Urinary Tract Obstruction

Saulo Klahr

Incidence and Causes Clinical Syndromes and Complications Pathophysiology of Urinary Tract Obstruction Factors Leading to Extracellular atrix !ccumulation in Obstructi"e #ephropathy $iagnosis of Urinary Tract Obstruction Treatment of Urinary Tract Obstruction

Obstructive nephropathy is a renal disorder that begins with hydrodynamic and hemodynamic responses, leading to cellular changes in all renal compartments, and, finally, to interstitial fibrosis and tubular atrophy. Urinary tract obstruction is a common cause of loss of renal function, which may be reversible with treatment. Urinary tract obstruction occurs in a variety of clinical circumstances, not only in diseases intrinsic to the urinary tract, but also in diseases originating in other organ systems. Symptoms and signs of urinary tract obstruction may be minimal or absent, and diagnosis, therefore, requires a high index of suspicion. Early recognition of the presence of obstruction is important, since the degree to which nephron function is irreversibly lost is related to the duration of obstruction. Several terms and definitions are used in this chapter Obstructive uropathy is used as a general term indicating complete or partial obstruction of the flow of urine at any level from the renal calyx to the external urethral meatus. !ydronephrosis refers to abnormal dilation of the renal pelvis and calyces with varying degrees of renal parenchymal atrophy and is usually, but not always, the result of obstructive uropathy. Obstructive nephropathy refers to the functional and pathologic changes in the "idney that result from obstruction to the flow of urine.

Incidence and Causes

Obstructive uropathy is a common clinical problem. #he incidence of hydronephrosis reported by $ell %&' in a series of (),(*+ autopsies was (.,- %(..- in males, (.*- in females'. #he incidence of clinical manifestations of obstructive uropathy prior to death was not reported, and it is li"ely that hydronephrosis was an incidental autopsy finding in many of these patients. #he incidence of hydronephrosis at autopsy is somewhat lower in children than in adults, being )- in one series of &*,+++ autopsies %)'. Over ,+- of children with hydronephrosis at autopsy were less than & year old, with the balance of childhood cases being distributed uniformly through the childhood years. /bout &** patients per &++,+++ population had a presumptive diagnosis of obstructive uropathy on admission to hospitals in the United States in &.,0 %('. /mong male patients with "idney and urologic disorders, obstructive uropathy ran"ed fourth at discharge %)1) patients2&++,+++ discharges'. 3n females with "idney and urologic problems, obstructive uropathy ran"ed sixth as a diagnosis at discharge %.1 patients2&++,+++ discharges'. 3n the United States in &.,0, about (,4 visits per &++,+++ population were related to obstructive uropathy %('. 5ew ultrasound techniques have made possible the diagnosis of obstructive uropathy in the fetus during pregnancy %1,0'. 3n the adult, the incidence and causes of urinary tract obstruction vary with the age and sex of the patient. &

3n young and middle6aged males, acute obstruction from renal calculi is common, but temporary, and such cases would not be included in autopsy surveys. 3n females of this age group, on the other hand, pelvic cancer is an important cause. 3n the older age group, urinary tract obstruction is more common in men, resulting from prostatic hypertrophy or malignancy. 3n the United States, 4,.&( patients with urologic problems were on dialysis in )++&. /natomic factors are also important in establishing the site of the obstruction. #he degree of obstruction in the urinary tract and whether it is intraluminal, intramural %intrinsic', or extramural %extrinsic' are helpful. #he usual sites of obstruction in the urinary tract are the urethra and the bladder nec", the bladder and ureterovesical 7unction, the ureter, and the renal pelvis and ureteropelvic 7unction. #able )06& shows a clinical8anatomic classification of the causes of urinary tract obstruction based on age, sex, and anatomic level of obstruction. 3ntraluminal obstruction may be because of renal calculi, blood clots, or sloughed renal papillae and most li"ely occurs at three locations9the ureteropelvic 7unction, the ureterovesical 7unction, or the bladder nec", although it may occur at any level. 3ntramural %intrinsic' obstruction may be because of functional or structural lesions in the wall of the urinary tract. :unctional obstruction is because of impaired peristaltic activity, such as neurogenic bladder, while structural lesions include inflammatory ureteric strictures or malignant disease of the uroepithelium. ;ommon extramural obstructive lesions include prostatic disease and gynecologic, colorectal, or retroperitoneal malignancy.

Clinical Syndromes and Complications

<atients with obstructive uropathy may present with an acute and life6threatening illness, with chronic and slowly progressive symptoms, or with virtually no symptoms or signs. #he clinical presentation will depend not only on the underlying cause of obstruction but also on the duration of the obstruction %acute or chronic', on its severity %unilateral or bilateral, partial or complete', and on the presence or absence of complications, such as urinary tract infection %U#3'. #here are five common clinical syndromes that may indicate the presence of obstructive uropathy and several additional clinical presentations because of complications of this disorder %#able )06)'. ;linical syndromes owing to urinary tract obstruction itself include lower urinary tract symptoms, such as difficulty in voiding, increasing frequency and nocturia, flan" pain and renal colic with or without an abdominal mass, or the finding of an asymptomatic abdominal mass, often in a child. <atients with obstructive uropathy may present with acute renal failure, particularly with anuria or widely varying urinary output, or with symptoms and signs of chronic renal failure, often with few symptoms and signs to suggest obstruction. Of interest because of their pathophysiology, are the renal tubular defects associated with obstructive nephropathy, including the clinical syndromes of polyuria %nephrogenic diabetes insipidus, postobstructive diuresis', salt and water depletion, and hyperchloremic hyper"alemic metabolic acidosis. TABLE 25-1 Common causes of obstructive uropathy, by a e an! "eve" of obstruction #nfants an! chi"!ren Urethra or bladder nec% =eatal stenosis <himosis Urethral valves %male' &ladder 5eurogenic bladder ;alculus %Southeast /sia' ) A!u"ts Urethral stricture %male' $enign prostatic hypertrophy

5eurogenic bladder $lood clot

$lood clot

;arcinoma of bladder :oreign body ;alculus ;alculus %male predominance' $lood clot >enal papilla Stricture9tuberculosis, radiation ?esicoureteral reflux %female preponderance' ;arcinoma of prostate >etroperitoneal tumor >etroperitoneal fibrosis <elvic neoplasm9carcinoma of cervix <regnancy, uterine prolapse 3nflammatory bowel disease /bdominal aortic aneurysm Surgical ligation ;arcinoma of ureter ;alculus $lood clot >enal papillary tissue /berrant renal artery :ibrous band

Ureter Stricture %congenital' Ureterocele =egaureter $lood clot >etroperitoneal tumor ?esicoureteral reflux %female preponderance'

Ureteropel"ic 'unction and renal pel"is ;ongenital stricture /berrant renal artery $lood clot

Unilateral obstruction of the ureter or ureteropelvic 7unction may be asymptomatic, may be accompanied by dull aching flan" pain, or, in the case of a renal stone obstructing the ureter, there may be severe renal colic presenting as an acute abdominal emergency with associated paralytic ileus. >enal colic in milder cases may subside spontaneously, leaving no symptoms or only intermittent mild flan" pain. $ilateral obstruction of acute onset may be accompanied by lower abdominal or bac" pain and progressive symptoms of renal failure. Since chronic lower urinary tract obstruction often precedes acute obstruction, as in the older male with benign prostatic hypertrophy, there may be a history of increasing @bladderA symptoms. Bross hematuria in a patient with acute or chronic renal failure should alert one to the possibility of obstructive uropathy from tumor, blood clots, or stones. <atients with slowly progressive bilateral urinary tract obstruction may present with symptoms of chronic renal failure, such as fatigue, anorexia, nausea, vomiting, dyspnea, peripheral edema, or drowsiness. >enal tubular defects resulting in water and salt depletion are particularly characteristic of obstructive nephropathy. <olyuria, nocturia, thirst, and polydipsia may be prominent symptoms. <atients with chronic partial urinary tract obstruction may present with hyperosmolar dehydration and hypernatremia because of severe impairment of urine6concentrating ability resulting in nephrogenic diabetes insipidus. #his is particularly true in older adults, who frequently have hypodipsia. 3f renal tubular damage results in urinary salt wasting, patients with chronic obstructive uropathy may present with postural hypotension and progressive manifestations of uremia owing to intravascular volume contraction. !yperchloremic acidosis, often with hyper"alemia, may also result from distal nephron or collecting duct damage %type 1 distal renal tubular acidosis'. /fter (

relief of severe bilateral obstruction, a disorder referred to as postobstructive diuresis may occur with a mar"ed increase in sodium and water excretion.

TABLE 25-2 C"inica" syn!romes of urinary tract obstruction C"inica" syn!rome &. $ladder symptoms ). /cute renal failure %often with anuria' (. ;hronic renal failure 1. >enal tubular disorder with <olyuria, polydipsia Sodium and water depletion >enal tubular acidosis 0. :lan" pain or enlarged tender "idney *. Other complications of obstruction >esistant or recurrent urinary tract infections 3nfective %struvite' calculi !ypertension <olycythemia 5eonatal ascites 3n addition to these clinical syndromes, patients with obstructive uropathy may present with the clinicopathologic consequences of urinary tract obstruction, specifically hydronephrosis, renal parenchymal atrophy, and chronic renal failure, or with other complications of obstruction, such as urinary tract infection, renal calculi, hypertension, polycythemia, and neonatal ascites. $y!ronephrosis, %ena" &arenchyma" Atrophy, an! %ena" 'ai"ure #he volume of urine normally contained in the calyces and pelvis of each "idney is small %0 to &+ mC', but with persistent obstruction the urinary tract proximal to the site of obstruction becomes dilated and, with long6standing obstruction, there can be massive enlargement of the "idney. 3n such situations, the calyces and pelvis are greatly dilated, the medulla is almost completely destroyed, and the cortex may be reduced to a thin, extensively sclerotic rim. Dith severe acute obstruction, in childhood, atrophy of the parenchyma may be very rapid, and a shrun"en "idney with minimal dilation of the pelvis and calyces may result. =icroscopic examination of obstructed "idneys shows tubular dilation and atrophy with chronic interstitial inflammatory changes and fibrosis, which are more severe than glomerular changes. !owever, glomeruli become hyaliniEed in a pattern similar to that seen in nephrosclerosis. Dhen both "idneys are affected by lower urinary obstruction, the changes are usually asymmetric, but chronic renal failure eventually results. 1 Type of obstruction <artial bilateral obstruction ;omplete bilateral obstruction %or complete obstruction of a solitary "idney' Severe partial bilateral obstruction ;hronic partial bilateral obstruction, or >elief of complete or severe partial bilateral obstruction %postobstructive diuresis' ;omplete or partial unilateral obstruction /ny obstructive lesion

/lthough hydronephrosis is a stri"ing sign of obstructive uropathy, it is the associated atrophy of the renal parenchyma that leads to loss of renal function. #hree mechanisms have been proposed to explain the loss of "idney function.

<ressure atrophy. 3ncreased pressure in the renal pelvis and calyces may be responsible for the atrophy observed in the renal medulla of obstructed "idneys. #he morphologic finding that renal papillae are often flattened and atrophied out of proportion to the cortex is in agreement with this concept. #his structural finding is compatible with the distal tubular and collecting duct defects in sodium, potassium, and water handling and urinary acidification that often accompany urinary tract obstruction. 3ntrarenal reflux. 3ntrarenal reflux refers to pyelotubular bac"flow of urine or of radiographic contrast material instilled in the bladder. 3t usually occurs during micturition and results in segmental radiographic opacification of the "idney parenchyma. >olleston and colleagues %*' found that intrarenal reflux, sometimes extending outward as far as the renal capsule, was common in children with severe vesicoureteral reflux, and, in addition, that the scarred and atrophic segments of the "idney corresponded exactly with the segments in which intrarenal reflux was observed. !odson and colleagues %4,,' made the same observations in piglets with experimental urethral obstruction and vesicoureteral reflux. 3ntrarenal reflux probably results from increased pyelocalyceal pressure, which changes the shape of the pliant renal papilla from conical to flat, causing the slitli"e openings of the ducts of $ellini %terminal collecting ducts' to gape open, thus allowing pyelotubular bac"flow of urine %.'. :urther evidence of retrograde intratubular movement of urine is obtained from the finding of #amm6!orsfall protein, which is secreted in the distal nephron, in the $owmanFs space of glomeruli, and in the interstitium of obstructed rat "idneys %&+'. #he finding of intrarenal reflux in the cortex helps explain the presence of cortical as well as medullary atrophy in the obstructed "idney. 3schemia. >enal blood flow is reduced in chronic obstruction not only because of the vasomotor changes but also because enlargement of the renal pelvis may cause arterial or venous obstruction owing to stretching or "in"ing of vessels. Gecreased renal blood flow predisposes the obstructed "idney to ischemic atrophy. ;ollapse of the inner medullary blood vessels and corresponding medullary tubular in7ury occur in rats with unilateral obstruction %&&'. 3f hypertension develops owing to obstructive nephropathy, there may be sclerosis and narrowing of the renal blood vessels. #he resultant ischemia could play an important role in the progression of parenchymal atrophy.

Urinary Tract #nfection Associate! (ith Urinary Tract Obstruction U#3 is a common and serious complication of obstruction. /cute pyelonephritis with fever, costovertebral angle pain, and tenderness, or bacteremia may be the presenting clinical picture. >ecurrent bacteriuria and2or U#3 may be present. 3n males, the first attac" of U#3 is sufficient 7ustification for performing an intravenous urogram to exclude a structural %often congenital' abnormality causing partial obstruction and predisposing to infection. ;hronic bacteriuria is frequent and difficult to eradicate in patients with obstructive uropathy. 3f the obstruction is below the level of the bladder, spontaneous development of bacteriuria is very common. #wo factors are important in the development of such infections. :irst, in the presence of an obstruction to bladder outflow, there is a larger than normal volume of residual urine after voiding. #his urine provides an excellent culture medium in which bacteria may persist and multiply. Second, defenses against bacterial growth may be impaired in the walls of the distended ureter and bladder. Obstructive uropathy above the level of the bladder is not necessarily associated with infection. $iopsy evidence shows that an obstructed "idney is more easily infected than an unobstructed 0

"idney %&),&('. Dith time, however, the susceptibility to infection induced by urinary tract obstruction may decrease function only modestly and not progressively. 3f urine from such a hydronephrotic "idney is sterile, it is important not to underta"e procedures such as retrograde pyelography. #his procedure can introduce infection that is often refractory to treatment and that may then cause progressive renal damage. %ena" Ca"cu"i >enal calculi are both a cause and a serious potential complication of obstruction. Stones complicating obstruction are invariably of the struvite %magnesium ammonium phosphate8calcium carbonate' type resulting from the association of urinary infection with urea6splitting bacteria, which produce urease and brea" down urea in the urine to ammonia, which, in turn, buffers hydrogen ions and raises urine p!, precipitating struvite. #he usual sequence of events is the presence of partial urinary tract obstruction followed by infection, with formation of a renal pelvic staghorn stone. Such stones tend to grow rapidly and recur after removal unless %a' all stone fragments are removed, %b' infection is eradicated on a long6term basis, and %c' obstruction to urine flow is corrected. #he combination of ureteropelvic 7unction obstruction with recurrent staghorn calculi may result in loss of renal function. $ypertension Associate! (ith Urinary Tract Obstruction 3n obstructive nephropathy, hypertension may develop because of fluid retention with extracellular fluid %E;:' volume expansion, increased renin secretion, or possibly from decreased synthesis of vasodepressor substances, such as prostaglandins %<Bs'. /fter relief of bilateral obstruction, volume6dependent hypertension may improve as fluid retention is corrected. !ypertension can occur as a consequence of unilateral urinary tract obstruction. !ypertension was associated with elevated renin concentration in the renal venous blood from the obstructed "idney %&1,&0,&*' and relief of the obstruction has, at times, resulted in disappearance of the hypertension and restoration of the renal venous renin levels to normal %&1'. #his sequence of events resembles the hypertension associated with unilateral renal artery stenosis. 3ndeed, ureteral occlusion does cause an acute increase in renin release %&4,&,'. ;omplicating an evaluation of the role of renin, however, are patients with hypertension and unilateral hydronephrosis, but normal renin secretion %&.,)+,)&'. Deidmann et al. %)&', however, studying six patients before and after surgery for unilateral ureteropelvic and ureteral obstruction, observed a correlation between the postoperative magnitude of the fall in blood pressure and the decrement in plasma renin levels. #hese authors emphasiEed that surgery is most li"ely to cure hypertension in patients who have not only elevated renin secretion in the ipsilateral "idney but also suppressed renin secretion in the contralateral "idney. Several clinical studies suggest that hypertension associated with unilateral hydronephrosis may be renin6dependent. !owever, other aspects of the pathophysiology of unilateral ureteral obstruction may also be contributing to the hypertension %)+'. &o"ycythemia Occasionally, patients with obstructive nephropathy have an abnormally high erythrocyte mass. #his polycythemia is because of increased synthesis and release of erythropoietin %))'. )eonata" Ascites Urinary tract obstruction %bilateral', usually owing to urethral valves in male infants, may present *

with ascites in the neonatal period.

Pathophysiology of Urinary Tract Obstruction

#he clinical syndromes outlined previously also influence the pathophysiology of obstructive uropathy. Specifically, the age of the patient and level of obstruction are important, as well as the severity and duration of obstruction and the presence or absence of complications. #he effects of obstruction on renal function and structure, that is, obstructive nephropathy, may be discussed by considering the functions of the "idney, including renal blood flow, glomerular filtration rate %B:>', and tubular function, as indicated by urinary6concentrating ability and salt, other solutes, and acid excretion. 3n addition, the endocrine8metabolic aspects of renal function must be considered, particularly the renin8angiotensin and prostaglandin systems. Some aspects of obstructive nephropathy have been studied in humans, usually with chronic obstruction, but our current understanding of this disorder is based largely on the use of animal models that resemble the clinical syndromes seen in humans. $y!ro!ynamics in the Urinary Tract #he movement of urine from the "idney to the bladder under normal conditions is the result of three factors %a' hydrostatic pressure, %b' ureteral and pelvic peristalsis, and %c' the rate of urine flow %)(,)1'. #he urinary collecting system is lined by a transitional epithelium and surrounded by circular and longitudinal layers of smooth muscle. /ction potentials that originate in smooth muscle cells of the renal pelvis are conducted along the pelvis and ureter and are followed by a wave of contraction. Urine leaves the renal pelvis and enters the ureter passively during the resting phase after contraction. #he normal ureteropelvic 7unction does not demonstrate an anatomic sphincter. #his 7unction, however, appears to act as a functional sphincter, since distortion of this area is a common cause of hydronephrosis. 3n the ureter, urine is propelled in boluses by the peristaltic waves of contraction. 3nitially, the circular smooth muscle components of the ureteral wall contract proximally and completely occlude the lumen, a process referred to as coaptation, and, subsequently, as circular muscle relaxes, the longitudinal smooth muscle components contract and the bolus of urine is propelled down the ureter. /n essential feature of normal peristalsis is bolus formation, which is achieved only by occlusion of the lumen. Gilation of the ureter clearly interferes with this process. #he nature of normal ureteral peristalsis also prevents retrograde transmission of the pressures generated during coaptation %&+ to )0 mm !g' to the renal pelvis and renal pelvic pressures seldom rise above 1 mm !g %)('. #he effects of obstructive uropathy on hydrodynamics will depend on the rate of urine flow at the time of obstruction, with very high pressures being generated during diuretic states. 3t will also depend on the level of obstruction, with higher pressures being generated by obstruction at higher levels in the urinary tract, particularly above the level of the bladder. Dhether obstruction is unilateral or bilateral and partial or complete is also important. 3mmediately after acute ureteral obstruction, both the baseline and pea" intraluminal pressures are increased, and & hour after obstruction, baseline and pea" pressures are similar and three to five times greater than pressures prior to obstruction %)0'. /t this point, coaptation of the ureteral walls does not occur, and pressures generated may be transmitted directly to the renal pelvis and papillae. #he effects of ureteral obstruction on ureteral diameter are best understood by examining the relationship between pressure and tension, which is expressed in CaplaceFs law p H " %t2r',

where p is the transmural pressure gradient pi %inside' po %outside', " is a constant, t is the wall tension, and r is the radius of the ureter. /ssuming constant extraluminal pressure, an increase in ureteral pressure will be observed after obstruction as long as the increase in wall tension %increased t' is greater than the degree of ureteral dilation %increased r' of the urinary tract. /fter acute obstruction, smooth muscle fibers in the urinary tract respond to the increase in pressure by contracting and increasing the tension. Dith persistent obstruction, the smooth muscle of the urinary tract contracts less forcefully, the tension of the walls of the obstructed tract increases no further, and, after prolonged obstruction with dilation, the tension may decrease. Dith superimposed urinary infection, as often occurs in chronic obstruction, the loss of muscle tone is even more dramatic and progressive dilation occurs with no further increase in wall tension, or with a decrease %)*'. :rom the Caplace formula it can be seen that with dilation %increased r and constant or decreased t', intraluminal pressure will decrease, and renal pelvic pressures will return to only mildly elevated levels as has been demonstrated with chronic obstruction in both animals and humans %)4'. #hese findings have several clinical implications, most notably %a' the ma7or renal damage resulting directly from increased pressure will occur early after the development of obstruction, and %b' patients with chronic partial obstruction may not experience deleterious effects owing to elevated ureteral pressures, since these are often in the near6normal range, unless conditions of high urine output or worsening obstruction ensue, when intrarenal pressure may increase. Gecompression of the chronically obstructed urinary tract cannot, however, be entirely accounted for by dilation and decreased smooth muscle tone in the walls of the urinary tract. #he driving force for intrarenal pressure and urine propulsion, namely, the glomerular filtration pressure, is also reduced. /fter &) to )1 hours of complete unilateral ureteral ligation or after relief of acute obstruction, intraluminal hydrostatic pressure is normal, but glomerular filtration pressure and renal blood flow are reduced %),,).,(+,(&,()'. #hese findings indicate that the B:> is depressed by factors other than high intraluminal hydrostatic pressure opposing filtration pressure. #his fall in B:> involves renal vasoconstriction associated with prolonged obstruction. #he escape of urine across walls of the collecting system is a third mechanism by which the urinary tract may be decompressed with prolonged obstruction. #here is evidence that complete obstruction of the urinary tract does not completely abolish glomerular filtration. Girect micropuncture of glomeruli and proximal tubules indicates the presence of significant filtration %).,((,(1'. 3f there is persistence of filtration, then reabsorption of filtrate must also occur. 3n addition to renal tubular reabsorption, urine may be reabsorbed directly across the walls of the renal pelvis through the lymphatics %pyelolymphatic reflux' or renal venous system %pyelovenous reflux'. =ar"ers of B:> experimentally introduced into the renal pelvis may appear in renal venous blood or renal lymph. #he lymphatic flow from the "idneys is increased mar"edly during acute and chronic obstruction. =ost of this increase in lymph flow, however, appears to be because of increased lymph production from the renal vascular bed, perhaps due to increased renal venous pressure rather than to urine reabsorbed from the renal pelvis %(0'. #hus, the quantitative significance of pyelolymphatic or pyelovenous bac"flow is uncertain, but probably small. Chan es in #ntrarena" &ressure, *"omeru"ar 'i"tration, an! %ena" $emo!ynamics #he factors determining the fall in B:> during obstructive uropathy have been clarified by micropuncture studies of glomerular dynamics in experimental animals. ;hanges in intratubular pressure, including stop6flow pressure, which represents glomerular filtration pressure, have provided an important insight on the pathophysiology of obstructive nephropathy after unilateral %UUO' and bilateral ureteral obstruction %$UO'. Blomerular filtration may be expressed by the formula

B:> H Kf %<B; 6 I<# J KBSL' where Kf is the glomerular ultrafiltration coefficient, <B; is the glomerular capillary pressure, <# is the intratubular pressure, and KB; is the mean oncotic pressure along the glomerular capillary. M< is the difference between <B; and <# and represents the pressure gradient across the glomerular capillary wall. /n increase in <# without a concomitant increase in <B; will result in a decrease in M<, the driving force for filtration. Blomerular filtration also depends on the rate of blood flow entering the glomerular capillaryN a decrease in glomerular blood flow during obstructive uropathy will decrease B:>, because the rate at which capillary oncotic pressure rises is accelerated when a given volume of filtrate is removed from a smaller volume of blood. $oth glomerular blood flow and hydrostatic pressure depend on renal vascular resistance, which is largely divided between two resistance segments9the preglomerular segment %afferent arteriole' and the postglomerular segment %efferent glomerular arteriole'. <eritubular capillaries may also provide a postglomerular vascular resistance in urinary tract obstruction. +urin Obstruction /fter either unilateral or bilateral ureteral obstruction, renal blood flow increases significantly %&0to )0-' in the first & to ) hours. #his decrease in renal vascular resistance immediately after complete ureteral obstruction is probably secondary to the synthesis and release of vasodilator <Bs. Dith persisting unilateral or bilateral ureteral obstruction, renal blood flow progressively decreases to 1+- to 0+- of normal by )1 hours %(),(*' %:ig. )06&'. B:> is more mar"edly reduced than renal blood flow8that is, filtration fraction is low, and B:> is )+- to (+- of normal in both UUO and $UO obstruction after )1 hours %).,(('. !owever, the site of changes in intrarenal vascular resistance and, therefore, the mechanisms responsible for the decrease in B:> differ in these two models of obstructive nephropathy.

FI(U)E *+,-. The triphasic relationships bet/een ipsilateral renal blood flo/ and left ureteral .

pressure during -0 hours of left ureteral occlusion. The three phases are designated by roman numerals and di"ided by "ertical dashed lines. In phase I1 the left renal blood flo/ and ureteral pressure rise together. In phase II1 the left renal blood flo/ begins to decline /hile the ureteral pressure remains ele"ated and1 in fact1 continues to rise. Phase III sho/s the left renal blood flo/ and ureteral pressure declining together. 2From3 oody TE1 4aughan E$1 (illen/ater 56. )elationship bet/een renal blood flo/ and ureteral pressure during -0 hours of total unilateral ureteral occlusion. In"est Urol -78+9-:3*;< /ith permission.= /fter acute UUO, there is an immediate increase in intrapelvic and proximal tubular hydrostatic pressure, the severity of which depends on the diuretic state of the animal %(4'. Gespite this increase in intratubular pressure, the B:> in surface nephrons is about ,+- of normal, because of an increase in glomerular capillary hydrostatic pressure and glomerular plasma flow, secondary to afferent arteriolar dilation and decreased renal vascular resistance %(1'. /s unilateral obstruction persists, progressive vasoconstriction and a decrease in nephron filtration rate develop within about 1 hours and, by )1 hours, surface nephron B:> is (+- of normal because of a decrease in glomerular capillary pressure and plasma flow associated with an increase in renal vascular resistance, presumably at the level of the afferent arteriole %).'. <roximal intratubular pressure is now normal rather than increased, as during the first few hours of obstruction %),,).,(+,(&,()'. Guring acute $UO, proximal tubular hydrostatic pressure increases to a higher level than after unilateral obstruction and, in sharp contrast to unilateral obstruction, intrarenal pressure remains twice normal after )1 hours. >enal blood flow increases for the first few hours after obstruction and then decreases to 1+- to 0+- of normal, similar to unilateral obstruction %(*,(,,(.'. Surface nephron B:> after )1 hours is reduced to about (+- of normal in $UO, as it is in UUO, but the decrease in B:> in $UO is because of a persistent increase in proximal tubular hydrostatic pressure while glomerular capillary pressure and plasma flow are normal %(('. ;omparison of UUO and $UO is shown in #able )06(. #he predominant site of increased vascular resistance thus appears to be postglomerular during bilateral obstruction compared to preglomerular with unilateral obstruction. TABLE 25-, Comparison of chan es in hemo!ynamics an! fi"tration !ynamics in comp"ete uni"atera" an! bi"atera" uretera" obstructiona Uni"atera" uretera" obstruction +urin 1-2 hr 1.-2/ hr After O P P O 5 5 P PP PP O P P O P P Bi"atera" uretera" obstruction +urin 1-2 hr 1.-2/ hr After O P P OO O 5 P PP PP O 5 P O 5 P

>$: <# B:> B<: <B;

a)&F,

renal blood flowN PT, proximal tubular pressureN (F), glomerular filtration rateN (PF, glomerular plasma flowN P(C, glomerular capillary pressureN O, P, #, increase, decrease, normal. #he increase in renal vascular resistance that develops after several hours of UUO also occurs at the level of the single nephron when it is bloc"ed with viscous oil for &) to )1 hours %),,1+,1&,1)'. <rolonged tubular obstruction results in decreased glomerular capillary hydrostatic pressure through slowly developing vasoconstrictor mechanisms at the level of the single nephron. #his single6 nephron vasoconstrictor response does not occur if both ureters have been ligated prior to individual &+

nephron obstruction %1+', again indicating the differing effects of bilateral, compared to unilateral obstruction, on the intrarenal sites determining renal vascular resistance. !eterogeneity of nephron function is also prominent in models of acute unilateral or bilateral obstruction after )1 hours, but does not appear to contribute significantly to the distinctive changes in total renal function %(+,(&,1(,11,10'. Similarly, changes in the intracortical distribution of blood flow, as measured by microspheres, do not explain the differences between bilateral and unilateral obstruction. 3nner medullary plasma flow, in contrast to the initial increase in total renal blood flow, decreases progressively during complete ureteral obstruction %1*'. /fter )1 hours, inner medullary plasma flow is more mar"edly decreased than total renal blood flow, being &+- to )+- of normal, and is more severely affected in bilateral than in unilateral ureteral obstruction. >eversible inner medullary vascular obstruction has also been demonstrated histologically %&&'. #hese changes in medullary blood flow may be important in the impaired sodium and water reabsorption in deep nephrons and collecting ducts of the postobstructive "idney. /cute ureteral obstruction has hemodynamic effects in addition to increasing renal blood flow for several hours and increasing pressures in the ureter and renal tubules %14'. ?asoconstrictor responses to several stimuli are blunted, decreasing responses to electrical stimulation of the renal nerves or brain or norepinephrine %1,'. 3n addition, autoregulation of renal blood flow is virtually abolished by high ureteral pressure of 40 mm !g and renal blood flow, while increased, becomes directly related to arterial blood pressure %1.,0+'. / third result of acute ureteral obstruction, which may also be associated with its vasodilator effect, is a mar"ed increase in renin release into the renal vein %&4,&,'. Guring chronic complete ureteral obstruction, renal blood flow progressively decreases. /fter )1 hours, renal blood flow is 1+- to 0+- of normal in both unilateral and bilateral obstruction. <rolonged UUO is associated with a further decrease in blood flow to (+- at * days, )+- at ) wee"s, and &)- at , wee"s %0&'. Guring chronic partial ureteral obstruction, B:> may remain unchanged or decrease, depending on the severity and duration of the obstruction and the extracellular fluid %E;:' volume status. =aintenance of normal nephron filtration rates appears to depend on an increase in glomerular capillary hydrostatic pressure, which results from a more mar"ed increase in efferent compared to afferent arteriolar vascular resistance and which may also be associated with a decrease in glomerular capillary ultrafiltration coefficient %0),0(,01'. Gecreased nephron filtration rates in chronic partial obstruction have been associated with a mild persistent increase in proximal pressure %00'. 5ephron loss, which may be more mar"ed in deep, compared to superficial nephrons %11,00,0*', also contributes to decreased B:> with chronic partial obstruction. After %e"ief of Obstruction :ollowing relief of unilateral obstruction of )1 hoursQ duration, intratubular pressure is normal, but B:> remains reduced and renal vascular resistance increased, with a gradual return to normal after approximately & wee" %).,(+,(&,04'. :ollowing relief of )1 hours of bilateral obstruction, intratubular pressure decreases from elevated levels to normal, but glomerular capillary pressure and plasma flow also decrease because of afferent arteriolar vasoconstriction, resulting in a persistent decrease in B:> %((,(.,10,04,0,'. #hus, the glomerular filtration dynamics and renal blood flow following relief of )1 hours of UUO or $UO appear to be similar and dominated by afferent arteriolar vasoconstriction. #he observation that mar"ed postobstructive diuresis occurs after relief of $UO, but not of UUO, indicates that factors other than changes in filtration and blood flow dynamics must be important in determining this state %see below'. #he recovery of glomerular filtration after relief of obstruction is a problem of ma7or clinical importance. #he potential for recovery of B:> will seriously affect decisions regarding treatment of obstructive uropathy. &&

#he factors that determine the extent to which the decrease in B:> is reversible have been studied in dogs by measuring the rate and degree of return of renal function after varying periods of complete UUO %0.,*+'. #he maximum B:> attained after the release of obstruction of 4 daysQ duration was about two6thirds of the B:> before obstruction. 3f the duration of ureteral obstruction was ), days, the B:> returned to only one6fifth of the original rate. 3n general, the maximal degree of recovery was observed within ) to 1 wee"s after release of the obstruction. #hese studies indicate that the longer the duration of obstruction, the less the degree of recovery that can be expected. >ecovery of nephron function after obstruction is not uniform throughout the "idney. #here is a greater decrease in filtering 7uxtamedullary nephrons as compared to superficial cortical nephrons immediately after release of )1 hours of UUO in the rat %(+'. Dhole "idney B:> recovered by ) wee"s to normal values %after release of )1 hours of obstruction', but only ,0- of nephrons in the postobstructive "idney were filtering compared to &++- in the contralateral "idney %*&'. Single6 nephron B:> of functioning superficial and 7uxtamedullary nephrons was higher in the postobstructive than in the contralateral normal "idney. #he normal whole "idney B:> in the postobstructive "idney was, therefore, at the expense of hyperfiltration in the remaining nephrons and there was a permanent decrement in functioning nephrons. #he mechanism responsible for this permanent loss of nephrons remains to be defined, as does its long6term significance for the development of chronic renal failure after obstructive uropathy. #he conclusion that recovery of function is related to the duration of obstruction also appears to apply to humans, but the number of supporting clinical studies is limited. 3n children with severe congenital lesions, the earlier the obstruction is relieved by reconstructive surgery, the greater is the B:> after long6term follow6up %*),*('. =ost reports of functional recovery following relief of urinary tract obstruction in humans have been based on radiographic or isotopic methods of assessing renal function rather than on renal clearance techniques. $y radiographic techniques, recovery of function is often observed after obstruction of less than ( wee"sQ duration, and some recovery of function was demonstrated in one case when the duration of obstruction was almost 0 months. #he obstruction in the latter case, however, may have been only partial %*1'. One patient was carefully studied after the relief of complete unilateral obstruction of ( monthsQ duration %*0'. 3n that case, the B:> in the postobstructed "idney returned to )+- of normal for one "idney %&+.) mC2min'. 3t is li"ely that the potential for recovery of function is better in partial than in complete obstruction and when the obstruction is not complicated by urinary tract infection %*(,**'. 0echanisms of Chan es in *"omeru"ar 'i"tration %ate an! %ena" $emo!ynamics #he factors responsible for the changes in renal hemodynamics and B:> in obstructive nephropathy are of interest, because of their potential clinical significance. 5ishi"awa et al. %*4' demonstrated increased <B synthesis in the hydronephrotic isolated perfused "idney. ?asodilator and vasoconstrictor <Bs have been studied in relation to the functional changes of urinary tract obstruction. #he relevance of such studies to human obstructive uropathy is suggested by reports of increased thromboxane %#R' synthesis by human hydronephrotic "idneys %*,' and increased prostaglandin E) %<BE)' excretion during postobstructive diuresis in humans %*.'. 1aso!i"ator &rosta "an!ins #he early hemodynamic consequences of acute ureteral obstruction are blunted or prevented by inhibition of <B synthesis. #he increase in ureteral pressure following UUO is reduced by prior administration of indomethacin %4+' and the increases in proximal intratubular pressure and glomerular capillary pressure are similarly reduced %4+,4&,4),4('. #he increase in renal blood flow that begins immediately after UUO is prevented by indomethacin or meclofenamate and a similar effect is seen on the vasodilation that follows $UO %0+,4&,4),41,40,4*'. #he impairment of &)

autoregulation that is seen in the "idney with ureteral obstruction is prevented by indomethacin and normal autoregulation of renal blood flow with changes in arterial pressure is restored in the obstructed "idney %41'. 3n addition, the renin release that accompanies ureteral obstruction is nearly abolished by inhibitors of <B synthesis %41,40'. #he stimulus for the release of vasodilatory <BE) or <B3) after acute ureteral obstruction is unclear, but appears to depend on elevated pressure in the renal tubule or lumen of $owmanFs space %14'. ?asodilator <Bs may also be important in maintaining B:> during chronic partial obstruction, as suggested by studies in an animal model %01'. /fter <B inhibition, nephron B:> and plasma flow fell from previously normal levels, suggesting that intrarenal <Bs were acting as a vasodilator and antagoniEing a local vasoconstrictor substance. #hromboxanes, the group of vasoconstrictor <Bs, were not thought to be involved because their release would also be inhibited by indomethacin and meclofenamate. /ngiotensin 33 %/ng 33' is "nown to increase efferent arteriolar constriction and reduce the ultrafiltration coefficient %Kf', changes that were observed with chronic partial ureteral obstruction. 3t was suggested that the vasoconstrictor /ng 33 may be interacting with vasodilator <Bs to determine glomerular filtration dynamics in this experimental model %01'. 1asoconstrictor &rosta "an!ins #wo vasoconstrictors, #R/) and /ng 33, play a ma7or role in the decrease in renal plasma flow per nephron and the decline in single6nephron B:> seen following ureteral obstruction %44'. $oth #R/) %4,' and /ng 33 %4.' are able to contract mesangial cells in culture and, therefore, can potentially reduce the glomerular capillary area available for filtration. :igure )06) summariEes the effects of these two hormones on renal function. #he central role of these two vasoconstrictors in modulating postobstructive renal hemodynamics is illustrated by the fact that if rats are pretreated with /;E inhibitors and thromboxane synthase inhibitors, the decline in renal function seen after ureteral obstruction is virtually prevented %,+'. /fter the onset of ureteral obstruction, the hydronephrotic "idney exhibits an enhanced ability to generate #R/) %,&,,)'. #his prostanoid is a potent vasoconstrictor in the hydronephrotic "idney %,('. 3nhibitors of #R synthesis partially reverse the decline in renal function seen after obstruction %,1,,0,,*', with prior administration giving more benefit %,+'. #he generation of #R after ureteral obstruction is conditioned by the diet of the animals prior to the onset of ureteral obstruction %,4,,,,,.'. /nimals fed a low6protein diet do not generate as much #R and exhibit less vasoconstriction in response to ureteral obstruction than animals fed a high6protein diet %,1'. :urthermore, thromboxane synthase inhibitors were not effective in reversing the postobstructive vasoconstriction in animals fed a low6protein diet. /lthough several studies support the suggestion that #R generation is important in the alteration in renal hemodynamics following ureteral obstruction, this has not universally been found %.+,.&'N the reason for this discrepancy is unclear.

&(

;hronic renal obstruction in rabbits is associated with a proliferation of interstitial fibroblasts and infiltration of mononuclear cells %.),.('. #his mononuclear cell infiltrate has been lin"ed to the increase in #R and <BE) production and release by the chronically hydronephrotic rabbit "idney %4(,.1,.0'. 3t is now apparent that there is an acute %within 1 hours' infiltration of leu"ocytes, predominantly macrophages, into the "idney following the onset of ureteral obstruction %,)' %:ig. )06(', which correlates with the increase in #R generation and the decline in B:>. :urthermore, when the macrophage infiltration is eliminated by prior irradiation of the animals, the enhanced #R generation is blunted and postobstructive renal function is improved %.*', suggesting that the infiltrate is, indeed functionally significant. Gespite irradiation of the animals prior to the onset of ureteral obstruction, #R generation remains significantly elevated over baseline values. #hus, in addition to the infiltrate of metabolically active cells acting as a source of #R in the hydronephrotic "idney, there is also an intrinsic renal source of enhanced #R production. 3ndeed, glomeruli isolated from rats following a short period of ureteral obstruction exhibit an enhanced production of prostanoids, including #R %.4,.,'. =esangial cells are most li"ely responsible for the increased production of eicosanoids in isolated glomeruli from rats with obstruction. #he mechanism underlying this increased synthesis may relate to exposure of these cells to increased /ng 33 secretion in vivo, as treatment of the animals with the /;E63 inhibitor enalapril, prior to ureteral obstruction, effectively prevented the enhanced glomerular prostanoid production %.,'. Enhanced activity of enEymes of both the cyclooxygenase and lipoxygenase pathways has been demonstrated in "idneys of rats with ureteral obstruction %..'.

FI(U)E *+,*. (lomerular filtration rate 2(F)= is reduced in obstructi"e nephropathy because of a decrease in both single nephron (F) 2S#(F)= and in the total number of filtering nephrons. The potential mechanisms responsible for the decrease in S#(F) in obstruction are sho/n. Initially 2: to < hours after the onset of obstruction= S#(F) falls because of reduced net filtration pressure as a conse>uence of a mar%ed ele"ation in hydrostatic pressure 2PT= in &o/man?s space /ithout a comparable increase in intraglomerular pressure 2P(C= !fter *; hours of obstruction1 the decrease in S#(F) is due mainly to a fall

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in intraglomerular hydrostatic pressure 2P(C= This decrease in P(C may be related to decreased plasma flo/ per nephron 2@!= as a conse>uence of increased intrarenal le"els of TA!* and !ng II. Inhibition of Tx synthesis in rats /ith ureteral obstruction increases @!1 decreases afferent 2)!= and efferent 2)E= arteriolar resistances1 and increases the ultrafiltration coefficient 2Bf=1 suggesting that this "asoconstrictor decreases @! and Bf and increases )! and )E1 !ngiotensin administration in normal rats has been sho/n to decrease @! and Bf and increase net filtration pressure 2CP=1 presumably due to preferential constriction of

the efferent arteriole. &oth TA!* and !ng II may decrease Bf by contraction of mesangial cells and1 hence1 decrease the total glomerular surface area a"ailable for filtration. 2From3 Blahr S1 Darris B1 Pur%erson L. Effects of obstruction on renal function. Pediatr #ephrol -7009*3:;*1 /ith permission.= %enin-An iotensin 2ystem Ureteral obstruction increases renin secretion into the renal vein %&4,&,'. #he maximum renin release during ureteral occlusion coincides with complete arteriolar dilation %&++', suggesting that arteriolar dilation is the predominant stimulus to renin secretion. $ecause the increased renin is almost completely abolished by pretreatment with the cyclooxygenase inhibitors indomethacin and meclofenamate %41,&+&', it is li"ely that the formation of vasodilatory prostaglandins such as prostacyclin or <BE) is a necessary step for the release of renin from 7uxtaglomerular cells %&+)'. 3n addition, the generation of renal cortical prostaglandins may act as a direct stimulus to the release of renin, as prostaglandins are able to release renin from renal cortical slices %&+('. #here is evidence that /ng 33 plays a central role in the modulation of hemodynamic changes following ureteral obstruction. #he angiotensin 33 antagonist saralasin ameliorates the vasoconstriction that is seen in response to ureteral obstruction in rats %&+1', although other authors found it ineffective in dogs %&+0'. Similarly, the /;E inhibitors captopril %,1,,*' and enalapril %,+' appear to be highly effective in ameliorating the decline in B:> and renal plasma flow in response to ureteral obstruction, and this effect is particularly mar"ed if the inhibitor is administered prior to the onset of obstruction %,+'. $ecause /;E inhibitors also activate "inins, their effect could be secondary to enhancing the levels of vasodilator "inins, rather than inhibiting the production of the vasoconstrictor angiotensin. !owever, neither aprotinin, a "alli"rein inhibitor that bloc"s "inin production, nor carboxypeptidase, an enEyme that increases "inin destruction, bloc" the beneficial effect of captopril on postobstructive renal function %,*'. #hus the beneficial effect of /;E inhibitors appears to be because of inhibition of /ng 33 generation. /ntidiuretic hormone %/G!' contributes to renal vasoconstriction and the decrease in B:> observed in rats with $UO %&+*'. >ats with $UO of )1 hoursQ duration had significantly higher plasma values of /G! than did sham6operated rats. <retreatment with a specific antagonist of the ?&6type receptor for /G! significantly increased B:> and effective renal plasma flow and decreased mean arterial blood pressure in rats with $UO. Ceu"otrienes %CKs', potent mediators of inflammation, are synthesiEed by cells through the 06lipoxygenase pathway. De found increased synthesis of leu"otriene $1 %CK$1' in isolated glomeruli from rats with $UO. 3nhibition of the 06 lipoxygenase pathway in vivo ameliorated the decrease in B:> and effective renal plasma flow seen after unilateral release of $UO %&+4'.

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FI(U)E *+,:. The effect of bilateral ureteral obstruction on the number of cells expressing the leu%ocyte common antigen in %idneys at timed inter"als after obstruction. The results represent the mean E SE of single %idneys of three rats. )epresentati"e portions of cortex and medulla /ere dissected out1 /eighed1 and sub'ected to enFymatic digestion and labeled. The control %idneys /ere ta%en from littermates that did not undergo any procedure. SE1 standard error. 2From3 Schreiner (1 Darris BP(1 Pur%erson L1 et al. The immunological aspects of acute ureteral obstruction3 immune cell infiltrate in the %idney. Bidney Int -7009:;3;08 /ith permission.= Atria" )atriuretic &epti!e / contributing factor to the differences in hemodynamics after UUO and $UO may be the differing plasma levels of atrial natriuretic peptide %/5<'. /5< levels are higher in animals with $UO than in those with UUO %&+,'. /trial peptide causes preglomerular vasodilation and postglomerular vasoconstriction %&+.' and increases Kf in the isolated perfused glomerulus preparation %&&+'. 3n addition, the administration of exogenous /5< is able to increase B:> following both UUO and $UO %,+,&+,'. / scheme for the interactions of the various vasoactive hormones following ureteral obstruction is shown in :igure )061. 5itric oxide %endothelium6derived relaxing factor', a vasodilator, appears to have a role in the hemodynamic changes that occur after ureteral ligation. 3n the model of $UO with unilateral release of obstruction after )1 hours, infusion of C6arginine, the substrate for nitric oxide synthase %5OS', increased B:> and effective renal plasma flow in postobstructed "idneys compared to control "idneys %&&&'. 3nfusion of the 5O synthase inhibitor 5*6nitro6C6arginine methyl ester %C65/=E' mar"edly impaired renal function after unilateral release of $UO of )1 hoursQ duration %&&&'. 3n another study %&&)', C65/=E produced greater vasoconstriction in "idneys with ipsilateral UUO than in those of sham6operated rats.

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Other 'actors >enal nerve activity is increased by elevated ureteral pressure %&&(', and the compensatory vasoconstriction that develops acutely in the contralateral normal "idney is prevented by ipsilateral or contralateral renal denervation %&&(,&&1'. Endogenous opioids may also be involved in mediating excretory responses in the contralateral "idney %&&0'. /cute renal denervation improves blood flow and B:> after release of UUO, but prior renal denervation was ineffective %&&*'. 3n contrast to the effect of renal denervation on unilateral obstruction, denervation had no effect on the "idney with postobstructive diuresis after release of bilateral obstruction, and such "idneys had decreased norepinephrine content compared to unilaterally obstructed "idneys, suggesting partial denervation %&&4,&&,'. <artial renal denervation could, therefore, be a contributing factor to postobstructive diuresis. #he possible role of the tubuloglomerular feedbac" %#B:' mechanism in determining changes in glomerular filtration dynamics in experimental obstructive nephropathy has also received attention %&&.,&)+'. /fter ) hours of UUO, the sensitivity of the #B: mechanism to increased flow through the loop of !enle is decreased when intrarenal pressure and renal blood flow are increased %&&.'. /fter )1 hours of UUO, however, #B: sensitivity is enhanced and could contribute to the afferent arteriolar vasoconstriction noted at this time, which persists after relief of obstruction %&)+'. Dith $UO, in contrast, #B: sensitivity is blunted at )1 hours before and after relief of obstruction. Gecreased #B: sensitivity after relief of $UO could contribute to the phenomenon of postobstructive diuresis %&)+'. 2o!ium E3cretion an! &ostobstructive +iuresis +urin an! After %e"ief of &artia" Obstruction Guring acute partial UUO, there is a significant decrease in sodium, potassium, and solute excretion, with a decrease in urine sodium concentration and an increase in urine osmolality %&*,&+1,&)&'. #he clinical importance of acute partial obstruction causing decreased urine sodium concentration and increased osmolality, thus mimic"ing prerenal oliguria owing to volume depletion, has been emphasiEed %&)&'. Gecreased sodium excretion was initially attributed to decreased B:> %&)),&)(', but studies underta"en during saline diuresis indicate that with mild or moderate increases in ureteral pressure there is a significant increase in tubular reabsorption of sodium and water %&)&'. #he factors responsible for this increased reabsorption are not clear. 3ncreased reabsorption is the reverse of that expected with an increase in blood flow to the 7uxtamedullary cortex that is "nown to occur during partial UUO %&)1' and increased renal nerve activity does not appear to be involved %&)0'. Gecreased flow rate in the distal nephron has been suggested %&*'. 3n one study during elevation of ureteral pressure to (+ mm !g, fractional reabsorption of fluid in the proximal tubule was not significantly increased %&)*'. Dith an increase in proximal tubular pressure to (+ mm !g during mannitol diuresis, however, a rapid and reversible increase in proximal and distal renal tubular permeability to creatinine, mannitol, sucrose, and iothalamate, but not inulin, was seen %&)4'. Guring chronic partial obstruction, the gradual decrease in B:> is accompanied by an increase in the fractional excretion of filtered sodium, indicating decreased tubular reabsorption. =icropuncture of surface nephrons in chronic partial UUO or of a solitary "idney with partial obstruction in the rat indicates that increased fractional excretion of sodium is not dependent on increased filtration or decreased proximal tubular reabsorption in surface nephrons, but results from decreased reabsorption in the distal tubule, in 7uxtamedullary nephrons, or in the collecting duct %00,&),'.

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FI(U)E *+,;. In obstructi"e nephropathy1 the acti"ities of the enFymes phospholipase C and cyclooxygenase are increased. There is also increased production of "asodilatory prostaglandins 2P(E*1 P(I*Gprostacyclin=9 P(E* and P(I*1 in turn1 may increase the production of the "asoconstrictor !ng II by acti"ating renin. The production of another "asoconstrictor1 thromboxane !* 2TA!*=1 is also increased in the obstructed %idney. This increased production of TA!* is1 in part1 because of its synthesis by macrophages that in"ade the renal parenchyma. Binin excretion1 per unit of glomerular filtration rate 2(F)=1 is also increased in obstruction. Plasma le"els of atrial peptide 2a "asodilator= are increased in rats /ith bilateral ureteral obstruction 2&UO=1 but not in rats /ith unilateral ureteral obstruction. !trial peptide1 in turn1 may antagoniFe the effects of !ng II. !ng II may acti"ate phospholipase C and increase the release of P(E*. Binins are also %no/n to acti"ate phospholipase C. It is suggested that these four interrelated systems encompassing both "asoconstrictor 2reninGangiotensin1 TA!*= and "asodilatory substances 2P(E*1 P(I*1 %inins1 atrial peptide= condition the changes in renal plasma flo/ and (F) seen in obstructi"e nephropathy. 2From3 Blahr S1 Darris B1 Pur%erson L. Effects of obstruction on renal function. Pediatr #ephrol -7009*3:;*1 /ith permission.=

/fter relief of chronic partial UUO in humans, there is no increase in absolute sodium and water excretion from the hydronephrotic "idney, although decreased concentrating ability and increased fractional excretion of sodium are observed %**', presumably because of altered function in the deep nephrons and collecting ducts. #he results indicate that other factors such as volume expansion or further reduction in functioning nephron mass with uremia are necessary to bring about an increase in salt and water excretion %postobstructive diuresis' following relief of obstruction. Dith hypotonic saline loading, there was a disproportionate diuresis from the hydronephrotic "idney %0*', which was associated with reduced reabsorption in the distal nephron, indicating that volume expansion may be a significant factor in postobstructive diuresis. / mild diuresis developed after relief of chronic partial ureteral obstruction of a solitary &,

hydronephrotic "idney in the rat %&),'. <artial obstruction of a solitary "idney in humans and animals is comparable to $UO in its association with aEotemia and postobstructive diuresis. 3n contrast to the mar"ed postobstructive diuresis seen after relief of acute complete $UO, the modest increase in urine flow and sodium excretion that occurred after relief of chronic partial obstruction was due entirely to an increase in B:> after release of obstruction and there was no increase in fractional sodium excretion. Surface6nephron B:> increased by only )+-, and tubular reabsorption did not change significantly after relief of obstruction, whereas whole "idney B:> doubled, suggesting an improvement in function of deep nephrons. /nimals with a high urea concentration in plasma had a greater diuresis and decreased water reabsorption in the distal tubule. #hus, changes in B:> and blood urea concentration may influence the degree of postobstructive diuresis after relief of chronic partial $UO. After %e"ief of Comp"ete Obstruction / mar"ed and sometimes prolonged diuresis may occur after the relief of obstruction of both "idneys or of a solitary "idney. #his diuresis is characteriEed by massive losses of water, sodium, and other solutes. 3n one case report, after relief of acute obstruction, the rate of urine flow approached one6half the B:> %&).'. 3f not replaced, such losses could lead to severe hypovolemia and life6threatening electrolyte imbalance. !owever, a bris" diuresis following relief of urinary tract obstruction may also be physiologically appropriate or even iatrogenic rather than an indicator of tubular malfunction. =any factors influence the urinary flow rate following relief of obstruction, and the appropriateness of fluid replacement in a given case will depend on the mechanisms involved. #able )061 lists some of the mechanisms contributing to postobstructive polyuria. Saline diuresis owing to expansion of E;: volume. Dhen obstruction of the urinary tract is bilateral and prolonged, renal insufficiency occurs, so that continued inta"e of fluid and electrolytes results in expansion of the E;: volume. E;: volume expansion activates natriuretic forces, such as /5<, which will become manifest when obstruction is relieved and B:> increases. Dith hypotonic expansion of E;: volume, the secretion of vasopressin may be suppressed, and a water diuresis may be superimposed on the natriuresis after release of the obstruction. Excretion of retained water and electrolytes allows normal restoration of the E;: volume and its composition. #his effect accounts, at least in part, for the diuresis in most patients who have polyuria after relief of $UO %&(+,&(&'. TABLE 25-/ 0echanisms responsib"e for postobstructive !iuresis <hysiologic mechanisms Excretion of excess salt and water retained during the period of obstruction Excretion of excess salt and water administered intravenously after relief of obstruction Osmotic diuresis because of retained urea or administered glucose <athologic mechanisms 3nappropriate losses of sodium and water because of intrinsic defect in tubular reabsorption of sodium or circulating natriuretic factors, such as atrial natriuretic peptide %/5<' 3nappropriate losses of water because of an impaired renalconcentrating capacity >ate and degree of recovery of glomerular filtration

Osmotic diuresis owing to retained urea. Guring urinary tract obstruction there is progressive aEotemia, with accumulation of urea and other poorly reabsorbable solutes. /fter relief of obstruction, the high concentration of urea and other solutes in the glomerular filtrate will create an osmotic diuresis similar to that produced by intravenous infusion of urea or mannitol %&(),&(('. !owever, some patients with high osmotic loads do not display a significant natriuresis or diuresis after relief of obstruction and, in those who do have a

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natriuresis, there may be no urea retention %&(1'. #his finding implicates factors other than, or in addition to, an osmotic load to account for the phenomenon of postobstructive diuresis. Osmotic diuresis owing to excessive infusion of intravenous solutions. #he bris" diuresis observed after relief of urinary tract obstruction is often so stri"ing that the replacement of urinary losses with intravenous fluids is begun before E;: volume has been restored to normal. Dhen this is done, however, the patient will continue to have iatrogenic polyuria and natriuresis until the rate of fluid administration is reduced and E;: volume is allowed to decrease to normal. #hus many cases of postobstructive polyuria attributed to abnormal tubular function are actually caused by infusion of intravenous solutions. >ecovery of glomerular filtration. #he rate and degree of recovery of glomerular filtration after relief of obstruction is important in determining the occurrence of a mar"ed postobstructive diuresis %&(0'. 3n spite of the presence of many factors favoring rapid diuresis, including urea retention and impaired tubular function, the ma7ority of patients with chronic obstructive uropathy do not demonstrate a clinically important natriuresis after correction of the obstructing lesion because the B:> is low. 3n the reported cases of stri"ing postobstructive diuresis, B:> was relatively high, (+- to 4+- of normal, thus delivering a large load of solute and water to tubules with impaired reabsorptive capacity. Giuresis owing to defect in tubular reabsorption of sodium. / massive and prolonged postobstructive diuresis associated with a defect in tubular sodium reabsorption and thus with @inappropriateA sodium losses in the urine has been described in %&).,&(),&(1,&(*,&(4'. Osmolar clearances of up to *) mC2min and fractional sodium excretion in the range of )+- to (+- have been observed. 3n the cases described, the obstruction was relatively acute and bilateral %or involved a solitary "idney', and, prior to relief of the obstruction, the patients were in severe renal failure. /nimal experiments indicate that a dramatic increase in sodium and water excretion %about fivefold' occurs after relief of bilateral obstruction for & day, despite the low B:>. ?olume expansion is not the ma7or factor involved, since food and water are withheld during the )1 hours of obstruction and animals lose weight. =icropuncture studies demonstrated decreased proximal %04' and distal %(.,1(,04' tubular sodium reabsorption, but the most dramatic abnormalities occur in the medullary collecting duct. $ilateral obstruction caused a mar"ed decline in sodium reabsorption in this segment of the nephron, and there was a net addition of sodium to the tubular fluid as it passes down the collecting duct %&(,'. 3mpairment of reabsorption in deep nephrons may also be important in postobstructive diuresis and papillary %terminal' collecting duct reabsorption was normal in this study %&(.'. /fter relief of unilateral obstruction in experimental animals, fractional reabsorption of sodium is decreased, but net sodium excretion is usually similar or less than that of the unobstructed "idney, because B:> is low %(+,(&'. 3n contrast, after relief of bilateral obstruction, proximal tubular reabsorption of sodium is normal or increased in the surface nephrons of the unilateral postobstructive "idney, and thus delivery of sodium to the collecting ducts is reduced %(+,&1+'. #herefore, in spite of impaired deep nephron %&1&' and collecting duct reabsorption %&(,', the excretion of sodium remains normal. #hese results are in agreement with the clinical findings that significant postobstructive natriuresis occurs only after relief of bilateral obstruction or obstruction of a solitary "idney %&(1,&1)'. / period of functional anuria from bilateral obstruction or obstruction of a solitary "idney may impair tubular sodium reabsorption directly %an intrinsic defect' or may be associated with the accumulation of natriuretic factors in the plasma. Experimental data indicate that both occur but that circulating natriuretic factors are critical for the occurrence of postobstructive diuresis. 3mpaired function of deep 7uxtamedullary nephrons and medullary collecting ducts has been described after relief of both unilateral and bilateral obstruction %&(,,&(.,&1+,&1('. ;ross6circulation studies, however, demonstrated the presence of plasma

)+

natriuretic factors only in rats with bilateral obstruction %&11' %:ig. )060'. #otal intravenous reinfusion of urine also resulted in mar"ed natriuresis and diuresis %0,,&11,&10' without impairment of medullary collecting duct function %&(,'. Urea acting as an osmotic agent in plasma is undoubtedly important, but did not account for the degree of natriuresis and diuresis observed %0,,&11'. /5< was recently shown to increase mar"edly in $UO compared to UUO and is probably an important critical circulating natriuretic factor in postobstructive diuresis %&+,'. ;linical studies have confirmed elevated /5< levels in patients with bilateral obstruction and aEotemia %&1*'. Giuresis owing to impaired water reabsorption. #he development of vasopressin6insensitive nephrogenic diabetes insipidus during partial urinary tract obstruction is discussed subsequently in this chapter. #his type of abnormality can also continue or become manifest after relief of obstruction. 3mpaired water reabsorption in the collecting duct has been observed following relief of bilateral urinary tract obstruction %&(,'. =icropuncture experiments in rats and chronic unilateral hydronephrosis indicate that volume expansion may magnify this defect in distal tubular salt and water reabsorption %0*'.

FI(U)E *+,+. Changes in sodium excretion in normal rats undergoing cross,circulation /ith donor rats ha"ing bilateral 2H= or unilateral 2o= ureteral ligation of *;,hour duration. Standard error of mean "alue is sho/n and significance of the difference from the mean control "alue. I1 P JK.K- or less9 P JK.K+. 2From3 5 Clin In"est -78<9+83:0K1 reprinted /ith permission from the L !merican Society of Clinical In"estigation.=

#mpaire! Urinary-Concentratin Abi"ity 3mpaired ability to concentrate the urine is a characteristic feature of obstructive nephropathy whether urinary tract obstruction has been acute or chronic, unilateral or bilateral, or complete or partial. #he only exception is seen during acute partial obstruction when urine osmolality is increased and sodium concentration decreased because of increased tubular reabsorption %&*,&)&'. 3n patients with chronic partial obstructive uropathy or with recently relieved partial or complete )&

obstruction, a decrease in renal6concentrating ability can usually be demonstrated %**,&14,&1,'. <atients with mar"ed impairment may present with nephrogenic diabetes insipidus and demonstrate polyuria and persistently hypotonic urine %&1.,&0+,&0&,&0)'. 3f fluid inta"e is inadequate in these patients, severe dehydration and hypernatremia can develop %&0('. /fter relief of partial or complete urinary tract obstruction, impairment of concentrating ability, which persists initially, may gradually disappear over a period of months %&0+'. #he loop of !enle, distal tubule, and collecting duct, particularly in the 7uxtamedullary nephrons, are the ma7or sites affected %&1(,&01'. Coss of the normal medullary solute concentration gradient and lac" of responsiveness to the administration of vasopressin %?<' are the two characteristic pathophysiologic features and, as expected, several mechanisms participate in producing these abnormalities, which lead to impaired urinary6 concentrating ability %:ig. )06*'.

))

FI(U)E *+,<. echanisms by /hich urinary tract obstruction may impair urinary concentrating capacity of the %idney. 2From3 Schrier )M. )enal and electrolyte disorders1 :rd ed. &oston3 Little1 &ro/n1 -70+1 /ith permission.= #nabi"ity to Estab"ish $ypertonicity in the 0e!u""ary #nterstitium / defect in the transtubular transport of sodium chloride in the ascending limb of the loop of !enle may contribute to the concentrating defect of urinary tract obstruction. Such a defect would lower the tonicity of the medullary interstitium and thus the osmotic driving force for water movement from the collecting duct into the interstitium. 3n support of this possibility is the finding that in dogs %&*,&00' and rabbits %&0*', the tissue concentration gradient of sodium and urea between the cortex and the papillary tip was abolished in the obstructed "idney. :urthermore, !anley and Gavidson %&1(' showed that chloride transport was mar"edly decreased in the thic" ascending limb of the loop of !enle, microdissected from obstructed "idneys and perfused in vitro. Gecreased 5a J8 KJ8 /#<ase activity in the outer medulla of obstructed "idneys contribute to this defect %&04,&0,' and enhanced <BE) production may play a role %&0.'. Coss of the medullary solute gradient has also been attributed to renal hemodynamic changes that @wash outA the medullary tonicity. !owever, inner medullary plasma flow is mar"edly decreased, not increased, during ureteral obstruction %&&,1*', and prior clamping of the renal artery did not prevent loss of the medullary solute concentration gradient %&0*'. =edullary plasma flow does, however, increase rapidly toward normal after relief of obstruction %1*,&1&' and could delay reestablishment of the medullary solute gradient. :lattening of the renal papillae and destruction of the long loops of !enle in chronic obstruction contribute to a decrease in the maximal tonicity of the medullary interstitium. #nsensitivity of the Tubu"e to 1asopressin /dministration of ?< to patients with water6losing states, secondary to partial urinary tract obstruction, may not decrease the urine flow rate nor increase the tonicity of the urine %&1.,&0)'. :urthermore, ?< did not increase urine cyclic adenosine monophosphate %c/=<' excretion or S ?<6sensitive adenyl cyclase in experimental animals %&*+,&*&'. / ?<6resistant isotonic urine can be attributed to factors that impair the generation of a hypertonic medullary interstitium. !owever, )(

since the medullary interstitium should never be less than isotonic, the presence of ?<6resistant hypotonic urine indicates a failure of complete osmotic equilibration between the collecting duct and the interstitium owing either to failure of ?< to increase water permeability of the collecting duct maximally or to rapid tubular flow through the collecting duct. ?<6dependent water reabsorption was reduced in the isolated perfused cortical collecting duct from obstructed "idneys and the ?< resistance was not overcome by c/=< %&1(,&01'. 3ncreased synthesis of <BE ) in the medulla of the obstructed "idney may play a role in the decreased collecting duct response to ?< %&0.,&*), &*('. %o"e of A4uaporins #he aquaporins are a family of membrane water channels. /quaporin6) %/T<)' is predominantly found in the apical domain of the collecting duct principal cells %&*1'. :ro"iaer and colleagues report %&*0,&**' that /T<) expression is decreased in the setting of bilateral or unilateral obstruction. #he reduction in aquaporin expression may explain the postobstructive polyuria and the impairment in urinary6concentrating capacity found in bilateral ureteral obstruction. >ecently Shi et al. %&*4' found that ma7or sodium transporters and aquaporins in the obstructed "idney are downregulated in response to neonatally induced partial UUO, which indicates that these transporters may play a crucial role for the persistent reduction in renal handling of sodium and water in response to partial UUO. #ncrease! Osmotic Loa!

)1

3ncreased solute excretion and thus increased solute delivery to the concentrating and diluting segment of the nephron, is associated with diminished urine concentration in spite of maximal doses of ?< %&(('. 3n chronic obstruction and in other forms of chronic renal disease, total solute excretion is normal, but, because of the fall in B:>, solute excretion per milliliter of glomerular filtrate or per nephron may be high. #hus the rate of solute delivery to the concentrating and diluting segment of each nephron may be high. Such an osmotic diuresis per nephron may provide a partial explanation for the impairment in renal6concentrating capacity associated with urinary tract obstruction. 3mpairment of urinary6concentrating ability is also observed, however, in acute and unilateral obstruction %&(&,&0+,&*,,&*.', situations in which aEotemia is not present, and the solute load per unit of B:> may not be excessive. +efects in Urinary Aci!ification an! &otassium E3cretion <atients with obstructive uropathy may be unable to acidify the urine. 3mpaired urinary acidification is seen in patients after relief of unilateral obstruction %*0,*,,&*.' and after relief of bilateral obstruction %&14,&1.' or obstruction of a solitary "idney %&1)'. Gistal renal tubular acidosis, with inability to lower the urine p! to a normal minimum value in response to acidemia, has been reported. <roximal, bicarbonate6wasting, renal tubular acidosis has also been reported during postobstructive diuresis %&1)'. $erlyne %&14' reports distal renal tubular acidosis in six of seven patients with chronic obstruction. 3n six patients studied by Billenwater et al. %**', & wee" after release of unilateral obstruction, !J excretion was significantly less in the previously obstructed "idney than in the contralateral "idney. /fter relief of obstruction, the acidification defect may disappear over a period of wee"s, or it may persist. 3n one study, the acidification defect correlated with recovery of function %&4+'N urine p! below *.+ in patients with chronic obstruction was associated with recovery of renal function after relief of obstruction, while with higher urine p!, recovery of function was only partial. /nimal studies found that the decreased !J excretion is because of either decreased bicarbonate reabsorption in the deep 7uxtamedullary nephrons or impaired !J secretion in the late distal tubule and collecting ducts %&4&,&4)'. Gefective acidification is associated with decreased excretion of both ammonium and titratable acid. Dalls and colleagues %&4)' found no significant change in fractional bicarbonate reabsorption in the proximal and distal tubules of surface nephrons of the rat, but a mar"ed decrease in urine <;O) during bicarbonate loading, suggesting impaired ability of the deep nephrons or collecting ducts to secrete hydrogen. #hira"omen et al. %&4&' found a low urine <;O) during bicarbonate loading in the dog. Sodium sulfate infusion failed to reduce urine p! to the same extent in the postobstructive "idney, thus suggesting impaired !J secretion. Studies of isolated perfused nephron segments suggest that !J secretion in the outer medullary and cortical collecting ducts is reduced by obstruction %&4(', a change associated with a decrease in !J6 /#<ase in the apical portion of intercalated cells %&4(,&41,&40'. $atlle and associates %&4*' describe hyper"alemic distal renal tubular acidosis in patients with chronic obstructive uropathy. !yper"alemia owing to decreased urinary KJ excretion was common in these patients. !yper"alemic hyperchloremic acidosis was the presenting feature of obstructive uropathy in several patients and resulted from three mechanisms

/ selective deficiency of aldosterone secretion, probably secondary to decreased renal renin production %hyporeninemic hypoaldosteronism'. Such patients lower urine p! appropriately in response to an ammonium chloride load, but have reduced ammonia excretion. / defect in !J secretion, with inability to maximally lower urine p! in the presence of systemic acidosis %distal renal tubular acidosis'.

)0

/ combination of the above two defects %type 1 distal renal tubular acidosis'. / defect in distal nephron %collecting duct' sodium reabsorption with decreased intraluminal negative potential difference could be the primary factor in both diminished !J secretion and KJ secretion %a so6called voltage6dependent defect'.

3n animal models, KJ excretion, both absolute and fractional, is mar"edly decreased from the UUO "idney after relief of )1 hours of obstruction. #his abnormality has been attributed to decreased sodium delivery to the distal nephron %&(0'. Gecreased potassium excretion persists, however, when distal sodium delivery is increased with volume expansion or sodium sulfate administration %&4&', suggesting that there may be an intrinsic defect in the distal K J6secreting mechanism that could be associated with the defect in sodium reabsorption. Guring postobstructive diuresis, KJ excretion is increased, both in absolute and in fractional terms. #his increased potassium excretion is due to enhanced secretion in the distal tubule and collecting duct %&(,', perhaps because of increased sodium delivery, increased tubular flow rate, and particularly increased plasma KJ levels. 3n vitro perfusion of the cortical collecting duct of the rabbit revealed that UUO led to decreases in the lumen6negative transepithelial voltage %&1(,&01' and in 5aJ8KJ pump in situ turnover %&44'. =uto and co6wor"ers %&4,' found that in the cortical collecting duct obtained from obstructed "idneys of rabbits with )1 hours of UUO, the conductances of 5aJ and KJ in the apical membrane were decreased. #he 5aJ8KJ8 /#<ase pump activity and the relative KJ conductance in the basolateral membrane of this nephron segment were also inhibited, whereas the relative chloride conductance in the basolateral membrane was stimulated. =uto and /sano %&4.' also showed that renal decapsulation in rabbits with UUO partially corrects the decreased conductances of 5aJ and KJ in the apical membrane and the basolateral 5aJ8 KJ pump activity. #hus, increased renal pressure may initiate the defects in 5aJ and KJ transport observed in the cortical collecting duct of the obstructed "idney. Others %&,+,&,&' also report transport defects in the thic" ascending limb and the inner medullary conducting ducts of obstructed "idneys in the rabbit. =agnesium and ;alcium Excretion !ypomagnesemia is seen in humans following relief of $UO %&,)'. =agnesium excretion increases inappropriately after release of both bilateral and unilateral obstruction %*0,&1),&,(' #he increase in =g)J excretion correlates with the increase in sodium excretion during postobstructive diuresisN a similar increase in calcium excretion is seen. =agnesium, but not ;a )J, excretion is high following release of UUO in both humans %*0' and animals %&,('. Gecreased reabsorptive capacity of the ascending limb of the loop of !enle during UUO or $UO has been suggested as the explanation for increased fractional excretion of =g)J. &hosphate E3cretion !ypophosphatemia because of high urinary excretion of inorganic prosphate %<i' may develop during postobstructive diuresis in humans %&1)' and animals %&,(,&,1,&,0,&,*'. #he stri"ing increase in absolute and fractional excretion of <i appears to parallel the increase in sodium and water excretion and may, in part, be because of extrarenal factors. <hosphaturia in experimental animals can be prevented by dietary restriction of <i, suggesting that changes in filtered phosphate load are important, while the fact that <i is largely reabsorbed in the proximal tubules suggests that this nephron segment must be a ma7or site of decreased reabsorption. /fter release of UUO, in contrast to bilateral obstruction, <i excretion is mar"edly decreased in humans and experimental animals %*0,&,(,&,0,&,*'. <i excretion and urinary c/=< excretion from the obstructed "idney are relatively insensitive to parathyroid hormone %<#!' %*0'. /nimal studies )*

indicate that decreased <i excretion is because of a decrease in nephron B:> and an increase in reabsorption of phosphate in the proximal tubule, similar to the changes that occur in sodium handling after release of UUO %&,0'. 5o intrinsic abnormality in phosphate transport or in the response to <#! has been found in the proximal tubule of the UUO "idney using brush6border vesicles from luminal membranes %&,*'. #hese results suggest that hemodynamic factors may enhance proximal tubular reabsorption of phosphate. %ecovery of Tubu"ar 'unction After Obstruction Dhile the effects of ureteral obstruction on tubular function in the immediate period that follows relief of obstruction have been extensively studied, the long6term effects of ureteral obstruction on tubular function are less well "nown. Studies after release of UUO of )1 hours in rats revealed that abnormalities of tubular function persist beyond a time %&1 days' when whole "idney B:> had returned to normal %*&'. Urine osmolality was lower in the postobstructed "idney up to *+ days following release of the obstruction. 5et acid secretion was decreased and ammonium excretion was less in the postobstructive "idney, the latter owing to a defect in ammonia reentrapment in the collecting duct. Urine p! remained higher in the postobstructive "idney up to &1 days after the release of the obstruction and KJ excretion remained lower. #hese observations on tubular function, following release of ureteral obstruction, are consistent with persistent alterations in distal tubule6 collecting duct function, a loss of functioning 7uxtaglomerular nephrons following the release of the obstruction, or both. #he temporal recovery of tubular function following the release of ureteral obstruction is illustrated in :igure )064. Effect of A e on Obstructive Uropathy Urinary tract obstruction is common in infants and children %*),*(,&,4'. 3t is almost always partial and congenital. Cong6term obstructive nephropathy is the most important cause of renal failure in infants and children %&,,'. Uosephson et al. %&,.' induced partial UUO in newborn rats and examined the effects at . wee"s in the adult animal. =ar"ed hydronephrosis occurred, the obstructed pelvis being enlarged sevenfold, but whole "idney blood flow and B:> were decreased by only &+-. #here was a compensatory increase in blood flow and B:> in the contralateral nonobstructed "idney. Kidney weights were similar to normal and, despite distortion, the degree of atrophy appeared to be small. #hus, the effects of partial ureteric obstruction on renal function were not proportionate to the degree of hydronephrosis and were fully compensated. #a"i et al. %&.+' examined the relationship between the age at which obstruction occurs and the resulting changes in renal function in guinea pigs. <artial ureteral obstruction at &, ), (, 1, or 0 wee"s of age resulted in a progressively decreasing amount of compensatory hypertrophy in the contralateral "idney. B:> was mar"edly reduced in the obstructed "idney at all ages, but younger animals were more severely affected. Urinary6concentrating ability, however, was similarly affected at all ages. %ena" 0etabo"ism in Obstructive )ephropathy ;hanges in enEyme activity and in energy and substrate metabolism in the obstructed "idney have been described %&.&'. /ltered responsiveness to hormones and altered hormone synthesis have also been described. #he significance of changes in enEyme activity, such as al"aline phosphatase and glucose *6phosphate dehydrogenase, which increase and decrease, respectively, with obstruction, has not been determined %.),&.),&.('. #he decrease in 5a8<6/#<ase observed & to 4 days following release of obstruction, particularly in the outer medullary portion of the "idney, could be important in the pathogenesis of increased fractional sodium and water excretion and impaired urinary6concentrating ability %&04,&0,'. )4

FI(U)E *+,8. !3 Effect of unilateral ureteral obstruction on the urine osmolality 2mean E SE= for the contralateral %idney 2N= and the postobstructed %idney 2= is depicted : hours 2K.-* day= and 01 -;1 and <K days postrelease. &3 )elation bet/een urine pD and the number of days after ureteral release. 2H= )epresents mean "alues obtained for the contralateral %idney9 2o= "alues obtained from the postobstructed %idney. C3 Long,term effects of unilateral ureteral obstruction on acid excretion. 2o= )epresents mean "alues for the postobstructed %idney9 2H= "alues for the contralateral %idney. Upper panel depicts absolute ammonium excretion 2U#D;O 4=. iddle panel depicts absolute titratable acid excretion 2UT!4=. Lo/er panel depicts the absolute excretion of net acid 2U#a4=. 4alues in !1 &1 and C are significantly different from those for the contralateral control %idney at IP JK.K+9 PP JK.K-9 QQP JK.KK+9 and RP JK.KK-. 2From3 &ander S51 &uer%ert 5E. Long,term effects of *; hour unilateral obstruction on renal function in the rat. Bidney Int -70+9*03<-;1 /ith permission.=

#he B:> decrease in the obstructed "idney is associated with decreased delivery and reabsorption of sodium and lower energy requirements. Oxygen consumption and substrate upta"e decrease in proportion to the fall in B:> and, with a decrease in oxygen consumption, there is a corresponding increase in anaerobic glycolysis %&.1'. /denine nucleotide %/#<' levels fall in the obstructed "idney after )1 hours of ureteral obstruction, probably because of mitochondrial damage and decreased oxidative metabolism %.(,&.0'. >enal gluconeogenesis is mar"edly reduced in the obstructed "idney within )1 hours, perhaps because of inhibition of phosphoenolpyruvate carboxy"inase %<E<;K' activity, and this may play a role in modulating the decrease in renal phosphate reabsorption %&.0'. >enal ammoniagenesis is reduced and probably plays a role in the defective urinary acidification %&.1'. !ormonal abnormalities in obstructive nephropathy include %a' altered hormonal responsiveness and2or sensitivity of the obstructed "idney and %b' altered production of hormones within the "idney, specifically renin8angiotensin and the <Bs. Gecreased renal excretion and2or altered metabolism of hormones also occur in obstructive nephropathy, but are not "nown to be affected in ),

a way that is different from other renal parenchymal diseases. ?< insensitivity of the collecting duct may be important in the decrease in urine6concentrating ability %&1(,&01,&*+,&*&'. Gecreased sensitivity to aldosterone %&4&,&4*' may be important in the syndrome of hyper"alemic distal renal tubular acidosis described in patients with obstructive uropathy. /dministration of mineralocorticoid fails to increase urinary KJ excretion in some patients, but it is uncertain whether blunting of the tubular response to aldosterone or a primary defect in KJ secretion, or both, is responsible. #he postobstructive "idney has an increased ability to release prostaglandins in response to /ng 33, and dose6response curves suggest that there is an increase in the number and2or affinity of the receptors for the hormone %*4'. 3n addition, the contractile response of strips of renal cortex to angiotensin was enhanced in rabbit "idneys that had been obstructed for , to () days compared to normal "idneys, which showed minimal response %&.*', suggesting that the sensitivity of the postobstructive "idney to angiotensin is increased. <#! responsiveness is blunted in the postobstructive "idney, as indicated by response of urinary c/=< and phosphate excretion %*0', but the abnormalities in phosphate excretion do not appear to be explained by this finding %&,0'. #his decrease in response to <#! is accompanied by decreased generation of c/=<, decreased activation of adenylate cyclase by the hormone in basolateral membranes obtained from the proximal tubule of postobstructive "idneys, and the apparent loss of <#! receptors in the same membrane %&.4'. /fter relief of $UO, absolute and fractional phosphate excretions are increased and do not increase further with exogenous <#! administration %*0,&,('. !owever, reducing the filtered load of phosphate %which is high following $UO because of hyperphosphatemia' restores phosphate excretion toward normal and the response to <#! is normaliEed. Ureteral obstruction blunts the calcemic response of the s"eleton to <#!, probably as a result of the decreased production of &,)06dihydroxyvitamin G by the obstructed "idney %&.,' or increased levels of circulating <#!. Cipid metabolism is altered in the obstructed "idney. #here is an increase in triglyceride content and a decrease in total phospholipid content %&..'. #he net synthetic rate of triglyceride by the obstructed "idney is increased because of a decrease in fatty acid oxidation and an increase in the release of fatty acids from phospholipids, presumably due to increased phospholipase activity. :ollowing obstruction, the phospholipid content of the basolateral membranes of tubular cells is decreased %)++'. $ecause the lipid composition or physical state of the membrane %fluidity' affects the activity of membrane6bound enEymes and water permeability, it is possible that selective changes in the lipid composition of basolateral membranes following obstruction could account for both the altered transport characteristics and the altered response to hormones seen following ureteral obstruction.

Factors Leading to Extracellular #ephropathy

*ro(th 'actors

atrix !ccumulation in Obstructi"e

3nterstitial fibrosis is a common outcome of long6term ureteral obstruction. #he process of fibrosis, in part, represents an imbalance between extracellular matrix %E;=' protein synthesis and degradation. /n initial event in the interstitial fibrosis process is macrophage infiltration of the tubulointerstitial compartment. $ecause the macrophage is a potent source of numerous peptide growth factors, it is not surprising that these moieties play a critical role in initiating and propagating the fibrogenic response to urinary tract obstruction. #he renal cortical tubular cell can also produce a myriad of peptide growth factors in response to ureteral obstruction. >enal proximal tubular cells and macrophages are a potent source of an array of growth factors, such as transforming growth factor %#B:'6V, interleu"in6& %3C6&', interleu"in6* %3C6*', fibroblast growth ).

factor %:B:', tumor necrosis factor %#5:', and platelet6derived growth factor %<GB:'. #hese peptide growth factors are important regulators of cell growth and differentiation. ;onsiderable attention has focused on the pluripotent peptide growth factor, #B:6V in the renal fibrotic response to in7ury %)+&'. #his polypeptide elicits a variety of cellular responses that promote fibrosis, including stimulation of E;= genes, downregulation of degradative matrix metalloproteinases, and upregulation of tissue inhibitor of metalloproteinase6& %#3=<6&' %)+),)+('. #B:6V& is a )0 "Ga protein secreted in an inactive %latent' form that requires activation before it can exert its biological effect. Catent #B:6V& is stored at the cell surface and in the E;= and is converted to active #B:6V& by an un"nown mechanism%s'. #B:6V& induces the production of collagen types 3, 333, and ? by cultured renal fibroblasts and stimulates production of proteoglycans and type 3? collagen. #he role of upregulated #B:6V& expression in tubulointerstitial fibrosis has been described in a number of experimental models of progressive renal disease. 3n these models a ma7or profibrogenic effect of #B:6V is to produce a state of net E;= accumulation, which is achieved by the disordered balance of oversynthesis of E;= components and a combination of inhibition of the degradation of matrix protein by increased generation of proteinase inhibitors and decreased expression of degradative proteins. 3n the model of UUO, increased #B:6V& expression occurs %)+1,)+0,)+*'. Dalton et al %)+*' noted a gradual increase in #B:6V messenger >5/ %m>5/' expression with time from the onset of ureteral ligation. Kaneto %)+0' found that ( days after ureteral ligation, the obstructed "idney exhibits significantly increased #B:6V& m>5/ expression, as compared with control %unoperated rats' "idneys. 3n addition, #B:6V& m>5/ levels in glomeruli from the obstructed "idney are essentially the same as those obtained in glomeruli from the contralateral "idney %)+0'. !owever, #B:6V& m>5/ in isolated tubules is increased in the obstructed, but not in the contralateral unobstructed "idney, supporting the contention that the tubular epithelium is the source for this growth factor in the obstructed "idney %)+0'. Giamond et al. %)+1' found highly significant ).*6, 0.,6, and 4.+6fold increments in renal cortical #B:6V& m>5/ levels at &), 1,, and .* hours, respectively, in the obstructed "idney versus the contralateral unobstructed specimens. 3ntracellular #B:6V&, on immunolabeling, was detected only in the obstructed "idneys of rats with unilateral ureteral obstruction at all three time points and was confined to peritubular cells of the renal interstitium. / significant correlation %p W+.++0' correlation %r H +..0' between interstitial macrophage number and cortical #B:6V& m>5/ levels was noted %)+1', suggesting the infiltrating renal interstitial macrophage as a cellular source for this growth factorFs upregulated expression. 3n subsequent studies %)+4', these investigators measured levels of active #B:6V& in tissue culture medium conditioned by obstructed and unobstructed cortical tissue, harvested at 1, and .* hours after unilateral ureteral obstruction. #he renal cortex of obstructed "idneys had &..6 and (.*6fold increments in active #B:6V& concentrations %pg2mC2mg cortical protein' at 1, and .* hours after unilateral ureteral ligation intervals, respectively, versus contralateral unobstructed "idney specimens from the same animals with unilateral ureteral obstruction or cortical specimens from normal, sham6operated rats. <imental et al. %)+,' noted a strong #B:6V immunoreactivity in $owmanFs capsule and in peritubular interstitial tissue in obstructed "idneys of rats at both & and 4 days after UUO. #hese investigators consistently found #B:6V& immunoreactive mononuclear cells within the interstitium at )1 hours after UUO %)+,'. ;ollectively, these data show that after ureteral ligation, macrophages increase within the obstructed renal cortex in association with increased renal cortical #B:6V& m>5/ and protein expression, as well as #B:6V& activity, implicating this inflammatory cell as a source for this pluripotent cyto"ine. 0o!u"ation of Tissue #nhibitors of 0eta""oproteinases an! 0atri3 0eta""oproteinases #he accumulation of E;= following tubulointerstitial in7ury represents an imbalance between E;= deposition and dysregulation of proteases, which degrade matrix components. <roteases are a (+

family of enEymes collectively termed metalloproteinases, capable of degrading both the collagenous and noncollagenous components of the extracellular matrix. =atrix metalloproteinases %==<s', such as meprin, stromelysin, collagenase, and gelatinase are present in renal tissue and play an important role in the regulation of normal tissue remodeling %)+.'. #he activity of ==< is controlled, in part, by inhibitory proteins or #3=<s, which are a family of at least three proteins that can bind to metalloproteinases to inhibit E;= degradation %)&+'. =acrophage6derived cyto"ines, <GB:, EB:, and :B:, can increase collagenase, transin, and stromelysin m>5/ expression and activity. 3C6& is a potent activator of #3=< expression. #B:6V is a potent repressor of collagenase and stromelysin and can activate increased #3=<6& expression, particularly in combination with 3C6 &. #he ability of #B:6V to inhibit collagenase expression has been shown in human fibroblast cultures. 3n situ hybridiEation studies have revealed that tissue localiEation of #3=<6& transcripts is present at sites of active tissue remodeling, where its expression significantly overlaps with that of #B:6V. /lterations in the regulation of #3=< expression by #B:6V may contribute to the development of interstitial fibrosis after unrelieved UUO. / mar"ed elevation of #3=<6& m>5/ expression was shown as early as &) hours after unilateral ureteral obstruction %)&&'. /fter .* hours of unilateral ureteral obstruction, there was a (+6fold increment in #3=<6& m>5/ in the obstructed "idneys compared with the contralateral unobstructed "idneys %)&&'. Sharma and co6wor"ers %)+(' found that expression of #3=< m>5/ is significantly increased at all time points after ureteral ligation, although it is maximal at day (. 3mmunohistochemically, increased #3=< reactivity localiEed to the interstitial space and #3=< m>5/ expression is observed to parallel the interstitial macrophage infiltration that accompanies ureteral obstruction %)+('. 3n regard to ==<6), which has degrading activity against both collagen 3? and denatured collagen, there is an early increase in m>5/ expression at day ( in the hydronephrotic rabbit "idneyN however, it returns to normal by day 4 after ureteral ligation %)+('. #he membrane6bound metalloproteinase, meprin, is also implicated in the development of renal in7ury. =eprin is a metalloendopeptidase located in the brush6border membranes of the rat and mouse "idney. / decreased meprin S and V m>5/ expression in "idneys has been observed in rats as early as &) hours after unilateral obstruction %)&)'. =eprin protein, on Destern blotting, is also decreased in a proximal tubule membrane preparation from obstructed "idneys as early as 1, hours after unilateral ureteral ligation and persists throughout .* hours of obstruction %)&)'. #hese studies suggest that dysregulation of the renal proximal tubule cells after ureteral obstruction may lead to diminished meprin activity and hence alterations in E;= accumulation. 3t has been shown %)&(,)&1' that macrophage6derived #B:6V& may be pivotal in the process of myofibroblast transformation. Uohnson et al. %)&0' note that infusion of /ng 33 to rats leads to focal tubulointerstitial in7ury. /lpers et al. %)&*' have identified accumulation of the renal cortical interstitial cells expressing S6smooth muscle actin %SS=/' at sites of chronic tubulointerstitial in7ury. Giamond and associates %)&4' show that SS=/ m>5/ and protein are only evident in the renal cortex of the obstructed "idney. Gecorin is a .).06"Ga protein that possesses a 1+6"Ga core protein and a single chondroitin sulfate side chain. #B:6V binds only to the core protein of decorin and becomes inactive. Dhen released from decorin, #B:6V regains activity, suggesting a biological interaction of this growth factor with decorin that transiently inactivates it in the E;=. 3n the rat unilateral ureteral obstruction model of hydronephrosis, active #B:6V& may induce a physiological upregulation of decorin m>5/ and protein with immunolocaliEation of this proteoglycan to the periglomerular and peritubular interstitium %)+4'. One possible explanation to account for the progressive interstitial fibrosis that develops in experimental rat hydronephrosis, despite an increased decorin m>5/ and protein expression %)+4', is that a physiological upregulation of renal cortical decorin is inadequate to neutraliEe the available #B:6V&, which, consequently, initiates a profibrogenic cascade by a variety of mechanisms. (&

$iagnosis of Urinary Tract Obstruction

2ymptoms an! 2i ns #he diagnosis of obstructive uropathy is not always obvious. Until excluded by specific diagnostic tests, urinary tract obstruction should be suspected in patients presenting with acute or chronic renal failure. Obstructive uropathy may present at any age9in the infant, child, and all stages of adulthood. Early recognition and prompt treatment are essential, since irreversible renal damage resulting from obstruction is related to its duration as well as its severity. #he clinical syndromes and complications of urinary tract obstruction have been described previously. Gifficulties with urinary stream, such as hesitancy, frequency, dribbling, nocturia, and the need to double6void are all obvious indications of a history of possible urinary tract obstruction. <atients may present with acute abdominal pain, because of sudden ureteral obstruction, with mild persistent flan" aching, with lower abdominal pain, or with gross hematuria. / past history of renal calculi, gynecologic disease or surgery, or bowel disease or surgery may also be clues. On physical examination, signs of intravascular volume contraction may be found in patients with salt and water depletion, secondary to chronic urinary tract obstruction. Dith severe renal failure, on the other hand, peripheral edema, pulmonary congestion, and hypertension may be observed. :eatures of chronic renal failure, such as pallor, drowsiness, increase in neuromuscular irritability, or pericarditis may be prominent. / palpable "idney or a distended bladder provides more direct evidence of urinary tract obstruction. <aralytic ileus may be prominent with acute renal colic. / careful rectal examination is essential and in the female a complete pelvic examination is required. Urina"ysis an! Laboratory 'in!in s Urinalysis may be normal in acute or chronic urinary tract obstruction despite the presence of severe impairment of renal function. Usually, however, there are both red cells and white cells in the urine depending on the cause of obstruction. <roteinuria is absent or mild %less than &.0 g2)1 h', in most cases. ;asts in the urine are also not distinctive and consist of granular, hyaline, or waxy casts, or occasionally white cell casts in the presence of renal infection. Urine culture should be obtained in all patients with obstructive uropathy even in the absence of pyuria. #he urine sediment should be examined carefully for the presence of crystals. Sulfonamides, cystine, or uric acid crystals may be the first indication as to the type of stone causing the ureteral obstruction or the intrarenal obstruction resulting in acute renal failure. Dhen acute renal failure is the presenting syndrome of obstructive nephropathy, urinary sodium, creatinine concentrations, and urine osmolality may be difficult to interpret. Usually the urinary diagnostic indices are similar to those seen with acute tubular necrosis with decreased osmolality, high urine sodium concentration, and decreased urine6to6plasma creatinine ratio %)&,' owing to previous chronic obstruction resulting in tubular damage. Dith recent obstruction and without severe renal failure, however, the indices may be similar to those for prerenal aEotemia with low urine sodium concentration and increased osmolality %&)&'. Serum electrolytes may indicate a hyperchloremic metabolic acidosis, because of acquired distal renal tubular acidosis and this may be combined with an anion gap type of metabolic acidosis when renal failure is present. !yper"alemia with hyperchloremic metabolic acidosis %type 1 distal renal tubular acidosis' may be a clue to the presence of obstructive nephropathy %&4*', although it also may be seen in chronic interstitial renal disease and diabetic nephropathy. #he blood urea nitrogen may be elevated out of proportion to the serum creatinine, the ratio normally being approximately &+ &, because in obstructive disease, with slowing of intratubular fluid flow, urea reabsorption is increased in the distal nephron or in the bladder. #he earliest functional abnormality in obstructive ()

nephropathy is impairment of maximum urinary6concentrating ability, which can be assessed by an overnight concentration test. /ssessment of urine acidification may also be importantN this is underta"en by using the short ammonium chloride load test or the bicarbonate loading urine < ;O) test or both. +ia nostic #ma in in Urinary Tract Obstruction Several diagnostic imaging techniques are available to detect urinary tract obstruction, to assess its severity, and to determine its cause. 3n all patients with acute or chronic renal failure when no obvious cause is found, obstructive uropathy must be excluded by appropriate investigation. / wide range of procedures is available and may be appropriate, depending on the circumstances, including abdominal plain films and tomograms, intravenous urography, ultrasonography, radionuclide scanning, computed tomography, and the invasive techniques of retrograde or antegrade pyelography %reviewed in reference )&.'. #he selection of diagnostic imaging techniques depends on the clinical setting and presenting symptoms. 3n patients with acute unilateral obstruction presenting with flan" pain, abdominal plain films, and intravenous urography are the initial and possibly the only tests required. Dith chronic unilateral hydronephrosis, however, an assessment of the severity and degree of parenchymal atrophy will require ultrasonography and diuresis urography, with possibly antegrade pyelography and pressure measurement, as well. Getermination of the cause of obstruction may require computed tomography %;#' and retrograde pyelography. Dith chronic bilateral obstruction, a similar range of tests may be needed, with invasive procedures usually applied first to the more severely affected "idney. 3n patients presenting with acute or chronic renal failure, abdominal plain films or renal tomograms and ultrasonography are the procedures of choice since urographic contrast agents may provide little visualiEation and are associated with a ris" of worsening renal function. 3f hydronephrosis is detected, other procedures are then required to determine the severity and cause of the obstruction. <lain :ilms and #omograms / plain abdominal radiograph %KU$9"idneys, uereters, bladder' may provide clues to the presence of obstructive uropathy. 3t should be obtained routinely in the early investigation of patients with renal failure and is a standard initial step prior to intravenous urography. / difference in siEe of more than ) cm between the two "idneys or the finding of suggestive intraabdominal calcifications is an immediate clue to possible obstructive uropathy. #he presence of normal6siEe "idneys in a patient with chronic renal failure is also suggestive. >enal tomograms provide better definition of renal siEe and shape and also detect smaller calcifications %as small as ) mm in diameter'. #ntravenous Uro raphy #he intravenous urogram or pyelogram %3?<' is the examination of choice in most cases of urinary tract obstruction. #he 3?< combines the features of accurate anatomic demonstration of the "idneys, calyces, pelvis, and ureters with gross estimate of renal function %))+'. Other diagnostic imaging procedures provide more precise information concerning one or another aspect of urinary tract structure and function, but the 3?< remains a helpful screening procedure. Urographic contrast agents are hypertonic water6soluble salts of iodinated benEoic acid derivatives %e.g., diatriEoate' that are rapidly excreted by the "idney following intravenous administration. #hese agents are excreted almost entirely by glomerular filtration, without significant tubular reabsorption, and are concentrated in the tubules by sodium and water reabsorption. Dith normal renal function, a uniform, dense nephrogram, because of contrast material in the proximal tubules and peritubular capillaries is seen within (+ seconds of in7ection, and approximately ) minutes later, contrast agent begins to appear in the renal calyces. #he 3?< may not be helpful in patients with severely compromised renal function. #he urinary tract is usually visualiEed poorly in patients with ((

serum creatinine levels greater than 0 mg2dC. 3n early acute obstruction there may be minimal dilation of the collecting system, whereas, with chronic or repeated episodes of obstruction, hydronephrosis may be mar"ed and is eventually accompanied by renal parenchymal atrophy. #he 3?< may also indicate the level of obstruction at the renal pelvis, ureter, ureterovesical 7unction, or bladder outlet. ;lose attention should be focused on the bladder for evidence of thic"ening %trabeculation' of the wall, an enlarged prostate, and, particularly, residual urine after voiding. Cower urinary tract %bladder nec"' obstruction may be further evaluated by a voiding cystourethrogram in which dye is inserted by catheter into the bladder and timed films are ta"en during voiding. #his technique is also useful for the assessment of vesicoureteral reflux. 3t is important to emphasiEe that dilation of the urinary tract cannot always be attributed to obstruction nor does the absence of hydronephrosis exclude obstruction. :unctional abnormalities of the ureter or bladder, vesicoureteral reflux, or even a chronic massive diuresis, such as that accompanying primary diabetes insipidus may produce urinary tract dilation. On the other hand, intermittent or partial obstruction may not be accompanied by urinary tract dilation unless urine flow rates are high. 3ntravenous urography during a diuresis induced by hypertonic saline or furosemide may be helpful in showing a dilated renal pelvis %))&' %:igs. )06, and )06.'. U"trasono raphy Giagnostic ultrasound is the procedure of choice to determine the presence or absence of dilated calyces or renal pelvis and, thus, to suggest the presence of obstructive uropathy %)))'. $ecause it is not invasive and not dependent on renal function, ultrasonography is particularly useful to exclude hydronephrosis in patients with acute or chronic renal failure %:ig. )06&+'. 3t is very useful in detecting hydronephrosis in the fetus during pregnancy %1,0,))(,))1'. Ultrasound is an extremely sensitive test for hydronephrosis, with a reported accuracy of greater than .+- %))0,))*,))4'. 3t can also be used to assess the degree of renal parenchymal atrophy accompanying hydronephrosis. Ci"e all diagnostic procedures, it is not foolproof. Examples of conditions causing obstruction without urinary tract dilation include staghorn calculi filling the renal pelvis, retroperitoneal fibrosis with constriction of the ureters and pelvis, and acute obstruction in a patient with E;? contraction and low urine flow rate.

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FI(U)E *+,0. Intra"enous pyelogram from a patient /ith se"ere left flan% pain that lasted for : hours. )adiograph ta%en < hours after in'ection of contrast media sho/s a "ery dense nephrogram on the left. ! faint right pyelogram is seen1 but a clear left pyelogram is not seen. The findings suggest nearly complete left ureteral obstruction9 a stone /as subse>uently passed. 2From3 Flamenbaum M1 Damburger )5. #ephrology Philadelphia3 Lippincott1 -70*1 /ith permission.=

/ limitation of ultrasonography is, paradoxically, its extreme sensitivity to detect small increases in volume of the renal pelvis. :alse6positive diagnosis has been reported in ,- to )*- of urographically nonobstructed "idneys %))0,)),'. / second drawbac" is its relative inability to provide information on the localiEation and cause of urinary tract obstruction. #sotopic %eno raphy #his procedure requires the intravenous in7ection of a radionuclide and imaging with a gamma scintillation camera. 3ntravenous in7ection of tracer amounts of technetium6labeled diethylenetriamine pentaacetic acid %..m#c6G<#/' or &(&iodine6labeled orthoiodohippurate and sequential imaging provide a dynamic pattern of urinary excretion. >adionuclide examinations are .+- sensitive in detecting obstruction, with false6negative diagnoses, because of poor excretory function and, therefore, poor visualiEation %)).'. 3t is also highly specific, although dilation of the renal pelvis or ureters from nonobstructive causes may result in a false6positive diagnosis. Giuresis renography carried out by administering a diuretic %furosemide +.( to +.0 mg2"g intravenously' during the study may help to determine the presence or absence of mechanical obstruction, since, with functional obstruction, the diuretic promptly and mar"edly increases tracer drainage from the urinary tract. /lternatively, diuretic administration may increase dilation during diuresisN an increase of greater than )+- suggests significant ureteropelvic 7unction obstruction %)(+,)(&'.

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FI(U)E *+,7. !3 Intra"enous pyelogram from a patient /ith right flan% pain and hematuria intermittently for se"eral /ee%s. )adiograph ta%en - hour after in'ection of contrast media sho/s a mar%edly dilated right renal pel"is and a dilated1 completely filled right ureter. &3 Examination of the plain radiograph before dye in'ection sho/s se"eral radiopa>ue stones o"erlying the sacrum. 2From3 Flamenbaum M1 Damburger )5. #ephrology Philadelphia3 Lippincott1 -70*.=

#he main limitation of isotopic renography compared to intravenous urography is the inferior anatomic definition, whereas its advantages are the small radiation dose and lac" of ris" of systemic reaction or renal in7ury. 5ewer developments with radionuclide imaging, including computer analysis of excretion of radioactivity %deconvolution analysis', suggest that while the upta"e function may be normal despite significant outflow obstruction, the renal parenchymal transit time of radionuclide is a more sensitive indicator of obstruction %)(),)(('. Similarly, analysis of activity in the renal parenchyma compared to the renal pelvis or whole "idney may provide a more accurate estimate of the potential recovery of renal function following surgical relief of obstruction %)((,)(1'. 3t is important to remember that even nonvisualiEation on renal scan does not preclude recovery of significant renal function after relief of obstruction %)(0'.

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FI(U)E *+,-K. Supine right sagittal sonogram of the abdomen in a patient presenting /ith anuric acute renal failure and a history of cer"ical carcinoma. The film sho/s mar%edly dilated calyces in the right %idney lying inferior to the li"er1 /ith the anterior abdominal /all at the top of the photograph. Similar findings /ere present in the left %idney. 2From3 Flamenbaum M1 Damburger )5. #ephrology Philadelphia3 Lippincott1 -70*.=

Compute! Tomo raphy an! 0a netic %esonance #ma in ;omputed tomography %;#' may be useful as a secondary study to determine the etiology of urinary tract obstruction %)(*'. 3t can provide detailed anatomic information, but is not used as an initial procedure because of its high cost, lac" of immediate availability, and relatively large radiation dose. ;# is particularly helpful to determine potential causes of obstructive uropathy in the retroperitoneal area, since it is able to determine the density of different types of tissues. 5onradiopaque calculi composed of uric acid are also readily detectable by ;#. #hus ;# scanning has replaced the invasive diagnostic procedures of retrograde and antegrade pyelography in evaluating patients with urinary tract obstruction %:ig. )06&&'. 5uclear magnetic resonance %5=>' or magnetic resonance imaging %=>3' provides computer6 generated displays showing the distribution of hydrogen nuclei6emitting 5=> when sub7ected to applied magnetic fields and radiofrequency energy. 5=> is particularly useful in determining tissue densities and, hence, li"e ;#, may prove to be useful in determining the etiology of obstructive uropathy %)(4,)(,'. Ureteropye"o raphy <yelography provides detailed information about the location and cause of urinary tract obstruction previously detected by 3?<, ultrasonography, or isotopic renography. Dhen further anatomic information is required or when renal contrast excretion is poor or nonexistent, pyelography becomes an essential part of the investigation. Urologic consultation is an integral part of the diagnosis and management of such patients. ;ystoscopy provides definitive information about possible causes of obstruction located in the posterior urethra and bladder, which are difficult to demonstrate by noninvasive methods. >etrograde ureteric catheteriEation permits samples of urine to be obtained for diagnosis from one or both ureters, allows the in7ection of contrast material for exact localiEation of the level of ureteric obstruction, and may be therapeutic in revealing ureteric or ureteropelvic obstruction. 3n the hands of a s"illed urologist, the incidence of infection or postcatheteriEation ureteral edema is minimal.

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FI(U)E *+,--. Trans"erse "ie/ of abdominal computeriFed axial tomogram 2CT= in a patient /ith intermittent left flan% aching in /hom a radiolucent filling /as "isualiFed in the renal pel"is by intra"enous pyelography. The CT scan sho/s that this filling defect at the ureteropel"ic 'unction is dense 2/hite=1 indicating that it is a uric acid stone rather than a tumor1 blood clot1 or necrotic papilla. 2From3 Flamenbaum M1 Damburger )5. #ephrology Philadelphia3 Lippincott1 -70*.=

/ntegrade ureteropyelography is also used as a diagnostic and, at times, therapeutic procedure in obstructive uropathy. #he technique involves the percutaneous puncture of the dilated renal pelvis that has been previously localiEed by ultrasonography or contrast in7ection. =easurement of resting pressures and samples of urine for culture or cytology are obtained from the renal pelvis, and, following in7ection of contrast media, excellent visualiEation of the ureter is obtained. 3f desired, temporary or permanent relief of obstruction may be accomplished by percutaneous nephrostomy. #he advantages of antegrade pyelography include the use of local anesthesia, sterile technique, physiologic route of contrast in7ection, and the ability to ma"e pressure measurements and obtain samples of fluid or brushings of intraluminal lesions. #he ris"s include bleeding or the extravasation of urine. 3n patients with chronic partial unilateral obstruction and hydronephrosis, it is difficult to determine whether a surgical procedure should be done for an abnormality at the ureteropelvic 7unction. #he gold standard in this situation is considered to be renal perfusion8pressure studies carried out by antegrade pyelography %)(.,)1+'. :or these studies, fluid is infused through a needle in the dilated renal pelvis at a standard rate and intrapelvic pressure is recorded while bladder pressure is monitored simultaneously through an indwelling catheter %Dhita"er test'. /t a flow rate of &+ mC2min, the pressure fall to the bladder should not exceed &0 cm of water. Dith significant obstruction, the pressure decrement will, in almost all cases, be more than )) cm of water %)(,'. 3t should be recogniEed, however, that such procedures have technical pitfalls and that factors other than outlet obstruction may affect the pressure drop.

Treatment of Urinary Tract Obstruction

#he overriding principles in the treatment of urinary tract obstruction should be as follows

Eliminate any life6threatening aspect of this disorder. <reserve renal function by relief of obstruction and treatment of complications, particularly, urinary tract infection %U#3'.

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Getermine the cause of obstruction and its specific treatment.

#he first principle in treating obstructive uropathy is to eliminate any life6threatening aspect of this disorder.

Bram6negative septicemia may occur when pyelonephritis develops in the presence of severe partial or complete obstruction. #hus, fever in a patient with urinary tract obstruction must be managed aggressively with diagnostic blood and urine cultures and appropriate antibiotics administered parenterally while awaiting the results of cultures. /cute papillary necrosis secondary to pyelonephritis and obstruction may cause rapid destruction of renal tissue and this possibility is another reason for using immediate corrective measures. Emergency surgical relief of obstruction by the most simple appropriate procedure, such as bladder catheteriEation or percutaneous nephrostomy, is usually required in such patients. /cute or chronic renal failure with hyper"alemia, acidosis, convulsions, coma, or pericarditis is another life6threatening clinical presentation of obstructive uropathy that may require immediate treatment by dialysis until definitive measures can be ta"en to correct the obstruction. Occasionally, intravascular volume contraction and hypotension may present as a complication of postobstructive diuresis or of chronic partial urinary tract obstruction with inadequate oral inta"e.

#he second principle of treatment is to prevent further deterioration of renal function and to allow recovery of function. Surgical therapy that decreases elevated intrarenal pressure or corrects progressive anatomic abnormality is essential. =eticulous management of urinary tract infection is also important. #reatment of other complications, such as renal calculi or hypertension, and detection of recurrent obstruction by careful follow6up, may preserve renal function. #he need to accurately determine the cause and rate of progression %natural history' of urinary tract obstruction is an important third principle of treatment. $efore a decision is made regarding the need for specific surgical therapy, it may be necessary to perform serial assessments of renal function over several months or longer. Elective surgical repair is required for progressive lower urinary tract symptoms, recurrent serious urinary tract infections, urinary retention, or evidence of progressive deterioration in renal function. Surgical treatment, however, is usually not indicated simply because of the finding of residual urine in the bladder, mild to moderate vesicoureteral reflux, or a dilated renal pelvis. Once a decision has been made that surgical intervention is required, optimal therapy consists of removal of the obstructing lesion and reestablishment of continuity of the urinary tract. /t times, however, the obstructing lesion cannot be removed, and urinary diversion may be required for wee"s, months, or years. <lacement of a bladder catheter %intermittent or continuous', nephrostomy, pyelostomy, cutaneous ureterostomy, suprapubic cystostomy, or ureteroileal cutaneous anastomosis %ileal conduit', as well as other procedures, may be used in appropriate cases, but each is accompanied by ris"s of recurrent obstruction, ascending urinary tract infection, electrolyte abnormalities, volume depletion, and formation of renal calculi. /t times, nephrectomy is the procedure of choice when return of useful renal function is unli"ely. 3t is clear that management of obstructive nephropathy should involve consultation with a s"illed urologist. Gefinitive therapy to preserve renal function and correct the cause of obstruction is frequently surgical. 5evertheless, it is appropriate for the internist or nephrologist to remain directly involved in the care of many of these patients, particularly with respect to evaluation of the underlying causes, such as renal calculi, treatment of complications, such as urinary tract infection, and careful follow6up of renal function. 2ur ica" Treatment

(.

#o determine the li"ely benefit from definitive surgical therapy, it is important to consider the potential for recovery of B:> after relief of obstruction. /ssessment of the severity, duration, and cause of obstruction by analysis of symptoms, signs, and appropriate specialiEed tests is essential. 3n general, if the obstruction is of recent onset %wee"s', a gradual increase in B:> over a period of & to 1 wee"s may be expected. !owever, if obstruction is long6standing %months or years', renal parenchymal function may be irreversibly lost and little or no improvement in function should be expected. / discussion of the surgical treatment of obstructive uropathy is available elsewhere %)1&'. %ena" &e"vic Obstruction ;ongenital ureteropelvic obstruction is usually corrected surgically in patients who are symptomatic %flan" pain or mass', patients who experience recurrent infections, or patients in whom progressive renal damage can be demonstrated. 3n addition to removal of any extrinsic obstructing lesion, such as an aberrant renal artery, surgical treatment %)1+' involves some form of plastic repair %pyeloplasty' of the ureteropelvic 7unction, such that redundant tissue is removed and the 7unction remains funnel6shaped and dependent. >adiographic improvement in the appearance of the renal pelvis following surgery should not be expected, but deterioration of renal function and recurrent infections can be largely eliminated. 3n patients in whom a stable level of renal function has been achieved with a dilated renal pelvis and mild ureteropelvic obstruction, surgery is not required. >enal calculi obstructing the ureteropelvic 7unction for several days usually require surgical removal, since they are too large to be passed spontaneously, and may cause progressive renal damage. Smaller stones in the renal pelvis or calyces are usually not removed surgically unless they are causing intermittent obstruction, as they may be difficult to locate and surgery is associated with significant ris" of renal damage. Surgical intervention for large, nonobstructing renal pelvic stones, which are usually of the staghorn infective %or struvite' type, is controversial, because surgery is difficult and rapid stone recurrence is frequent unless all infected stone fragments can be removed and recurrent infection prevented. Uretera" Obstruction >enal calculi are a common cause of ureteric obstruction in the adult. =ost stones pass spontaneously if they are less than 0 to 4 mm in diameter and, on occasion, larger stones may be passed. #hus, in the absence of infection, such stones should be treated conservatively at first with control of renal colic by analgesics and increased hydration. 3f the stone reaches the lower end of the ureter, bas"et extraction through cystoscopy may be possible, whereas stones impacted higher in the ureter require surgical removal by ureterolithotomy. Extracorporeal shoc"6wave lithotripsy %)1)' involves the focusing of electrohydraulically or ultrasonically generated shoc" waves to disintegrate the stone. #he procedure is effective for calculi of 4 to &0 mmN in .+- of patients, the stone will be fragmented and all particulate matter will pass within a (6month period. =orbidity is low. 3n selected individuals, the procedure can be done on an outpatient basis. =ost patients are bac" at wor" ) to ( days after shoc"6wave therapy. Ureteric obstruction from other causes, such as tuberculous stricture or extrinsic compression from tumor or retroperitoneal fibrosis, often requires more extensive surgical therapy, which may include urinary diversion. #he management of vesicoureteral reflux and reflux nephropathy is discussed in ;hapter )1 %?esicoureteric >eflux and >eflux 5ephropathy'. Lo(er Urinary Tract Obstruction Surgical treatment for bladder nec" or urethral obstruction is indicated for patients with severe difficulties in voiding, decreased renal function, or recurrent urinary tract infection. 3n patients with mild or moderate symptoms, a decision should be made on an individual basis with periodic assessment of renal function. Severe bladder dysfunction, such as a neurogenic bladder or 1+

obstruction from pelvic malignant disease, may require surgical urinary diversion, usually in the form of an ileal conduit. )ephrectomy as a Treatment for Uni"atera" Obstruction #here are few indications for removing an obstructed "idney. 3n general, refractory pyelonephritis in a unilaterally obstructed, but functioning, "idney is not sufficient reason for a nephrectomy, because it is li"ely that pyelonephritis has developed in the unobstructed contralateral "idney by ascending spread from infected bladder urine. 3n this situation, removal of functioning tissue in the obstructed "idney could hasten development of chronic renal failure. 5ephrectomy is warranted only if the obstructed "idney is severely and irreversibly damaged and pyelonephritis within it is recurrent, severe, and refractory to treatment. >arely, removal of a functioning, but obstructed, "idney may be indicated if surgical repair has been unsuccessful and acute infection in that "idney appears to have been the source of life6threatening episodes of Bram6negative septicemia. 0e!ica" Treatment '"ui! an! E"ectro"yte 0ana ement <atients with chronic partial obstruction and renal tubular dysfunction may have excessive losses of water %including nephrogenic diabetes insipidus', sodium chloride, or sodium bicarbonate in the urine. /ccordingly, they may require oral sodium chloride and2or sodium bicarbonate supplements, as well as a high fluid inta"e. #hey should be warned to replace excessive fluid losses occurring with intercurrent illness causing diarrhea, vomiting, or excessive sweating. <ostobstructive diuresis after relief of severe partial or complete obstruction is an uncommon event, but requires careful assessment and management of fluid and electrolyte balance including replacement of deficits of sodium chloride, bicarbonate, potassium, and water, and replacement of insensible losses and of ongoing losses in the urine. Usually +.10- 5a;l is a suitable replacement solution for urinary losses, but urinary electrolytes should be chec"ed periodically, and potassium supplements are usually required. <ostobstructive diuresis must be distinguished from the physiologic diuresis of retained fluid and from iatrogenic diuresis resulting from overenthusiastic administration of intravenous fluids. <rolongation of the natriuresis by volume expansion may be assessed by decreasing the intravenous replacement of urinary losses for , to &) hours, combined with clinical assessment of intravascular volume and of changes in urine volume and body weight. Urinary Tract #nfection $acteriuria is difficult to eradicate in the presence of urinary tract obstruction and occurs with increased frequency in such patients. /cute U#3, with or without clinical pyelonephritis, should be treated with appropriate antibiotics based on in vitro bacterial sensitivity testing, although therapy must often be initiated before such results are available and then altered as required. /ntibiotics that reach high concentrations in the "idney and urine should generally be used. <rophylactic antibiotics given parenterally & hour before and a few hours after instrumentation of the urinary tract in patients with obstructive nephropathy may reduce the incidence of infection. <rolonged prophylactic antibiotic therapy, for months or years, may be useful to reduce episodes of recurrent acute symptomatic U#3 with pyelonephritis in patients with chronic obstruction and2or struvite stones. Other Comp"ications5 $ypertension an! %ena" 'ai"ure !ypertension associated with obstructive uropathy is usually treated medically with antihypertensive drugs, although occasionally surgical correction of acute unilateral obstruction may result in control of blood pressure. >enal failure associated with obstruction is treated by 1&

dialysis as required for management of acute renal failure or end6stage renal disease resulting from obstruction. <atients with end6stage renal disease owing to obstruction are suitable for renal transplantation, but usually require bilateral nephrectomy prior to such a procedure in order to eliminate foci of infection. Even patients with urinary diversions, such as an ileal conduit, may receive a "idney transplant, although the high ris" of infective complications often ma"es long6term dialysis a safer alternative. Lon -Term 'o""o(-Up <atients who have had surgical treatment for obstruction or who have chronic obstruction require careful long6term follow6up by a physician. Such follow6up involves careful clinical assessment, urinalysis and urine culture, periodic radiologic evaluation, and, most important, an assessment of renal function, usually by endogenous creatinine clearance. Obstructive )ephropathy an! %ena" 'ibrosis / model of renal fibrosis that encompasses many aspects of other models of "idney disease is unilateral ureteral obstruction %UUO' %)1(,)11,)10,)1*' #here are features of the UUO model that occur within & wee" of the onset of ureteral ligation. #here are many readily quantifiable cellular and molecular events during the initiation and progression of renal fibrosis that ma"e UUO an increasingly good experimental model for study. #able )060 describes factors, the expression of which is increased in "idneys with ureteral obstructionN #able )06* depicts factors, the expression of which is decreased in "idneys with ureteral obstruction. 3n a rat model of UUO, Sweeney et al. %)14' visualiEed changes in renal blood flow %>$:' using a radiolabeled compound and radioautography. #hey measured an initial vasodilation in the cortex within &+ min of obstruction. #his was followed by a significant vasoconstriction in both the cortical and medullary beds %)14'. #he changes in blood flow were mediated by prostanoid, /ng 33, and 5O. De have identified a significant pathophysiological role of several vasoconstrictive substances during ureteral obstruction. #hese vasoconstrictors include /ng 33, #R/), and /G! %)1,'. TABLE 25-5 'actors that are increase! in the settin of uretera" obstruction ?asoactive compounds /ngiotensinogen /ngiotensin 33 Endothelin #hromboxane /) <rostaglandins #ransforming growth factor6V <rotein 0( <rotein )& %D/:&' #issue inhibitor of metalloproteinase6& Gecorin 5uclear factor X$ #umor necrosis factor6V <rotooncogenes c,fos 1)

c,'un 'un & c,myc cD,)as Browth factors 3nterleu"in6* <latelet6activating factor $asic fibroblast growth factor <roteins involved in apoptosis ;lusterin %SB<6)' Osteopontin ;hemoattractants =onocyte chemoattractant peptide6& Osteopontin /dhesion proteins 3ntercellular adhesion molecule6& ?ascular cell adhesion molecule6& :ibronectin %alternate splice forms' =atrix2basement membrane proteins ;ollagen types 3, 333, 3?, R?, and R?333 / recent study by =oridaira et al. %)1.' confirms that enalapril inhibits the interstitial fibrosis in UUO "idneys. 3t also suggests a beneficial and unforeseen effect of enalapril on the obstructed "idney by potentially stimulating the production of 5O through an increased expression of the E#$ receptor. TABLE 25-6 'actors that are !ecrease! in the settin of uretera" obstruction Browth or homeostatic factors $one morphogenetic protein64 %$=<6 4' !epatocyte growth factor Epidermal growth factor >edox state ;opper, Einc superoxide dismutase ;atalase >educed glutathione Others =eparin 3nducible nitric oxide synthase %i5OS' TABLE 25-7 Effects of vasoconstrictors an! vaso!i"ators on rena" hemo!ynamics in rats after uni"atera" re"ease of bi"atera" uretera" obstructiona *'% 89: 0aneuver Before maneuver After maneuver 3nhibition of synthesis or activity of vasoconstrictors >/S inhibition )+.4 40., 1(

>/S and #R/) inhibition <revention of macrophage infiltration #R/) synthesis inhibition C# synthesis inhibition 3nhibition of /G! ?& receptors Endothelin antibody GeendothelialiEation of main renal arteries /dministration or activation of vasodilators C6/rginine administration %for 5O synthesis' #R/) inhibition and </: administration /5< administration
aB:>,

)(.0 )&.0 &4.+ )&.0 )).( )&.+ )&.+ )1.( &4.+ )1.,

.+.0 0).( )..4 1..0 (0., ((., &+.) 1..) 04.* (..0

glomerular filtration rate was measured in rats after unilateral release of bilateral obstruction versus that in one "idney of sham6operated ratsN )!S, renin8angiotensin systemN TA!*, thromboxane /)N LT, leu"otrienesN !$D, antidiuretic hormoneN #O, nitric oxideN P!F, platelet6activating factorN !#P, atrial natriuretic peptide. %:rom Baudio K=, et al. >enal perfusion and intratubular pressure during ureteral occlusion in the rat. !m 5 Physiol &.,+N)(, :)+0N =ene <, Gunn =U. ;ontractile effects of #R/ ) and endoperoxidase analogues on cultured rat glomerular mesangial cells. !m 5 Physiol &.,*N)0& :&+)., with permission.'

De also found a vasoconstrictive effect of leu"otrienes in the setting of bilateral ureteral obstruction %)1,'. On the other hand, it is li"ely that vasodilatory substances are decreased in the setting of ureteral obstruction or are not increased to a sufficient degree to balance the increased activity of the vasoconstrictor compounds. /dministration of vasodilators %<BE) and <B3)' and platelet6 activating factor %</:' after inhibition of the synthesis of #R/) increased B:> and effective renal plasma flow %E><:' significantly but not to normal levels. De also found that endothelin has an important role in the renal functional alterations observed in rats after unilateral release of )16hour duration bilateral ureteral ligation %)0+'. >ats given a specific anti6endothelin antibody had significantly higher B:> and E><: values than untreated rats sub7ected to bilateral ureteral obstruction. #able )064 summariEes the overall role of vasoconstrictors and vasodilators in the renal hemodynamics observed after unilateral release of bilateral ureteral obstruction. #he overall role of endothelin in the altered hemodynamics of bilateral ureteral obstruction seems to be modest compared with that of other vasoconstrictors or the decreased activity of other vasodilators "nown to have a role in this setting. C6/rginine, </:, and atrial natriuretic peptide %/5<' are among the vasodilators that have a role in the hemodynamics of bilateral ureteral ligation. #he administration of C6arginine, the substrate for 5O synthesis, increased B:> to Y0+- of the values obtained for one "idney in sham6operated rats. 3nducible nitric oxide synthase %i5OS' has been identified by immunohistochemistry in the renal tubules after UUO %)0&' ?asodilation of the afferent arteriole during acute UUO %W0 hours' may account for the increase in >$: and ureteral pressure. Several studies have explored the role of 5O during ureteral obstruction. 3ntrarenal infusion of 5B6monomethyl6C6arginine, a nonspecific 5OS inhibitor, attenuated the increase in >$: after acute ureteral obstruction %)0&'. #hese effects of 5B6 monomethyl6C6arginine were reversed by the intrarenal infusion of C6arginine. #he protective effect of 5O has been demonstrated in several renal disease models. De augmented renal 5O production by transfer of the inducible nitric oxide synthase %i5OS' gene into rat "idney in controls and in unilateral ureteral obstruction %UUO'. #his study demonstrates the feasibility of liposome6mediated i5OS gene transfer into the "idney. :urthermore, the improvement of renal function in UUO demonstrates that the transfected i5OS 11

gene is active and suggests that decreased i5OS activity contributes to the decreased renal function in UUO. #his i5OS construct may have therapeutic utility in the pathophysiologic sequelae of UUO and other renal diseases %)0)'. /nother aid in the recovery from acute ischemic renal in7ury is treatment with hepatocyte growth factor %!B:' %)0('. 3ndeed, a decrease in !B: levels induced by either an increase in /ng 33 or #B:6V was hypothesiEed to be a factor in the development of glomerulonephritis %)01'. !B: has been described as a substance produced by mesenchymal cells that maintains epithelial homeostasis %)00'. =iEuno et al. %)0*' used a mouse model of UUO and treated the animals with vehicle, a neutraliEing antibody to !B:, or recombinant human !B:. #reatment with the !B:6neutraliEing antibody was found to increase #B:6V expression, decrease tubular cell proliferation, and accelerate apoptosis. #reatment with exogenous !B: attenuated apoptosis and #B:6V expression %)0*'. #he authors suggested that the reduction in endogenous !B: can account for the progression of renal fibrosis in tubulointerstitial6based disease %)0*'. #his was underscored by a study in which !:B was administered by tail6vein in7ection every &) hours for the 4 days of UUO %)04'. #he in7ection of !B: blunted the expected increase in #B:6V& m>5/ and various histological indices of fibrosis %)04'. >ecently, another protein has emerged as a potential renotrophic factor bone morphogenetic protein64 %$=<64'. 3n a preventative protocol, $=<64 treatment was found to significantly decrease renal in7ury in a rat model of UUO when treatment was initiated at the time of in7ury %)0,'. Subsequent studies suggested that $=<64 treatment will also attenuate renal fibrosis when administered after renal fibrosis has begun %)0.'. #his treatment protocol was also found to significantly increase renal function from the levels measured in the vehicle6treated group %)0.'. #hese studies underscore the value of histological parameters as an indicator of renal function and the potential of renal homeostatic factors in the treatment of "idney disease. >ecently, arginine infusions in dogs with &, hours of UUO were shown to increase renal blood flow, leading to the conclusion that a lac" of substrate may contribute to the profound vasoconstriction resulting from chronic UUO %)*+,)*&'. ;hronic UUO in mice leads to a progressive reduction in the production of i5OS by the obstructed "idney and tubular apoptosis is even more severe following UUO in mice lac"ing the gene for i5OS %)*)'. =echanical stretch of tubular epithelial cells, because of tubular dilatation, appears to be a ma7or factor contributing to apoptosis following UUO, and axial strain on cultured tubular cells increases i5OS expression %)*('. =oreover, inhibition of endogenous i5OS increases stretch6induced apoptosis in rat renal tubular cells %)*)'. 3n this very well6controlled study using cationic liposomes as the vehicle, i5OS was localiEed to collecting ducts, distal tubules, and glomeruli. 3mportantly, renal expression of i5OS and urinary 5O)25O( remained elevated more than (+ days after transfection %previous reports of "idney6 targeted viral6mediated delivery of genes have not shown long6term expression' %)0)'. Dhile i5OS transduction was performed 4 days prior to ureteral obstruction, and functional studies were performed after only )1 hours of UUO, the authors indicate that longer6term studies of morphologic effects of i5OS transduction are to follow.

10

%eferences
&. $ell E#. >enal diseases. <hiladelphia Cea Z :ebiger, &.1*. ). ;ampbell =>. Urinary obstruction. 3n ;ampbell =:, !arrison U!, eds. Urology, vol. 3, (rd ed. <hiladelphia Saunders, &.4+. (. 5ational Kidney and Urologic Giseases /dvisory $oard. #he scope and impact of "idney and urologic diseases. 3n Cong6range plan. Dashington G; 5ational 3nstitutes of !ealth, 53! <ublication .+60,(, &..+ 4. 1. !adloc" :<, Geter >C, ;arpenter >U. Sonography of the fetal genitourinary tract. Semin Ultrasound &.,1N0 )&(. 0. =ontana =/, et al. Sonographic detection of fetal ureteral obstruction. /m U >adiol &.,0N&10 0.0. *. >olleston BC, =aling #=, !odson ;U. 3ntrarenal reflux and the scarred "idney. /rch Gis ;hild &.41N1. 0(&. 4. !odson ;U, et al. Experimental obstructive nephropathy in the pig. 3. >adiology. $r U Urol &.*.N1&%Suppl' &. ,. !odson ;U, et al. #he pathogenesis of reflux nephropathy %chronic atrophic pyelonephritis'. $r U >adiol &.40%Suppl &(' &. .. >oberts U/, /ngel U>, >oth UK, Ur. #he hydrodynamics of pyelorenal reflux. 33. #he effect of chronic obstructive changes on papillary shape. 3nvest Urol &.,&N&, ).*. &+. GEiu"as CU, et al. >enal localiEation of #amm6!orsfall protein in unilateral obstructive uropathy in rats. Cab 3nvest &.,)N14 &,0. &&. SchwartE =S, ?en"atachalam =/, ;otran >S. >eversible inner medullary vascular obstruction in acute experimental hydronephrosis. /m U <athol &.44N,* 1)0. &). BuEe C$, $eeson <$. Experimental pyelonephritis. 3. Effect of ureteral ligation on the course of bacterial infection in the "idney of the rat. U Exp =ed &.0*N&+1 ,+(. &(. BuEe C$, $eeson <$. Experimental pyelonephritis. 33. Effect of partial ureteral obstruction on the course of bacterial infection in the "idney of the rat and the rabbit. [ale U $iol =ed &.0,N(+ (&0. &1. $elman /$, Kropp K/, Simon 5=. >enal6pressor hypertension secondary to unilateral hydronephrosis. 5 Engl U =ed &.*,N)4, &&((. &0. 5emoy 5U, :ichman =<, Sellers /. Unilateral ureteral obstruction a cause of reversible high renin content hypertension. U/=/ &.4(N))0 0&). &*. Su"i D, et al. <atterns of nephron perfusion in acute and chronic hydronephrosis. U ;lin 3nvest &.**N10 &)). 1*

&4. Kaloyanides BU, $astron >G, Gi$ona B:. Effect of ureteral clamping and increased renal arterial pressure on renin release. /m U <hysiol &.4(N))0 .0. &,. ?ander /U, =iller >. ;ontrol of renin secretion in the anesthetiEed dog. /m U <hysiol &.*1N)+4 0(4. &.. <almer U=, \weiman :B, /ssay"een #/. >enal hypertension due to hydronephrosis with normal plasma renin activity. 5 Engl U =ed &.4+N),( &+(). )+. ?aughan EG, Ur, $uhler :>, Caragh U!. 5ormal renin secretion in hypertensive patients with primarily unilateral chronic hydronephrosis. U Urol &.41N&&) &0(. )&. Deidmann <, et al. ;urable hypertension with unilateral hydronephrosis studies of the role of circulating renin. /nn 3ntern =ed &.44N,4 1(4. )). Uawors"i \:, Dolan ;#. !ydronephrosis and polycythemia a case of erythrocytosis relieved by decompression of unilateral hydronephrosis and cured by nephrectomy. /m U =ed &.*(N(1 0)(. )(. Kiil :, Sete"leiv U. <hysiology of ureter and renal pelvis. 3n Orloff U, $erliner >D, eds. $oo" of physiology, Section , >enal physiology. Dashington, G; /merican <hysiological Society, &.4(. )1. Deiss >=. ;linical correlations of ureteral physiology. /m U Kidney Gis &.,(N) 1+.. )0. >ose UB, Billenwater U[. <athophysiology of ureteral obstruction. /m U <hysiol &.4(N))0 ,(+. )*. >ose UB, Billenwater U[, Dy"er /#. #he recovery of function of chronically obstructed and infected ureters. 3nvest Urol &.40N&( &)0. )4. =ichaelson B. <ercutaneous puncture of the renal pelvis, intrapelvic pressure and the concentrating capacity of the "idney in hydronephrosis. /cta =ed Scand &.41N00.%Suppl' &. ),. /rendshorst DU, :inn D:, Bottschal" ;D. 5ephron stop6flow pressure response to obstruction for )1 hours in the rat "idney. U ;lin 3nvest &.41N0( &1.4. ).. Gal ;anton /, et al. Effects of )16hour unilateral ureteral obstruction on glomerular hemodynamics in rat "idney. Kidney 3nt &.4.N&0 104. (+. !arris >!, [arger DE. >enal function after release of unilateral ureteral obstruction in rats. /m U <hysiol &.41N))4 ,+*. (&. Uaeni"e U>. #he renal response to ureteral obstruction a model for the study of factors which influence glomerular filtration pressure. U Cab ;lin =ed &.4+N4* (4(. (). =oody #E, ?aughan EG, Ur, Billenwater U[. >elationship between renal blood flow and ureteral pressure during &, hours of total unilateral ureteral occlusion implications for changing sites of increased renal resistance. 3nvest Urol &.40N&( )1*. ((. Gal ;anton /, et al. Blomerular hemodynamics before and after release of )16hour bilateral ureteral obstruction. Kidney 3nt &.,+N&4 1.&. (1. Gal ;anton /, et al. Effects of acute ureteral obstruction on glomerular hemodynamics in rat "idney. Kidney 3nt &.44N&) 1+(. (0. !olmes =U, OF=orchoe <U, OF=orchoe ;;. #he role of renal lymph in hydronephrosis. 3nvest Urol &.44N&0 )&0. (*. =oody #E, ?aughan EG, Ur, Billenwater U[. ;omparison of the renal hemodynamic response to unilateral and bilateral ureteral occlusion. 3nvest Urol &.44N&1 100. (4. Bottschal" ;D, =ylle =. =icropuncture study of pressure in proximal tubules and peritubular capillaries of rat "idney and their relation to ureteral and renal venous pressures. /m U <hysiol &.0*N&,0 1(+. (,. Uaeni"e U>. #he renal functional defect of postobstructive nephropathy the effects of bilateral ureteral obstruction in the rat. U ;lin 3nvest &.4)N0& ).... (.. [arger DE, /yned7ian !S, $an" 5. / micropuncture study of postobstructive diuresis in the rat. U ;lin 3nvest &.4)N0& *)0. 1+. #anner B/. 5ephron obstruction and tubuloglomerular feedbac". Kidney 3nt &.,)N))%Suppl &)' S)&(. 1&. #anner B/. Effects of "idney tubule obstruction on glomerular function in rats. /m U <hysiol 14

&.4.N)(4 :(4.. 1). #anner B/, et al. Blomerular and proximal tubular morphology after single nephron obstruction. Kidney 3nt &.,.N(* &+0+. 1(. !arris >!, Bill U=. ;hanges in glomerular filtration rate during complete ureteral obstruction in rats. Kidney 3nt &.,&N&. *+(. 11. Dilson G>, !onrath U. 5ephron functional heterogeneity in the postobstructive "idney. Kidney 3nt &.40N4 &.. 10. [arger DE, Briffith CG. 3ntrarenal hemodynamics following chronic unilateral ureteral obstruction in the dog. /m U <hysiol &.41N))4 ,&*. 1*. SoleE K, et al. 3nner medullary plasma flow in the "idney with ureteral obstruction. /m U <hysiol &.4*N)(& &(&0. 14. Dright :S. Effects of urinary tract obstruction on glomerular filtration rate and renal blood flow. Semin 5ephrol &.,)N) 0. 1,. Schramm C<, ;arlson GE. 3nhibition of renal vasoconstriction by elevated ureteral pressure. /m U <hysiol &.40N)), &&)*. 1.. 5avar CB, $aer <B. >enal autoregulatory and glomerular filtration responses to gradated ureteral obstruction. 5ephron &.4+N4 (+&. 0+. Olsen U$, =agnussen =<, Eilertsen E. <rostaglandins, a lin" between renal hydro6 and hemodynamic in dogs. /cta <hysiol Scand &.4*N.4 (*.. 0&. ?aughan EG Ur, Sorenson EU, Billenwater U[. #he renal hemodynamic response to chronic unilateral complete ureteral occlusion. 3nvest Urol &.4+N, 4,. 0). $lantE >;, Konnen KS, #uc"er $U. Blomerular filtration response to elevated ureteral pressure in both the hydropenic and the plasma6expanded rat. ;irc >es &.40N(4 ,&.. 0(. !umes !G, Gieppa >/, $renner $=. Blomerular dynamics in rats with hereditary hydronephrosis. 3nvest Urol &.,+N&, 1*. 01. 3chi"awa 3, $renner $=. Cocal intrarenal vasoconstrictor6vasodilator interactions in mild partial ureteral obstruction. /m U <hysiol &.4.N)(* :&(&. 00. Dilson G>. =icropuncture study of chronic obstructive nephropathy before and after release of obstruction. Kidney 3nt &.4)N) &&.. 0*. Dilson G>. #he influence of volume expansion on renal function after relief of chronic unilateral ureteral obstruction. Kidney 3nt &.41N0 1+). 04. =cGougal DS, Dright :S. Gefect in proximal and distal sodium transport in post6obstructive diuresis. Kidney 3nt &.4)N) (+1. 0,. !arris >!, [arger DE. #he pathogenesis of post6obstructive diuresis the role of circulating natriuretic and diuretic factors, including urea. U ;lin 3nvest &.40N0* ,,+. 0.. Kerr DS, Ur. Effects of complete ureteral obstruction in dogs on "idney function. /m U <hysiol &.0*N&,1 0)&. *+. ?aughan EG, Ur, Billenwater U[. >ecovery following complete chronic unilateral occlusion functional, radiographic and pathologic alterations. U Urol &.4&N&+* )4. *&. $ander SU, et al. Cong6term effects of )16hour unilateral obstruction on renal function in the rat. Kidney 3nt &.,0N), *&1. *). =ayor B, et al. >enal function in obstructive nephropathy long6term effect of reconstructive surgery. <ediatrics &.40N0* 41+. *(. =c;rory DD, et al. Studies of renal function in children with chronic hydronephrosis. <ediatr ;lin 5orth /m &.4&N&, 110. *1. Shapiro S>, $ennett /!. >ecovery of renal function after prolonged unilateral ureteral obstruction. U Urol &.4*N&&0 &(*. *0. $etter OS, et al. Studies on renal function after relief of complete unilateral ureteral obstruction of three months duration in man. /m U =ed &.4(N01 )(1. **. Billenwater U[, et al. >enal function after release of chronic unilateral hydronephrosis in man. 1,

Kidney 3nt &.40N4 &4.. *4. 5ishi"awa K, =orrison /, 5eedleman <. Exaggerated prostaglandin biosynthesis and its influence on renal resistance in the isolated hydronephrotic rabbit "idney. U ;lin 3nvest &.44N0. &&1(. *,. =orrison />, et al. #hromboxane /) is the ma7or arachidonic acid metabolite of human cortical hydronephrotic tissue. <rostaglandins &.,&N)& 14&. *.. :radet [, et al. Enhanced urinary prostaglandin E) in postobstructive diuresis in humans. <rostaglandins =ed &.,+N0 ).. 4+. S7odin UB, Dahlberg U, <ersson /E. #he effect of indomethacin on glomerular capillary pressure and pelvic pressure during ureteral obstruction. U Urol &.,)N&)4 &+&4. 4&. /llen U#, ?aughan EG, Ur, Billenwater U[. #he effect of indomethacin on renal blood flow and ureteral pressure in unilateral ureteral obstruction in awa"e dogs. 3nvest Urol &.4,N&0 ()1. 4). Edwards B/, Su"i D5. Effect of indomethacin on changes of acute ureteral pressure elevation in the dog. >enal <hysiol &.4,N& &01. 4(. O"egawa #, et al. =etabolic and cellular alterations underlying the exaggerated renal prostaglandin and thromboxane synthesis in ureter obstruction in rabbits inflammatory response involving fibroblasts and mononuclear cells. U ;lin 3nvest &.,(N4& ,&. 41. $lac"shear UC, Dathen >C. Effects of indomethacin on renal blood flow and renin secretory responses to ureteral occlusion in the dog. =iner Electrolyte =etab &.4,N& )4&. 40. ;adnapaphornchai <, et al. <rostaglandin6mediated hyperemia and renin6mediated hypertension during acute ureteral obstruction. <rostaglandins &.4,N&* .*0. 4*. Baudio K=, et al. >enal perfusion and intratubular pressure during ureteral occlusion in the rat. /m U <hysiol &.,+N)(, :)+0. 44. Klahr S. <athophysiology of obstructive nephropathy a &..& update. Semin 5ephrol &..&N&& &0*. 4,. =ene <, Gunn =U. ;ontractile effects of #x/) and endoperoxide analogues on cultured rat glomerular mesangial cells. /m U <hysiol &.,*N)0& :&+).. 4.. /usiello G/, Kreisberg U3, >oy ;, et al. ;ontraction of cultured rat glomerular cells of apparent mesangial origin after stimulation with angiotensin 33 and arginine vasopressin. U ;lin 3nvest &.,+N*0 401. ,+. <ur"erson =C, Klahr S. <rior inhibition of vasoconstrictors normaliEes B:> in postobstructed "idneys. Kidney 3nt &.,.N(0 &(+*. ,&. =orrison />, 5ishi"awa K, 5eedleman <. #hromboxane /) biosynthesis in the ureter obstructed isolated perfused "idney of the rabbit. U <harmacol Exp #her &.4,N)+0 &. ,). Schreiner B:, et al. 3mmunological aspects of acute ureteral obstruction immune cell infiltrate in the "idney. Kidney 3nt &.,,N(1 1,4. ,(. Kawasa"i /, 5eedleman <. ;ontribution of thromboxane to renal resistance changes in the isolated perfused hydronephrotic rabbit "idney. ;irc >es &.,)N0+ 1,*. ,1. 3chi"awa 3, et al. Gietary protein inta"e conditions the degree of renal vasoconstriction in acute renal failure caused by ureteral obstruction. /m U <hysiol &.,0N)1. :01. ,0. Klotman <E, et al. #hromboxane synthetase inhibition improves function of hydronephrotic rat "idneys. /m U <hysiol &.,*N)0+ :),). ,*. [arger DE, Schoc"en GG, !arris >!. Obstructive nephropathy in the rat possible roles for the renin8angiotensin system, prostaglandins, and thromboxanes in postobstructive renal function. U ;lin 3nvest &.,+N*0 1++. ,4. [anagisawa !, et al. <rotein increases glomerular eicosanoid production and activity of related enEymes. Kidney 3nt &..)N1& &+++. ,,. [anagisawa !, et al. Gietary protein restriction normaliEes eicosanoid production in isolated glomeruli from rats with bilateral ureteral obstruction. Kidney 3nt &..1N1* )10. ,.. [anagisawa !, et al. Effects of dietary protein on glomerular eicosanoid production in rats with 1.

bilateral ureteral obstruction. <roc Soc Exp $iol =ed &..1N)+4 )(1. .+. Coo =!, et al. #he effect of the thromboxane /) synthesis inhibitor OK[6+1* on renal function in rabbits following release of unilateral ureteral obstruction. U Urol &.,4N&(4 04&. .&. Strand U;, et al. Effect of imidaEole on renal function in unilateral ureteral6obstructed rat "idneys. /m U <hysiol &.,&N)1+ :0+,. .). 5agle >$, et al. Unilateral obstructive nephropathy in the rabbit. 3. Early morphologic, physiologic and histochemical changes. Cab 3nvest &.4(N), 10*. .(. 5agle >$, Uohnson =E, Uervis !>. <roliferation of renal interstitial cells following in7ury induced by ureteral obstruction. Cab 3nvest &.4*N(0 &,. .1. Gavis $$, #homason G, \enser #?. >enal disease profoundly alters cortical interstitial cell function. Kidney 3nt &.,(N)( 10,. .0. Cef"owith U$, et al. =acrophage6dependent arachidonate metabolism in hydronephrosis. Kidney 3nt &.,1N)* &+. .*. !arris K<B, Schreiner B:, Klahr S. Effect of leu"ocyte depletion on the function of the postobstructed "idney in the rat. Kidney 3nt &.,.N(* )&+. .4. :ol"ert ?=, Schlondorff G. /ltered prostaglandin synthesis by glomeruli from rats with unilateral ureteral ligation. /m U <hysiol &.,&N)1& :),.. .,. [anagisawa !, et al. >ole of angiotensin 33 in eicosanoid production by isolated glomeruli from rats with bilateral ureteral obstruction. /m U <hysiol &..+N),, :,0. <.4&1 ... [anagisawa !, et al. 3ncreases in glomerular eicosanoid production in rats with bilateral ureteral obstruction are mediated by enhanced enEyme activities of both the cyclooxygenase and 06 lipoxygenase pathways. <roc Soc Exp $iol =ed &..(N)+( ).&. &++. Eide 3, et al. =echanism of renin release during acute ureteral constriction in dogs. ;irc >es &.44N1+ ).(. &+&. ;adnapaphornchai <, $ondar 5<, =cGonald :G. Effect of imidaEole on the recovery from bilateral ureteral obstruction in dogs. /m U <hysiol &.,)N)1( :0(). &+). Berber UB, Olson >G, 5ies /S. 3nterrelationship between prostaglandins and renin release. Kidney 3nt &.,&N&. ,&*. &+(. Uac"son EK, et al. *6Keto prostaglandin E& is more potent than prostaglandin 3) as a renal vasodilator and renin secretagogue. U <harmacol Exp #her &.,&N)&* )1. &+1. Su"i D5, et al. Effects of ureteral pressure elevation on renal hemodynamics and urine concentration. /m U <hysiol &.4&N))+ (,. &+0. =oody #E, et al. #he role of intrarenal angiotensin 33 in the hemodynamic response to unilateral obstructive uropathy. 3nvest Urol &.44N&1 (.+. &+*. >eyes //, >obertson B, Klahr S. >ole of vasopressin in rats with bilateral ureteral obstruction. <roc Soc Exp $iol =ed &..&N&.4 1.. &+4. >eyes /, et al. #he role of the 06lipooxygenase pathway in obstructive nephropathy. Kidney 3nt &..)N1& &++. &+,. <ur"erson =C, et al. >ole of atrial peptide in the natriuresis and diuresis that follows relief of obstruction in rat. /m U <hysiol &.,.N)0* :0,(. &+.. =arin6BreE =, :leming U#, Steinhausen =. /trial natriuretic peptide causes pre6glomerular vasodilatation and post6glomerular vasoconstriction in rat "idney. 5ature %Condon' &.,*N()1 14(. &&+. :ried #/, et al. Effect of atriopeptin 33 on determinants of glomerular filtration rate in the in vitro perfused dog glomerulus. /m U <hysiol &.,*N)0+ :&&&.. &&&. >eyes /, et al. EG>: role in renal function and blood pressure of normal rats and rats with obstructive uropathy. Kidney 3nt &..)N1& 1+(. &&). ;hevalier >C, #hornhill $/, BomeE >. EG>: role in renal function and blood pressure of normal rats and rats with obstructive uropathy. Kidney 3nt &..)N1) 1++. 0+

&&(. /strom /, ;rafoord U. /fferent activity recorded in the "idney nerves of rats. /cta <hysiol Scand &.*4N4+ &+. &&1. :rancisco CC, !oversten CB, Gi$ona B:. >enal nerves in the compensatory adaptation to ureteral occlusion. /m U <hysiol &.,+N)(, :)).. &&0. >ibstein U, !umphreys =!. Endogenous opioids and electrolyte excretion after contralateral renal exclusion. /m U <hysiol &.,(N)11 :(.). &&*. Dilson G>, !onrath U, Sole =. Effect of acute and chronic renal denervation on renal function after release of unilateral ureteral obstruction in the rat. ;an U <hysiol <harmacol &.4.N14 4(&. &&4. Dilson G>, !onrath U. Effect of renal denervation, furosemide, and acute saline loading on postobstructive diuresis in the rat. ;an U <hysiol <harmacol &.,&N0. 0.. &&,. Dilson G>, !onrath U, Sole =U. #issue catecholamines in obstructive nephropathy and acute uremia in the rat. ;an U <hysiol <harmacol &.,(N*& &(&. &&.. <ersson /E, et al. #he effect of ) hours of complete unilateral ureteral obstruction on tubuloglomerular feedbac" control. /cta <hysiol Scand &.,1N&)) (0. &)+. Dahlberg U, et al. #ubuloglomerular feedbac" and interstitial pressure in obstructive nephropathy. Kidney 3nt &.,1N)* ).1. &)&. :ulop =, $raEeau <. 3ncreased ureteral bac" pressure enhances renal tubular sodium reabsorption. U ;lin 3nvest &.4+N1. )(&0. &)). Sel"urt EE, $randfonbrener =, Beller !=. Effects of ureteral pressure increase on renal hemodynamics and handling of electrolytes and water. /m U <hysiol &.0)N&4+ *&. &)(. Share C. Effect of increased ureteral pressure on renal function. /m U <hysiol &.0)N&*, .4. &)1. $ay D!, et al. >edistribution of renal cortical blood flow during elevated ureteral pressure. /m U <hysiol &.4)N))) ((. &)0. Dilson G>, ;usimano =, !onrath U. Cac" of effect of chronic renal denervation on altered sodium reabsorption during increased ureteral pressure. ;an U <hysiol <harmacol &.,+N0, 144. &)*. $renner $=, $ennett ;=, $erliner >D. #he relationship between glomerular filtration rate and sodium reabsorption by the proximal tubule of the rat nephron. U ;lin 3nvest &.*,N14 &(0,. &)4. CorentE D$, Ur, Cassiter DE, Bottschal" ;D. >enal tubular permeability during increased intrarenal pressure. U ;lin 3nvest &.4)N0& 1,1. &),. Dilson G>. =echanisms of post6obstructive diuresis in the solitary hydronephrotic "idney of the rat. ;lin Sci =ol =ed &.40N1, &*4. &).. Ditte =!, Short :/, !ollander D, Ur. =assive polyuria and natriuresis following relief of urinary tract obstruction. /m U =ed &.*1N(4 ()+. &(+. ;hander =, et al. #he influence of extracellular fluid volume expansion on postobstructive diuresis in the dog. 3nvest Urol &.4(N&& &&1. &(&. =uldowney :<, et al. Sodium diuresis after relief of obstructive uropathy. 5 Engl U =ed &.**N)41 &).1. &(). =aher U:, Schreiner BE, Dater #U. Osmotic diuresis due to retained urea after release of obstructive uropathy. 5 Engl U =ed &.*(N)*, &+... &((. >aisE CB, /u D[, Scheer >C. Studies on the renal concentrating mechanism. 3?. Osmotic diuresis. U ;lin 3nvest &.0.N(, &4)0. &(1. <eterson CU, et al. <ost6obstructive diuresis a varied syndrome. U Urol &.40N&&( &.+. &(0. =cGougal DS, <ers"y C. >enal functional abnormalities in post6unilateral ureteral obstruction in man a comparison of these defects to post6obstructive diuresis. U Urol &.40N&&( *+&. &(*. $ric"er 5S, et al. /n abnormality in renal function resulting from urinary tract obstruction. /m U =ed &.04N)( 001. &(4. =assry SB, et al. Studies on the mechanism of diuresis after relief of urinary6tract obstruction. /nn 3ntern =ed &.*4N** &1.. &(,. Sonnenberg !, Dilson G>. #he role of medullary collecting ducts in postobstructive diuresis. 0&

U ;lin 3nvest &.4*N04 &0*1. &(.. $uer"ert U, !ead =, Klahr S. Effects of acute bilateral ureteral obstruction on deep nephron and terminal collecting duct function in the young rat. U ;lin 3nvest &.44N0. &+00. &1+. $uer"ert U, et al. On the site of decreased fluid reabsorption after release of ureteral obstruction in the rat. U Cab ;lin =ed &.4*N,4 (.4. &1&. $uer"ert U, et al. Geep nephron function after release of acute unilateral ureteral obstruction in the young rat. U ;lin 3nvest &.4,N*) )),. &1). :alls D:, Ur, Stacy DK. <ostobstructive diuresis studies in a dialyEed patients with a solitary "idney. /m U =ed &.4(N01 1+1. &1(. !anley =U, Gavidson K. 3solated nephron segments from rabbit models of obstructive nephropathy. U ;lin 3nvest &.,)N*. &*0. &11. Dilson G>, !onrath U. ;ross6circulation study of natriuretic factors in postobstructive diuresis. U ;lin 3nvest &.4*N04 (,+. &10. !arris >!, [arger DE. Urine6reinfusion natriuresis evidence for potent natriuretic factors in rat urine. Kidney 3nt &.44N&& .(. &1*. Bulmi :/, et al. /trial natriuretic peptide in patients with obstructive uropathy. U Urol &.,.N&1) )*,. &14. $erlyne B=. Gistal tubular function in chronic hydronephrosis. T U =ed &.*&N(+ ((.. &1,. \etterstr]m >, Ericsson 5O, Dinberg U. Separate renal function studies in predominantly unilateral hydronephrosis. /cta <ediatr &.0,N14 01+. &1.. Earley CE. Extreme polyuria in obstructive uropathy. >eport of a case of @water6losingA nephritis in an infant, with a discussion of polyuria. 5 Engl U =ed &.0*N)00 *++. &0+. Knowlan G, et al. <eriureteral fibrosis, with a diabetes insipidus6li"e syndrome occurring with progressive partial obstruction of a ureter unilaterally. /m U =ed &.*+N), )). &0&. =ees EU. >eversible water loosing state, caused by incomplete ureteric obstruction. /cta =ed Scand &.*+N&*, &.(. &0). >oussa" 5U, Olees"y S. Dater6losing nephritis a syndrome simulating diabetes insipidus. T U =ed &.01N)( &14. &0(. Candsberg C. !ypernatremia complicating partial urinary6tract obstruction. 5 Engl U =ed &.4+N),( 41*. &01. ;ampbell !#, $ello6>euss E, Klahr S. !ydraulic water permeability and transepithelial voltage in the isolated perfused rabbit cortical collecting tubule following acute unilateral ureteral obstruction. U ;lin 3nvest &.,0N40 )&.. &00. $erlyne B=, =ac"en /. On the mechanism of renal inability to produce a concentrated urine in chronic hydronephrosis. ;lin Sci &.*)N)) (&0. &0*. !onda 5, et al. Effect of elevated ureteral pressure on renal medullary osmolal concentration in hydropenic rabbits. /m U <hysiol &.4&N))& *.,. &04. Dilliams >G, :anestil GG, $lac"ard ;E. Etiology of postobstructive diuresis ouabain6 sensitive adenosine triphosphatase deficit and elevated solute excretion in the postobstructed dog "idney. 3nvest Urol &.4*N&1 &1,. &0,. Dilson G>, et al. <ostobstructive nephropathy in the rat relationship between 5a6K6/#<ase activity and renal function. 5ephron &.4,N)) 00. &0.. Dhinnery =/, Shaw UO, $ec" 5. #hromboxane $) and prostaglandin E) in the rat "idney with unilateral ureteral obstruction. /m U <hysiol &.,)N)1) :))+. &*+. $ec" 5, Debster SK. 3mpaired urinary concentrating ability %U;/' and vasopressin %?<'6 dependent cyclic /=< %c/=<' in post6obstructive %<O' "idneys. Kidney 3nt &.40N, 100%abst'. &*&. Schlondorff G, et al. ;hanges in glomerular and cortical tubular c/=< metabolism in "idneys from rats with unilateral ureteral obstruction. >enal <hysiol &.,(N* &4&. &*). /nderson >U, et al. Evidence for an in vivo antagonism between vasopressin and prostaglandin in the mammalian "idney. U ;lin 3nvest &.40N0* 1)+. 0)

&*(. Sto"es U$. Effect of prostaglandin E) on chloride transport across the rabbit thic" ascending limb of !enle. Selective inhibition of the medullary portion. U ;lin 3nvest &.4.N*1 1.0. &*1. :ushimi K, et al. ;loning and expression of apical membrane water channel of rat "idney collecting tubule. 5ature %Condon' &..(N(*& 01.. &*0. :ro"iaer U, et al. $ilateral ureteral obstruction downregulates expression of vasopressin6 sensitive /T<6) water channel in rat "idney. /m U <hysiol &..*N)4+ *04. &**. :ro"iaer U, et al. Gownregulation of aquaporin6) parallels changes in renal water excretion in unilateral ureteral obstruction. /m U <hysiol &..4N)4( :)&(. &*4. [imin Shi, et al. 5eonatal ureteral obstruction alters expression of renal sodium transporers and aquaporin water channels. Kidney 3nt )++1N*1 )+(. &*,. Stec"er U:, Ur, Billenwater U[. Experimental partial ureteral obstruction. 3. /lteration in renal function. 3nvest Urol &.4&N, (44. <.4&0 &*.. Klahr S, !arris K, <ur"erson =C. Effects of obstruction on renal functions. <ediatr 5ephrol &.,,N) (1. &4+. 3brahim /, /bu /sha !. <rediction of renal recovery in hydronephrotic "idneys. $r U Urol &.4,N0+ ))). &4&. #hira"omen K, et al. >enal hydrogen ion secretion after release of unilateral ureteral obstruction. /m U <hysiol &.4*N)(& &)((. &4). Dalls U, et al. 5ature of the acidifying defect after the relief of ureteral obstruction. Kidney 3nt &.40N4 (+1. &4(. Sabatini S, KurtEman 5/. EnEyme activity in obstructive uropathy basis for salt wastage and the acidification defect. Kidney 3nt &..+N(4 4.. &41. Cas"i =E, KurtEman 5/. Site of the acidification defect in the perfused postobstructed collecting tubule. =iner Electrolyte =etab &.,.N&0 &.0. &40. <urcell !, et al. ;ellular distribution of !J6/#<ase following acute unilateral ureteral obstruction in rats. /m U <hysiol &..&N)*& :(*0. &4*. $atlle G;, /rruda U/, KurtEman 5/. !yper"alemic distal renal tubular acidosis associated with obstructive uropathy. 5 Engl U =ed &.,&N(+1 (4(. &44. Kimura !, =u7ais SK. ;ortical collecting duct 5a6K pump in obstructive nephropathy. /m U <hysiol &..+N)0, :&()+. &4,. =uto S, =iyata [, /sano [. Electrical properties of the rabbit cortical collecting duct from obstructed and contralateral "idneys after unilateral ureteral obstruction. U ;lin 3nvest &..(N.) 04&. &4.. =uto S, /sano [. Electrical properties of the rabbit cortical collecting duct from obstructed "idneys after unilateral ureteral obstruction. U ;lin 3nvest &..1N.1 &,1*. &,+. !wang SU, et al. #ransport defects of rabbit medullary thic" ascending limb cells in obstructive nephropathy. U ;lin 3nvest &..(N.& )&. &,&. !wang SU, et al. #ransport defects of rabbit inner medullary collecting duct cells in obstructive nephropathy. /m U <hysiol &..(N)*1 :,+,. &,). Gavis $$, <reuss !B, =urdaugh !?, Ur. !ypomagnesemia following the diuresis of post6 renal obstruction and renal transplant. 5ephron &.40N&1 )40. &,(. <ur"erson =C, Slatopols"y E, Klahr S. Urinary excretion of magnesium, calcium and phosphate after release of unilateral ureteral obstruction in the rat. =iner Electrolyte =etab &.,&N* &,). &,1. $ec" 5. <hosphaturia after release of bilateral ureteral obstruction in rats. /m U <hysiol &.4.N)(4 :&1. &,0. <ur"erson =C, et al. #ubular reabsorption of phosphate after release of complete ureteral obstruction in the rat. Kidney 3nt &.41N0 ()*. &,*. Deinreb S, et al. Upta"e of <i in brush border vesicles after release of unilateral ureteral 0(

obstruction. /m U <hysiol &.,)N)1( :).. &,4. Darshaw $C, et al. <rogression to end6stage renal disease in children with obstructive uropathy. U <ediatr &.,)N&++ &,(. &,,. 5a7arian US, /lmond <S, Billingham KU. >enal transplantation in the first five years of life. Kidney 3nt &..(N11%Suppl 1(' S1+. &,.. Uosephson S, Dolgast =, O7teg B. Experimental obstructive hydronephrosis in newborn rats. 33. Cong6term effects on renal blood flow distribution. Scand U Urol 5ephrol &.,)N&* &4.. &.+. #a"i =, Boldsmith G3, SpitEer /. 3mpact of age on effects of ureteral obstruction on renal function. Kidney 3nt &.,(N)1 *+). &.&. Kuro"awa K, :ine CB, Klahr S. >enal metabolism in obstructive nephropathy. Semin 5ephrol &.,)N) (&. &.). Kissane U=, !eptinstall >!. Experimental hydronephrosis morphologic and enEymatic studies of renal tubules in ureteric obstruction and recovery in the rat. 3. /l"aline and acid phosphatases. Cab 3nvest &.*1N&( 0(.. &.(. Kissane U=, !eptinstall >!. Experimental hydronephrosis morphologic and enEymatic studies of renal tubules in ureteric obstruction and recovery in the rat. 33. <entose phosphate pathway. Cab 3nvest &.*1N&( 014. &.1. $londin U, et al. >enal function and metabolism after relief of unilateral ureteral obstruction. <roc Soc Exp $iol =ed &.40N&0+ 4&. &.0. 5ito !, et al. Effect of unilateral ureteral obstruction on renal cell metabolism and function. U Cab ;lin =ed &.4,N.& *+. &.*. 5agle >$, Evans CD, >eynolds GB. ;ontractility of renal cortex following complete ureteral obstruction. <roc Soc Exp $iol =ed &.40N&1, *&&. &.4. Sto"es #U, =artin KU, Klahr S. 3mpaired parathyroid hormone receptor6adenylate cyclase system in the postobstructed canine "idney. Endocrinology &.,0N&&* &+*+. &.,. =assry SB, et al. S"eletal resistance to the calcemic action of parathyroid hormone in uremia role of &,)0%O!').G(. Kidney 3nt &.4*N. 1*4. &... #annenbaum U, <ur"erson =C, Klahr S. Effect of unilateral ureteral obstruction on metabolism of renal lipids in the rat. /m U <hysiol &.,(N)10 :)01. )++. =orrissey U, et al. Ureteral occlusion decreases phospholipid and cholesterol of renal tubular membranes. /m U <hysiol &.,*N)0+ :&(*. )+&. Sharma K, \iyadeh :5. #he emerging role of transforming growth factor6V in "idney disease. /m U <hysiol &..1N)** :,).. )+). Uones ;C, et al. >enal extracellular matrix accumulation in acute puromycin aminonucleoside nephrosis in rats. /m U <athol &..&N&1& &(,&. )+(. Sharma /K, et al. /ltered expression of matrix metalloproteinase6), #3=<, and #3=<6) in obstructive nephropathy. U Cab ;lin =ed &..0N&)0 401. )+1. Giamond U>, et al. =acrophages, monocyte chemoattractant peptide6& and #B:6b& in experimental hydronephrosis. /m U <hysiol &..1N)** :.)*. )+0. Kaneto !, =orrissey U, Klahr S. 3ncreased expression of #B:6b& m>5/ in the obstructed "idney of rats with unilateral ureteral ligation. Kidney 3nt &..(N11 (&(. )+*. Dalton B, et al. >enal growth factor expression during the early phase of experimental hydronephrosis. U Urol &..)N&1, 0&+. )+4. Giamond U>, et al. 3ncreased expression of decorin in experimental hydronephrosis. Kidney 3nt &..4N0& &&((. )+,. <imental UC, et al. >ole of angiotensin 33 in the expression and regulation of transforming growth factor6V in obstructive nephropathy. Kidney 3nt &..0N1, &)((. )+.. Gavies =, =artin U, #homas BU. <roteinases and glomerular matrix turnover. Kidney 3nt &..)N1& *4&. )&+. Kleiner GE, Stetler6Stevenson, DB. Structural biochemistry and activation of matrix 01

metalloproteinases. ;urr $iol &..(N0 ,.&. )&&. Engelmyer E, et al. Gifferential m>5/ expression of renal cortical tissue inhibitor of metalloproteinase6&, 6), and 6( in experimental hydronephrosis. U /m Soc 5ephrol &..0N0 &*40. )&). >icardo SG, et al. Gown6regulated expression of meprin in experimental hydronephrosis. /m U <athol &..*N(* :**.. )&(. Gesmouliere /, et al. #ransforming growth factor6V& induces S6smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. U ;ell $iol &..(N&)( &+1. )&1. ?yalov S, Gesmouliere /, Babbiani B. B=6;S:6induced granulation tissue formation relationships between macrophage and myofibroblast accumulation. ?irchows /rch $ ;ell <athol &..(N*( )(&. )&0. Uohnson >U, /lpers ;E, [oshimura /, et al. >enal in7ury from angiotensin 336mediated hypertension. !ypertension &..)N&. 1*1. )&*. /lpers ;E, et al. !uman renal cortical interstitial cells with some features of smooth muscle cells participate in tubulointerstitial and crescentic glomerular in7ury. U /m Soc 5ephrol &..1N0 )+&. )&4. Giamond U>, et al. =yofibroblasts in experimental hydronephrosis. /m U <athol &..0N&1* &)&. )&,. =iller #>, et al. Urinary diagnostic indices in acute renal failure a prospective study. /nn 3ntern =ed &.4,N,. 14. )&.. Kaye /G, <ollac" !=. Giagnostic imaging approach to the patient with obstructive uropathy. Semin 5ephrol &.,)N) 00. ))+. $anner =<, <ollac" !=. Evaluation of renal function by excretory urography. U Urol &.,+N&)1 1(4. ))&. Dhitfield !5, et al. :urosemide intravenous urography in the diagnosis of pelviureteric 7unction obstruction. $r U Urol &.4.N0& 110. ))). >aymond !D, \weibel DU, eds. Seminars in ultrasound, ;#, and =>. 3n #he urinary tract, vol. ?33, no. (. 5ew [or" Brune Z Stratton, &.,*. ))(. ;rombleholme #=, et al. <renatal diagnosis and management of bilateral hydronephrosis. <ediatr 5ephrol &.,,N) ((1. ))1. Bray GC, ;rane U<. <renatal diagnosis of urinary tract malformation. <ediatr 5ephrol &.,,N) ()*. ))0. Ellenbogen <!, et al. Sensitivity of gray scale ultrasound in detecting urinary tract obstruction. /m U >oentgenol &.4,N&(+ 4(&. ))*. =alave S>, et al. Giagnosis of hydronephrosis comparison of radionuclide scanning and sonography. /m U >oentgenol &.,+N&(0 &&4.. ))4. #alner C$, et al. !ow accurate is ultrasonography in detecting hydronephrosis in axotemic patients^ Urol >adiol &.,&N( &. )),. Scheible D, #alner C$. Bray scale ultrasound and the genitourinary tract a review of clinical applications. >adiol ;lin 5orth /m &.4,N&4 ),&. )).. <owers #/, et al. Getection of obstructive uropathy using ..mtechnetium diethylenetriaminepentaacetic acid. U Urol &.,+N&)1 0,,. )(+. Koff S/, #hrall U5, Keyes UD, Ur. Giuretic radionuclide urography. / non6invasive method for evaluating nephro6ureteral dilatation. U Urol &.4.N&)) 10&. )(&. Dhitfield !5, et al. #he distinction between obstructive uropathy and nephropathy by radioisotope transit times. $r U Urol &.4,N0+ 1((. )(). $ritton KE, et al. Obstructive nephropathy successful evaluation with radionuclides. Cancet &.4.N& .+0. )((. Kali"a ?, et al. <rediction of renal functional recovery after relief of upper urinary tract obstruction. U Urol &.,&N&)* (+&. 00

)(1. #homsen !S, et al. ;ombination of G=S/6scintigraphy and hippuran renography in unilateral obstructive nephropathy improved prediction of recovery after intervention. /cta >adiol &.,4N), *0(. )(0. Sherman >/, $laufox =G. Obstructive uropathy in patients with nonvisualiEation on renal scan. 5ephron &.,+N)0 ,). )(*. =egibow /U, =itnic" US, $osnia" =/. #he contribution of computed tomography to the evaluation of the obstructed ureter. Urol >adiol &.,)N1 .0. )(4. #Ei"a //, et al. >apid, contrast6enhanced, diuretic magnetic resonance imaging of unilateral partial ureteral obstruction an experimental study in micropigs. 3nvest >adiol &.,.N)1 (4. )(,. ?igneron G$, et al. ;omplete and partial ureteral obstruction evaluation of renal effects with <6(& => spectroscopy and #c6G=S/ scintigraphy. >adiology &.,,N&*, *10. )(.. Dhita"er >!. /n evaluation of &4+ diagnostic pressure flow studies of the upper urinary tract. U Urol &.4.N&)& *+). )1+. Dhitherow >O, Dhita"er >!. #he predictive accuracy of antegrade pressure flow studies in equivocal upper tract obstruction. $r U Urol &.,&N0( 1.*. )1&. Smart D>. Surgical correction of hydronephrosis. 3n !arrison U!, et al., eds., ;ampbellFs Urology, vol. (, 1th ed. <hiladelphia Saunders, &.4,. )1). Grach BD, et al. >eport of the United States cooperative study of extracorporeal shoc" wave lithotripsy. U Urol &.,*N&(0 &&)4. <.4&* )1(. Klahr S. 5ephrology :orum obstructive nephropathy. Kidney 3nt &..,N01 ),*. )11. Klahr S, =orrissey UU. #he role of growth factors, cyto"ines and vasoactive compounds in obstructive nephropathy. Semin 5ephrol &..,N&, *)). )10. Klahr S, =orrissey UU. /ngiotensin 33 and gene expression in the "idney. /m U Kidney Gis &..,N(& &4&. )1*. =orrissey UU, Klahr S. #ranscription factor 5:6X$ regulation of renal fibrosis. Semin 5ephrol &..,N&, *+(. )14. Sweeney <, [oung CS, :itEpatric" U=. /n autoradiographic study of regional blood flow distribution in the rat "idney during ureteric obstruction the role of vasoactive compounds. $UU 3nt )++&N,, )*,. )1,. >eyes //, et al. >ole of the 06lipooxygenase pathway in obstructive nephropathy. Kidney 3nt &..)N1& &++. )1.. =oridaira K, et al. /;E inhibition increases expression of the E#$ receptor in "idneys of mice with unilateral obstruction. /m U <hysiol >enal <hysiol )++(N),1 :)+.. )0+. >eyes //, Klahr S. >enal function after release of ureteral obstruction role of endothelin, and the renal artery endothelium. Kidney 3nt &..)N1) *(). )0&. !egarty 5U, et al. 5itric oxide in unilateral ureteral obstruction effect on regional renal blood flow. Kidney 3nt )++&N0. &+0.. )0). 3to K, et al. Ciposome6mediated transfer of nitric oxide synthase gene improves renal function in ureteral obstruction in rats. Kidney 3nt )++1N** &(*0. )0(. =iller S$, et al. !epatocyte growth factor accelerates recovery from acute ischemic renal in7ury in rats. /m U <hysiol >enal :luid Electrolyte <hysiol &..1N)** :&).. )01. [o [, et al. /ctions of hepatocyte growth factor as a local modulator in the "idney potential role in pathogenesis of renal disease. Kidney 3nt &..,N0( 0+. )00. Kopp U$. !epatocyte growth factor mesenchymal signal for epithelial homeostasis. Kidney 3nt &..,N01 &(.). )0*. =iEuno S, =atsumoto K, 5a"amura #. !epatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy. Kidney 3nt )++&N0. &(+1. )04. [ang U, Ciu [. $loc"age of tubular epithelial to myofibroblast transition by hepatocyte growth 0*

factor prevents renal interstitial fibrosis. U /m Soc 5ephrol )++)N&( .*. )0,. !rus"a K/, et al. Osteogenic protein6& prevents renal fibrogensis associated with ureteral obstruction. /m U <hysiol >enal <hysiol )+++N)4. :&(+. )0.. =orrissey UU, et al. $one morphogenetic protein64 %$=<64' improves renal fibrosis and accelerates the return of renal function. U /m Soc 5ephrol )++)N( S&1. )*+. ;hevalier > C. <romise for gene therapy in obstructive nephropathy. Kidney 3nt )++1N** &4+.. )*&. :elsen G, et al. >enal hemodynamic and ureteral pressure changes in response to ureteral obstruction the role of nitric oxide. U Urol )++(N&*. (4(. )*). =iya7ima /, et al. >ole of nitric oxide in renal tubular apoptosis of unilateral ureteral obstruction. Kidney 3nt )++&N0. &).+. )*(. =iya7ima /, et al. 3nteraction of nitric oxide and transforming growth factor6V& induced by angiotensin 33 and mechanical stretch in rat renal tubular epithelial cells. U Urol )+++N&*1 &4)..

04