Obstructive Nephropathy: Pathophysiology and Management


Obstructive Nephropathy: Pathophysiology and Management

Kevin P. G. Harris


Urine that is produced by the kidney is conveyed to the urinary bladder by the renal pelvis and ureter. This relies on peristalsis occurring within the ureters and, during high urine flow rates, the pressure gradient along them. The urinary bladder is a muscular and distensible storage compartment with a capacity of up to 800 mL in humans. At about a capacity of 150 to 400 mL, stretch receptors result in neurologic signals which relax the involuntary internal urethral sphincter and result in the sensation of needing to urinate, although urination may be delayed by conscious control of the external urethral sphincter as long as the capacity of the bladder is not exceeded. Conscious relaxation of the external urethral sphincter allows urine to be voided through the urethra.

The normal elimination of urine from the body may be affected by pathology anywhere along the urinary tract which either results in a physical barrier to urine flow or disrupts the complex neurologic processes which control it. This is referred to as obstructive uropathy. Typically dilatation of the urinary tract or hydronephrosis then occurs proximal to the site of obstruction, a change which can be readily detected with a variety of imaging techniques. However, hydronephrosis is not synonymous with obstructive uropathy as it can occur without functional obstruction to the urinary tract and can be absent in established obstruction, for example in vesicoureteral reflux (VUR), primary megaureter, and diabetes insipidus.

Impedance to the flow of urine initially results in a high back pressure which causes a number of direct and indirect functional effects on the renal parenchyma, referred to as obstructive nephropathy.

Immediately following acute urinary tract obstruction, changes within the kidney are mainly functional resulting in acute kidney injury (AKI) which may recover with prompt and effective relief of the obstruction. If left untreated, obstruction will result in irreversible structural damage and scarring within the kidney leading to chronic kidney disease (CKD). The management of obstruction to the urinary tract requires close collaboration between nephrologists and urologists in order to minimize long-term and irreversible damage to the kidney, but despite this urinary tract obstruction remains a major cause of CKD worldwide.

Obstructive uropathy is classified as to whether it is acute (less than a few days duration) or chronic and whether it is complete (high grade) or incomplete and partial (low grade). Obstruction is further subdivided into whether it affects the upper urinary tract obstruction (usually unilateral obstruction occurring above the vesicoureteral junction [VUJ]) or lower urinary tract obstruction (usually bilateral obstruction located below the VUJ). Classifying obstruction in this way predicts the likely pathophysiologic effects on the patient; for example, unilateral obstruction in a patient with two normal kidneys will not result in significant renal impairment because the contralateral kidney compensates, but bilateral obstruction or the obstruction of a single functioning kidney will result in renal failure.

Obstruction may result from either acquired or congenital abnormalities. Acquired urinary tract obstruction may affect either the upper or lower urinary tract and can result from either intrinsic or extrinsic causes. Intrinsic causes of obstruction may be intraluminal or intramural.

With increased use and improved sensitivity of antenatal scanning, congenital abnormalities of the urinary tract are now frequently identified early, allowing prompt postnatal (and in some cases antenatal) intervention to relieve the obstruction and hence preserve renal function (1). If obstruction occurs early during development, the kidney fails to develop and becomes dysplastic. If the obstruction is bilateral, there is a high mortality rate as a result of severe renal failure. If the obstruction occurs later in gestation and is low grade or unilateral, hydronephrosis and nephron loss will still occur but renal function may be sufficient to allow survival. Such patients may not present until later in life or only be discovered as an incidental finding.

Incidence and Prevalence

Obstructive uropathy is a common entity and can occur at all ages. The exact incidence of obstructive uropathy is difficult to ascertain, since obstruction occurs in a variety of diseases that may warrant hospitalization and surgical intervention and may be transient. However, the prevalence of hydronephrosis at autopsy is 3.5% to 3.8% of adults and 2% of children, with about equal distribution between males and females (2).

The frequency and etiology of obstruction vary in both sexes with age. Congenital urinary tract obstruction occurs most frequently in males, commonly as a result of either posterior urethral valves or pelvic-ureteral junction (PUJ) obstruction explaining the higher rate of obstructive uropathy in male children less than 10 years old.

In the United States, congenital obstructive uropathy remains the single most common cause of end-stage renal disease (ESRD) in pediatric patients (0–21 years) accounting for about 9% of incident patients (3) and despite improvements in the treatment, this condition may continue to impact into adult life.

Beyond 20 years of age, obstruction becomes more common in females, mainly as a result of pregnancy and gynecologic malignancies. Urolithiasis occurs predominantly in young adults (25–45 years old) and is three times more common in men than in women. In patients older than 60 years, obstructive uropathy is seen more frequently in men, secondary to benign prostatic hyperplasia and prostatic carcinoma. About 80% of men older than 60 years have some symptoms of bladder outflow obstruction, and up to 10% have hydronephrosis. Although the exact relationship between symptoms of bladder outflow obstruction and CKD is unclear, there appears to be a significant association between a decreased peak flow rate and CKD (4).

In the United States the incidence of ESRD due to acquired obstruction is 0.9% with 76% being male and 61% being over the age of 65 (3). However, this is dwarfed by comparison with other causes of ESRD in the adult population such as glomerular disease, diabetes, and hypertension.

Causes of Obstructive Uropathy

The major causes of obstructive uropathy are described in Table 12-1.

Intrarenal tubular obstruction can result from the deposition of uric acid crystals in the tubular lumen after treatment of hematologic malignancies (tumor lysis syndrome), with the precipitation of Bence Jones protein in myeloma and with the precipitation or crystal formation of a number of drugs, including sulfonamides, acyclovir, methotrexate, and indinavir.

Renal calculi, which typically lodge in the calyx, PUJ, or VUJ and at the level of the pelvic brim are the most common cause of extrarenal intraluminal obstruction. Calcium oxalate stones (the most common form) typically cause intermittent acute unilateral urinary tract obstruction in young adults, but rarely significant renal impairment. Struvite, urate, and cystine stones are more often bilateral and more likely to cause long-term renal impairment. Papillary necrosis and a sloughed papilla from diabetes mellitus, sickle cell trait or disease, analgesic nephropathy, renal amyloidosis, and acute pyelonephritis may result in intraluminal obstruction as may blood clots following macroscopic hematuria as a result of renal tumors, arteriovenous malformations, renal trauma, or in patients with polycystic kidney disease (clot colic).

Intramural obstruction can result from either functional or anatomic changes. Functional disorders include VUR, adynamic ureteral segments (usually at the junction of the ureter with the pelvis or bladder), and neurologic disorders. The latter may result in a contracted (hypertonic) bladder or a flaccid (atonic) bladder, depending on whether the lesion affects upper or lower motor neurons, and lead to impaired bladder emptying with VUR. Bladder dysfunction is very common in patients with multiple sclerosis and after spinal cord injury, and is also seen in diabetes mellitus and Parkinson disease and after cerebrovascular accidents. Some drugs (anticholinergics, levodopa) can alter neuromuscular activity of the bladder and result in functional obstruction, especially if there is preexisting bladder outflow obstruction (e.g., prostatic hypertrophy). Anatomic causes of intramural obstruction of the upper urinary tract include transitional cell carcinoma of the renal pelvis and ureter and ureteral strictures secondary to radiotherapy or retroperitoneal surgery. Rarely, obstruction may result from ureteral valve malfunction, polyps, or strictures after therapy for tuberculosis. Intramural obstruction of the lower urinary tract can result from urethral strictures, which are usually secondary to chronic instrumentation or previous urethritis, or malignant and benign tumors of the bladder. Infection with Schistosoma haematobium, when the ova lodge in the distal ureter and bladder, is a common cause of obstructive uropathy worldwide, with up to 50% of chronically infected patients developing ureteral strictures and fibrosis with contraction of the bladder.

Table 12–1 Causes of Obstruction in the Urinary Tract

Upper Urinary Tract

Lower Urinary Tract

Intrinsic Causes


Intratubular deposition of crystals (uric acid, drugs) or Bence Jones protein

Ureter: stones, clots, renal papillae, fungus ball


Ureteropelvic or ureterovesical junction dysfunction

Ureteral valve, polyp, stricture, or tumor

Anatomic Causes

Phimosis, meatal stenosis, paraphimosis

Urethra: strictures, stones, diverticulum, posterior anterior urethral valves, urethral infections, periurethral abscess, uretheral surgery

Prostate: benign prostatic hyperplasia, abscess, prostatic carcinoma

Bladder: calculus, malignancy

Trauma, straddle injury

Pelvic fracture

Extrinsic Causes

Originating in the reproductive system

Uterus: pregnancy, prolapse, tumors, endometriosis

Ovary: abscess, tumors,

Cervix: carcinoma

Prostate: carcinoma

Vascular system

Aneurysm: abdominal aorta, iliac vessels

Aberrant vessels: ureteropelvic junction

Venous: retrocaval ureter, ovarian vein

Fibrosis following vascular reconstructive surgery

Lesions of the gastrointestinal tract

Crohn disease


Appendiceal abscess

Tumors, abscess, cyst

Diseases of the retroperitoneum

Retroperitoneal fibrosis (idiopathic radiation)

Inflammatory: tuberculosis, sarcoidosis


Primary retroperitoneal tumors (lymphoma, sarcoid)

Metastatic disease in the retroperitoneum (cervix, bladder, colon, prostate)


Inadvertent surgical ureteric ligation

Functional Causes

Neurogenic bladder: spinal cord defect or trauma, diabetes, multiple sclerosis, cerbrovascular accidents, Parkinson disease

Drugs: anticholinergics, antidepressants, L-DOPA

While ureteral dilation without functional obstruction is commonly seen in pregnancy as a result of hormonal effects (especially progesterone) on smooth muscle, extrinsic obstruction sometimes resulting from compression of the urinary tract is pressure from a gravid uterus on the pelvic rim with the right ureter being more commonly affected. It is usually asymptomatic, the changes resolve rapidly after delivery, and AKI from bilateral obstruction is very rare.

Extrinsic obstruction may result from malignancy compressing or directly invading the urinary tract. Direct extension of the tumor to involve the urinary tract occurs in up to 30% of patients with carcinoma of the cervix. Other pelvic pathologies that can cause ureteral compression include benign and malignant uterine and ovarian masses, abscesses, endometriosis, and pelvic inflammatory disease.

In males, the most common cause of extrinsic obstruction of the lower urinary tract is benign prostatic hypertrophy. Carcinoma of the prostate can also result in obstruction either from direct tumor extension to the bladder outlet or ureters or from metastases to the ureter or lymph nodes.

Retroperitoneal pathology such as primary or secondary tumors or inflammatory disease may also result in extrinsic obstruction of the ureters. Retroperitoneal fibrosis, in which a thick fibrous tissue extends out from the aorta to encase the ureters and draw them medially, may be idiopathic or result from inflammatory aortic aneurysms, certain drugs (e.g., β-blockers, bromocriptine, and methysergide), previous radiation, trauma or surgery, and granulomatous disease.

Inadvertent ureteric ligation is a rare but recognized complication of pelvic surgical procedures and may go unrecognized.

The Effects of Urinary Tract Obstruction on Renal Function

The increased pressure that occurs after the onset of ureteral obstruction triggers profound functional and structural changes within the kidney. This increase in pressure is greatest immediately after the onset of obstruction and tends to fall with time with incomplete obstruction. Damage in the obstructed kidney is potentiated by those conditions that acutely increase ureteral pressure, such as increases in urine flow (i.e., an increase in fluid intake or after administration of diuretics) or augmentation of the degree of obstruction or both.

It is rarely possible to accurately define the time of onset of obstruction in humans or to obtain repetitive measurements of renal function. Therefore, our understanding of the consequences of urinary tract obstruction stems mainly from the study of animal models (5). The majority of studies have used invasive techniques to examine the effects of complete short-term ureteral obstruction in rodents. Investigators have also examined models of chronic complete, partial, or reversible obstruction in adult and neonatal animals and modern imaging techniques have been used to noninvasively examine the effects of obstruction on glomerular and tubular function (6). In general, there appears to be little species-to-species variation in the response to acute obstruction, suggesting similar changes are likely to occur in humans. Although initially the changes are predominantly functional and potentially reversible, chronic obstruction results in irreversible structural changes (7), and models of obstruction are often used to examine the pathogenetic mechanisms underlying the development of renal fibrosis from any cause (8).


Experimental evidence suggests that ureteral obstruction may reduce glomerular filtration rate (GFR) though effects on (a) the mean difference in hydrostatic pressure between the glomerular capillary lumen and Bowman’s space (ΔP); (b) renal plasma flow (QA); (c) the ultrafiltration coefficient of the glomerular capillary wall (Kf), which reflects both the total surface area available for filtration and the intrinsic permeability characteristics of the filtering apparatus. The manner in which these parameters are affected depends on the duration of the obstruction, the volume status of the animal, and whether or not a contralateral functioning kidney is present.

GFR falls progressively following the onset of complete ureteral obstruction (9) but can be maintained to some extent by continuous reabsorption of salt and water along the nephron, the ability of the renal tract to dilate, and alterations in renal hemodynamics.

Changes in Hydrostatic Pressure Gradients

Ligation of the ureter increases ureteral pressure causing an immediate increase in proximal tubular pressure, the latter being higher than that in the ureter. The rise in intratubular pressure depends on the degree of hydration of the animal, mean urine flow rate, and whether one or both kidneys are obstructed. Nevertheless, independent of the volume status, intratubular pressure rises within an hour of ureteral obstruction (Fig. 12-1). Concomitantly, there is an increase in glomerular capillary hydrostatic pressure; however, this increase in intraglomerular pressure is not proportional to the rise in intratubular pressure (10). Therefore, the net hydrostatic pressure difference across glomerular capillaries decreases. This results in a decline in GFR. After approximately 5 to 6 hours of ureteral obstruction, proximal intratubular pressure begins to decline (11). After 24 hours, intratubular pressures are lower than (11,12) or equal to (13) values before obstruction in animals with unilateral ureteral obstruction (UUO), but this does not restore an effective filtration pressure, because intraglomerular capillary hydrostatic pressure declines at an even faster rate (11,12) and falls below the levels seen before obstruction. In animals with bilateral ureteral obstruction, proximal intratubular pressures are initially twofold higher (11,14) than those seen in rats with UUO (Fig. 12-1). By 24 hours, the levels of intratubular pressure have fallen but not back to the baseline (14,15). At this time, glomerular capillary pressure is no different from preobstruction values. Thus, in this setting, high intratubular pressures contribute significantly to the decrease in GFR.

Figure 12–1 Pressure in proximal renal tubules (PT) before, during, and after release of complete obstruction of one ureter (UUO), both ureters (BUO), or single nephrons (SNO). BUO, bilateral ureteral obstruction; SNO, single-nephron obstruction; UUO, unilateral ureteral obstruction.

Changes in Renal Blood Flow

Ureteral obstruction causes a transient increase in renal blood flow (16). Decreased resistance of the afferent arteriole accounts for the increase in blood flow to the unilaterally obstructed kidney (16,17). This phenomenon is observed in both the denervated and the isolated perfused kidney, suggesting that this hyperemic phase is mediated through an intrarenal mechanism. Measurements of the distribution of blood flow during this phase indicate that inner cortical blood flow is increased (1820). There is a progressive decrease in blood flow to the inner medulla during ureteral obstruction (21). This increase in renal blood flow may represent a hemodynamic response intended to maintain GFR. The increase in renal blood flow and afferent arteriolar dilatation leads to an increase in glomerular capillary pressure. This response maintains GFR at approximately 80% of preobstruction values despite the substantial increase in proximal tubular pressure. The mechanism underlying this response involves a signal generated at the single-nephron level because a wax plug placed in the proximal tubule generates an identical hemodynamic response in a single glomerulus. Tanner (22) suggested that the fall in afferent arteriolar resistance was caused by tubular-glomerular feedback related to interrupting acutely distal delivery of tubular fluid to the macula densa. Ichikawa (23), however, demonstrated that glomerular blood flow does not rise if proximal tubular pressure is maintained in the normal range in the face of tubule blockade, suggesting that the altered glomerular hemodynamics are a result of intratubular dynamics rather than cessation of distal delivery of tubule fluid. The transient increase in renal blood flow after ureteral obstruction can be prevented by the administration of inhibitors of prostaglandin synthesis such as indomethacin (24). Thus, vasodilator prostaglandins, such as prostaglandin E2 and prostacyclin, may account for this initial vasodilator effect. At this time interval, the renal vascular bed is particularly resistant to vasoconstriction induced by either electrical stimulation of renal nerves or an infusion of catecholamines. In addition, autoregulation of renal blood flow is impaired, suggesting a prominent vasodilating influence following the onset of ureteral obstruction. Usually the increase in blood flow following obstruction peaks at about 2 to 3 hours.

In a second phase, approximately 3 to 5 hours after the onset of obstruction, renal blood flow starts to decline, while ureteral pressure continues to increase. In part, this may be a consequence of augmented renal resistance owing to increased interstitial pressure. In this phase, ureteral pressure starts to fall toward control values, and renal plasma flow continues to decline, reaching about 30% to 50% of control values by 24 hours (25,26). This vasoconstrictive response of the kidney to UUO results predominantly from an increased resistance of afferent arterioles.

In animals with bilateral ureteral obstruction, the changes in renal hemodynamics are similar to those seen following UUO. There also is an initial hyperemic phase (14,16) that is blocked by cyclooxygenase inhibitors (24), and the decline in GFR thus is secondary to a rise in intratubular pressure. Renal plasma flow falls progressively and is similar at 24 hours to that seen after UUO, although afferent arteriole resistance may not increase as much. As a result of the persistently high proximal tubular pressure and decline in renal plasma flow, it would be expected that the decline in GFR would be greater after bilateral ureteral obstruction than after UUO. However, this is not the case and may reflect the effect of a higher intraglomerular capillary pressure and greater number of filtering nephrons before and after release of obstruction of 24 hours’ duration in rats with bilateral ureteral obstruction than in those with UUO (27).

Changes in the Ultrafiltration Coefficient

After ureteral obstruction, GFR falls to a greater extent than renal plasma flow (9). Thus, the filtration fraction decreases. This may reflect preferential constriction of the preglomerular blood vessels because this would lower both blood flow and glomerular capillary pressure, thus resulting in a greater decrement in GFR than in blood flow. Alternatively, it is suggested that there is either diversion of blood to nonfiltering areas of the kidney or a reduced area available for filtration per glomerulus. That the latter occurs is suggested by the finding that Kf values in rats with ureteral obstruction are lower than those typically obtained in normal rats (28).

In summary, the fall in single-nephron GFR in obstruction is caused by a decrease in net hydrostatic pressure across the glomerular capillary wall. The fall in net hydrostatic filtration pressure initially is caused by an increase in intratubular pressure. After 24 hours of obstruction, the main mechanism responsible for the decrement in net hydrostatic pressure across the glomerular capillary wall is a fall in intraglomerular pressure. In animals with bilateral ureteral obstruction, both a persistent increase in intratubular pressure and a decrease in intraglomerular pressure contribute to the decrease in net hydrostatic pressure across glomerular capillaries. There also is evidence that Kf is decreased. The greater decrease in total kidney GFR than in single-nephron GFR after 24 hours of obstruction results from the fact that some nephrons cease to function during the period of obstruction.


After complete ureteral obstruction in the rat, GFR reaches 2% of control values by 48 hours and remains at this low level. Renal plasma flow also declines but to a lesser extent (25). The effects of partial chronic obstruction of the ureter depend on both the degree and the duration of the obstruction. Whole-kidney GFR may be reduced to one-third of control values 2 to 4 weeks following partial ureteral obstruction in the rat (29). Single-nephron GFR, however, is reduced by only 20% of control levels, suggesting that the decline in whole-kidney function is a result of a loss in the number of functioning nephrons not accessible to micropuncture, that is, juxtamedullary nephrons (30).

Rats with partial obstruction of 2 to 4 weeks’ duration have a 30% decrease in Kf. GFR and single-nephron plasma flow are maintained near normal because of an increase in glomerular capillary pressure secondary to a greater decrease in afferent than efferent arteriolar resistance. This vasodilatation is prostaglandin mediated, and indomethacin administration increases both afferent and efferent arteriolar resistance and causes a decline in single-nephron GFR (31).


Experimental studies suggest that the vasoconstrictors angiotensin II and thromboxane A2 play a central role in the changes in plasma flow per nephron and single-nephron GFR seen after obstruction. Inhibition of thromboxane A2 synthesis in rats with ureteral obstruction increases plasma flow per nephron, owing to decreased vasoconstriction of both afferent and efferent arterioles (29). Thromboxane also may decrease Kf through mesangial cell contraction and a decrease in the surface area available for filtration. Although infusion of angiotensin II into normal animals increases net filtration pressure, presumably because of greater vasoconstriction of the efferent than the afferent arteriole, blockade of angiotensin II formation after relief of obstruction increases GFR (29). This increase in GFR may result from a greater filtering surface area, because angiotensin II causes mesangial cell contraction and therefore can reduce the total glomerular capillary area available for filtration. In addition, angiotensin II decreases plasma flow per nephron, which also contributes to the fall in single-nephron GFR. The central and critical role of these two vasoconstrictors in modulating postobstructive renal hemodynamics is illustrated by the fact that rats pretreated with both angiotensin-converting enzyme (ACE) and thromboxane synthase inhibitors, before obstruction, demonstrate almost normal renal function after release of obstruction (32).

Vasodilator prostaglandins, produced in increased amounts by the obstructed kidney, may prevent further decrements in GFR by antagonizing the vasoconstrictive effects of thromboxane A2 and angiotensin II. Indeed, it has been demonstrated that after release of obstruction in rats, in the setting of prior inhibition of the thromboxane synthase, administration of inhibitors of the cyclooxygenase causes a marked decrease in whole-kidney GFR and renal plasma flow (31).

Atrial natriuretic peptide (ANP), which can cause preglomerular vasodilatation and postglomerular vasoconstriction and increase Kf, are higher in rats with bilateral ureteral obstruction than in rats with UUO (33). ANP antagonizes the vasoconstrictive effects of angiotensin II, raising the possibility that the elevated levels of endogenous ANP in animals with bilateral ureteral obstruction minimize the renal vasoconstriction that occurs compared with animals with UUO.

An interstitial leukocyte infiltrate, predominantly macrophages, is an early event following ureteral obstruction. This begins to increase as early as 4 to 12 hours after ureteral obstruction and continues to increase over the course of days thereafter. By 4 days after left ureteral ligation, there is a 20-fold increment in the renal cortical macrophage number in the obstructed kidney versus either the contralateral unobstructed kidney or normal kidneys from age-matched, sham-operated animals (34). The signal for renal leukocyte recruitment immediately after ureteral obstruction is predominantly macrophage specific and appears to plays a key role in the acute functional changes after ureteral obstruction (35).


The degree of recovery of GFR after release of ureteral obstruction depends on the severity and duration of the obstruction. After release of a 2-week complete ureteral obstruction in the dog, GFR in the postobstructed kidney averages 25% of ipsilateral control values and 16% of concurrent values for the contralateral kidney, the latter having undergone a compensatory increase in GFR (36). Subsequently, the GFR of the postobstructed kidney increases, and the GFR of the normal kidney falls, stabilizing at about 2 months after the release of obstruction. However, GFR does not return to normal in the postobstructed kidney, remaining approximately 50% below the value obtained for the contralateral kidney at 2 years. The changes in effective renal plasma flow mirror the changes seen in GFR.

In rats, a permanent decrease in GFR occurs if ureteral obstruction has been present for >72 hours. After obstruction lasting <30 hours, recovery of whole-kidney GFR is complete, although the normalization in GFR may not be a consequence of homogeneous recovery in single-nephron GFR for all nephrons (37). When single-nephron GFR and the number of filtering nephrons are determined using a modification of Hansen’s technique, only 85% of the nephrons filter in the postobstructed kidney (37), suggesting the normalization of whole-kidney GFR occurs at the expense of hyperfiltration (increase in single-nephron GFR) in the remaining functional nephrons (Fig. 12-2). There appears to be a permanent decrement in the total number of functional nephrons.

Figure 12–2 SNGFR in SUP and JM nephrons of rats 8 and 60 days after release of UUO of 24 hours’ duration. The SNGFR values for the POK were significantly greater (asterisk) than those of the contralateral kidney. JM, juxtamedullary; POK, postobstructed kidney; SNGFR, single-nephron glomerular filtration rate; SUP, superficial; UUO, unilateral ureteral obstruction.

The permanent loss of nephrons is likely to be a consequence of fibrosis resulting from renal ischemia and the infiltration into the kidney of biologically active macrophages. The long-term significance of this on the development of significant CKD in adults is unclear particularly if the period of obstruction has been short. However, obstruction to the developing kidney either prenatally or in childhood appears to have important effects on renal function later in adult life even with effective relief of the obstruction (38).


Urinary tract obstruction results in altered renal handling of electrolytes and changes in the regulation of water excretion with a decreased ability to concentrate the urine. The degree and nature of the tubular defects after obstruction depend in part on whether the obstruction is bilateral or unilateral as a result of the dissimilar hemodynamic responses, different intrinsic changes within the nephron, and differences in extrinsic factors (e.g., volume expansion and accumulation of natriuretic substances in bilateral obstruction).

Sodium and Water Handling

In spite of a decrease in GFR and hence in the filtered load of sodium, the excretion of sodium by the postobstructed kidney of rats with UUO is similar to that of the contralateral kidney (39). Thus, fractional sodium excretion is greater from the postobstructed than from the contralateral kidney. Similar findings have been reported in the dog and in humans after more prolonged periods of obstruction. These findings indicate significant changes in the tubular reabsorption of sodium and water by the previously obstructed kidney. Changes in intravascular volume may affect the absolute and fractional excretion of salt and water by the postobstructed kidney. Absolute sodium excretion after release of UUO is reduced in rats with volume depletion studied under anesthesia when compared with awake rats. In contrast, expansion of the extracellular fluid (ECF) volume with saline solution increases both absolute and fractional sodium excretion. These increases are greater in the postreleased kidney than in the contralateral untouched kidney.

The release of bilateral ureteral obstruction results in a different quantitative excretion of salt and water than what occurs after release of UUO. There is a dramatic increase in the absolute amount of sodium and water excreted in the urine after release of bilateral ureteral obstruction in humans (40) and experimental animals (41,42), resulting in the so-called postobstructive diuresis. The differences in salt and water excretion after release of bilateral ureteral obstruction and UUO may result from accumulation of osmolytes such as urea and the expansion of the ECF volume during the period of bilateral ureteral obstruction. In addition, the circulating levels of ANP are significantly greater in rats with bilateral ureteral obstruction than in those with unilateral obstruction (33).

Urinary Concentration

Patients with partial obstruction of the urinary tract or patients after relief of partial or complete urinary obstruction have impaired renal concentrating capacity (43), which may take some months to recover following the release of obstruction.

After relief of unilateral obstruction of 24 hours’ duration in rats, the urine osmolality from the postobstructed kidney seldom exceeds 400 mOsm/kg H2O compared with approximately 2,000 mOsm/kg H2O in the contralateral untouched rat kidney.

The urinary concentrating defect may be explained by both a decreased hypertonicity of the medullary interstitium and a failure of the cortical collecting duct to respond to the action of antidiuretic hormone (ADH). The later may result from a decrease in expression of aquaporin-2 following obstruction to the urinary tract (44).

