b.third-space sequestration of fluid is greater with UUO.

c.atrial natriuretic peptide secretion decreases during UUO.

d.contralateral increases in transporters attenuate natriuresis of UUO.

e.greater increases in vasopressin (ADH) with BUO inhibit sodium transport.

Answers

1.d. Increased collagen deposition and extensive glomerulosclerosis. Histopathologic findings may predict recovery of renal function. The presence of increased collagen deposition in the renal parenchyma at the time of pyeloplasty and the presence of extensive glomerulosclerosis have both been shown to have a negative impact on recovery of renal function (Kim et al, 2005; Kiratli et al, 2008; Elder et al, 1995).*

2.e. All of the above. All listed techniques can be used to assess renal function. MRU has been demonstrated to have an excellent correlation with the renal isotope GFR in the adult (Abo El-Ghar-2 et al, 2008) and pediatric patients (Jones et al, 2008) with obstructed kidneys. The incorporation of intravenous administration of gadopentetate-DTPA has allowed a dynamic, functional assessment of the collecting system that correlates well with diuretic renal scintigraphy, yet provides far greater anatomic detail than nuclear studies. Differential GFR can be assessed with postimaging processing, and contrast washout can be measured to calculate renal clearance, differentiating dilated systems from obstructed systems (Rohrschneider et al, 2002; Chu et al, 2004).

3.b. Normal renal function. The use of gadodiamide-based magnetic resonance imaging (MRI) in patients with renal insufficiency

[GFR < 30 mL/min] has been seen to increase the risk of nephrogenic systemic fibrosis (NSF). The risk of NSF is associated with the use of some gadolinium agents (especially gadodiamide) in patients with renal insufficiency [GFR < 30 mL/min], limiting the utility of contrast MRI in such patients (Broome et al, 2007; Frokaier et al, 2007; Sadowski et al, 2007; Abo El-Ghar-2 et al, 2008).

4.a. Advanced cancer. Ureteral stenting may not be as effective for treating patients with extrinsic ureteral obstruction. Docimo and Dewolf (1989) reported a mean 43% failure rate in ureteral stents placed for extrinsic ureteral obstruction, the majority related to malignancy. The recent

development of metallic stents, however, composed of a unique continuous unfenestrated coil, has improved stent indwelling times in patients with extrinsic ureteral compression.

5.e. All of the above. The pathophysiology of obstruction-induced renal fibrosis involves an expansion in the number of matrix-producing fibroblasts. Although resident renal fibroblasts and bone marrow–derived fibroblasts contribute to this population, evidence suggests that the phenotypic transformation of renal tubular epithelial cells into matrixproducing fibroblasts (epithelial mesenchymal transition) is an important source of fibroblasts during renal injury (Healy et al, 1998; Strutz et al, 1995).

6.a. Absence of pyelolymphatic backflow. Factors that have a positive influence on functional recovery include a smaller degree of obstruction, greater compliance of the collecting system, and presence of pyelolymphatic backflow (Shokeir et al, 2002). Conversely, older age and decreased renal cortical thickness are predictors of diminished recovery of renal function (Lutaif et al, 2003).

7.b. Uncorrected coagulopathy. If the patient with obstructive uropathy has an uncorrectable coagulopathy or platelet abnormality, ureteral stenting is indicated. Compared with percutaneous nephrostomy placement, stent insertion may require greater x-ray exposure (Mokhmalji et al, 2001). This may be of concern in pregnant patients, particularly early in gestation when the fetus is most sensitive to radiation effects (McAleer and Loughlin, 2004).

Percutaneous nephrostomy should be strongly considered if pyonephrosis is suspected.

8.b. Usually self-limited. Postobstructive diuresis is generally self-limited and is generally associated with initial hyposthenuric urine. Release of obstruction can result in marked diuresis and natriuresis.

9.a. Angiotensin II. The release of TNF-α, a potent inflammatory cytokine, is stimulated by angiotensin, especially in the first few hours of renal obstruction. It can upregulate its own expression as well as that of other inflammatory mediators, such as interleukin-1, platelet-activating factor, nitric oxide, eicosanoids, and cell adhesion molecules.

.c. Renal function impairment. The term obstructive nephropathy should be reserved for the damage to the renal parenchyma that results from an obstruction to the flow of urine anywhere along the urinary tract. The term hydronephrosis implies dilatation of the renal pelvis and calyces and can occur without obstruction.

.a. Increased sodium excretion. There is a profound diuresis and an increase in sodium excretion after relief of bilateral ureteral obstruction. This is due to ANP and, perhaps, reduced sodium transporters. The massive natriuresis enhances excretion of phosphate, potassium, and

magnesium.

.d. Increased atrial natriuretic peptide (ANP). The accumulation of extracellular volume stimulates the synthesis and release of ANP, which promotes increased GFR and sodium excretion. Decreases in the aquaporin

water channels in the kidney further promote the diuresis.

.d. Decreased ureteral pressure. In the late phase after UUO, there is a decline in both renal blood flow and ureteral pressure resulting in a gradual loss in renal function. In addition, there is a shift of blood flow from the outer

to inner cortex with UUO that is opposite to that which is seen with BUO.

.b. Increase in afferent arteriolar dilation. By promoting dilation of the afferent arteriole and constriction of the efferent arteriole, ANP increases GFR. It also decreases the sensitivity of tubuloglomerular feedback, inhibits renin release, and increases the ultrafiltration coefficient.

.a. Shift of blood flow to the outer renal cortex. There is a shift of blood flow to the outer renal cortex with BUO in contrast to the reversed pattern with UUO.

.b. Increase in expression of transforming growth factor-β. There is increased expression of TGF-β with obstruction that contributes to an increase in the extracellular matrix of the kidney and promotes inflammation. TGF-β is activated by angiotensin II, and animal models have demonstrated that pharmacologic methods of inhibiting angiotensin II reduce the fibrosis occurring after obstruction.

.a. Fractional excretion of sodium after relief of obstruction is greater in BUO. The increased fractional excretion of sodium in BUO is due to volume expansion, resulting in increased levels of ANP and the overall increased solute load.

.c. Inflammatory cell infiltration. Inflammatory cell infiltration occurs early in the course of obstruction (Diamond et al, 1994, 1998) and results in the release of a variety of cytokines and growth factors that stimulate fibroblast proliferation and activation, and an imbalance in extracellular

matrix (ECM) synthesis, deposition, and degradation.

.d. It is primarily related to cellular hypertrophy rather than hyperplasia. Compensatory renal growth of the unaffected kidney has been

demonstrated, and studies indicate that when the kidney enlarges an increase in the number of nephrons or glomeruli does not occur, indicating that the increase in volume is primarily a consequence of cellular hypertrophy (Peters et al, 1993). These growth patterns may depend on the age of the subject. Insulin-like growth factor-1 is thought to stimulate this event. It is more prominent in the immature kidney and appears to be directly proportional to the duration of obstruction and more prominent with complete obstruction.

.a. Early relief of obstruction. Although the other factors influence recovery of renal function after release of obstruction, prompt eradication of

obstruction provides the best approach for salvage.

.b. Downregulation in sodium transporters. Obstruction results in a reduction in sodium transporters, including Na+,K+-ATPase. It also promotes tubulointerstitial fibrosis, a reduction in aquaporin channels, and acidification defects. The collecting system pressure should not be increased at this point.

.E. A dramatic delay in radiotracer uptake on MAG3 Lasix renogram.

Although an elevated resistive index and a pelvic calcification on noncontrast CT may suggest obstruction, the presence of a significant delay in radiotracer uptake on a MAG3 Lasix renogram is most suggestive of high-grade obstruction. A T1/2 of 15 minutes suggests an equivocal delay in drainage from

the collecting system, and obstruction is associated with a decrease, not an increase, in ureteral jet frequency.

.d. Decreased renal aquaporin-2 water channels. The concentrating defect that occurs with obstruction is not due to inadequate levels of ADH. Choices b, c, and e result in enhanced concentrating ability, whereas a reduction in aquaporin-2 water channels does the opposite.

.b. Decreased synthesis of aquaporins. Li and coworkers (2001) showed that the polyuria after release of BUO correlated with a decreased expression of aquaporins 1, 2, and 3. Over a 30-day period, the expressions of AQP-2 and -3 gradually normalized, but the expression of AQP-1 remained decreased. The reduced rate of synthesis and mobilization of water channels into the nephron membranes accounts for a decreased response to exogenous vasopressin or cyclic AMP.

.d. Increase over an hour and then steadily decrease. Renal blood flow initially rises in the first phase, because of afferent arteriolar vasodilatation. In phase 2, efferent arteriolar constriction keeps ureteral pressure elevated, but in

phase 3, both preglomerular and postglomerular vasoconstriction reduce renal blood flow and ureteral pressure.

.c. An increase followed by a decrease. The first phase is characterized by a rise in both ureteral pressure and renal blood flow lasting 1 to 1.5 hours. This is followed by a decline in renal blood flow (RBF) and a continued increase in ureteral (tubular) pressure lasting until the fifth hour of

occlusion. The final phase involves a further decline in RBF and a progressive decline in ureteral pressure.

.d. Prostaglandin and nitric oxide. Studies during the early, vasodilatory phase of UUO have shown that the increase in RBF can be prevented by prostaglandin synthesis inhibitors, such as indomethacin or other NSAIDs. Intravenous administration of indomethacin before ureteral ligation results in

a decline in renal blood flow without the initial vasodilatation. In addition, administration of nitric oxide (NO) synthesis inhibitors, such as N-nitro-l- arginine methyl ester (L-NAME) or N-monomethyl-l-arginine (L-NMMA), attenuates the initial rise in RBF with occlusion in rats, and when L-NMMA was discontinued, the rise in RBF was restored in 10 minutes. These findings provide evidence for a role of prostaglandins and nitric oxide in reducing preglomerular afferent arteriolar vascular resistance in the early phase of UUO.

.b. Greater expansion of extracellular volume with BUO than with UUO. With bilateral obstruction, the contralateral renal unit does not have the opportunity for compensation as with UUO. Extracellular volume may be greatly expanded so that postobstructive diuresis is most commonly seen in this type of obstruction. After relief of BUO, the increased extracellular volume with attendant salt and water buildup, urea and other osmolytes, and increased production of atrial natriuretic peptide and potentially

other natriuretic substances all contribute to a profound natriuresis and a fractional excretion for sodium that is greater than after relief of UUO.

.b. Decreased H+-adenosine triphosphate (ATP)ase expression in the collecting duct. The cumulative evidence shows a major acidification defect in the distal nephron. Release of obstruction does not result in bicarbonaturia, indicating that proximal reclamation remains intact. There is a defect in the proximal handling and breakdown of glutamine, which means that a higher proportion of protons are buffered as titratable acid. The best evidence indicates a defect in the expression of H+-ATPase in the collecting duct. Even so, because there is a deficit in filtered and excreted

phosphate, fewer protons can be buffered by phosphate so that the pH of the urine may be lower in spite of a total net decrease in H+ secretion.

.d. Ultrasound. Because of emerging concerns about radiation exposure with CT and a documented increased risk of brain cancer and leukemia in children receiving cumulative radiation doses from CT of 50 mGy or 30 mGy, respectively (Miglioretti et al, 2013; Pearce et al, 2012), ultrasound remains the primary imaging modality of choice in children suspected to have renal obstruction. Low-dose CT is indicated if the ultrasound is inconclusive. MRU

holds great promise as an imaging modality that avoids ionizing radiation, but because of cost and restricted availability, it is not a first-line imaging tool.

.e. All of the above. Tubule cells, macrophages, and fibroblasts all contribute to the fibrotic process. The mediators of angiotensin II, growth factors, and

cytokines contribute to the process and offer opportunities for pharmacologic intervention.

.b. Caspases. Cysteinyl aspartate-specific proteinases (caspases) are known to mediate apoptotic cell death in obstructed kidneys. This is a family of 12 enzymes that cleave nuclear and cytoplasmic substrates, resulting in nuclear fragmentation and condensation. Caspases can be activated by either an intrinsic pathway involving disturbances in the mitochondrial membrane and release of cytochrome c or by a death receptor signaling pathway (i.e., Fas or TNF-α binding to their receptor on the cell membrane).

.d. Dimercaptosuccinic acid (DMSA) renogram. The DMSA renogram has been shown to be superior to DTPA or MAG-3 for the prediction of renal recovery (Thompson and Gough, 2001). Although some have successfully used these other radiotracers to predict functional recovery, the cortical phase of the renogram is the critical factor. Doppler ultrasonography and MRU have not been demonstrated to predict renal recovery.

.e. a, b, and d. TNF-α, TGF-β, and IL-18 have all been implicated in obstruction-induced apoptosis. The role of angiotensin II in this process is less convincing, with recent studies suggesting no benefit of either ACE inhibitors or angiotensin II type 2 receptor antagonists in preventing obstruction-induced apoptosis.

.a. They reduce collecting system pressure. In clinical trails, NSAIDs have proven superior to opioids in managing renal colic, and are associated with less emesis and less potential for abuse. NSAIDs reduce the pain associated with renal colic by reducing collecting system pressure and distention. This effect appears to be primarily mediated by a reduction in renal

blood flow, but NSAIDs may also reduce hydrostatic pressures in the collecting system by preventing the downregulation in aquaporin and major sodium channels in the renal tubule. Because NSAIDs reduce renal blood flow, they are contraindicated in patients with renal insufficiency, and opioids are therefore the preferred method of pain control in this patient population.

.c. MAG3 Lasix renogram. Although hydronephrosis is suggestive of renal obstruction in the presence of pain, hydronephrosis alone does not indicate urinary tract obstruction, and significant hydronephrosis can be present in the absence of obstruction. The most appropriate next step in management would therefore be a Lasix renogram to evaluate the function and drainage of the kidney. Although an MRU would provide this information as well, it is

considered a second-line test because of its cost and lesser availability.

.b. 10%. The usual cutoff point for nephrectomy is 10% or less of total renal function being supplied by the affected kidney. This has not been prospectively studied but is based on common clinical practice, and, as such, this must be tempered by clinical insight into the overall status of the patient.

.a. Afferent arteriole. Reduced preglomerular resistance increases glomerular capillary pressure and filtration rate.

.c. Involves conversion of renal tubular epithelial cells into matrixproducing fibroblasts. Growing evidence suggests that under pathologic conditions, renal tubular epithelial cells can also undergo a phenotypic transformation into matrix producing myofibroblasts by a process called epithelial-mesenchymal transition (Healy et al, 1998; Strutz et al, 1995).

These activated fibroblasts acquire mesenchymal markers, migrate into the interstitial space across damaged tubular basement membranes, and become capable of producing extracellular matrix. EMT appears to be a major

contributing factor to tubulointerstitial fibrosis in the obstructed kidney, and a number of growth factors, cytokines, and ECM compounds regulate EMT, of which TGF-β1 is the chief and most studied mediator.

BMP-7 is a member of the TGF-β family that has been shown to reverse the process of EMT and promote resolution of fibrosis and the restoration of the normal architecture of the obstructed kidney (Patel et al, 2005; Manson et al, 2011).

.d. Contralateral increases in transporters attenuates natriuresis of UUO.

Diuresis and natriuresis occurs primarily after release of BUO because volume expansion, release of ANP, and decreases in the tubular sodium transporters

all occur. With UUO, transporter synthesis increases in the unobstructed kidney to help compensate and reduce excretory losses in the obstructed kidney.

Chapter review

1.With unilateral ureteral obstruction, renal blood flow increases during the first 1 to 2 hours. It begins to decrease at 3 to 4 hours and markedly declines after 5 hours of obstruction.

2.The increase in renal blood flow in unilateral ureteral obstruction is a result of relaxation of afferent arterials in which prostaglandin E2 and

nitrous oxide play a role.

3.Reduction in whole-kidney GFR after prolonged obstruction is due to afferent arteriolar vasoconstriction mediated by the renin-angiotensin system. Thus angiotensin II is an important mediator of reduced renal blood flow in the second and third phases of ureteral obstruction.

Moreover, thromboxane A2 may also contribute.

4.In bilateral ureteral obstruction, there is a modest increase in renal blood flow lasting approximately 2 hours, followed by a profound decline in renal blood flow.

5.In unilateral ureteral obstruction, there is a shift of blood flow from the outer cortex to the inner cortex. In bilateral ureteral obstruction, the shift is in the opposite direction toward the outer cortex.

6.With the release of bilateral obstruction, a postobstructive diuresis may occur that is much greater than in unilateral ureteral obstruction due to accumulated solutes and volume expansion.

7.Partial neonatal obstruction may impair nephrogenesis.

8.Following complete ureteral obstruction, urine is reabsorbed by (1) extravasation at the calyceal fornix, (2) pyelovenous backflow, (3) pyelolymphatic backflow, and (4) tubular reabsorption.

9.Following obstruction, there is a dysregulation of the aquaporin water channels in the proximal tubule, descending loop, and collecting duct, which may contribute to long-term polyuria.

10.The excretion of sodium following the relief of bilateral ureteral obstruction is greater than after unilateral ureteral obstruction, because in bilateral obstruction there is retention of sodium, water, urea, and other osmotic substances and an increase of atrial natriuretic factor, all of which stimulate a profound natriuresis.

11.Obstruction causes a defect in urinary acidification(proton secretion) in the distal tubule and collecting duct.

12.Compensatory renal growth decreases progressively with increasing age. