system as an important contributor to the vasoconstriction has recently been highlighted in studies where AT1 receptor antagonist treatment attenuated the reduction in GFR in the postobstructive period in both adult[215] and rats with neonatally induced obstruction in response to chronic AT1 receptor antagonist treatment.[220]

Thromboxane A2 (TXA2) may also play a major role in postobstructive vasoconstriction. [219] [224] Chronically hydronephrotic kidneys exhibit increased TXA2 accumulation, as measured by accumulation of its more stable metabolite, TXB2.[221] Furthermore, administration of thromboxane synthase inhibitors into the renal artery (but not systemically[222]) under conditions shown to reduce renal TXA2 generation[223] ameliorated the vasoconstrictive effects of release of obstruction. In these studies both whole-kidney GFR and renal blood flow were increased. [219] [222] [226] [227] Glomerular micropuncture following relief of obstruction showed that a thromboxane synthase inhibitor reduced afferent arteriolar resistance and increased Kf.[213] From these results, TXA2 appears to be generated in the kidney following release of obstruction and mediates afferent vasoconstriction and reductions in Kf. The source of TXA2 generation remains unclear.

In some,[225] but not all [229] [230] cases, glomeruli isolated from obstructed kidneys have shown increased ability to synthesize TXA2. Although increased TXA2 generation in the glomerulus could act to reduce Kf, because the afferent arteriole is upstream of the glomerulus, it would be unlikely to respond to glomerular thromboxane generation. Further studies have suggested inflammatory cells as the source of TXA2. During the first 24 hours of obstruction, suppressor T cells and macrophages migrate to the renal cortex and medulla, reaching levels 15-fold higher than those observed in normal kidneys.[228] Release of obstruction leads to a gradual decline in these leukocyte populations. Following the onset of obstruction, the numbers of these cells in the renal parenchyma rise in parallel with the increase in TXA2 release and the fall in GFR.[228] In addition, attenuating leukocyte accumulation by renal irradiation reduces also urinary TXB2 excretion (an index of renal TXA2 generation), and increases GFR above levels seen in kidneys with obstruction in the absence of irradiation. These results indicate that obstruc-tion stimulates immigration of inflammatory leukocytes (see later) which, in turn, generate vasoconstrictors such as TXA2. [231] [232] These vasoconstrictors may contribute to the increased RA and decreased GFR observed following release of obstruction. Additional studies in dogs and rats have implicated endothelin as contributors to reduced GFR in obstruction, and have suggested that nitric oxide may play an ameliorating role in glomerular vasoconstriction in obstructed kidneys. [233] [234]

Because irradiation only partially blocked the decrease in GFR observed with obstruction, it is likely that renal cells themselves release important mediators that reduce SNGFR. Indeed, glomeruli isolated from obstructed kidneys showed increased eicosanoid synthesis after angiotensin II stimulation.[232] In addition, treatment of obstructed animals with converting enzyme inhibitors enhanced GFR and reduced TXA2 generation by glomeruli isolated from these animals.[233]

Because vasoconstriction is less severe in animals with bilateral ureteral obstruction, as noted earlier, it is likely that extrarenal factors play a major role in modulating the hemodynamic response of the kidney to obstruction and release of obstruction. We have already mentioned the renorenal reflexes stimulated in bilateral obstruction reduce the compensatory vasodilator response normally observed in the early stages of unilateral obstruction. Multiple additional factors, including accumulation of volume and solutes such as urea, atrial natriuretic peptide (ANP) and its congeners, and other natriuretic substances may ameliorate the vasoconstrictive effects of obstruction when both ureters are ligated. Following 24 hours of obstruction, GFR is preserved to some degree if the contralateral kidney is also obstructed or removed.[234] In addition, in animals following release of 24 hours of unilateral obstruction, if the urea, salt, and water content of the urine from the contralateral kidney is reinfused into the animal, a striking increase in GFR over standard unilateral obstruction is observed. [237] [238] On the basis of these and other studies, it appears that urea and other excreted urine solutes have a protective effect, and can ameliorate vasoconstriction following release of ureteral obstruction. [237] [238]

It is also likely that ANP reduces the vasoconstrictive effects of release of obstruction. Animals and humans with bilateral obstruction undergo volume expansion, which stimulates ANP release.[236] Enhanced release and reduced ANP degradation in obstructed kidneys lead to marked increases in circulating levels of ANP.[236] In line with this view, ANP levels have been shown to rise markedly in bilateral, but not unilateral, obstruction. [222] [239] In the basal state, ANP at high levels augments renal blood flow and GFR by direct vasodilation of afferent arterioles, constriction of efferent arterioles, and an increase in Kf.[236] In addition, ANP antagonizes release of renin by the macula densa, lowering levels of angiotensin II. On this basis, it is not surprising that infusions of ANP can enhance GFR in the setting of unilateral or bilateral ureteral obstruction. [222] [240]

Prostaglandin E2 (PGE2) and nitric oxide may also reduce vasoconstriction in obstruction. Renal PGE2 levels increase markedly in obstruction (see later) and in states of extracellular volume expansion, as occurs in bilateral ureteral obstruction. Given the vasodilator effects of PGE2, it appears likely that increased levels could ameliorate falls in GFR in obstruction. Bilateral obstruction may reduce generation of NO, leading to a net vasoconstrictive effect.[232]

In summary, both intra- and extrarenal factors combine to decrease profoundly GFR during and immediately after release of obstruction. The decrease in GFR is caused by a sharp reduction in the number of perfused glomeruli and by a reduction in the SNGFR of functioning nephrons. Decreased Kf and increased RA reduce SNGFR. Increases in various vasoconstrictors, such as angiotensin II and TXA2, as well as other vasoconstrictors, some coming from inflammatory cells, augment these hemodynamic effects. In the setting of bilateral obstruction, retention of urea and other solutes, as well as volume expansion and increases in circulating levels of vasodilators such as ANP, help to offset these vasoconstrictive effects, but only partially.

Recovery of Glomerular Function After Relief of Obstruction

The extent of recovery of glomerular filtration following release of obstruction depends on several factors, including the duration and extent of obstruction, the presence or absence of a functioning contralateral kidney, the presence or absence of associated infection, and the level of preobstruction renal blood flow.[211] In dogs subjected to a 1-week period of complete unilateral ureteral obstruction, GFR fell to 25% of normal on release of the obstruction and recovered gradually to 50% of normal levels 2 years later.[238] Mechanisms involved in the development of long-term renal damage in response to prolonged obstruction are discussed in detail later. In rats, release of unilateral ureteral obstruction of 7 and 14 days' duration left residual GFR at 17% and 9% of control levels, respectively, when the contralateral kidney was left in place, and 31% and 14% when the animals underwent contralateral nephrectomy at the time of release of the obstruction.[206] A similar beneficial effect on the obstructed kidney of contralateral nephrectomy was observed in rats subjected to chronic partial obstruction.[206] As discussed earlier, this beneficial effect likely results from the accumulation of urea and other solutes and increased levels of ANP when the functioning contralateral kidney is absent.

The partial recovery of total renal GFR following release of obstruction masks a very uneven distribution of blood flow and nephron function. In micropuncture studies, some nephrons never regain filtration function, whereas others reveal striking hyperfiltration.[211] It appeared in some studies that surface nephrons exhibited normal SNGFR, whereas the whole-kidney GFR was reduced to 18% of normal.[239] These results suggest that chronic partial obstruction causes selective damage to juxtamedullary and deep cortical nephrons. [206] [214] [242] Similarly, studies of the long-term outcome of complete 24-hour ureteral obstruction revealed that total renal GFR recovered to normal levels by 14 and 60 days after release of obstruction. However, 15% of the glomeruli were not filtering in recovered kidneys, and other nephrons were hyperfiltering. In this model of complete obstruction, there appeared to be no selective advantage for surface glomeruli over deep cortical and juxtamedullary glomeruli.[211]

Similarly, in the developing kidney, the duration of obstruction and timing of release have a striking impact on long-term renal function. Release after 1 week of obstruc-tion completely prevented development of hydronephrosis, reduction in RBF, and glomerular filtration rate in rats subjected to partial UUO at birth, whereas release after 4 weeks resulted in little or no renal function in the obstructed kidney demonstrating that early release of neonatal obstruction provides dramatically better protection of renal function than release of obstruction after the maturation process is completed.[240]

Effects of Obstruction on Tubule Function

Obstruction severely impairs the ability of renal tubules to transport Na, K, and H, and reduces their ability to concentrate and dilute the urine ( Table 35-4 ). [2] [244] [245] [246] [247] [248] [249] [250] [251] [252] [253] The resulting inability to reabsorb water and solutes helps cause postobstructive diuresis and natriuresis. As is the case with glomerular filtration, the extent of disruption of tubular transport depends directly on the duration and severity of the obstruction. Pathologically, prolonged obstruction leads to profound tubular atrophy and chronic interstitial inflammation and fibrosis (see later), whereas at early time points following the onset of obstruction, such as at 24 hours, there are only slight structural and ultrastructural changes. [244] [245] These changes include some mitochondrial swelling, modest blunting of basolateral interdigitations in the thick ascending limb and proximal tubule epithelial cells, as well as flattening of the epithelium and some widening of the intercellular spaces in the collecting ducts. [244] [245] The only cell death at early time points is observed at the very tip of the papilla, where focal necrosis may be observed.[241]Because there is so little cell damage, and because of the simplicity of the model, most investigators have examined the effect of 24 hours of complete ureteral obstruction on tubular function. As with glomerular filtration, impairment of tubular transport in obstruction is due both to direct damage to tubular epithelial cells and the action of extratubular mediators, arising both from the kidney and extrarenal sources.

TABLE 35-4   -- Segmental Reabsorption in Superficial and Juxtamedullary Nephrons and in Collecting Ducts in Normal Rats after Release of Bilateral or Unilateral Obstruction


Water Remaining (%)

Na Remaining (%)


























After bilateral obstruction

























After unilateral obstruction


























S1–4, values found in superficial nephrons: S1, Bowman space; S2, end of proximal convoluted tubule; S3, earliest portion of distal tubule; S4, end of distal tubule/beginning of collecting duct. J1–2, values found in juxtamedullary nephrons; J1, Bowman space; J2, tip of loop of Henle. CD1, collecting duct at base of papilla, first accessible portion of inner medullary collecting duct; CD2, end of collecting duct as it opens into renal pelvis.




Effects of Obstruction on Tubular Sodium Reabsorption

Following release of 24 hours of unilateral ureteral obstruction, volume excretion from the postobstructed kidney is normal or slightly increased [2] [213] [237] [246] (see Table 35-4 ). However, as discussed earlier, normal volume excretion occurs in the setting of a markedly reduced (20% of normal) GFR. On this basis the fractional excretion of sodium FENa is markedly elevated in the postobstructed kidney. After release of bilateral obstruction, salt and water excretion jumps up to five to nine times normal [2] [213] [247] [248] GFR is also decreased in this setting, so that FENa may be 20-fold higher than normal.

The micropuncture studies summarized in Table 35-4 demonstrate that the reabsorption defect following release of obstruction is localized similarly in both unilateral and bilateral ureteral obstruction. In superficial nephrons, proximal tubule reabsorption is normal or enhanced in the S1 and S2 segments. By contrast, in juxtamedullary nephrons, increased proportions of filtered salt and water delivered to the loop of Henle (J1 and J2 in Table 35-4 ) indicate decreased reabsorption. Delivery of salt and water to the first accessible portion of the inner medullary collecting duct, labeled CD1, was also increased, and net salt and water reabsorption along the inner medullary collecting duct (between CD1 and CD2) was diminished in both bilateral and unilateral obstruction. In fact, in bilateral obstruction, there was net addition or secretion of salt and water into the lumen of the inner medullary collecting duct, suggesting that in this setting the inner medullary collecting duct secretes salt and water.[244] On the basis of these results, obstruction reduced net salt and water reabsorption in the medullary thick ascending limb (MTAL), the distal convoluted tubule, and the entire length of the collecting duct, including its cortical, outer medullary, and inner medullary segments.

These studies in whole animals were confirmed and extended by a series of studies from multiple laboratories using isolated perfused tubule and cell suspension preparations ( Table 35-5 ). Isolated perfused superficial proximal convoluted tubules (SPCTs) isolated from animals with unilateral or bilateral obstruction exhibited normal volume reabsorption (JV).[246] By contrast, JV in proximal straight tubules, which are derived from juxtamedullary nephrons, was markedly impaired in both forms of obstruction.[246] To determine the rate of MTAL volume reabsorption, maximal rates of Cl- reabsorption from lumen to bath was measured. As shown in Table 35-5 , MTAL isolated from unilaterally or bilaterally obstructed animals exhibited profound impairment of reabsorptive capacity.[246] This finding was confirmed in studies of freshly prepared suspensions of MTAL cells from obstructed kidneys, in which transport-dependent oxygen consumption, a measure of salt reabsorptive capacity, was markedly reduced.[247]

TABLE 35-5   -- Function of Isolated Perfused Tubules in Obstructive Nephropathy


Jv SPCT (nL/mm/minute)

Jv PST (nL/mm/minute)


22Na Flux (pmol/mm/minute)

Jv CCT(ADH) (nL/mm/minute)


0.75 ± 0.08

0.25 ± 0.02

-37 ± 3

38.2 ± 4.0

0.90 ± 0.08

Unilateral obstruction

0.73 ± 0.11

0.12 ± 0.03

-9 ± 1

26.2 ± 3.3

0.22 ± 0.04

Bilateral obstruction

0.80 ± 0.08

0.16 ± 0.02

-10 ± 1


0.23 ± 0.04

Data from Buerkert J, Martin D, Head M, et al: Deep nephron function after release of acute unilateral ureteral obstruction in the young rat. J Clin Invest 62:1228, 1978; Hanley MJ, Davidson K: Isolated nephron segments from rabbit models of obstructive nephropathy. J Clin Invest 69:165, 1982; Miyata Y, Muto S, Ebata S, et al: Sodium and potassium transport properties of the cortical collecting duct following unilateral ureteral obstruction. J Am Soc Nephrol 3:815, 1992.

Jv, volume reabsorption; SPCT, superficial proximal convoluted tubule; PST, proximal straight tubule; ΔCl, change in Cl concentration; MTAL, medullary thick ascending limb; CCT, cortical collecting tubule; ADH, antidiuretic hormone.





In the cortical collecting duct, rates of salt reabsorption, as determined using flux of isotopic sodium or transepithelial voltage, were markedly reduced in unilateral or bilateral obstruction (see Table 35-5 ). [249] [251] Given the major regulatory role of mineralocorticoid in the collecting duct, it is important to note that these decreases in collecting duct reabsorptive capacity occurred in tubules taken from obstructed kidneys, whether or not the animal had been pretreated with mineralocorticoid. [249] [251] [252] Because it is highly branched and difficult to perfuse reliably in vitro, transport in the inner medullary collecting duct has been studied in cell suspensions. In these preparations, transport-dependent oxygen consumption was markedly reduced in cells isolated from animals with bilateral obstruction.[250]

Taken together, the data derived from micropuncture, tubule perfusion, and cell suspension studies reveal a striking impairment of volume reabsorption in the proximal straight tubule, the MTAL, and the entire collecting duct. Because these functional derangements occur in the absence of clear-cut ultrastructural damage to the epithelial cells, obstruction likely induces a selective lesion in cellular active transport mechanisms. Unlike the situation with glomerular filtration, the functional lesion appears similar in both unilateral and bilateral obstruction. [249] [252] On this basis it appears that a major component of impaired active transport is likely due to direct tubular cell injury, rather than to the continuous action of natriuretic substances. Added onto this intrinsic injury, natriuretic substances may be responsible for the apparent secretion of salt and water in the inner medullary collecting duct of animals following release of bilateral obstruction (see Table 35-4 ).

A combination of studies of cell suspensions and specific antisera to relevant transporter proteins has begun to define the mechanisms by which tubular epithelial cell salt reabsorption is impaired in the setting of obstruction. Active tubular Na transport requires an apical entry step (e.g., Na/K/2Cl cotransporter in MTAL or epithelial Na channels [ENaCs] in the collecting duct) coupled to the basolateral Na, K-ATPase. In addition, the cell must generate sufficient adenosine triphosphate (ATP) to fuel active transport by the ATPase. Suspensions of MTAL cells from obstructed kidneys exhibited markedly reduced furosemide-sensitive oxygen consumption,[247] indicating striking decreases in apical Na/K/2Cl cotransporter activity in these cells. Isotopic bumetanide binding revealed a marked reduction in the number of cotransporter protein molecules available for binding on the membrane, with no change in affinity of binding, indicating that obstruction down-regulates the expression of the cotransporter protein on the membrane surface.[247] More recent studies using specific anti-cotransporter antibodies demonstrated clearly that obstruction diminishes expression of the cotransporter protein on the MTAL cell apical membrane.[251] To determine whether obstruction affected Na/K-ATPase activity as well, ouabain-sensitive oxygen consumption was measured, and was also found to be markedly reduced in obstructed kidneys, a finding explained by reduced ex-pression of both α- and β-subunits in the preparations from these kidneys.[247] Measurement of mRNA expression revealed that the down-regulation of pump subunits in obstruction was due to both transcriptional and post-transcriptional mechanisms.[253]

Results in inner medullary collecting duct paralleled closely those in the MTAL. Cell suspensions from obstructed animals revealed marked decreases in amiloride-sensitive oxygen consumption as well as amiloride-sensitive isotopic sodium entry into hyperpolarized cells.[250] These results agreed well with prior findings of decreased apical membrane conductance in tubules from obstructed, as compared with control animals.[248] Together, these studies demonstrated a striking down-regulation of Na channel of ENaC activity. More recent studies with specific antisera against ENaC subunits have revealed reduced expression of ENaC proteins on the apical membranes of collecting duct cells in obstructed animals.[254] As occurred in MTAL cells, the rates of ouabain-sensitive oxygen consumption and of ouabain-sensitive ATPase were markedly diminished in inner medullary collecting duct cells from obstructed animals, and the levels of both pump subunits were also reduced in these preparations.[250] Patterns of mRNA expression were also similar to those in MTAL, indicating transcriptional and post-transcriptional down-regulation of pump subunit expression.

Using a targeted antibody-based approach with specific antisera directed against Na transporter proteins, recent studies have extended the results in MTAL and inner medullary collecting duct to the proximal tubule and distal convoluted tubule. In unilateral ureteral obstruction, the overall synthesis and apical localization of the apical Na/H exchanger (NHE3) and the Na/PO4[3] exchanger (NaPi-2) were strikingly decreased in the proximal tubule.[251]These decreases occurred in both the proximal convoluted and proximal straight tubule, even though the micropuncture and tubule perfusion studies cited earlier revealed preserved proximal convoluted tubule salt reabsorption and inhibition of proximal straight tubule reabsorption.[251] The same study demonstrated significant down-regulation of total transporter protein and apical membrane expression of the distal convoluted tubule (DCT) Na/Cl cotransporter, indicating that obstruction likely reduces DCT Na reabsorption by mechanisms similar to those observed in the MTAL and collecting duct.[251]

Taken together, these results suggest that obstruction down-regulates membrane expression of transporter proteins responsible for apical sodium entry and of basolateral sodium exit. Interestingly, metabolic studies reveal that obstruction reduces activities as well of several enzymes of the oxidative and glycolytic pathways, consistent with a down-regulation of metabolic capacity for energy generation in these cells. In addition, reduced metabolic capacity in MTAL is accompanied by reductions in the extent of basolateral infolding and in the density of mitochondria in tubules of obstructed kidneys.[241] Interestingly, in MTAL and collecting duct suspension, obstruction reduces transport-dependent but not transport-independent oxygen consumption, indicating that the rate of ATP generation (oxygen consumption) is not rate-limiting for active transport in these cells. [250] [253] On this basis, it appears more likely that obstruction down-regulates sodium transport, and that reduced metabolic demand results in down-regulation of metabolic machinery (as reflected in enzyme activities, basolateral infolding, and mitochondrial density).

The signals involved in down-regulation by obstruction of transporter activity and expression in tubular epithelial cells remain unclear. Possible signals include the halting of urine flow, increased hydrostatic pressure on tubular epithelial cells,[252] changes in blood flow to the tubules or in interstitial pressure, and generation of natriuretic substances in the kidney that result in long-term inhibition of transporter function.

Obstruction stops or nearly stops urine flow. With the stoppage of urine flow, sodium delivery to each tubular segment stops, and apical membrane Na entry slows dramatically because the electrochemical gradients for Na entry between the stationary apical fluid and the cell interior become increasingly unfavorable for continued sodium transport. Reduced Na entry might then stimulate down-regulation of transporter activity or expression. In both MTAL and inner medullary collecting duct cells, blocking Na entry by furosemide or amiloride, respectively, promptly reduces ouabain-sensitive oxygen consumption, [250] [258] [259] [260] indicating acute down-regulation of Na, K-ATPase. In addition, in mineralocorticoid-clamped animals, chronic blockade of N entry at the MTAL or cortical collecting duct by administration of furosemide or amiloride, respectively, reduced the levels of ouabain-sensitive ATPase in microdissected tubule segments. [261] [262]

These results suggest that the halt in urine flow might represent a major signaling mechanism by which obstruction down-regulates Na transport.[256] To test this idea, apical Na entry was inhibited for 24 hours in a cell line that mimics cortical collecting duct cells, A6 cells, grown on permeable supports. When apical Na entry was blocked either by substituting another cation for sodium in the apical solution, or by adding amiloride to the apical solution apical sodium entry was markedly reduced for some hours after the blockade was removed.[260] This down-regulation is accompanied by selective reduction in the levels of expression of the β-, but not the α- or γ-subunits of ENaC in the apical membranes of the A6 cells, but not in whole cell content of these subunits.[261] Interestingly, and in contrast to the results in cell suspensions or whole kidney, [250] [253] [254] inhibition of apical sodium entry had no effect on expression of either subunit of Na/K-ATPase.[261] These results provide direct evidence that reductions in the rate of Na entry, which may occur when urine flow is blocked, can directly down-regulate Na transport in renal epithelial cells. The discordant regulation of the different subunits of the ENaC observed in this model may provide some insights into the mechanisms of channel regulation.

In addition to the direct effects of halting urine flow, changes in intrarenal mediators play a critical role in the reduction of salt transport observed with obstruction. Obstruction markedly accelerates the already-rapid generation of PGE2 in the renal medulla. [224] [226] [229] [265] [266] The molecular basis for this is a dramatic medullary COX-2 induction, as shown in Figure 35-9 . [267] [268] [269] Studies in isolated perfused tubules and in cell suspensions taken from normal animals have shown that PGE2 markedly inhibits Na reabsorption in the MTAL, as well as in the cortical and inner medullary collecting ducts, and that a major component of the inhibition occurs at the Na, K-ATPase[270] [271] [272] [273] PGE2 can reduce trafficking of Na, K-ATPase to the plasma membrane,[270] and chronic blockade of cyclooxygenase with indomethacin increases pump activity,[270] indicating that, by several mechanisms, PGE2 regulates the activity and expression of the sodium pump. From these results, obstruction likely reduces sodium pump activity in tubular epithelia in part by increasing renal levels of PGE2.



FIGURE 35-9  Immunohistochemistry for COX-2 in kidney IM of sham-operated (A) and rats subjected to 24 hours of bilateral ureteral obstruction (B). There is a strong labeling at the base of IM in obstructed kidneys located exclusively to the interstitial cells (B), and labeling is not detectable in sham kidneys (A).



As discussed earlier, obstruction brings on a monocellular infiltrate in the kidney[228]; this infiltrate tends to follow a peritubular distribution.[228] When obstructed kidneys were irradiated, the level of medullary inflammation was diminished, and there was a modest decrease in the fractional excretion of sodium.[229] In addition, it has been shown that obstruction causes an enhanced renal angiotensin II generation. This may have important implications for regulation of renal sodium handling. Blockade of the angiotensin II receptor (AT1) was associated with a marked attenuation of down-regulation of NHE3 and NKCC2, which was paralleled by a reduction in renal sodium loss.[266]

In summary, obstruction reduces net reabsorption of salt in several nephron segments, including the proximal straight tubule, the MTAL, and the cortical and inner medullary collecting ducts, by down-regulating the expression and activities of specific transporter proteins. Several signals mediate this down-regulation, including the cessation of urine flow with its attendant reduction of the rate of Na entry across the apical membrane, increased levels of natriuretic substances such as PGE2, and infiltration of the obstructed kidney by mononuclear cells.

When both ureters are obstructed, extrarenal factors markedly enhance the salt wasting tendency already present in the obstructed kidney. One mechanism involves the volume expansion that occurs when bilateral obstruction ablates all renal function. Volume expansion down-regulates the sympathetic nervous system, reduces circulating levels of aldosterone, and, along with reduced renal clearance, increases levels of ANP. Reduced sympathetic tone and aldosterone, coupled with increased ANP, markedly stimulate salt excretion. ANP likely represents a particularly important mediator of salt wasting in bilateral obstruction. Levels of ANP are markedly elevated in bilateral, but not unilateral, obstruction.[219] ANP enhances salt wasting at several nephron segments. By blocking renin release in the macula densa and angiotensin action in the proximal tubule, ANP reduces proximal tubule salt reabsorption. [222] [239] [240] ANP also reduces aldosterone release, and directly inhibits salt reabsorption in the collecting ducts. [222] [239] [240] In agreement with this mechanism, infusion of ANP into animals in which obstruction has just been released leads to marked increases in salt and water excretion.[219] Moreover, efforts to reduce circulating ANP levels following bilateral obstruction attenuated salt excretion somewhat.[219]

In addition, accumulation of urea and other solutes enhance salt wasting by obstructed kidneys. Following release of 24 hours of unilateral obstruction, removal or obstruction of the contralateral kidney markedly enhances salt wasting by the obstructed kidney.[234] If the contralateral kidney is left in place but amounts of urea, salt, and water equivalent to what the contralateral kidney is excreting are infused into the animal, there is a striking increase in salt excretion in both the obstructed and the contralateral kidney. [237] [238] On this basis, bilateral obstruction induces hormonal changes and promotes accumulation of solutes and volume that together enhance natriuresis from the obstructed kidney.

Effects of Obstruction on Urinary Concentration and Dilution

Because obstruction eliminates the ability of the renal tubules to concentrate and dilute the urine, urine osmolality following release of obstruction in humans and experimental animals approaches that of plasma. [2] [24] Dilution of the urine requires that the thick ascending limb reabsorb salt without water and that the collecting duct maintain the dilute urine by not reabsorbing water along its length, despite the presence of a concentrated medullary interstitium.[274] [275] [276] Concentration of the urine requires active salt reabsorption in the thick limb and the action of the countercurrent multiplier to generate a concentrated medullary interstitium, as well as the ability of the collecting duct to insert aquaporin-2 water channels into the apical membrane in response to antidiuretic hormone. [277] [278]

Obstructive nephropathy disrupts several of these mechanisms. As noted earlier, obstruction markedly reduces MTAL salt reabsorption, limiting this segment's ability to dilute the urine and to generate a high medullary interstitial osmolality. Indeed, interstitial osmolality has been shown to be reduced in obstructed kidneys.[2] In addition, collecting ducts isolated from obstructed kidneys reveal normal basal water permeabilities, but a marked reduction in their ability to increase water permeability in response to antidiuretic hormone or other stimulants of cyclic adenosine monophosphate (cAMP) accumulation in the cells. As was the case with salt transport, the effects were similar in unilateral and bilateral obstruction. [263] [266] Detailed mechanistic studies show that obstruction markedly reduces transcription of mRNA encoding aquaporin-2, as well as synthesis of aquaporin-2 water channels, and that collecting duct cells in obstructed kidneys do not traffic aquaporin-2–containing vesicles effectively to the apical surface in response to vasopressin or increased cAMP. [275] [276] [277] [278] Part of this failure in trafficking results from a decrease in phosphorylation of aquaporin-2 in obstructed kidneys.[276] In addition, unilateral ureteral obstruction markedly decreases synthesis and deployment to the basolateral membrane of aquaporin-3 and -4; when aquaporin-2 is in the apical membrane, these aquaporins mediate the flux of water across the basolateral membrane.[276] Enhancing the causal relationship of the changes in aquaporin activity and ability to concentrate the urine, expression of aquaporin-2 remains suppressed for 7 days following relief of the obstruction, and the rise in urinary concentration parallels the recovery in aquaporin-2 expression. [276] [277] [278] [280] [281] [282] The fact that collecting ducts from obstructed kidneys do not respond to cAMP indicates that the lesion is at a site beyond the receptor for antidiuretic hormone. Finally, in unilateral obstruction, the contralateral kidney also exhibits reduced ability to concentrate the urine and a diminution of aquaporin-2 expression below the levels observed in sham-operated controls.[275] The mechanism for this effect remains unclear.