Obstruction results in a permanent decrease in the number of juxtamedullary nephrons (37). As these have the longest loops of Henle and are responsible for the reabsorption of solutes and the creation of a hypertonic medulla, their loss causes a permanent defect in the concentrating ability of the postobstructed kidney, although this is not as marked as that seen in the acute stages of obstruction.

In addition to the mechanisms described above, following release of bilateral ureteral obstruction, the osmotic effect of solutes retained during the period of obstruction contributes to the generation of isotonic urine after relief of bilateral ureteral obstruction.

Urinary Acidification

In humans (43) and experimental animals (45,46), acid excretion is impaired after the release of obstruction, and returns to normal after some time (months). Studies in experimental animal models of urinary tract obstruction (46) as well as in patients (43) suggest there is a form of distal renal tubular acidosis with an inability to lower the urine pH to normal minimum values in response to acidemia or acid loading.

Potassium Excretion

At any given level of GFR, the fractional excretion of potassium is less in patients with obstructive uropathy than in a comparable group of patients with renal insufficiency caused by a variety of renal diseases (Fig. 12-3). There is a hyperkalemic hyperchloremic acidosis (47) which may be explained at least in part by (a) a deficiency of aldosterone secretion probably secondary to diminished production of renin by the kidney (hyporeninemic hypoaldosteronism), (b) a defect in renal hydrogen ion secretion with an inability to lower pH of the urine maximally in the presence of systemic acidosis and decreased urinary excretion of both ammonium and titratable acid (type 4 distal renal tubular acidosis), (c) a combination of these two defects, or (d) a decreased sensitivity of the distal tubule to the action of aldosterone on potassium secretion.

Excretion of Divalent Cations and Phosphate

Experimental studies have demonstrated a number of changes to the way the kidney handles divalent cations and phosphate following obstruction (48). Fractional excretion of calcium is decreased after release of unilateral obstruction but magnesium excretion increases following release of bilateral or UUO and may result in profound hypomagnesemia.

The reabsorption of phosphate by the postobstructed kidney depends on both the duration of the obstruction and whether the obstruction is bilateral or unilateral. After release of UUO, altered phosphate excretion results primarily from altered renal hemodynamics, and following release of bilateral ureteral obstruction, phosphate excretion is modulated to a large extent by extrarenal factors, mainly the serum levels of phosphate. The obstructed kidney can still respond to exogenous parathyroid hormone administration with an increase in urine phosphate and cyclic 3′5′-adenosine monophosphate excretion, but the magnitude of the response is less in the postobstructed kidney than in the contralateral kidney.

Figure 12–3 Relation of FEK to GFR under baseline conditions. The area inside the broken line depicts the normal adaptive increase in fractional potassium excretion observed with a chronic reduction in GFR. These data were obtained from 14 normokalemic controls (triangles) with different GFRs. Each patient (circle and square symbols) had a baseline FEK lower than that expected for the corresponding GFR. Circles denote patients with distal renal tubular acidosis (group I); open squares represent patients with hyperkalemic metabolic acidosis owing to selective aldosterone deficiencies (group II). FEK, fractional excretion of potassium; GFR, glomerular filtration rate. (From Batlle DC, Arruda JAL, Kurtzman NA. Hyperkalemic distal renal tubular acidosis associated with obstructive uropathy. N Engl J Med. 1981;304(7):373–380, Copyright ¿ 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

The Effects of Ureteral Obstruction on Renal Structure

Following ureteral obstruction, a number of factors result in morphologic changes to the kidney, including the increase in ureteral pressure, the decrease in renal blood flow (ischemia), an invasion by macrophages and lymphocytes, and bacterial infection. The subsequent macroscopic structural changes that are found in the kidney depend on both the duration and degree of the obstruction.

Following acute complete obstruction initially, there is pelvicalyceal dilation, renal enlargement, and edema (Fig. 12-4, left panel). Microscopically, tubular dilation develops that predominantly affects the collecting duct and distal tubular segments (49), though cellular flattening and atrophy of proximal tubular cells can also occur. Glomerular structures are usually preserved initially, although Bowman’s space may be dilated and may contain Tamm–Horsfall protein. Ultimately, some periglomerular fibrosis may develop.

In chronic partial obstruction a grossly hydronephrotic kidney develops with a widely dilated renal pelvis, with the renal papilla either flattened or hollowed out. The first structures to be affected are the ducts of Bellini. Subsequently, other papillary structures are damaged. Ultimately, there is an encroachment on renal cortical tissue, which in advanced cases may be reduced to a thin rim of renal tissue surrounding a large saccular ureteral pelvis (Fig. 12-4, right panel).

Prolonged obstruction results in the development of interstitial fibrosis with obliteration of nephrons. There is tubular proliferation and apoptosis, epithelial–mesenchymal transition (EMT), (myo)fibroblast accumulation, increased extracellular matrix deposition, and tubular atrophy. Ischemia as a result of the decreased renal blood flow contributes to the parenchymal damage after obstruction.

Both angiotensin II and transforming growth factor-β (TGF-β) appear to play an important pathogenetic role in the development of renal fibrosis following obstruction (50,51). Over the past two decades or so, experimental models of ureteral obstruction have been used to elucidate the mechanisms which underlie the development of fibrosis in CKD resulting in an in-depth understanding of the role played by signaling pathway networks and profibrotic cytokines in the regulation of kidney fibrosis (52).

Figure 12–4 Kidney specimens demonstrating the contrasting macroscopic structural effects of complete short-term and partial long-term urinary tract obstruction. Left Panel: An acutely obstructed kidney showing a dilated pelvicalyceal system (a) and an edematous but well preserved renal parenchyma (b). Right Panel: A chronically partially obstructed kidney due to pelvic-ureteral junction obstruction showing gross dilatation of the pelvicalyceal system (c) and a thin and atrophic renal cortex (d).

Invading cells, particularly macrophages, by releasing inflammatory and growth factors, may contribute to interstitial cell proliferation and scarring and widening of the interstitium space. Superimposed bacterial infection (pyelonephritis) may play an additive role in the development of parenchymal fibrosis and in the pathologic changes that are observed (53).

The sequence of events whereby the acute functional and reversible alterations in kidney function following obstruction transform into chronic irreversible structural abnormalities involves a complex interplay between infiltrating and resident cells, the production of hormones, cytokines, and growth factors, as well as the modulation of matrix production and degradation. These factors are discussed below and are summarized in Figure 12-5.


The tubulointerstitium occupies approximately 80% of total kidney volume. Renal interstitial fibrosis is a common consequence of long-standing obstructive uropathy (54) and develops because of an imbalance between extracellular matrix synthesis, matrix deposition, and matrix degradation. Typical findings include a widening of the interstitial space, a mononuclear cell infiltrate and a proliferation of interstitial cells in the renal parenchyma, and an increase in the renal synthesis of several extracellular matrix components (collagen types I, III, and IV; fibronectin; heparan sulfate proteoglycans) in the renal interstitium (55). These changes are associated with an increase in the level of messenger RNA (mRNA) for TGF-β1 within the interstitium of the obstructed kidney after only short periods of obstruction suggesting that the events which lead to interstitial fibrosis are initiated promptly after the onset of obstruction (56).

Renal tubular cells in culture produce collagen types I, III, and IV, and the expression of collagen α1 (type IV) mRNA increases in the tubules of the obstructed kidney. Therefore, renal tubule cells may contribute to the increased production of collagen IV in both tubular basement membrane and the interstitium, which in turn may contribute to alterations in tubular function in the obstructed kidney.

Figure 12–5 The sequence of events whereby the acute functional and reversible alterations in kidney function following obstruction transform into chronic irreversible structural abnormalities. Note the pivotal role of infiltrating macrophages in both modulating acute functional changes and promoting the development of irreversible structural damage and fibrosis.

At the same time, factors derived from infiltrating macrophages and T-lymphocytes stimulate fibroblast migration and proliferation in the interstitium of the obstructed kidney. Several cytokines secreted by infiltrating macrophages and T-lymphocytes act as chemoattractants and stimulate fibroblast proliferation. Interstitial fibroblasts produce collagens I, III, and IV, and therefore contribute to the increase in the production of collagens in the obstructed kidney. The substantial increase in collagens I and III in the interstitium of the obstructed kidney at 3 or 5 days after UUO is consistent with the increased cellularity caused by fibroblast proliferation and infiltrating mononuclear cells.

The increased expression of TGF-β1 mRNA in the obstructed kidney is confined to tubular cells (56). TGF-β1 has substantial effects on matrix protein production (52,57). It causes (a) an increase in the mRNA of extracellular matrix components, particularly the collagens; (b) a decrease in proteinases degrading these proteins; and (c) an increase in metalloproteinase inhibitors (Fig. 12-6).

In contrast, the amount of glomerular collagens I, III, and IV is unchanged as is mRNA for TGF-β1 at day 5 after UUO (56), consistent with the finding that glomeruli appear normal by light microscopy after 7 days of obstructive nephropathy (58).


Distinct patterns of cell proliferation and apoptosis have been described for tubular, interstitial, and glomerular cells, as well as infiltrating cells in chronic obstructive nephropathy. The development of interstitial inflammation and fibrosis following prolonged obstruction is accompanied by tissue loss and atrophy of the tubular epithelial cells (59,60). Apoptosis of renal tubular cells in chronic obstructive nephropathy increases rapidly, reaching 30-fold that of controls by 25 days of obstruction (61). This is accompanied by a decrease in the dry weight of the kidney, suggesting apoptosis participates in the tubular atrophy and renal loss observed in prolonged obstructive nephropathy.

Apoptosis is a prominent feature of obstruction to the urinary tract in utero and leads to the loss of renal mass commonly observed in this condition. There is increasing evidence that apoptosis may also act as a trigger for the subsequent development of progressive interstitial fibrosis.

Figure 12–6 Pathogenesis of tubule-interstitial fibrosis in progressive renal disease. AII, angiotensin II; ECM, extracellular matrix; mRNA, messenger RNA; TGF-b1, transforming growth factor beta-1; EMT, epithelial–mesenchymal transition.


Following ureteral obstruction, there is an increased synthesis and expression of adhesion proteins and chemoattractants in the kidney, which contribute to monocytic infiltration. Monocyte chemo-attractant protein-1 (MCP-1) mRNA and protein expression is increased within the proximal tubular epithelium of the obstructed but not the contralateral unobstructed kidney (6264). The resulting macrophage infiltrate plays a pivotal role in the chronic tissue injury and fibrosis that result from prolonged ureteral obstruction (65) by releasing profibrogenic factors such as TGF-β and galectin-3 that promote progressive fibrosis (66). The critical role for infiltrating macrophages in the pathogenesis of the late structural changes that occur after obstruction is demonstrated by the observation that macrophage depletion markedly limits the development of interstitial fibrosis. In addition to macrophages, the cellular infiltrate following obstruction also contains a number of T cells. The exact way in which the various cell types and local cytokine networks interact to modulate the fibrotic response is complex and may represent a final common pathway to the development of fibrosis in a number of renal diseases with different etiologies (67).


Following ureteral obstruction, local angiotensin II generation can stimulate the production of TGF-β by tubular cells and promote the deposition of the type IV collagen and the development of tubulointerstitial fibrosis within the obstructed kidney (Fig. 12-6).

ACE inhibitors and angiotensin receptor antagonists exert a beneficial effect on the UUO model of experimental hydronephrosis (68,69). Administration of ACE inhibitors in rats with unilateral obstruction results in a decrease in interstitial volume, a marked decrease in the number of monocytes/macrophages infiltrating the renal parenchyma, a decrease in the expression of TGF-β, and lesser activation of nuclear factor kappa B (NF-κB) (69). In addition, there is a marked decrease in fibroblast proliferation and myofibroblast phenotype. The administration of ACE inhibitors after 5 days of established UUO prevents the progressive fibrosis that occurred in untreated rats from day 5 to day 10 of ureteral obstruction. Administration of an angiotensin I receptor antagonist has a similar effect, with the exception of the infiltration of the renal parenchyma by monocytes/macrophages and the expression of clusterin, which decreases in the kidney of rats with UUO treated with ACE inhibitors but not in rats treated with angiotensin I receptor antagonist (70). These differences may be explained by the effects of ACE inhibitors on nitric oxide, through the activation of bradykinin (71). Treatment with an angiotensin II receptor antagonist has no effect on interstitial volume, macrophage infiltration, expression of TGF-β, or fibroblast proliferation in rats with UUO (70). However, antagonism of the angiotensin II receptor decreases the appearance of a myofibroblast phenotype and markedly decreases the expression of clusterin, with an intermediate effect on the activation of NF-κB.


The activation of a number of genes associated with tissue inflammation and the development of fibrosis is controlled by the NF-κB family of transcription factors (67,72). NF-κB has been shown to be activated during experimental ureteral obstruction (73). Enalapril, given to rats with ureteral ligation, significantly decreases the ability of proteins extracted from the nucleus to bind to an NF-κB consensus oligonucleotide compared with similar extracts obtained from kidneys of untreated animals (74). This suggests ACE inhibitors might protect against the development of renal fibrosis by directly decreasing activation of NF-κB, in addition to their well-known hemodynamic effects.


A growing body of evidence supports the concept that oxidative stress, resulting in generation of reactive oxygen species (ROS), plays a critical role in the development and progression of renal fibrosis by inducing extracellular matrix accumulation (75). ROS can mediate the profibrotic effects of TGF-β1 and also activate intercellular adhesion molecule 1 (ICAM-1) and thus may play a central role in the mediation of inflammatory cell proliferation and extracellular matrix accumulation. In obstructive nephropathy, oxidants generated by infiltrating leukocytes and intrinsic renal cells may account for some of the functional and morphologic changes observed. Probucol, an antioxidant and lipid-lowering agent, improves GFR and renal plasma flow both at 4 hours and 3 days after release of 24 hours of bilateral obstruction (76), whereas lipid lowering with lovastatin, which is devoid of antioxidant properties, has no effect.

A decrease in mRNA and protein expression of cellular antioxidant enzymes and increased generation of ROS may play an integral role in the development of tubulointerstitial injury and fibrosis associated with experimental hydronephrosis. As early as 24 hours after UUO, levels of total cortical mRNA for catalase and Cu-ZnSOD are significantly decreased in the obstructed kidney and there is a decreased immunohistochemical staining intensity for Cu-ZnSOD and catalase protein in the cortical tubules (77). Thus, in addition to an increased generation of ROS within the obstructed kidney cortex, there is impairment of normal antioxidant defense mechanisms.

The importance of oxidative stress in the development of renal fibrosis has been recently confirmed by studies on intermedin, a peptide inhibitor of oxidative stress. Overexpression of intermedin within the kidney was able to attenuate the increase in oxidative stress, macrophage infiltration, tubular injury, and fibrotic response to ureteral obstruction (78).


The majority of studies have investigated the role that the upregulation of hormones and cytokines plays in the development of tubulointerstitial fibrosis. However, a decrease in the production of growth and homeostatic factors, which are normally endogenously produced by the kidney to downregulate the fibrotic process, may also be important in the development of fibrosis.

The expression of preproepidermal growth factor is suppressed in the kidney with an obstructed ureter in both the neonatal and adult rat (79,80). Treatment with epidermal growth factor significantly reduces tubule cell apoptosis, blunts tubule atrophy, and preserves renal function when the obstruction is relieved.

Endogenous insulin-like growth factor-1 (IGF-1) expression is not changed during UUO in neonatal rats. Although IGF-1 treatment does not affect the suppression of nephrogenesis or tubule cell proliferation seen in obstructed neonatal rat kidneys, it does significantly blunt tubule cell apoptosis, tubule atrophy, and interstitial collagen deposition following relief of obstruction (81), suggesting that IGF-1 treatment could offer another means of preserving the capacity of renal function once flow is reestablished.

In a mouse model of unilateral obstruction, treatment with recombinant human hepatocyte growth factor (HGF) attenuates apoptosis and TGF-β expression, whereas treatment with an HGF-neutralizing antibody increases TGF-β expression, decreases tubule cell proliferation, and accelerates apoptosis, suggesting that a reduction in endogenous HGF could account for progression of renal fibrosis in tubulointerstitial disease (82).

Bone morphogenetic protein-7 (BMP-7) treatment significantly decreases renal injury in a rat model of UUO both when treatment is initiated at the time of injury (83) and when administered after renal fibrosis has begun (84).

Tubular epithelial cells are one of the major sites of active vitamin D synthesis. Paricalcitol, a synthetic vitamin D analogue, has been shown to significantly attenuate the development of renal interstitial fibrosis in mouse kidney after ureteral obstruction. It reduces interstitial volume, decreases collagen deposition, and lowers mRNA expression of fibronectin and type I and type III collagens. In addition, paricalcitol suppresses the expression of renal TGF-β1 and its type I receptor and inhibits cell proliferation and apoptosis after obstructive injury. In vitro, paricalcitol was able to block EMT. These data suggest that paricalcitol is able to ameliorate renal interstitial fibrosis in obstructive nephropathy, possibly by preserving tubular epithelial integrity through suppression of EMT (85).

Heat shock protein (HSP72) has also been shown to ameliorate renal tubulointerstitial fibrosis in obstructive nephropathy by inhibiting both renal tubular epithelial cell apoptosis and EMT (86).

An understanding of the complex interactions between profibrotic cytokines and homeostatic factors in modulating the development of tubulointerstitial inflammation and fibrosis, EMT, and tubular cell apoptosis following obstruction has contributed to the development of putative therapeutic targets for blunting the development of progressive fibrotic renal disease (87).

Clinical Findings in Urinary Tract Obstruction

Obstruction of the urinary tract is a common and potentially reversible cause of AKI, and therefore it is important to diagnose and treat it promptly to minimize the chances of long-term chronic damage to the kidney.

Obstruction of the urinary tract can present with a wide range of clinical findings, depending on the site, degree, and duration of obstruction. The clinical manifestations of upper and lower urinary tract obstruction differ. Mechanical obstruction of the urinary tract, causing pain, and lower urinary tract symptoms (prostatism) are common presenting complaints. Symptoms can also result from the complex alterations in glomerular and tubular function that may occur in obstructive nephropathy. However, it is important to note that obstructive uropathy and hence obstructive nephropathy can occur without symptoms. In some cases, the symptoms may be related to urinary tract infection or the underlying pathologic process responsible for the development of obstructive uropathy such as tumors or metastases. Obstruction of the urinary tract must be considered in the differential diagnosis of any patient with renal impairment.



Pain is a common presenting complaint in patients with obstructive uropathy, particularly in those with ureteral calculi or where the obstruction has developed rapidly. The pain is believed to result from stretching of the collecting system or the renal capsule, with its severity correlating with the degree of distention and not with the degree of dilation of the urinary tract. Occasionally, the location of the pain helps to determine the site of obstruction. With upper ureteral or pelvic obstruction, flank pain and tenderness typically occur, whereas lower ureteral obstruction causes pain that radiates to the groin, the ipsilateral testicle, or the labia. Acute high-grade ureteral obstruction may be accompanied by a steady and severe crescendo flank pain radiating to the labia, the testicles, or the groin (“classic” renal colic). The acute attack may last less than half an hour, or as long as a day. In contrast, pain radiating into the flank during micturition is said to be pathognomonic of VUR. By comparison, patients with a chronic, slowly progressive obstruction may have no pain or minimal pain during the course of their disease. In such patients, any pain that does occur is rarely colicky in nature. In PUJ obstruction, pain may only occur after fluid loading or the use of diuretics to promote a high urine flow rate.


Calculi may cause trauma to the urinary tract uroepithelium and result in either macroscopic (visible) or microscopic (nonvisible) hematuria. Any neoplastic lesion that obstructs the urinary tract, especially uroepithelial malignancies, may bleed, resulting in macroscopic hematuria. Urinary tract bleeding may also result in obstruction, giving rise to clot colic when in the ureter or clot retention when in the bladder.

Alterations in Urine Output

Patients with complete bilateral obstruction or obstruction in a single functioning kidney present with anuria and AKI. In contrast, partial obstruction may present with polyuria and polydipsia (88) as a result of acquired resistance to ADH. Alternatively, there may be a fluctuating urine output, alternating from oliguria to polyuria. A pattern of alternating oliguria and polyuria or the presence of anuria strongly suggests obstructive uropathy.

Lower Urinary Tract Symptoms

Obstructive lesions of the bladder neck or bladder pathology may cause a decrease in the force or caliber of the urine stream, intermittency, postmicturition dribbling, hesitancy, or nocturia. Urgency, frequency, and urinary incontinence can result from incomplete bladder emptying. Such symptoms commonly result from prostatic hypertrophy and are frequently referred to as prostatism, but they are not pathognomonic of this condition.

Urinary Tract Infection

Urinary tract infections are common and in most cases will not be associated with obstruction to the urinary tract (89). However, a urinary tract infection in neonates, young children of either sex or men, recurrent or persistent infections in women, or infections with unusual organisms, such as Pseudomonas species should prompt further investigation to exclude obstruction. Obstruction should also be excluded following a single episode of upper urinary tract obstruction (acute pyelonephritis). The presence of ongoing obstruction can make the effective eradication of the infection difficult. In a study of adult males with simple or recurrent urinary tract infections, a significant underlying lower urinary tract abnormality, mainly bladder outflow obstruction, was found in 80% of cases (90).

Infection tends to be more common with obstruction of the lower urinary tract (below the ureterovesical junction) and presents with symptoms of cystitis such as dysuria and frequency. The increase of residual urine in the bladder (urine is an excellent culture medium) and altered properties of the bladder that facilitate bacterial adhesion and growth predispose to infection. Alterations in the glycoprotein composition of epithelial cells of the bladder may explain the greater predisposition to infection in certain patients with urinary tract obstruction than in others.

Although obstruction of the upper urinary tract is not necessarily accompanied by infection, when it occurs (acute pyelonephritis) life-threatening systemic sepsis may result.

Infections of the urinary tract with a urease-producing organism such as Proteus mirabilis predispose to stone formation. These organisms generate ammonia, which results in urine alkalinization and favors the development of magnesium ammonium phosphate (struvite) stones. Struvite calculi can fill the entire renal pelvis to form a staghorn calculus that eventually leads to loss of the kidney if untreated. Thus, stone formation and papillary necrosis can also be a consequence of urinary tract obstruction as well as a cause of obstruction.

Obstruction in Neonates or Infants

Oligohydramnios at the time of delivery should raise the suspicion of obstructive uropathy, as should the presence of congenital anomalies of the external genitalia. Nonurologic anomalies such as ear deformities, a single umbilical artery, an imperforate anus, or a rectourethral or rectovaginal fistula should prompt investigation for urinary tract obstruction. The urinary tract also should be examined in infants born with an imperforate anus or a rectourethral or rectovaginal fistula. The existence of a neurogenic bladder with associated obstructive uropathy should be suspected in infants with neurologic abnormalities.

However, the symptoms of obstructive uropathy in neonates and infants are frequently nonspecific and may not be suspected until failure to thrive, voiding difficulties, fever, hematuria, or symptoms of renal failure appear.

The advent of routine antenatal scanning has improved the early diagnosis of congenital anomalies of the kidney and urinary tract, and antenatal hydronephrosis is now one of the most commonly detected birth defects. If congenital urinary tract obstruction goes undiagnosed, the child may present in the postnatal period with failure to thrive, voiding difficulties, fever, hematuria, or symptoms of renal failure. Complete obstruction to the renal tract has rapid and devastating consequences on renal development but is relatively rare. Partial obstruction, for example from ureteropelvic junction obstruction, is more frequently observed but can still cause longer term complications such as hypertension and CKD (91). The development of accurate antenatal diagnosis offers the prospect of offering prompt intervention to relive obstruction to those infants at risk of developing CKD (92). However, the benefit of such strategies still requires careful evaluation to identify the impact on important long-term outcomes such as proteinuria, hypertension, and CKD (93).


General Examination

Physical examination can be completely normal. Some patients with upper urinary tract obstruction may have flank tenderness. Kidney size may increase significantly, particularly in long-standing obstruction. Patients may note increased abdominal girth, and a palpable flank mass may be found. Muscle rigidity over the kidney may be found, and rebound tenderness may be elicited, particularly if acute infection is present. Marked hydronephrosis may present as a flank mass on physical examination, particularly in children with hydronephrosis who are younger than 2 years.

Lower urinary tract obstruction causes a distended, palpable, and occasionally painful bladder. A rectal examination and, in women, a pelvic examination should be performed because they may reveal a local malignancy or prostatic enlargement.

Evidence of an underlying pathologic process responsible for the development of obstructive uropathy, such as tumors or metastases from distal tumors, may be detected.

Blood Pressure

Hypertension may occur in patients with either unilateral or bilateral acute or chronic hydronephrosis. This may be the result of either an increase in ECF volume, owing to decreased sodium excretion, or to an abnormal release of renin and increased generation of angiotensin II. In patients with bladder outflow obstruction and bilateral hydronephrosis, the hypertension typically resolves promptly with the diuresis that occurs after the insertion a urinary catheter or corrective surgery, suggesting that the hypertension was volume dependent. In addition, the concentrations of renin in renal venous blood and peripheral venous blood are normal in hypertensive patients with bilaterally hydronephrotic kidneys.

In contrast, elevated values for renal vein renin have been found in unilaterally hydronephrotic kidneys and after appropriate surgery, the hypertension abates, and the renin values return to normal (94).

Animal studies have demonstrated an increase in renin release following acute ureteral obstruction (95). However, with prolonged unilateral ureteral occlusion in animals, the renin release is not sustained and the peripheral renin is normal. Thus the mechanism of established hypertension in the setting of long-standing unilateral obstruction is more complex.

Occasionally, in patients with partial urinary tract obstruction, hypotension occurs as a result of polyuria and volume depletion.


Urine Abnormalities

Urinalysis may show hematuria, bacteriuria, pyuria, crystalluria, and low-grade proteinuria, depending on the cause of obstruction. However, urinalysis is commonly completely negative in obstructive nephropathy. In the acute phase of obstruction, urinary electrolytes are similar to those seen in a “prerenal” state, with a low urinary sodium (<20 mmol/L), a low fractional excretion of sodium (<1%), and a high urinary osmolality (>500 mOsm/kg). However, with more prolonged obstruction, there is a decreased ability to concentrate the urine and an inability to reabsorb sodium and other solutes. These changes are particularly marked after the release of chronic obstruction and give rise to the syndrome commonly referred to as postobstructive diuresis.

Serum Electrolyte Abnormalities

Hyperkalemic hyperchloremic acidosis (renal tubular acidosis type 4) may be a clinical manifestation of partial obstruction of the urinary tract (96) (see pathophysiology section of this chapter for the mechanisms).

Children with partial obstructive uropathy may develop hypernatremia because polyuria causes a greater loss of water than sodium.

Renal Impairment

Bilateral obstruction of the urinary tract, or obstruction to a single functioning kidney, will result in AKI with a rapidly rising urea and creatinine. Obstruction should always be considered when AKI presents with complete anuria or if periods of anuria alternate with periods of polyuria.

If left untreated urinary tract obstruction will result in CKD, and urinary tract obstruction should always be considered in patients with CKD and no previous history of renal disease and a relatively benign urinary sediment. Elderly men can present with advanced CKD and hydronephrosis secondary to bladder outflow obstruction despite remarkably few lower urinary tract symptoms, and in patients with retroperitoneal fibrosis in whom the onset of obstruction is slow and progressive, far-advanced CKD may also be the initial presenting finding.

Urinary tract obstruction may also accelerate progression of an underlying parenchymal renal disease of another etiology so obstruction should also be excluded in patients with known renal disease who develop an abrupt decrease in renal function that is otherwise unexplained.


Polycythemia has been reported in a few instances of hydronephrosis and is probably related to increased production of erythropoietin by the obstructed kidney. In experimental animals, unilateral hydronephrosis results in elevated plasma levels of erythropoietin that precede the increase in hemoglobin levels.


Prompt diagnosis of urinary tract obstruction is essential to allow treatment to limit any long-term adverse consequences. Symptoms such as “renal colic” may suggest the diagnosis and prompt appropriate investigation. However, there should be a high index of suspicion of urinary tract obstruction in any patient with unexplained AKI or CKD. The diagnostic approach has to be tailored to the clinical presentation (Fig. 12-7), but a careful history and thorough physical examination are mandatory in all patients.

A history of similar symptoms, the presence or absence of lower urinary tract symptoms or urinary tract infection, and the kinds of drugs ingested should be noted. Review of hospital records may reveal abrupt changes in urine output with anuria being suggestive of complete obstruction. However, polyuria may occur in partial obstruction and may mimic that of patients with nephrogenic diabetes insipidus. In children, the manifestations of obstructive uropathy may include gastrointestinal symptoms such as nausea, vomiting, and abdominal pain.

Physical examination with particular reference to the flank and abdomen is important.

Laboratory analysis of urine and serum as outlined above are mandatory. However, a definitive diagnosis of obstruction requires imaging of the renal tract to confirm the diagnosis, elucidate the cause, and plan treatment.


As the sites, causes, and consequences of obstruction to the renal tract are so variable, no single imaging investigation is able to diagnose renal tract obstruction with certainty. Modern imaging technology particularly computed tomography (CT) scanning and magnetic resonance (MR) urography, have improved the ability to accurately diagnose both the site and the cause of obstruction. The protocols which are used in the investigation of obstruction will depend on the local expertise, the availability of resources, and concerns about radiation exposure (97), and it is important to remember that older imaging techniques can still be used effectively to evaluate patients with obstructive uropathy.

Generally, the approach to the patient with suspected obstruction may require the complementary use of a number of different imaging techniques, and no single imaging investigation should be relied on to definitively exclude obstruction, especially if the clinical suspicion of obstruction is high.

Several radiologic techniques can be used to infer the presence of upper urinary tract obstruction from the finding of dilatation of the pelvicalyceal system (hydronephrosis). However, it must be remembered that not all dilated collecting systems represent obstruction.

Figure 12–7 Algorithm demonstrating an approach to the investigation and management of suspected urinary tract obstruction. The initial investigations (boxes) are dictated by the history and examination. The patient pathway allows rapid relief of the obstruction by nephrostomy or ureteric stenting, while a definitive diagnosis and treatment plan are made. CT, computed tomography; MR, magnetic resonance; USS, ultrasound scan.

Plain Abdominal X-Ray

A plain abdominal X-ray (or kidneys, ureters, and bladder [KUB]) provides information on renal and bladder morphology, such as size differences between the two kidneys or a large bladder, suggestive of outlet obstruction. It can frequently demonstrate renal calculi, since about 90% of calculi are radiopaque.

Intravenous Urography

Historically, intravenous urography (IVU) was the first-line investigation for suspected upper urinary tract obstruction but is now rarely used as a first-line investigation having been superseded by the use of ultrasound, CT, and MR.

In patients with normal renal function, IVU can usually define both the site and the cause of the obstruction. However, the excretion of contrast may be poor or delayed in patients with low GFR because of a decreased filtered load of contrast, and films as long as 1 day after radiocontrast injection may be required. In addition, the contrast media is potentially nephrotoxic to an already damaged kidney, particularly in patients older than 60 years and those with diabetes mellitus, preexisting CKD, or dehydration.

Oblique films of the bladder and urethra during voiding (excretory cystogram) may be used to evaluate the site of any lower urinary tract obstruction.


Ultrasonography is a noninvasive test used as a screening procedure for obstruction. Ultrasonography can define renal size and demonstrate calyceal dilation (98) (Fig. 12-8), but its sensitivity and specificity depend heavily on the expertise of the operator. Ultrasound is rarely able to detect the cause of obstruction, since pathology within the ureter is difficult to demonstrate and tiny stones will not generate acoustic shadows. However, unilateral hydronephrosis suggests obstruction of the upper urinary tract by stones, blood clots, or tumors. Bilateral hydronephrosis is more likely to result from a pelvic problem obstructing both ureters or obstruction of the bladder outlet, in which case the bladder will also be enlarged. Ultrasonography is often combined with a KUB to ensure that ureteral stones or small renal stones are not overlooked.

Ultrasonography produces false-negative results in cases of nondilated obstructive uropathy. Immediately after acute obstruction (<24 hours), the relatively noncompliant collecting system may not have dilated such that an ultrasound examination may be normal. Furthermore, if urine flow is low, as in severe dehydration or renal failure, there may be little dilation of the urinary tract. Dilatation may also be absent in slowly progressive obstruction when the ureters are encased by fibrous tissue (as in retroperitoneal fibrosis) or by tumor. The acoustic shadow of a staghorn calculus can also mask dilation of the upper urinary tract. The sensitivity of ultrasound for diagnosing obstruction can be improved by measuring the resistive index using color Doppler sonography. A resistive index >0.7 reflects the increased vascular resistance present in obstruction and effectively discriminates between obstructed and nonobstructed kidneys (98). Ultrasound techniques are particularly useful when it is important to avoid the use of ionizing radiation such as with pregnant women and children and for the follow-up of patients requiring repeated imaging, such as after extracorporeal shock wave lithotripsy (ESWL).

Even in experienced hands, ultrasound may have a significant false-positive rate, especially if minimal criteria are adopted to diagnose obstruction. The echogenicity produced by multiple renal cysts may be mistaken for hydronephrosis on ultrasonography, and anatomic variations of the pelvicalyceal system (e.g., extrarenal pelvis) may be interpreted as dilatation of the urinary tract. There are also a number of nonobstructive causes of upper renal tract dilation, for example, VUR.

Figure 12–8 Renal ultrasound scan showing a hydronephrotic kidney. There are markers to define renal length and cortical width. There is marked dilation of the pelvicalyceal system with clubbing of the calyces (arrow). This is suggestive (but in isolation not diagnostic) of obstruction to the urinary tract.

Ultrasound may also provide useful information about the lower urinary tract. Pre and postmicturition volumes can be measured to assess bladder emptying and the bladder wall can be assessed for wall thickening and trabeculation which suggests the presence of long-term bladder outflow obstruction. Using a full bladder as an acoustic window, ultrasound may also be used to assess the prostate in males and gynecologic structures in females.

In adults older than 60 years, 50 to 100 mL of residual urine may remain after each voiding because of the decreased contractility of the detrusor muscle. In chronic retention, ultrasound of the bladder may show massive increase in bladder capacity with very large (sometimes >500 mL) postmicturition volumes. This suggests significant bladder outflow obstruction predisposing to recurring urinary tract infections and requires further urologic investigation and treatment.

Ultrasound is used for follow-up in neonates with hydronephrosis diagnosed antenatally. If there is no calyceal dilatation (grade 1–2 hydronephrosis) surveillance may be continued, but the presence of increasingly severe pelvicalyceal dilatation (grade 3–5 hydronephrosis) requires further investigation with voiding cystourethrography to distinguish between megaureter resulting from obstruction or reflux and diagnose posterior urethral valves and ureteropelvic junction obstruction.

Computed Tomography

Noncontrast-enhanced spiral CT scanning is often the primary imaging modality for the evaluation of patients who present with undifferentiated acute flank pain (99,100) and can very accurately detect renal stones because of their high density (Fig. 12-9). However, there is concern that this modality is being overused both from the point of view of the resultant exposure to ionizing radiation (CT represents only 11% of radiologic examinations but is responsible for two-thirds of the ionizing radiation associated with medical imaging in the United States with recent estimates suggesting that there will be 12.5 cancer deaths for every 10,000 CT scans) and the cost involved.

Figure 12–9 Abdominal CT scan of a patient with BUO secondary to renal calculi. In the upper panel, a nephrostomy has been inserted into the right kidney (a) to decompress the obstruction, while the left kidney remains obstructed and hydronephrotic (b). The lower panel demonstrates a ureteric calculus (c). BUO, bilateral ureteral obstruction; CT, computed tomography.

In patients where obstruction has been detected by other modalities, CT can be particularly useful in determining the site and nature of the obstructing lesion, especially when it is extrinsic to the urinary tract. CT demonstrates retroperitoneal pathology such as para-aortic and paracaval lymphadenopathy, while retroperitoneal fibrosis is evident as increased attenuation within the retroperitoneal fat, with encasement of one or both ureters. Hematomas, primary ureteral tumors, and polyps are also detectable. Enhancements to the technique such as virtual CT pneumoendoscopy have been described, which may provide an important adjunctive diagnostic aid for urologic pathologies, thus avoiding the need for urinary tract endoscopy (101). The diagnostic potential of CT is also enhanced by the use of contrast, but concerns over nephrotoxicity limit its use in patients with renal impairment. The main drawback of CT remains the considerable exposure to ionizing radiation, making it unsuitable when frequent repetitive examinations may be required.

Magnetic Resonance Urography

MR urography (combined with KUB) can diagnose ureteral obstruction due to renal calculi with similar accuracy to spiral CT scanning but without exposure to a contrast medium or ionizing radiation and is increasingly being used to evaluate obstruction to the renal tract. The technique has less observer variability and is more accurate than CT in detecting indirect evidence of obstruction such as perirenal fluid (102). MR urography can rapidly and accurately depict the morphologic features of dilated urinary tracts and provide information regarding the degree and level of obstruction (103). MR urography also allows functional as well as anatomic parameters of the obstructed kidneys to be determined, as there is an excellent correlation between the GFR determined by MR urography and the isotope GFR (104). However, there is a possible risk of nephrogenic systemic fibrosis from gadolinium exposure in patients with a GFR <30 mL/minute which restricts its use in patients with significant renal impairment.

MR urography is a particularly attractive imaging modality for the evaluation of hydronephrosis in children as it provides both anatomic and functional data and can indicate whether the hydronephrosis is compensated (symmetrical changes in signal intensity of the nephrogram) or decompensated (105). Signs of decompensation (acute on chronic obstruction) include edema of the renal parenchyma, a delayed and increasingly dense nephrogram, a delayed calyceal transit time, and a >4% difference in the calculated differential renal function.

Retrograde Pyelography

Retrograde pyelography involves the retrograde injection of radiocontrast material and is used to visualize the ureter and the collecting system. This technique may be helpful when nondilated urinary tract obstruction is suspected or when there is a history of allergic reactions to contrast material. Urinary tract infection which may become overwhelming during instrumentation of the renal tract is a contraindication to retrograde pyelography.

Retrograde pyelography can identify both the site and the cause of the obstruction (106). It is helpful to include a postdrainage film, which is generally obtained 10 minutes after the retrograde injection of the radiocontrast. If the contrast medium does not persist in the collecting system, obstruction is unlikely, although residual contrast material can sometimes remain on a postdrainage film in a patient with a dilated but nonobstructed ureter if they are dehydrated and supine.

Instrumentation can introduce infection into the urinary tract; so should an obstructing lesion be found, it is essential to provide prompt adequate drainage to reduce any risk of overwhelming infection. It may be possible to effectively relieve the obstruction by placing a stent endoscopically in the ureter during the same procedure.

Isotopic Renography (Renal Scintigraphy)

Isotopic renography can be used to determine the functional significance of dilation of the collecting system (107,108). It requires the intravenous injection of the radionuclide technetium-99m mercaptoacetyltriglycine (99mTc-MAG3), combined with intravenous furosemide, administered 20 to 30 minutes after injection of the isotope (diuretic isotopic renography). Normally, there is a rapid washout of the isotope from the kidney. If there is functional dilatation of the collecting system, the isotope will be retained in the kidney. However, if there is no functional obstruction, the administration of the diuretic should cause a rapid washout of the isotope. Persistence of the isotope suggests that the system is not only dilated but also obstructed. Idealized tracings are summarized in Figure 12-10. Tracing I is a patient with a normal urinary tract. Tracing II strongly suggests obstruction because the radioisotope is retained in the pelvis and collecting system and there is no excretion following furosemide administration. Tracing III suggests dilatation without obstruction, because after furosemide administration there is rapid disappearance of the isotope. The isotopic renogram is relatively noninvasive and can be performed in most hospitals and clinics but is seldom the definitive test. Markedly reduced renal function limits the usefulness of this test because the diuretic response to furosemide may be absent, making interpretation difficult.

Figure 12–10 Pattern of isotopic renography. Tracing 1, normal excretory patter; tracing II, obstruction of the urinary tract; tracing III, stasis of urine with obstruction. (Republished with permission of Elsevier Inc, from ­Gonzalez R, Chiou RK. The diagnosis of upper urinary tract obstruction in children: comparison of diuresis renography and pressure flow studies. J Urol. 1985;133:646–649; permission conveyed through ­Copyright Clearance Center, Inc.)

Pressure-Flow Studies (Whitaker Test)

Pressure-flow studies may be helpful when upper urinary tract obstruction is difficult to diagnose (109), although with modern imaging it is now rarely required. The collecting system is punctured with a fine-gauge needle, and the bladder is catheterized. Fluid is perfused at a rate of 10 mL/minute. At this perfusion rate, the differential pressure between the bladder and the collecting system should not exceed 15 cm H2O. A differential pressure >20 cm H2O indicates obstruction, and a pressure gradient between 15 and 20 cm H2O is equivocal. The pressure-flow study should be done both with an empty and with a full bladder because sometimes the obstruction is only evident when the bladder is full. An antegrade pyeloureterogram can be performed during pressure-flow studies to define the site of any obstruction, eliminating the need for retrograde pyelography.

Additional Tests to Evaluate Lower Urinary Tract Obstruction

A voiding cystourethrogram can be used to investigate the presence of VUR as a cause of the dilatation of the urinary tract.

Obstruction of the lower urinary tract may be evaluated by urodynamic studies and cystoscopy. Cystoscopy allows visual inspection of the entire urethra and bladder and can usually be carried out under local anesthetic in adults.

Urodynamic tests measure the urine flow rate per unit of time (debimetry) which depends on the expulsive force of the detrusor muscle and urethral resistance. The patient voids into a container that has a sensor connected to a recorder that plots micturition time and urine flow rate (110). From this plot, the urine volume, duration of micturition, average urine flow rate, maximum urine flow, and time required to reach the maximum flow rate can be calculated and compared to normal values (111). The maximum flow rate is useful in assessing bladder outlet obstruction, but the pattern (continuous or intermittent) of flow also is useful. Physiologic filling of the bladder makes this test more reliable. Residual urine may be measured after voiding. A normal flow rate with no significant postmicturition urine volume excludes significant bladder outflow obstruction. Cystometry remains the gold standard in differentiating obstructed from nonobstructed men with lower urinary tract symptoms (LUTS) but a number of newer techniques are under evaluation (112).

Treatment of Urinary Tract Obstruction


Despite the detailed understanding of the pathophysiologic changes that follow ureteral obstruction, the best treatment to hasten the recovery of renal function and limit permanent renal damage remains the prompt and effective relief of the obstruction.

Treatment is dictated by the location of the obstruction, the underlying cause, and the degree of any renal impairment. If renal impairment is present, the treatment of obstruction requires close collaboration between nephrologists and urologists in order to reduce the risks associated with the metabolic and electrolyte consequences of renal failure and to optimize the chances for long-term recovery of renal function. For example, complete bilateral ureteral obstruction presenting as AKI is a medical emergency and requires rapid intervention to salvage renal function. Prompt intervention to relieve the obstruction should result in a rapid improvement in renal function. Dialysis should rarely be required in a patient with AKI secondary to obstruction unless treatment of life-threatening hyperkalemia or severe fluid overload is needed to get the patient fit for intervention. The rapid relief of obstruction will limit permanent renal damage, but renal function may not recover immediately if acute tubular necrosis has occurred as a result of obstruction or any accompanying sepsis.

Surgical intervention can be delayed in patients with low-grade acute obstruction or partial chronic obstruction. However, prompt relief of partial obstruction is indicated when (a) the patient has significant symptoms (flank pain, dysuria, voiding dysfunction), (b) there is urinary retention, (c) there are multiple repeated episodes of urinary tract infection, and (d) there is evidence of progressive renal damage.


Calculi are a common cause of ureteral obstruction. Their treatment includes relief of pain, elimination of obstruction, and treatment of infection (113). Pain can be relieved by intramuscular injection of a nonsteroidal antiinflammatory drug, which may help dilate the ureter and aid passage of the stone. In some cases a narcotic analgesic may be needed. High fluid intake to increase urine volume to at least 1.5 to 2.0 L daily may also help mobilize the stone. If possible, any calculi should be recovered for analysis by straining the urine through a gauze sponge or sieve. If the stone is small, the obstruction is partial, there is no infection, and the pain is controlled, expectant management should be followed as many stones will pass spontaneously. Subsequent investigation should be performed to look for metabolic causes for recurrent stone formation and treatment directed accordingly (114).

Intervention may be required for stones larger than 7 mm, since these usually are not passed spontaneously, or if there is persistent colic, urinary tract infection, complete obstruction, or when the calculus has not moved despite an adequate period of observation and increased fluid intake.

There has been a great expansion in minimally invasive techniques for stone removal and open surgery is now rarely required. Options include:

a. Retrograde endoscopic removal using a variety of loops or baskets. This is particularly suitable for calculi located distal to the pelvic brim. This procedure is successful in about 70% of patients. If it fails, dilatation of the ureter or ultrasonic disintegration of the stone can be accomplished using the ureterorenoscope.

b. Percutaneous nephrolithotomy (PCNL), where a nephrostome is placed and the track dilated to provide a direct conduit to the kidney for removal of obstructing pelvic and upper ureteral stones. Rigid or flexible endoscopes can be introduced through the nephrostomy tract to remove calculi <1.5 cm in diameter. For larger stones, lithotripter probes that use ultrasonic or electrohydraulic energy to disintegrate calculi have been used under direct visualization. Endourologic methods can be used to treat obstructing stones successfully in about 98% of patients, shortening the hospital stay and the convalescence period.

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Dec 22, 2019 | Posted by in NEPHROLOGY | Comments Off on Obstructive Nephropathy: Pathophysiology and Management

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