As mentioned already obstruction leads to enhanced renal PGE2 production. Recent studies have demonstrated that PGE2 does not affect directly cAMP levels but may have post-cAMP effects rather than actions via cAMP regulation.[277] The importance of PGE2-derived production for regulation of renal water and sodium transport has been demonstrated by COX-2 upregulation in response to obstruction. Importantly, selective COX-2 inhibition prevented dysregulation of AQP2, NKCC2, and NHE3 in response to obstruction suggesting that increased PGE2 synthesis in response to urinary tract obstruction may play an important role in the dysregulation of renal aquaporins and sodium transporters, which are crucial for the impaired urinary concentration capacity in obstructive nephrogenic diabetes insipidus. [268] [281]

On the basis of these results, the defect in urinary dilution in obstruction is due to reduced ability of the thick ascending limb to dilute the urine by transporting salt from the lumen of the tubule to its basolateral side. The collecting duct in obstructed kidneys maintains its low water permeability in the absence of antidiuretic hormone, so that the failure to dilute the urine is not due to collapse of osmotic gradients in the collecting duct. The inability to concentrate the urine results from the failure of the thick limb to generate a concentrated interstitium, as well as the inability of the collecting duct to synthesize and to traffic aquaporin-2 and other water channels in response to antidiuretic hormone.

Effects of Relief of Obstruction on Urinary Acidification

Obstruction dramatically reduces urinary acidification in both experimental animals and humans. In humans, release of obstruction does not lead to bicarbonate wasting, indicating that proximal tubular bicarbonate reclamation is maintained. By contrast, in both experimental animals and patients following release of obstruction, the urine pH does not decrease in response to an acid load, indicating that obstruction impairs the ability of the distal nephron to acidify the urine. [265] [283] [284] This defect likely resides in the collecting duct. [283] [284]

Reduced collecting duct acid secretion could result from defects in H (H, ATPase or H K-ATPase) or HCO3 (e.g., Cl/HCO3 exchange) transport pathways, back-leak of protons down their electrochemical gradient from the lumen to the basolateral side of the tubule, or, in the cortical collecting duct, the failure to generate a sufficiently lumen-negative transepithelial voltage. [283] [284] [285] As described in detail earlier, obstruction reduces the activity of apical ENaC in the cortical collecting duct; the resulting loss of luminal negativity may attenuate acid secretion in these segments. [283] [284]

In the rat inner medullary collecting duct (studied by micropuncture) and in isolated perfused rat and rabbit outer medullary collecting duct (OMCD), obstruction markedly reduces luminal acidification rates.[280] Because Na transport does not play a major role in acidification in these segments, the defect must be due to direct inhibition of acid or HCO3 transport pathways, or back-leak of protons from lumen to interstitium.[282] At low perfusion rates, OMCDs from obstructed animals maintain the ability to generate steep pH gradients,[280] indicating that obstruction does not block the ability of the tubule to prevent back-flux of protons. By contrast, at high perfusion rates, acidification was markedly lower in tubules from obstructed, as opposed to normal, kidneys,[280] demonstrating that obstruction inhibits activity or expression of H or HCO3 transport pathways.

Specific antisera directed against the Cl/HCO3 exchanger and subunits of the H, ATPase were used to examine the expression of these transporters in collecting ducts of unilaterally obstructed, contralateral, and control kidneys.[282]Two possible mechanisms of reduced acid secretion were explored. One was that the intercalated cells in obstructed kidneys would exhibit a high proportion of “reverse” orientation, with the proton pump in the basolateral membrane, and the Cl/HCO3 exchanger in the apical membrane. The other possibility was that the orientation of intercalated cells would not change, but there would be reduced expression of the H or HCO3 transporter. The orientation of the intercalated cells was not altered by obstruction. However, obstruction did reduce the appearance of H, ATPase along the apical membranes of intercalated cells, without altering the total content of H ATPase in extracts of renal cortex or medulla, in unilaterally obstructed, as compared with contralateral kidneys.[282] In obstructed kidneys, fewer intercalated cells exhibited an apical labeling pattern and many that did showed discontinuities or gaps in apical membrane labeling.[282] These results suggest that obstruction inhibits trafficking of H, ATPase to the apical membranes of intercalated cells. However, this disorder alone cannot account for the entire acidification defect in obstructive nephropathy, because the labeling pattern returns to control levels as the obstruction as the obstruction persists, whereas the acidification defect remains.[282] In addition, the extent of the decrease in labeling appears to be too small to account for the profound defect in acidification.

In addition to defective collecting duct H transport, reduced generation of the main buffer that carries acid equivalents in the urine, ammonia, has also been observed in kidneys released from obstruction. Cortical slices of obstructed kidneys exhibit reduced glutamine uptake and oxidation, reduced gluconeogenesis, and reduced total oxygen consumption, all adding up to a reduced ability to generate ammonia from glutamine. [286] [287]

Effects of Relief of Obstruction of Excretion of Potassium

As with in sodium excretion, potassium excretion increases markedly following release of bilateral obstruction. [288] [289] Micropuncture and microcatheterization studies show that proximal potassium reabsorption is unchanged by obstruction while potassium is more rapidly secreted in the collecting duct, likely due to increased distal delivery and therefore more rapid distal luminal flux of sodium and volume following release of obstruction. [247] [288] By contrast, following release of unilateral obstruction, potassium excretion falls roughly in proportion to the reduction in GFR,[287] an effect that may be related to reduced distal delivery of sodium. However, administration of sodium sulfate in this state does not stimulate potassium excretion in obstructed kidneys as it does in controls, suggesting that collecting ducts in unilateral obstructed kidneys have an intrinsic defect in potassium secretion.[288] This intrinsic defect may represent a response similar to the downregulation of sodium transporters in obstructed kidneys described in detail earlier. The kaliuretic effect observed in bilateral obstruction may well be due as well to the influence of elevated levels of ANP, which, at high levels, can stimulate potassium secretion in the distal nephron.

Effects of Relief of Obstruction on Excretion of Phosphate and Divalent Cations

When bilateral ureteral obstruction is released, phosphate excretion rises in proportion to sodium excretion.[289] Phosphate restriction before the release of the obstruction prevents phosphate accumulation during bilateral obstruction, thereby blocking the increase in phosphate excretion.[289] This can also be achieved by blockade of angiotensin II-mediated effects, highlighting the importance of enhanced renal angiotensin II levels in the obstructed kidney.[266] In addition, phosphate wasting of similar magnitude to that observed following release of bilateral obstruction can be duplicated by phosphate loading of normal animals.[289] By contrast, release of unilateral obstruction results in phosphate retention, likely due to reduced GFR and avid proximal phosphate reabsorption.[290] Calcium excretion may be increased or decreased, depending on whether the obstruction is unilateral or bilateral, and depending on the species studied. [292] [293] Magnesium excretion is markedly increased following release of either bilateral or unilateral obstruction. This magnesium wasting probably occurs because both forms of obstruction markedly attenuate thick ascending limb sodium reabsorption, leading to reduced positive luminal transepithelial voltages and therefore a reduced driving force for lumen-to-basolateral magnesium flux across the paracellular pathway.[291]

Effects of Obstruction on Metabolic Pathways and Gene Expression

Obstruction inhibits oxidative metabolism and promotes anaerobic respiration, leading to decreased ATP levels, and increased levels of adenosine diphosphate (ADP) and AMP. [287] [295] [296] In addition, obstruction alters a wide variety of metabolic enzymes, as well as the expression of many different gene products. [245] [287] [296] [297] [298] These changes are summarized in Table 35-6 . Many of these changes are difficult to link mechanistically with changes in GFR or tubular transport function observed in obstruction. It is possible, however, that reduced ability to generate ATP, along with reductions in Na, K-ATPase expression, contributes to the natriuresis observed following release of obstruction (see earlier discussion).

TABLE 35-6   -- Effects of Urinary Tract Obstruction on Renal Enzymes and Renal Gene Expression



Changes in Energy and Substrate Metabolism



Decreased oxygen consumption



Decreased substrate uptake



Increased anaerobic glycolysis



Decreased ATP/(ADP+AMP)



Decreased ammoniagenesis



Changes in enzyme activity






Alkaline phosphatase



Na, K-ATPase






Succinate dehydrogenase



NADH/NADHP dehydrogenase






Glucose-6-phosphate dehydrogenase



Phosphogluconate dehydrogenase



Changes in gene expression



Reduction in glomerular Gαs and Gαq/11 proteins



Reduction in pre-proepidermal growth factor and Tamm-Horsfall protein



Transient induction of growth factors FOS and MYC



Striking induction of cellular damage (TRPM2) genes





A great deal of experimental work has focused on the renal effects of longer-term obstruction.[296] In part these studies use UUO as a convenient model for chronic renal damage, because the timing of the injury is clear and because the extent of injury should be reproducible from animal to animal.[296] These studies, which have been conducted almost entirely in rodents, have elucidated an overall pathway for renal tubular epithelial damage, and have identified several potential targets for intervention. It is thought that chronic obstruction damages tubular epithelial cells by increasing hydrostatic pressure, reducing blood flow (due to the renal vasoconstriction that occurs in obstruction, see earlier) and increases oxidative stress.[296] In response, tubular epithelial cells release a number of autocrine factors and cytokines, including angiotensin II, [299] [300] transforming growth factor beta (TGFb), [300] [301] [302] platelet activator inhibitor 1,[300] and tumor necrosis factor (TNF).[301] These factors, along with the presence and increase in levels of adhesion factors, lead to the infiltration of the renal interstitium with inflammatory cells, including macrophages. [305] [306] [307] These in turn release additional cytokines.[296] The combination of renal and inflammatory cell cytokines and factors accelerates the apoptosis of tubular epithelial cells and conversion of some of them to tubulointerstitial fibroblasts. [308] [309] The entire cascade leads to tubulointerstitial fibrosis and permanent loss of renal function, which may continue to progress after the obstruction has been relieved. [299] [310] Figure 35-10presents a schema that outlines a possible sequence of signaling events leading to the development of fibrosis in chronic obstruction. Several studies have shown that antagonism of angiotensin II, TGFb, TNF, or factors that attract inflammatory cells may ameliorate post obstructive renal damage. [299] [300] [301] [302] [303] [304] [305] [306] [307] [308] [309] [310] Similarly, augmentation of expression of factors that favor epithelial growth and differentiation, such as hepatocyte growth factor,[308] insulin-like growth factor or BMP-7,[296] may also have a protective effect. Given species differences and the fact that obstruction in humans is often partial, the animal models may not predict entirely the behavior of postobstructive kidneys in humans. However, if the studies are relevant to human obstructive nephropathy, they suggest that patients undergoing release of obstruction may benefit from therapies that block pro-apoptotic, pro-inflammatory or pro-fibrotic mediators, or from treatments that stimulate epithelial cell growth and differentiation. [299] [300] [301] [302] [303] [304] [305] [306] [307] [308] [309] [310] [311]



FIGURE 35-10  Possible signaling cascade relating urinary obstruction to chronic renal damage. Urinary tract obstruction causes an enhanced expression of angiotensin II. Increasing levels of ANG II may, in turn, up-regulate the expression of other factors through specific angiotensin II receptors type 1 (AT1) and type 2 (AT2) and directly activates the release of nuclear factor-κB (NF-κB). This leads to activation of at least two autocrine-reinforcing loops that amplify angiotensin II and tumor necrosis factor (TNF)-α generation. Subsequently, this leads to cell migration including fibroblast accumulation in the renal interstitium and stimulation of the tubule cells to release chemoattracts and adhesion proteins and stimulation of other profibrotic cytokines such as transforming growth factor-β1, osteopontin, vascular cell adhesion molecule-1 among others. If the condition persists this leads to fibrosis of the renal parenchyma.



Experimentally, protection from obstruction induced detrimental effects on renal function can also be achieved by nitric oxide (NO) supplementation. This can either be accomplished by ACE inhibition, which increases kinin levels and subsequently increase NO formation or by stimulation of endogenous NOS with L-arginine.[309] L-arginine is a semi essential amino acid and is also substrate and the main source for generation of NO via NO synthase (NOS). Importantly, chronic unilateral obstruction in mice leads to significant reduction in inducible (i)NOS activity and the obstructed kidney of iNOS knockout mice exhibited significant more apoptotic renal tubules than controls underscoring the important role NO plays for protecting the cellular functions in the obstructed kidney.[310] In a recent study it was demonstrated that dietary L-arginine supplementation attenuated renal damage of a 3-day unilateral ureteral obstruction in rats indicating that L-arginine treatment may be a pharmacological useful avenue in obstructive nephropathy.[296] It was also shown recently that several of the detrimental effects to obstruction can also be attenuated by treatment of the α-melanocyte stimulating hormone (a-MSH), which is a potent anti-inflammatory hormone supporting the view that inflammation is a crucial determinant for the onset of renal deterioration in urinary tract obstruction.[312]

Fetal Urinary Tract Obstruction

Obstructive uropathy comprises the largest fraction of identifiable causes of renal insufficiency and renal failure in infants and children. Compared with adult obstructive nephropathy, fetal obstructive nephropathy is particularly devastating because renal growth and continued nephron development are impaired by the progression of fibrosis. Several studies have examined aspects of obstructive nephropathy in the newborn using a neonatal rat model of unilateral obstruction. At the time of birth, the rodent kidney is not fully developed and is representative of human renal development at about the mid-trimester. Fetal urinary obstruction may lead to changes in tissue differentiation. Experiments in animal models reveal that fetal obstruction causes aberrations of morphogenesis, gene expression, cell turnover, and urine composition. [316] [317] The earlier the kidney is obstructed in utero, the greater will be the changes in renal tissue. [316] [317] After birth, obstruction may affect renal growth, especially in neonates and during the first year of life, but the obstruction will not cause tissue dedifferentiation.

Studies demonstrated the up-regulation of the renin-angiotensin system, as well as involvement of other substrates (transforming growth factor-β1, endothelin-1, and many other mediators in obstructed kidneys). [316] [317] [318] [319]The exact mechanisms of action of these molecules in the alteration of renal morphogenesis are not fully understood. It is not well known either if obstruction alone is enough to induce renal dysplasia, [316] [317] or if the latter results from secondary obstruction-induced mesenchymal disruption. To know the exact role of obstruction in the kidney malformation is very important clinically, because, as mentioned earlier, it is now possible to detect and potentially relieve obstruction in utero. If urinary obstruction is not the cause of subsequent renal impairment, then some may argue whether it is worthwhile to relieve the obstruction in utero. However in experimental models, obstruction in utero can cause pulmonary hyperplasia and renal impairment directly or indirectly, leading to significant morbidity and mortality. [316] [317] [320] In addition, shunting of urinary outflow from obstructed kidneys in animals before the end of nephrogenesis may allow reversal of the arrest of glomerulogenesis seen in this setting,[318] favoring early intervention.[308]


Once the presence of obstruction is established, intervention is usually strongly indicated to relieve it. The type of intervention depends on the location of the obstruction, its degree, and its etiology, as well as the presence or absence of concomitant diseases and complications, and the general condition of the patient.[190] The initial emphasis focuses on prompt relief of the obstruction, followed by the definitive treatment of its cause. Obstruction below the bladder (e.g., benign prostatic hyperplasia or urethral stricture) is easily relieved with placement of a urethral catheter. If the urethra is impassable, suprapubic cystostomy may be needed. For obstruction above the bladder, insertion of a nephrostomy tube or ureteral stent may be indicated. The urgency of the intervention depends on the degree of renal function, the presence or absence of infection, and the overall risk of the procedure.[321] The presence of the infection in an obstructed urinary tract, or urosepsis, represents a urologic emergency that requires immediate relief of the obstruction, in addition to antibiotic treatment. Acute renal failure, associated with bilateral ureteral obstruction or with the obstruction of single functioning kidney, also calls for emergent intervention.

Calculi, the most common form of acute unilateral urinary obstruction, can usually be managed conservatively with analgesics to control the exquisite pain that they cause, and intravenous fluids to increase urine flow. Ninety percent of stones smaller than 5 mm pass spontaneously, but as stones get larger, it becomes progressively less likely that they will pass spontaneously. Active efforts to fragment or remove the stone are indicated for persistent obstruction, uncontrollable pain, or urinary tract infection. Current possibilities for treatment include extracorporeal shock wave lithotripsy (which may require ureteral stent placement if the patient is symptomatic),[322] ureteroscopy with stone fragmentation (usually with laser lithotripsy), and, in rare cases, open excision of the stone. [190] [191] [192] In general, a combination of lithotripsy and endourological procedures will succeed in removing the stone. In the past, complex stones high up in the ureter or in the renal pelvis have been difficult to remove without open surgery. However, improved methods of lithotripsy, including the use of laser lithotripsy through the ureteroscope has made more stones amenable to fragmentation, while miniaturization of flexible ureteroscopes has made the entire upper urinary tract accessible in nearly all patients, except those with severe anatomic abnormalities. [190] [191] Once the stone has been removed, of course, appropriate medical therapy is needed to prevent recurrence.[188]

Intramural or extrinsic ureteral obstruction may be relieved by placement of a ureteral stent through the cystoscope.[322] If this cannot be accomplished, or is ineffective (especially in cases of extrinsic ureteral compression by the tumors), then nephrostomy tubes will need to be inserted to effect prompt relief of the obstruction.[322]

For infravesical obstruction due to benign prostatic hyperplasia, surgery can be safely delayed or completely avoided in patients with minimal symptoms, lack of infection, and an anatomically normal upper urinary tract.[323] If needed, transurethral resection of the prostate, laser ablation, or other techniques can be used for definitive treatment. Internal urethrotomy with direct visualization may be effective in the treatment of urethral strictures, as dilation usually has only temporary effect. Suprapubic cystostomy may be necessary in patients with impassable urethral strictures, followed by open urethroplasty to restore urinary tract continuity, when possible.

Patients with neurogenic bladder require a variety of approaches, including frequent voiding, often by external compression or crede, medications to stimulate bladder activity or relax the urethral sphincter, and intermittent catheterization using meticulous technique to avoid infection. [327] [328] Long-term indwelling bladder catheters should be avoided because they increase the risk of infection and renal damage. If more conservative measures such as frequent voiding or intermittent catheterization are not effective, ileovesicostomy or other forms of urinary diversion should be considered. Electrical stimulation has also been attempted with varying success.[326]

In many forms of obstruction, initial stabilization of the patient's condition is followed by a decision as to whether to continue observation or to move on to definitive surgery or nephrectomy. The actual course chosen depends on the likelihood that renal function will improve with the relief of obstruction. Factors that help decide whether to operate and what form of surgical intervention to use include the age and general condition of the patient, the appearance and function of the obstructed kidney and the contralateral one, the cause of the obstruction, and the absence or presence of infection.[190] As noted earlier, the extent of recovery of renal function depends on the extent and duration of the obstruction.

A detailed discussion of the indications and surgical techniques for intervention to treat urinary tract obstruction is beyond the scope of this chapter, and may be found in other sources. [330] [331]

Estimating Renal Damage and Potential for Recovery

As noted earlier, when deciding whether to bypass or reconstruct drainage of an obstructed kidney rather than excise it, the potential for meaningful recovery of function in the affected kidney represents a critical issue. In many cases, obstruction may be partial, so that it is difficult on the basis of the history alone to predict the outcome. In addition, imaging studies that reveal the anatomy of the obstructed kidney such as ultrasonography or IVU predict the extent of functional recovery poorly, because the extent of anatomic distortion during obstruction correlates poorly with the extent of recovery once the obstruction is relieved.[329] Isotopic renography with a variety of isotopes can be used to examine renal function, as outlined earlier. This approach is a far more reliable indicator of potential renal function when applied well after temporary drainage of the obstructed kidney (e.g., by nephrostomy tubes) has been achieved than if it is performed while the obstruction is still present.[329] Of course, anatomic studies will reveal the remaining size and volume of the kidney, and can provide some idea of the extent to which the tissue remains viable. All of these considerations figure into the clinical judgment as to whether attempts should be made to salvage the kidney. However, there are presently no methods available to predict reliably the functional potential recovery of an obstructed kidney.

In cases of prenatal urinary tract obstruction, clinical decision making is complex because the risks of not intervening can be very high, as can the risks of prenatal surgery. Because fetal intervention can be associated with frequent complications and a high rate of fetal wastage, subjects for the intervention should be carefully chosen. Fetal renal biopsy, which demonstrated a 50% to 60% success rate, correlates well with outcome and has few maternal complications. [8] [9] [316] [322] It may be used as one of the methods to determine treatment strategy. Studies demonstrate that antenatal intervention may help fetuses with the most severe forms of obstructive uropathy, otherwise usually associated with a fatal neonatal course. [8] [9] [10] [320]

Recovery of Renal Function after Prolonged Obstruction

In patients the potential for renal recovery depends primarily on the extent and duration of the obstruction. However, other factors, such as the presence of other illnesses and the presence or absence of urinary tract infection, play an important role as well. In dogs subjected to 40 days of ureteral ligation, release of the obstruction led to no recovery of renal function. However, recovery of renal function in humans has been documented following release of obstruction of 69 days or longer. [333] [334] Because it is difficult to predict whether renal function will recover when temporary relief of obstruction has been achieved, it makes sense to measure function repeatedly with isotopic renography over time, before deciding on a definitive surgical course. Chronic bilateral obstruction, as seen in benign prostatic hyperplasia, can cause chronic renal failure, especially when the obstruction is of prolonged duration and when it is accompanied by urinary tract infections. [334] [335] Progressive loss of renal function can be slowed or halted by relieving the obstruction and treating the infection.

When obstruction has been relieved and there is poor return of renal function, interstitial fibrosis and inflammation may have supervened. To ensure that there is no other process hampering recovery of renal function, renal biopsy may be indicated. As noted earlier, studies in experimental animals have implicated a variety of factors in chronic renal failure due to prolonged obstruction, including excessive production of renal vasoconstrictors such as renin and angiotensin, growth factors that may enhance fibrosis, and ammoniagenesis, which also affects cell growth. Based on these findings, inhibitors like captopril and angiotensin receptor antagonists have been shown to ameliorate to some degree the long-term damage observed following prolonged obstruction.[332]


Release of obstruction can lead to marked natriuresis and diuresis with the wasting of potassium, phosphate, and divalent cations. It is notable that clinically significant postobstructive diuresis usually occurs only in the setting of prior bilateral obstruction, or unilateral obstruction of a solitary functioning kidney. The mechanisms involved have been described in detail earlier and involve the combination of intrinsic damage to tubular salt, solute, and water reabsorption, as well as the effects of volume expansion, solute (e.g., urea) accumulation, and attendant increases in natriuretic substances such as ANP. When the obstruction is unilateral and there is a functioning contralateral kidney, the volume expansion, solute accumulation, and increases in natriuretic substances do not occur, and the contralateral kidney may retain salt and water, resulting in some compensation for the natriuresis and diuresis occurring in the postobstructive kidney. Treatment of the patient with postobstructive diuresis focuses on avoiding severe volume depletion due to salt wasting, and other electrolyte imbalances, such as hypokalemia, hyponatremia, hypernatremia, and hypomagnesemia.

Postobstructive diuresis is usually self-limited. It usually lasts for several days to a week, but may, in rare cases, persist for months. Acute massive polyuria or prolonged postobstructive diuresis may deplete the patient of Na, K, Cl, HCO3, and water, as well as divalent cations and phosphate. Volume or free water replacement is appropriate only when the salt and water losses result in volume depletion or a disturbance of osmolality. In many cases, excessive volume or fluid replacement prolongs the diuresis and natriuresis. Because the initial urine is isosthenuric, with an initial Na of approximately 80 mEq/L, an appropriate starting fluid for replacement may be 0.45% saline, given at a rate somewhat slower than that of the urine output. During this period, meticulous monitoring of vital signs, volume status, urine output, and serum and urine chemistry and osmolality is imperative. This will determine the need for ongoing replacement of salt, free water, and other electrolytes. With massive diuresis, these measurements will need to be repeated frequently, up to four times daily, with frequent adjustment of replacement fluids, as needed.


1. Bricker NS, Klahr S: Obstructive nephropathy.   In: Strauss MB, Welt LG, ed. Diseases of the Kidney,  Boston: Little, Brown; 1971:997-1037.

2. Yarger WE: Urinary tract obstruction.   In: Brenner BM, Rector FCJ, ed. The Kidney,  Philadelphia: WB Saunders; 1971:1768-1808.

3. Bell ET: Renal Diseases,  Philadelphia, Lea & Febiger, 2006.

4. Campbell MF: Urinary Obstruction.   In: Campbell MF, Harrison JH, ed. Urology,  Philadelphia: WB Saunders; 1970:1772-1793.

5. Tan PH, Chiang GS, Tay AH: Pathology of urinary tract malformations in a paediatric autopsy series.  Ann Acad Med Singapore  1994; 23:838.

6. Klahr S, Buerkert J, Morrison A: Urinary tract obstruction.   In: Brenner BM, Rector FCJ, ed. The Kidney,  Philadelphia: WB Saunders; 1986:1443-1490.

7. System URD: USRDS 1993 Annual Data Report,  Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 1993.

8. Becker A, Baum M: Obstructive uropathy.  Early Human Dev  2006; 82:15-22.

9. Thomas DFM: Prenatal diagnosis: Does it alter outcome?.  Prenat Diagn  2001; 21:1004-1111.

10. Kilby MD, Daniels JP, Khan K: Congenital lower urinary tract obstruction: To shunt or not to shunt?.  Br J Urol  2006; 97:6-8.

11. Snyder III HM, Lebowitz RL, Colodny AH, et al: Ureteropelvic junction obstruction in children.  Urol Clin North Am  1980; 7:273.

12. Young DW, Lebowitz RL: Congenital abnormalities of the ureter.  Semin Roentgenol  1986; 21:172.

13. Fefer S, Ellsworth P: Prenatal hydronephrosis.  Pediatr Clin North Am  2006; 53:429-447.

14. Graversen HP, Tofte T, Genster HG: Uretero-pelvic stenosis.  Int Urol Nephrol  1987; 19:245.

15. Lowe FC, Marshall FF: Ureteropelvic junction obstruction in adults.  Urology  1984; 23:331.

16. Clark WR, Malek RS: Ureteropelvic junction obstruction. I. Observations on the classic type in adults.  J Urol  1987; 138:276.

17. Buscemi M, Shanske A, Mallet E, et al: Dominantly inherited ureteropelvic junction obstruction.  Urology  1985; 26:568.

18. Elder JS, Duckett JW: Perinatal urology.   In: Gillenwater J, Grayhack J, Howards S, Duckett J, ed. Adult and Pediatric Urology,  Mosby-Year Book; 1991:1711-1810.

19. Rickwood AM, Godiwalla SY: The natural history of pelvi-ureteric junction obstruction in children presenting clinically with the complaint.  Br J Urol  1997; 80:793.

20. Peters CA: Urinary tract obstruction in children.  J Urol  1995; 154:1874.

21. Murthy LN: Urinary tract obstruction during pregnancy: Recent developments in imaging.  Br J Urol  1997; 80(Suppl 1):1.

22. Novick AC: Surgery of the kidney.   In: Walsh PC, Retik AB, Vaughan ED, Wein AJ, ed. Campbell's Urology,  Philadelphia: WB Saunders; 2002:3570-3644.

23. Hanna MK, Jeffs RD, Sturgess JM, Barkin M: Ureteral structure and ultrastructure. Part II. Congenital ureteropelvic junction obstruction and primary obstructive megaureter.  J Urol  1976; 116:725.

24. Klahr S, Harris KPG: Obstructive uropathy.   In: Seldin DW, Giebisch G, ed. The Kidney: Physiology and Pathophysiology,  New York: Raven Press; 1992:3327-3369.

25. Hanna MK: Some observations on congenital ureteropelvic junction obstruction.  Urology  1978; 12:151.

26. Karaca I, Sencan A, Mir E, et al: Ureteral fibroepithelial polyps in children.  Pediatr Surg Int  1997; 12:603.

27. Stephens FD: Primary obstructing megaureter.   In: Stephens FD, ed. Congenital Malformations of the Urinary Tract,  New York: Praeger Publishers; 1983:267-281.

28. Sant GR, Barbalias GA, Klauber GT: Congenital ureteral valves—an abnormality of ureteral embryogenesis?.  J Urol  1985; 133:427.

29. Ayyat FM, Adams G: Congenital midureteral strictures.  Urology  1985; 26:170.

30. Eidelman A, Yuval E, Simon D, Sibi Y: Retrocaval ureter.  Eur Urol  1978; 4:279.

31. Brown T, Mandell J, Lebowitz RL: Neonatal hydronephrosis in the era of sonography.  AJR Am J Roentgenol  1987; 148:959.

32. Tanagho EA, Pugh RC: The anatomy and function of the ureterovesical junction.  Br J Urol  1963; 35:151.

33. Lockhart JL, Singer AM, Glenn JF: Congenital megaureter.  J Urol  1979; 122:310.

34. Coplen DE: Prune belly syndrome.   In: Gillenwater JY, Grayhack JT, Howards SS, Mitchell ME, ed. Adult and Pediatric Urology,  Philadelphia: Lippincott Williams & Wilkins; 2002:2209-2225.

35. Fenelon MJ, Alton DJ: Prolapsing ectopic uretroceles in boys.  Radiology  1981; 140:373.

36. Snyder HM, Johnston JH: Orthotopic ureteroceles in children.  J Urol  1978; 119:543.

37. Sekine H, Kojima S, Mine M, Yokokawa M: Intravesical ureterocele presenting bladder outlet obstruction in an adult male.  Int J Urol  1996; 3:74.

38. Lee SS, Sun GH, Yu DS, et al: Giant hydronephrosis of a duplex system associated with ureteral ectopia: A cause of retrograde ejaculation.  Arch Androl  2000; 45:19.

39. Livne PM, Gonzales Jr ET: Congenital bladder diverticula causing ureteral obstruction.  Urology  1985; 25:273.

40. Krishnan A, De Souza A, Konijeti R, Baskin LS: The anatomy and embryology of posterior urethral valves.  J Urol  2006; 175:1214-1220.

41. Kurth KH, Alleman ER, Schroder FH: Major and minor complications of posterior urethral valves.  J Urol  1981; 126:517.

42. Martin J, Anderson J, Raz S: Posterior urethral valves in adults: A report of 2 cases.  J Urol  1977; 118:978.

43. Cohen HL, Susman M, Haller JO, et al: Posterior urethral valve: Transperineal US for imaging and diagnosis in male infants.  Radiology  1994; 192:261.

44. Freeny PC: Congenital anterior urethral diverticulum in the male.  Radiology  1974; 111:173.

45. Norbeck JC, Ritchey MR, Bloom DA: Labial fusion causing upper urinary tract obstruction.  Urology  1993; 42:209.

46. Novotny MJ, Graves GG, Couillard DR: Ureteral obstruction due to colonic duplication.  J Urol  2001; 166:216.

47. Bauer SB: Neurologic dysfunction of the lower urinary tract in children.   In: Walsh PC, Retik AB, Vaughan ED, Wein AJ, ed. Campbell's Urology,  Philadelphia: WB Saunders; 2006:2019-2054.

48. McLorie GA, Perez-Marero R, Csima A, Churchill BM: Determinants of hydronephrosis and renal injury in patients with myelomeningocele.  J Urol  1988; 140:1289.

49. Thorup J, Mortensen T, Diemer H, et al: The prognosis of surgically treated congenital hydronephrosis after diagnosis in utero.  J Urol  1985; 134:914.

50. Fine RN: Diagnosis and treatment of fetal urinary tract abnormalities.  J Pediatr  1992; 121:333.

51. Crombleholme TM, Harrison MR, Longaker MT, Langer JC: Prenatal diagnosis and management of bilateral hydronephrosis.  Pediatr Nephrol  1988; 2:334.

52. Mandell J, Peters CA, Retik AB: Current concepts in the perinatal diagnosis and management of hydronephrosis.  Urol Clin North Am  1990; 17:247.

53. Allen TD: The swing of the pendulum.  J Urol  1992; 148:534.

54. Conger JD: Acute uric acid nephropathy.  Semin Nephrol  1981; 1:69.

55. Simon DI, Brosius III FC, Rothstein DM: Sulfadiazine crystalluria revisited. The treatment of Toxoplasma encephalitis in patients with acquired immunodeficiency syndrome.  Arch Intern Med  1990; 150:2379.

56. Sawyer MH, Webb DE, Balow JE, Straus SE: Acyclovir-induced renal failure. Clinical course and histology.  Am J Med  1988; 84:1067.

57. Deeks SG, Smith M, Holodniy M, Kahn JO: HIV-1 protease inhibitors. A review for clinicians.  JAMA  1997; 277:145.

58. Chopra N, Fine PL, Price B, Atlas I: Bilateral hydronephrosis from ciprofloxacin induced crystalluria and stone formation.  J Urol  2000; 164:438.

59. DeFronzo RA, Humphrey RL, Wright JR, Cooke CR: Acute renal failure in multiple myeloma.  Medicine (Baltimore)  1975; 54:209.

60. Crittenden DR, Ackerman GL: Hyperuricemic acute renal failure in disseminated carcinoma.  Arch Intern Med  1977; 137:97.

61. Molina JM, Belenfant X, Doco-Lecompte T, et al: Sulfadiazine-induced crystalluria in AIDS patients with toxoplasma encephalitis.  AIDS  1991; 5:587.

62. Goldschmidt H, Lannert H, Bommer J, Ho AD: Multiple myeloma and renal failure.  Nephrol Dial Transplant  2000; 15:301-304.

63. Waugh DA, Ibels LS: Multiple myeloma presenting as recurrent obstructive uropathy.  Aust N Z J Med  1980; 10:555.

64. Johnson CM, Wilson DM, O'Fallon WM, et al: Renal stone epidemiology: A 25-year study in Rochester, Minnesota.  Kidney Int  1979; 16:624.

65. Eknoyan G, Qunibi WY, Grissom RT, et al: Renal papillary necrosis: An update.  Medicine (Baltimore)  1982; 61:55.

66. Pham PT, Pham PC, Wilkinson AH, Lew SQ: Renal abnormalities in sickle cell disease.  Kidney Int  2000; 57:1-8.

67. Shapeero LG, Vordermark JS: Papillary necrosis causing hydronephrosis in the renal allograft. Sonographic findings.  J Ultrasound Med  1989; 8:579.

68. Desport E, Bridoux F, Ayache RA, et al: Papillary necrosis following segmental renal infarction: An unusual cause of early renal allograft dysfunction.  Nephrol Dial Transplant  2005; 20:830-833.

69. Jameson RM, Heal MR: The surgical management of acute renal papillary necrosis.  Br J Surg  1973; 60:428.

70. Amos AM, Figlesthaler WM, Cookson MS: Bilateral ureteritis cystica with unilateral ureteropelvic junction obstruction.  Tech Urol  1999; 5:108.

71. de Groat WC, Yoshimura N: Pharmacology of the lower urinary tract.  Ann Rev Phamacol Toxicol  2001; 41:691-721.

72. Wein AJ: Neuromuscular dysfunction of the lower urinary tract and its treatment.   In: Walsh PC, Retik AB, Vaughan ED, Wein AJ, ed. Campbell's Urology,  Philadelphia: WB Saunders; 1998:953-1006.

73. Novicki DE, Willscher MK: Case profile: Anticholinergic-induced hydronephrosis.  Urology  1979; 13:324.

74. Murdock MI, Olsson CA, Sax DS, Krane RJ: Effects of levodopa on the bladder outlet.  J Urol  1975; 113:803.

75. Crew JP, Donat R, Roskell D, Fellows GJ: Bilateral ureteric obstruction secondary to the prolonged use of tiaprofenic acid.  Br J Clin Pract  1997; 51:59.

76. Hadas-Halpern I, Farkas A, Patlas M, et al: Sonographic diagnosis of ureteral tumors.  J Ultrasound Med  1999; 18:639.

77. Graham JB, Abad RS: Ureteral obstruction due to radiation.  Am J Obstet Gynecol  1967; 99:409.

78. MacGregor GA, Jones NF, Barraclough MA, et al: Ureteric stricture with analgesic nephropathy.  Br Med J  1973; 2:271.

79. Neal PM: Schistosomiasis, an unusual cause of ureteral obstruction: A case history and perspective.  Clin Med Res  2004; 2:216-227.

80. Christensen WI: Genitourinary tuberculosis: Review of 102 cases.  Medicine (Baltimore)  1974; 53:377.

81. Scerpella EG, Alhalel R: An unusual cause of acute renal failure: Bilateral ureteral obstruction due to Candida tropicalis fungus balls.  Clin Infect Dis  1994; 18:440.

82. Murao F: Ultrasonic evaluation of hydronephrosis during pregnancy and puerperium.  Gynecol Obstet Invest  1993; 35:94.

83. Klein EA: Urologic problems of pregnancy.  Obstet Gynecol Surv  1984; 39:605.

84. Roy C, Saussine C, Lebras Y, et al: Assessment of painful ureterohydronephrosis during pregnancy by MR urography.  Eur Radiol  1996; 6:334.

85. Loughlin KR: Management of acute ureteral obstruction in pregnancy utilizing ultrasound-guided placement of ureteral stents.  Urology  1994; 43:412.

84. Beach EW: Urologic complications of cancer of the uterine cervix.  J Urol  1952; 68:178.

85. Gomes CM, Rovner ES, Banner MP, et al: Simultaneous upper and lower urinary tract obstruction associated with severe genital prolapse: Diagnosis and evaluation with magnetic resonance imaging.  Int Urogynecol J Pelvic Floor Dysfunct  2001; 12:144.

86. Resnick MI, Kursh ED: Extrinsic obstruction of the ureter.   In: Walsh PC, Retik AB, Vaughan ED, Wein AJ, ed. Campbell's Urology,  Philadelphia: WB Saunders; 1998:387-422.

87. Philips JC: Spectrum of radiologic abnormalities due to tubo-ovarian abscess.  Radiology  1974; 110:307.

88. Carpenter AA: Pelvic lipomatosis: Successful surgical treatment.  J Urol  1973; 110:397.

89. Sakellariou PG, Protopapas AG, Kyritsis NI, et al: Retroperitoneal endometriosis causing cyclical ureteral obstruction.  Eur J Obstet Gynecol Reprod Biol  1996; 67:59.

90. Deprest J, Marchal G, Brosens I: Obstructive uropathy secondary to endometriosis.  N Engl J Med  1997; 337:1174.

91. Nasu K, Narahara H, Hayata T, et al: Ureteral obstruction caused by endometriosis.  Gynecol Obstet Invest  1995; 40:215.

92. Dowling RA, Corriere Jr JN, Sandler CM: Iatrogenic ureteral injury.  J Urol  1986; 135:912.

93. Fitzpatrick JM: The natural history of benign prostatic hyperplasia.  Br J Urol Int 97: Suppl  2006; 2:3-6.

94. Burnett AL, Wein AJ: Benign prostatic hyperplasia in primary care: What you need to know.  J Urol  2006; 175:S19-S24.

95. Alam AM, Sugimura K, Okizuka H, et al: Comparison of MR imaging and urodynamic findings in benign prostatic hyperplasia.  Radiat Med  2000; 18:123.

96. Marks LS, Gallo DA: Ureteral obstruction in the patient with prostatic carcinoma.  Br J Urol  1972; 44:411.

97. Batata MA, Whitmore WF, Hilaris BS, et al: Primary carcinoma of the ureter: A prognostic study.  Cancer  1975; 35:1626.

98. Present DH, Rabinowitz JG, Banks PA, Janowitz HD: Obstructive hydronephrosis. A frequent but seldom recognized complication of granulomatous disease of the bowel.  N Engl J Med  1969; 280:523.

99. Ben-Ami H, Lavy A, Behar DM, et al: Left hydronephrosis caused by Crohn disease successfully treated conservatively.  Am J Med Sci  2000; 320:286.

100. Schofield PF, Staff WG, Moore T: Ureteral involvement in regional ileitis (Crohn's disease).  J Urol  1968; 99:412.

101. Shield DE, Lytton B, Weiss RM, Schiff Jr M: Urologic complications of inflammatory bowel disease.  J Urol  1976; 115:701.

102. Cook GT: Appendiceal abscess causing urinary obstruction.  J Urol  1969; 101:212.

103. Bissada NK, Redman JF: Ureteral complications in diverticulitis of the colon.  J Urol  1974; 112:454.

104. Knobel B, Rosman P, Gewurtz G: Bilateral hydronephrosis due to fecaloma in an elderly woman.  J Clin Gastroenterol  2000; 30:311.

105. Kiviat MD, Miller EV, Ansell JS: Pseudocysts of the pancreas presenting as renal mass lesions.  Br J Urol  1971; 43:257.

106. Gibson GE, Tiernan E, Cronin CC, Ferriss JB: Reversible bilateral ureteric obstruction due to a pancreatic pseudocyst.  Gut  1993; 34:1267.

107. Morehouse HT, Thornhill BA, Alterman DD: Right ureteral obstruction associated with pancreatitis.  Urol Radiol  1985; 7:150.

108. Loughlin K, Kearney G, Helfrich W, Carey R: Ureteral obstruction secondary to perianeurysmal fibrosis.  Urology  1984; 24:332.

109. Schapira HE, Mitty HA: Right ovarian vein septic thrombophlebitis causing ureteral obstruction.  J Urol  1974; 112:451.

110. Weisman MH, McDanald EC, Wilson CB: Studies of the pathogenesis of interstitial cystitis, obstructive uropathy, and intestinal malabsorption in a patient with systemic lupus erythematosus.  Am J Med  1981; 70:875.

111. Lie JT: Retroperitoneal polyarteritis nodosa presenting as ureteral obstruction.  J Rheumatol  1992; 19:1628.

112. Plaisier EM, Mougenot B, Khayat R, et al: Ureteral stenosis in Wegener's granulomatosis.  Nephrol Dial Transplant  1997; 12:1759.

113. Kher KK, Sheth KJ, Makker SP: Stenosing ureteritis in Henoch-Schonlein purpura.  J Urol  1983; 129:1040.

114. Pfister C, Liard-Zmuda A, Dacher J, et al: Total bilateral ureteral replacement for stenosing ureteritis in Henoch-Schonlein purpura.  Eur Urol  2000; 38:96.

115. Marzano A, Trapani A, Leone N, et al: Treatment of idiopathic retroperitoneal fibrosis using cyclosporin.  Ann Rheum Dis  2001; 60:427.

116. Vaglio A, Salvarani C, Buzio C: Retroperitoneal fibrosis.  Lancet  2006; 367:241-251.

117. Cohen WM, Freed SZ, Hasson J: Metastatic cancer to the ureter: A review of the literature and case presentations.  J Urol  1974; 112:188.

118. Goldman SM, Fishman EK, Rosenshein NB, et al: Excretory urography and computed tomography in the initial evaluation of patients with cervical cancer: Are both examinations necessary?.  AJR Am J Roentgenol  1984; 143:991.

119. Jones CR, Woodhouse CR, Hendry WF: Urological problems following treatment of carcinoma of the cervix.  Br J Urol  1984; 56:609.

120. Blum MD, Bahnson RR, Carter MF: Urologic manifestations of von Recklinghausen neurofibromatosis.  Urology  1985; 26:209.

121. David HS, Lavengood Jr RW: Bilateral Wilms' tumor. Treatment, management, and review of the literature.  Urology  1974; 3:71.

122. Schoenfeld RH, Belville WD, Buck AS, et al: Unilateral ureteral obstruction secondary to sarcoidosis.  Urology  1985; 25:57.

123. Bloomberg SD, Neu HC, Ehrlich RM, Blanc WA: Chronic granulomatous disease of childhood with renal involvement.  Urology  1974; 4:193.

124. Maeda H, Shichiri Y, Kinoshita H, et al: Urinary undiversion for pelvic actinomycosis: A long-term follow up.  Int J Urol  1999; 6:111.

125. de Feiter PW, Soeters PB: Gastrointestinal actinomycosis: An unusual presentation with obstructive uropathy: Report of a case and review of the literature.  Dis Colon Rectum  2001; 44:1521.

126. Emir L, Karabulut A, Balci U, et al: An unusual cause of urinary retention: A primary retrovesical echinococcal cyst.  Urology  2000; 56:856.

127. Mark IR, Mansoor A, Derias N, Tiptaft RC: Retroperitoneal malacoplakia: An unusual cause of ureteric obstruction.  Br J Urol  1995; 76:520.

128. Casserly LF, Reddy SM, Rennke HG, et al: Reversible bilateral hydronephrosis without obstruction in hepatitis B-associated polyarteritis nodosa.  Am J Kidney Dis  1999; 34:e11.

129. Talreja D, Opfell RW: Ureteral metastasis in carcinoma of the breast.  West J Med  1980; 133:252.

130. Gore RM, Shkolnik A: Abdominal manifestations of pediatric leukemias: Sonographic assessment.  Radiology  1982; 143:207.

131. Richmond J, Sherman RS, Diamond HD, Craver LF: Renal lesions associated with malignant lymphomas.  Am J Med  1962; 32:184.

132. Vaidyanathan S, Singh G, Soni BM, et al: Silent hydronephrosis/pyonephrosis due to upper urinary tract calculi in spinal cord injury patients.  Spinal Cord  2000; 38:661.

133. Covington T, Reeser W: Hydronephrosis associated with overhydration.  J Urol  1950; 63:438.

134. Tebyani N, Candela J, Patel H, Bellman G: Ureteropelvic junction obstruction presenting as early satiety and weight loss.  J Endourol  1999; 13:445.

135. Chute CG, Panser LA, Girman CJ, et al: The prevalence of prostatism: A population-based survey of urinary symptoms.  J Urol  1993; 150:85.

136. Akcay A, Altun B, Usalan C, et al: Cyclical acute renal failure due to bilateral ureteral endometriosis.  Clin Nephrol  1999; 52:179.

137. Shimada K, Katsumi T, Fujita H: Appendiceal granuloma causing bilateral hydronephrosis and macroscopic haematuria.  Br J Urol  1976; 48:418.

138. Whiting JC, Stanisic TH, Drach GW: Congenital ureteral valves: Report of 2 patients, including one with a solitary kidney and associated hypertension.  J Urol  1983; 129:1222.

139. Decramer S, Wittke S, Mischak H, et al: Predicting the clinical outcome of congenital unilateral ureteropelvic jundtion obstruction in newborn by urinary proteome analysis.  Nature Med  2006; 12:398-400.

139. Shokeir AA: The diagnosis of upper urinary tract obstruction.  BJU Int  1999; 83:893.

140. Noble VE, Brown DF: Renal ultrasound.  Emerg Med Clinics North Am  2004; 22:641-659.

141. Gottlieb RH, Weinberg EP, Rubens DJ, et al: Renal sonography: Can it be used more selectively in the setting of an elevated serum creatinine level?.  Am J Kidney Dis  1997; 29:362.

142. Talner LB: Urinary obstruction.   In: Pollack HM, ed. Clinical Urology: An Atlas and Textbook of Urological Imaging,  Philadelphia: WB Saunders; 1990:1535-1628.

143. Maillet PJ, Pelle-Francoz D, Laville M, et al: Nondilated obstructive acute renal failure: Diagnostic procedures and therapeutic management.  Radiology  1986; 160:659.

144. Lalli AF: Retroperitoneal fibrosis and inapparent obstructive uropathy.  Radiology  1977; 122:339.

145. Amis Jr ES, Cronan JJ, Pfister RC, Yoder IC: Ultrasonic inaccuracies in diagnosing renal obstruction.  Urology  1982; 19:101.

146. Cronan JJ, Amis ES, Scola FH, Schepps B: Renal obstruction in patients with ileal loops: US evaluation.  Radiology  1986; 158:647.

147. Garcia-Pena BM, Keller MS, Schwartz DS, et al: The ultrasonographic differentiation of obstructive versus nonobstructive hydronephrosis in children: A multivariate scoring system.  J Urol  1997; 158:560.

148. Cronan JJ, Amis Jr ES, Yoder IC, et al: Peripelvic cysts: An impostor of sonographic hydronephrosis.  J Ultrasound Med  1982; 1:229.

149. Charasse C, Camus C, Darnault P, et al: Acute nondilated anuric obstructive nephropathy on echography: Difficult diagnosis in the intensive care unit.  Intensive Care Med  1991; 17:387.

150. Garrett WJ, Grunwald G, Robinson DE: Prenatal diagnosis of fetal polycystic kidney by ultrasound.  Aust N Z J Obstet Gynaecol  1970; 10:7.

151. Roth JA, Diamond DA: Prenatal hydronephrosis.  Curr Opin Pediatr  2001; 13:138.

152. Kessler RM, Ouevedo H, Lankau CA, et al: Obstructive vs nonobstructive dilatation of the renal collecting system in children: Distinction with duplex sonography.  AJR Am J Roentgenol  1993; 160:353-357.

153. Tublin ME, Bude RO, Platt JF: Review: The resistive index in renal Doppler sonography. Where do we stand?.  AJR Am J Roentgenol  2003; 180:885-892.

154. Shoeir AA, Nijman RJ, el-Azab M, Provoost AP: Partial ureteral obstruction: Effect of intravenous normal saline and furosemide upon the renal resistive index.  J Urol  1997; 157:1074-1077.

155. Reddy PP, Mandell J: Prenatal diagnosis. Therapeutic implications.  Urol Clin North Am  1998; 25:171.

156. Kaefer M, Peters CA, Retik AB, Benacerraf BB: Increased renal echogenicity: A sonographic sign for differentiating between obstructive and nonobstructive etiologies of in utero bladder distension.  J Urol  1997; 158:1026.

157. Siemens DR, Prouse KA, MacNeily AE, Sauerbrei EE: Antenatal hydronephrosis: Thresholds of renal pelvic diameter to predict insignificant postnatal pelviectasis.  Tech Urol  1998; 4:198.

158. Woodward M, Frank D: Postnatal management of antenatal hydronephrosis.  BJU Int  2002; 89:149.

159. Feldman DM, DeCambre M, Kong E, et al: Evaluation and follow-up of fetal hydronephrosis.  J Ultrasound Med  2001; 20:1065.

160. Little MA, Stafford Johnson DB, O'Callaghan JP, Walshe JJ: The diagnostic yield of intravenous urography.  Nephrol Dial Transplant  2000; 15:200.

161. Parfrey PS, Griffiths SM, Barrett BJ, et al: Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency, or both. A prospective controlled study.  N Engl J Med  1989; 320:143.

162. Dalla PL: What is left of i.v. urography?.  Eur Radiol  2001; 11:931.

163. Sheth S, Fishman EK: Multi-detector row CT of the kidneys and urinary tract: techniques and applications in the diagnosis of benign diseases.  Radiographics  2004; 24:e20.

164. Grenier N, Hauger O, Cimpean A, Perot V: Update of renal imaging.  Semin Nucl Med  2006; 36:3-15.

165. Smith RC, Rosenfield AT, Choe KA, et al: Acute flank pain: Comparison of non-contrast-enhanced CT and intravenous urography.  Radiology  1995; 194:789.

166. Boridy IC, Kawashima A, Goldman SM, Sandler CM: Acute ureterolithiasis: Nonenhanced helical CT findings of perinephric edema for prediction of degree of ureteral obstruction.  Radiology  1999; 213:663.

167. Lacey NA, Massouh H: Use of helical CT in assessment of crossing vessels in pelviureteric junction obstruction.  Clin Radiol  2000; 55:212.

168. Dorio PJ, Pozniak MA, Lee Jr FT, Kuhlman JE: Non-contrast-enhanced helical computed tomography for the evaluation of patients with acute flank pain.  World Med J  1999; 98:30.

169. Testa HJ: Nuclear medicine.   In: O'Reilly PH, George NJR, Weiss RM, ed. Diagnostic Techniques in Urology,  Philadelphia: WB Saunders; 1990:99-118.

170. English PJ, Testa HJ, Lawson RS, et al: Modified method of diuresis renography for the assessment of equivocal pelviureteric junction obstruction.  Br J Urol  1987; 59:10.

171. O'Reilly PH, Testa HJ, Lawson RS, et al: Diuresis renography in equivocal urinary tract obstruction.  Br J Urol  1978; 50:76.

172. O'Reilly PH, Lawson RS, Shields RA, Testa HJ: Idiopathic hydronephrosis—the diuresis renogram: A new non-invasive method of assessing equivocal pelvioureteral junction obstruction.  J Urol  1979; 121:153.

173. Conway JJ: “Well-tempered” diuresis renography: its historical development, physiological and technical pitfalls, and standardized technique protocol.  Semin Nucl Med  1992; 22:74.

174. Upsdell SM, Leeson SM, Brooman PJ, O'Reilly PH: Diuretic-induced urinary flow rates at varying clearances and their relevance to the performance and interpretation of diuresis renography.  Br J Urol  1988; 61:14.

175. Frokiaer J, Eskild-Jensen A, Dissing T: Antenatally detected hydronephrosis: the nuclear medicine techniques.   In: Prigent A, Piepez A, ed. Functional Imaging in Nephrourology,  London: Taylor and Francis; 2005.

176. Grenier N: Functional MRI of the kidney.  Abdom Imaging  2003; 28:164-175.

177. Dockery WD, Stolpen AH: State-of-the-art magnetic resonance imaging of the kidneys and upper urinary tract.  J Endourol  1999; 13:417.

178. Sadowski EA, Bennett LK, Chan MR, et al: Nephrogenic systemic fibrosis: risk factors and incidence estimation.  Radiology  2007; 243:148-157.

179. Broome DR, Girguis MS, Baron PW, et al: Gadolinium-associated nephrogenic systemic fibrosis: why radiologists should be concerned.  AJR Am J Radiol  2007; 188:586-592.

180. Roy C, Saussine C, Guth S, et al: MR urography in the evaluation of urinary tract obstruction.  Abdom Imaging  1998; 23:27.

181. Jorgensen B, Keller AK, Radvanska E, et al: Reproducibility of contrast enhanced MR renography in children.  J Urol  2006; 176:1171-1176.

182. Prasad PV: Functional MRI of the kidney: Tools for translational studies of pathophysiology of renal disease.  Am J Physiol  2006; 290:F958-F974.

183. Pedersen M, Dissing TH, Stodkilde-Jorgensen H, et al: Validation of quantitative BOLD MRI measurements in kidney: Application in unilateral ureteral obstruction.  Kidney Int  2005; 67:2305-2312.

184. Wolf Jr JS, Siegel CL, Brink JA, Clayman RV: Imaging for ureteropelvic junction obstruction in adults.  J Endourol  1996; 10:93.

185. Whitaker RH: Perfussion pressure flow studies.   In: O'Reilly PH, George NJR, Weiss RM, ed. Diagnostic Techniques in Urology,  Philadelphia: WB Saunders; 1990:135-141.

186. Whitaker RH, Buxton-Thomas MS: A comparison of pressure flow studies and renography in equivocal upper urinary tract obstruction.  J Urol  1984; 131:446.

187. Streem SB, Perminger GM: Surgical management of calculous diseases.   In: Gillenwater JY, Grayhack JT, Howards SS, Mitchell ME, ed. Adult and Pediatric Urology,  Philadelphia: Lippincott Williams & Wilkins; 2002:393-448.

188. Alivizatos G, Skolarikos A: Is there still a role for open surgery in the management of renal stones?.  Curr Opin Urol  2006; 16:106-111.

189. Moe OM: Kidney stones: Pathophysiology and medical management.  Lancet  2006; 367:333-344.

190. Streem SB, Franke JJ, Smith AJ: Management of upper urinary tract obstruction.   In: Walsh PC, Retik AB, Vaughan ED, Wein AJ, ed. Campbell's Urology,  Philadelphia: WB Saunders; 2002:463-512.

191. Dal Canton A, Stanziale R, Corradi A, et al: Effects of acute ureteral obstruction on glomerular hemodynamics in rat kidney.  Kidney Int  1977; 12:403.

192. Ichikawa I: Evidence for altered glomerular hemodynamics during acute nephron obstruction.  Am J Physiol  1982; 242:F580-F585.

193. Gaudio KM, Siegel NJ, Hayslett JP, Kashgarian M: Renal perfusion and intra-tubular pressure during ureteral occlusion in the rat.  Am J Physiol  1980; 238:F205-F209.

194. Vaughan Jr ED, Shenasky JH, Gillenwater JY: Mechanism of acute hemodynamic response to ureteral occlusion.  Invest Urol  1971; 9:109.

195. Navar LG, Baer PG: Renal autoregulatory and glomerular filtration responses to gradated ureteral obstruction.  Nephron  1970; 7:301.

196. Wright FS, Briggs JP: Feedback control of glomerular blood flow, pressure, and filtration rate.  Physiol Rev  1979; 59:958.

197. Schramm LP, Carlson DE: Inhibition of renal vasoconstriction by elevated ureteral pressure.  Am J Physiol  1975; 228:1126.

198. Francisco LL, Hoversten LG, DiBona GF: Renal nerves in the compensatory adaptation to ureteral occlusion.  Am J Physiol  1980; 238:F229-F234.

199. Allen JT, Vaughan Jr ED, Gillenwater JY: The effect of indomethacin on renal blood flow and uretral pressure in unilateral ureteral obstruction in awake dogs.  Invest Urol  1978; 15:324.

200. Blackshear JL, Wathen RL: Effects of indomethacin on renal blood flow and renin secretory responses to ureteral occlusion in the dog.  Miner Electrolyte Metab  1978; 1:271.

201. Harris RH, Gill JM: Changes in glomerular filtration rate during complete ureteral obstruction in rats.  Kidney Int  1981; 19:603.

202. Moody TE, Vaughn Jr ED, Gillenwater JY: Relationship between renal blood flow and ureteral pressure during 18 hours of total unilateral uretheral occlusion. Implications for changing sites of increased renal resistance.  Invest Urol  1975; 13:246.

203. Harris RH, Yarger WE: Renal function after release of unilateral ureteral obstruction in rats.  Am J Physiol  1974; 227:806.

204. Yarger WE, Griffith LD: Intrarenal hemodynamics following chronic unilateral ureteral obstruction in the dog.  Am J Physiol  1974; 227:816.

205. Dal Canton A, Corradi A, Stanziale R, et al: Glomerular hemodynamics before and after release of 24-hour bilateral ureteral obstruction.  Kidney Int  1980; 17:491.

206. Provoost AP, Molenaar JC: Renal function during and after a temporary complete unilateral ureter obstruction in rats.  Invest Urol  1981; 18:242.

207. Jaenike JR: The renal functional defect of postobstructive nephyropathy. The effects of bilateral ureteral obstruction in the rat.  J Clin Invest  1972; 51:2999.

208. Dal Canton A, Corradi A, Stanziale R, et al: Effects of 24-hour unilateral ureteral obstruction on glomerular hemodynamics in rat kidney.  Kidney Int  1979; 15:457.

209. Tanner GA: Effects of kidney tubule obstruction on glomerular function in rats.  Am J Physiol  1979; 237:F379-F385.

210. Yarger WE, Aynedjian HS, Bank N: A micropuncture study of postobstructive diuresis in the rat.  J Clin Invest  1972; 51:625.

211. Bander SJ, Buerkert JE, Martin D, Klahr S: Long-term effects of 24-hr unilateral ureteral obstruction on renal function in the rat.  Kidney Int  1985; 28:614.

212. Ichikawa I, Brenner BM: Local intrarenal vasoconstrictor-vasodilator interactions in mild partial ureteral obstruction.  Am J Physiol  1979; 236:F131-F140.

213. Ichikawa I, Purkerson ML, Yates J, Klahr S: Dietary protein intake conditions the degree of renal vasoconstriction in acute renal failure caused by ureteral obstruction.  Am J Physiol  1985; 249:F54-F61.

214. Wahlberg J, Stenberg A, Wilson DR, Persson AE: Tubuloglomerular feedback and interstitial pressure in obstructive nephropathy.  Kidney Int  1984; 26:294.

215. Jensen AM, Li C, Praetorius HA, et al: Angiotensin II mediates downregulation of aquaporin water channels and key renal sodium transporters in response to urinary tract obstruction.  Am J Physiol Renal Physiol  2006; 291:F1021-F1032.

216. Yarger WE, Schocken DD, Harris RH: Obstructive nephropathy in the rat: possible roles for the renin-angiotensin system, prostaglandins, and thromboxanes in postobstructive renal function.  J Clin Invest  1980; 65:400.

217. Vaughan Jr ED, Sweet RC, Gillenwater JY: Peripheral renin and blood pressure changes following complete unilateral ureteral occlusion.  J Urol  1970; 104:89.

218. Moody TE, Vaughan Jr ED, Wyker AT, Gillenwater JY: The role of intrarenal angiotensin II in the hemodynamic response to unilateral obstructive uropathy.  Invest Urol  1977; 14:390.

219. Purkerson ML, Blaine EH, Stokes TJ, Klahr S: Role of atrial peptide in the natriuresis and diuresis that follows relief of obstruction in rat.  Am J Physiol  1989; 256:F583-F589.

220. Topcu O, Pedersen M, Norregaard R, et al: Candesartan prevents long-term impairment of renal function in response to neonatal partial unilateral ureteral obstruction.  Am J Physiol Renal Physiol  2007; 292:F736-F748.

221. Morrison AR, Benabe JE: Prostaglandins in vascular tone in experimental obstructive nephropathy.  Kidney Int  1981; 19:786.

222. Strand JC, Edwards BS, Anderson ME, et al: Effect of imidazole on renal function in unilateral ureteral-obstructed rat kidneys.  Am J Physiol  1981; 240:F508-F514.

223. Klotman PE, Smith SR, Volpp BD, et al: Thromboxane synthetase inhibition improves function of hydronephrotic rat kidneys.  Am J Physiol  1986; 250:F282-F287.

224. Loo MH, Egan D, Vaughan Jr ED, et al: The effect of the thromboxane A2 synthesis inhibitor OKY-046 on renal function in rabbits following release of unilateral ureteral obstruction.  J Urol  1987; 137:571.

225. Yanagisawa H, Morrissey J, Morrison AR, Klahr S: Eicosanoid production by isolated glomeruli of rats with unilateral ureteral obstruction.  Kidney Int  1990; 37:1528.

226. Folkert VW, Schlondorff D: Altered prostaglandin synthesis by glomeruli from rats with unilateral ureteral ligation.  Am J Physiol  1981; 241:F289-F299.

227. Schlondorff D, Folkert VW: Prostaglandin synthesis in glomeruli from rats with unilateral ureteral obstruction.  Adv Prostaglandin Thromboxane Res  1980; 7:1177.

228. Schreiner GF, Harris KP, Purkerson ML, Klahr S: Immunological aspects of acute ureteral obstruction: immune cell infiltrate in the kidney.  Kidney Int  1988; 34:487.

229. Harris KP, Schreiner GF, Klahr S: Effect of leukocyte depletion on the function of the postobstructed kidney in the rat.  Kidney Int  1989; 36:210.

230. Bhangdia DK, Gulmi FA, Chou S-Y, et al: Alterations of renal hemodynamics in unilateral ureteral obstruction mediated by activation of endothelin receptor subtypes.  J Urol  2003; 170:2057-2062.

231. Moridaira K, Yanagisawa H, Nodera M, et al: Enhanced expression of vsmNOS mRNA in glomeruli from rats with unilateral ureteral obstruction.  Kidney Int  2000; 57:1502-1511.

232. Reyes AA, Karl IE, Klahr S: Bilateral ureteral obstruction decreases plasma and tissue L-arginine, the substrate for EDRF synthesis.  J Am Soc Nephrol  1992; 3:551.

233. Yanagisawa H, Morrissey J, Morrison AR, et al: Role of ANG II in eicosanoid production by isolated glomeruli from rats with bilateral ureteral obstruction.  Am J Physiol  1990; 258:F85-F93.

234. Harris RH, Yarger WE: The pathogenesis of post-obstructive diuresis. The role of circulating natriuretic and diuretic factors, including urea.  J Clin Invest  1975; 56:880.

235. Harris RH, Yarger WE: Urine-reinfusion natriuresis: Evidence for potent natriuretic factors in rat urine.  Kidney Int  1977; 11:93.

236. Brenner BM, Ballermann BJ, Gunning ME, Zeidel ML: Diverse biological actions of atrial natriuretic peptide.  Physiol Rev  1990; 70:665.

237. Purkerson ML, Klahr S: Prior inhibition of vasoconstrictors normalizes GFR in postobstructed kidneys.  Kidney Int  1989; 35:1305.

238. Kerr Jr WS: Effect of complete ureteral obstruction for one week on kidney function.  J Appl Physiol  1954; 6:762.

239. Wilson DR: Micropuncture study of chronic obstructive nephropathy before and after release of obstruction.  Kidney Int  1972; 2:119.

240. Shi Y, Pedersen M, Li C, et al: Early release of neonatal ureteral obstruction preserves renal function.  Am J Physiol Renal Physiol  2004; 286:1087-1099.

241. Nagle RB, Bulger RE, Cutler RE, et al: Unilateral obstructive nephropathy in the rabbit. I. Early morphologic, physiologic, and histochemical changes.  Lab Invest  1973; 28:456.

242. McDougal WS, Rhodes RS, Persky L: A histochemical and morphologic study of postobstructive diuresis in the rat.  Invest Urol  1976; 14:169.

243. Wilson DR: The influence of volume expansion on renal function after relief of chronic unilateral ureteral obstruction.  Kidney Int  1974; 5:402.

244. Sonnenberg H, Wilson DR: The role of the medullary collecting ducts in postobstructive diuresis.  J Clin Invest  1976; 57:1564.

245. Buerkert J, Martin D, Head M, et al: Deep nephron function after release of acute unilateral ureteral obstruction in the young rat.  J Clin Invest  1978; 62:1228.

246. Hanley MJ, Davidson K: Isolated nephron segments from rabbit models of obstructive nephropathy.  J Clin Invest  1982; 69:165.

247. Hwang SJ, Haas M, Harris Jr HW, et al: Transport defects of rabbit medullary thick ascending limb cells in obstructive nephropathy.  J Clin Invest  1993; 91:21.

248. Miyata Y, Muto S, Ebata S, et al: Sodium and potassium transport properties of the cortical collecting duct following unilateral ureteral obstruction.  J Am Soc Nephrol  1992; 3:815.

249. Campbell HT, Bello-Reuss E, Klahr S: Hydraulic water permeability and transepithelial voltage in the isolated perfused rabbit cortical collecting tubule following acute unilateral ureteral obstruction.  J Clin Invest  1985; 75:219.

250. Hwang SJ, Harris Jr HW, Otuechere G, et al: Transport defects of rabbit inner medullary collecting duct cells in obstructive nephropathy.  Am J Physiol  1993; 264:F808-F815.

251. Li C, Wang W, Kwon TH, et al: Altered expression of major renal Na transporters in rats with unilateral ureteral obstruction.  Am J Physiol Renal Physiol  2003; 284:F155-F166.

252. Hegarty NJ, Watson RWG, Young LS, et al: Cytoprotective effects of nitrates in a cellular model of hydronephrosis.  Kidney Int  2002; 62:70-77.

253. Hwang S, Hu G, Charness ME, et al: Regulation of Na/K-ATPase expression in obstructive uropathy.  Clin Res  1993; 41:141A.(abstract).

254. Li C, Wang W, Norregaard R, et al: Dysregulation of ENaC subunit expression and targeting in rats with urinary tract obstruction.  FASEB J  2005; 19:351.19

255. Zeidel ML, Seifter JL, Lear S, et al: Atrial peptides inhibit oxygen consumption in kidney medullary collecting duct cells.  Am J Physiol  1986; 251:F379-F383.

256. Zeidel ML: Hormonal regulation of inner medullary collecting duct sodium transport.  Am J Physiol  1993; 265:F159-F173.

257. Eveloff J, Bayerdorffer E, Silva P, Kinne R: Sodium-chloride transport in the thick ascending limb of Henle's loop. Oxygen consumption studies in isolated cells.  Pflugers Arch  1981; 389:263.

258. Grossman EB, Hebert SC: Modulation of Na-K-ATPase activity in the mouse medullary thick ascending limb of Henle. Effects of mineralocorticoids and sodium.  J Clin Invest  1988; 81:885.

259. Petty KJ, Kokko JP, Marver D: Secondary effect of aldosterone on Na-KATPase activity in the rabbit cortical collecting tubule.  J Clin Invest  1981; 68:1514.

260. Rokaw MD, Sarac E, Lechman E, et al: Chronic regulation of transepithelial Na+ transport by the rate of apical Na+ entry.  Am J Physiol  1996; 270:C600-C607.

261. Lebowitz J, An B, Edinger RS, et al: Effect of altered Na+ entry on expression of apical and basolateral transport proteins in A6 epithelia.  Am J Physiol Renal Physiol  2003; 285:524-531.

262. Okegawa T, Jonas PE, DeSchryver K, et al: Metabolic and cellular alterations underlying the exaggerated renal prostaglandin and thromboxane synthesis in ureter obstruction in rabbits. Inflammatory response involving fibroblasts and mononuclear cells.  J Clin Invest  1983; 71:81.

263. Smith WL, Bell TG, Needleman P: Increased renal tubular synthesis of prostaglandins in the rabbit kidney in response to ureteral obstruction.  Prostaglandins  1979; 18:269.

264. Cheng X, Zhang H, Lee HL, Park JM: Cyclooxygenase 2 inhibitor preserves medullary aquaporin 2 expression and prevents polyuria after ureteral obstruction.  J Urol  2004; 172:2387-2390.

265. Nørregaard R, Jensen BL, Li C, et al: COX-2 inhibition prevents downregulation of key renal water and sodium transport proteins in response to bilateral ureteral obstruction.  Am J Physiol Renal Physiol  2005; 289:F322-F333.

266. Jensen AM, Li C, Praetorius HA, et al: Angiotensin II mediates downreglation of aquaporin water channels and key renal sodium transporters in response to urinary tract obstruction.  Am J Physiol Renal Physiol  2006; 291:F1021-F1032.

267. Lear S, Silva P, Kelley VE, Epstein FH: Prostaglandin E2 inhibits oxygen consumption in rabbit medullary thick ascending limb.  Am J Physiol  1990; 258:F1372-F1378.

268. Jabs K, Zeidel ML, Silva P: Prostaglandin E2 inhibits Na+-K+-ATPase activity in the inner medullary collecting duct.  Am J Physiol  1989; 257:F424-F430.

269. Stokes JB, Kokko JP: Inhibition of sodium transport by prostaglandin E2 across the isolated, perfused rabbit collecting tubule.  J Clin Invest  1977; 59:1099.

270. Cordova HR, Kokko JP, Marver D: Chronic indomethacin increases rabbit cortical collecting tubule Na+-K+-ATPase activity.  Am J Physiol  1989; 256:F570-F576.

271. Zeidel ML, Strange K, Emma F, Harris Jr HW: Mechanisms and regulation of water transport in the kidney.  Semin Nephrol  1993; 13:155.

272. Harris Jr HW, Strange K, Zeidel ML: Current understanding of the cellular biology and molecular structure of the antidiuretic hormone-stimulated water transport pathway.  J Clin Invest  1991; 88:1.

273. Zeidel ML: Recent advances in water transport.  Semin Nephrol  1998; 18:167.

274. Frokiaer J, Marples D, Knepper MA, Nielsen S: Bilateral ureteral obstruction downregulates expression of vasopressin-sensitive AQP-2 water channel in rat kidney.  Am J Physiol  1996; 270:F657-F668.

275. Frokiaer J, Christensen BM, Marples D, et al: Downregulation of aquaporin-2 parallels changes in renal water excretion in unilateral ureteral obstruction.  Am J Physiol  1997; 273:F213-F223.

276. Li C, Wang W, Knepper MA, et al: Downregulation of renal aquaporins in response to unilateral ureteral obstruction.  Am J Physiol Renal Physiol  2003; 284:F1066-F1079.

277. Nadler SP, Zimpelmann JA, Hebert RL: PGE2 inhibits water permeability at a post-cAMP site in renal terminal inner medullary collecting duct.  Am J Physiol  1992; 262:F229-F235.

278. Norregaard R, Jensen BL, Topcu SO, et al: Cyclooxygenase type 2 is increased in obstructed rat and human ureter and contributes to pelvic pressure increase after obstruction.  Kidney Int  2006; 70:872-881.

279. Li C, Wang W, Kwon TH, et al: Downregulation of AQP1, -2, and -3 after ureteral obstruction is associated with a long-term urine-concentrating defect.  Am J Physiol Renal Physiol  2001; 281:F163-F171.

280. Ribeiro C, Suki WN: Acidification in the medullary collecting duct following ureteral obstruction.  Kidney Int  1986; 29:1167.

281. Laski ME, Kurtzman NA: Site of the acidification defect in the perfused postobstructed collecting tubule.  Miner Electrolyte Metab  1989; 15:195.

282. Purcell H, Bastani B, Harris KP, et al: Cellular distribution of H(+)-ATPase follow-ing acute unilateral ureteral obstruction in rats.  Am J Physiol  1991; 261:F365-F376.

283. Blondin J, Purkerson ML, Rolf D, et al: Renal function and metabolism after relief of unilateral ureteral obstruction.  Proc Soc Exp Biol Med  1975; 150:71.

284. Klahr S, Schwab SJ, Stokes TJ: Metabolic adaptations of the nephron in renal disease.  Kidney Int  1986; 29:80.

285. Buerkert J, Head M, Klahr S: Effects of acute bilateral ureteral obstruction on deep nephron and terminal collecting duct function in the young rat.  J Clin Invest  1977; 59:1055.

286. McDougal WS, Wright FS: Defect in proximal and distal sodium transport in post-obstructive diuresis.  Kidney Int  1972; 2:304.

287. Buerkert J, Martin D, Head M: Effect of acute ureteral obstruction on terminal collecting duct function in the weanling rat.  Am J Physiol  1979; 236:F260-F267.

288. Thirakomen K, Kozlov N, Arruda JA, Kurtzman NA: Renal hydrogen ion secretion after release of unilateral ureteral obstruction.  Am J Physiol  1976; 231:1233.

289. Beck N: Phosphaturia after release of bilateral ureteral obstruction in rats.  Am J Physiol  1979; 237:F14-F19.

290. Purkerson ML, Rolf DB, Chase LR, et al: Tubular reabsorption of phosphate after release of complete ureteral obstruction in the rat.  Kidney Int  1974; 5:326.

291. Purkerson ML, Slatopolsky E, Klahr S: Urinary excretion of magnesium, calcium, and phosphate after release of unilateral ureteral obstruction in the rat.  Miner Electrolyte Metab  1981; 6:182.

292. Stecker Jr JF, Vaughan Jr ED, Gillenwater JY: Alteration in renal metabolism occurring in ureteral obstruction in vivo.  Surg Gynecol Obstet  1971; 133:846.

293. Nito H, Descoeudres C, Kurokawa K, Massry SG: Effect of unilateral obstruction on renal cell metabolism and function.  J Lab Clin Med  1978; 91:60.

294. Storch S, Saggi S, Megyesi J, et al: Ureteral obstruction decreases renal prepro-epidermal growth factor and Tamm-Horsfall expression.  Kidney Int  1992; 42:89.

295. Sawczuk IS, Hoke G, Olsson CA, et al: Gene expression in response to acute unilateral ureteral obstruction.  Kidney Int  1989; 35:1315.

296. Docherty NG, O'Sullivan OE, Healy DA, et al: Evidence that inhibition of tubular cell apoptosis protects against renal damage and development of fibrosis following ureteric obstruction.  Am J Physiol Renal Physiol  2006; 290:4-13.

297. Ma L-J, Yang H, Gaspert A, et al: Transforming growth factor b dependent and independent pathways of induction of tubulointerstitial fibrosis in β6--/- mice.  Am J Pathol  2003; 163:1261-1273.

298. Yokoi H, Mukoyama M, Sugawara A, et al: Role of connective tissue growth factor in fibronectin expression and tubulointerstitial fibrosis.  Am J Physiol Renal Physiol  2002; 282:F933-F942.

299. Sato M, Muragaki Y, Saika S, et al: Targeted disruption of TGFb1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction.  J Clin Invest  2003; 112:1486-1494.

300. Matsuo S, Lopez-Guisa JM, Cai X, et al: Multifunctionality of PAI-1 in fibrogenesis: Evidence from obsructive nephropathy in PAI-1 overexpressing mice.  Kidney Int  2005; 67:2221-2238.

301. Misseri R, Meldrum DR, Dinarello CA, et al: TNF-α mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling.  Am J Physiol Renal Physiol  2005; 288:F406-F411.

302. Lenda DM, Kikawada E, Stanley ER, Kelley VR: Reduced macrophage recruitment, proliferation, and activation in colony stimulating factor 1 deficient mice results in decreased tubular apoptosis during renal inflammation.  J Immunol  2003; 170:3254-3262.

303. Anders H-J, Vielhauer V, Frink M, et al: A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation.  J Clin Invest  2002; 109:251-259.

304. Naruse T, Yuzawa Y, Akahori T, et al: P-selectin dependent macrophage migration into the tubulointerstitium in unilateral ureteral obstruction.  Kidney Int  2002; 62:94-105.

305. Iwano M, Plieth D, Danoff TM, et al: Evidence that fibroblasts derive from epithelium during tissue fibrosis.  J Clin Invest  2002; 110:341-350.

306. Herzlinger D: Renal interstitial fibrosis: Remembrance of things past?.  J Clin Invest  2002; 110:305-306.

307. Ito K, Chen J, El Chaar M, et al: Renal damage progresses despite improvement of renal function after relief of unilateral ureteral obstruction in adult rats.  Am J Physiol Renal Physiol  2004; 287:1282-1293.

308. Gao X, Mae H, Ayabe N, et al: Hepatocyte growth factor gene therapy retards the progression of chronic obstructive nephropathy.  Kidney Int  2002; 62:1238-1248.

309. Morrissey JJ, Ishidoya S, McCracken R, Klahr S: Nitric oxide generation ameliorates the tubulointerstitial fibrosis of obstructive nephropathy.  J Am Soc Nephrol  1996; 7:2202-2212.

310. Felsen D, Dardashti K, Ostad M, et al: Inducible nitric oxide synthase promotes pathophysiological consequences of experimental bladder outlet obstruction.  J Urol  2003; 169:1569-1572.

311. Ito K, Chen J, Seshan SV, et al: Dietary arginine supplementation attenuates renal damage after relief of unilateral ureteral obstruction in rats.  Kidney Int  2005; 68(2):515-528.

312. Li C, Shi Y, Wang W, et al: alpha-MSH prevents impairment in renal function and dysregulation of AQPs and Na-K-ATPase in rats with bilateral ureteral obstruction.  Am J Physiol Renal Physiol  2006; 290(2):F384-F396.

313. Chevalier RL: Perinatal obstructive nephropathy.  Semin Perinatol  2004; 28:124-131.

314. Chevalier RL: Pathogenesis of renal injury in obstructive nephropathy.  Curr Opin Pediatr  2006; 18:153-160.

315. Silverstein DM, Travis BR, Thornhill BA, et al: Altered expression of immune modulator and structural genes in neonatal unilateral ureteral obstruction.  Kidney Int  2003; 64:25-35.

316. Lange-Sperandio B, Schimpgen K, Rodenbeck B, et al: Distinct roles of Mac-1 and its counter-receptors in neonatal obstructive nephropathy.  Kidney Int  2006; 69:81-88.

317. Agarwal SK, Fisk NM: In utero therapy for lower urinary tract obstruction.  Prenat Diagn  2001; 21:970.

318. Edouga D, Hugueny B, Gasser B, et al: Recovery after relief of fetal urinary obstruction: Morphological, functional and molecular aspects.  Am J Physiol Renal Physiol  2001; 281:F26-F37.

319. Bunduki V, Saldanha LB, Sadek L, et al: Fetal renal biopsies in obstructive uropathy: Feasibility and clinical correlations—preliminary results.  Prenat Diagn  1998; 18:101.

320. Freedman AL, Johnson MP, Smith CA, et al: Long-term outcome in children after antenatal intervention for obstructive uropathies.  Lancet  1999; 354:374.

321. Chevalier RL, Klahr S: Therapeutic approaches in obstructive uropathy.  Semin Nephrol  1998; 18:652.

322. Auge BK, Preminger GM: Ureteral stents and their use in endourology.  Curr Opin Urol  2002; 12:217.

323. Lepor H, Lowe FC: Evaluation and nonsurgical management of benign prostatic hyperplasia.   In: Walsh PC, Retik AB, Vaughan ED, Wein AJ, ed. Campbell's Urology,  Philadelphia: WB Saunders; 2002:1337-1378.

324. Wyndaele JJ: Intermittent catheterization: which is the optimal technique?.  Spinal Cord  2002; 40:432.

325. Nijman RJ: Neurogenic and non-neurogenic bladder dysfunction.  Curr Opin Urol  2001; 11:577.

326. Jezernik S, Craggs M, Grill WM, et al: Electrical stimulation for the treatment of bladder dysfunction: Current status and future possibilities.  Neurol Res  2002; 24:413.

327. Gillenwater JY, Howards SS, Grayhack JT: Adult and Pediatric Urology,  Philadelphia, Lippincott Williams and Wilkins, 2002.

328. Walsh PC, Retik AB, Vaughan ED, Wein AJ: Campbell's Urology,  Philadelphia, WB Saunders, 2002.

329. Gulmi FA, Felsen D, Vaughan EDJ: Pathophysiology of urinary tract obstruction.   In: Walsh DS, Retik AB, Vaughan Jr ED, Wein AJ, ed. Campbell's Urology,  Philadelphia: WB Saunders; 2002:411-462.

330. Lewis HY, Pierce JM: Return of function after relief of complete ureteral obstruction of 69 days' duration.  J Urol  1962; 88:377.

331. Shapiro SR, Bennett AH: Recovery of renal function after prolonged unilateral ureteral obstruction.  J Urol  1976; 115:136.

332. Moridaira K, Morrissey J, Fitzgerald M, et al: ACE inhibition increases expression of the ETB receptor in kidneys of mice with unilateral obstruction.  Am J Physiol Renal Physiol  2003; 284:F209-F217.

If you find an error or have any questions, please email us at Thank you!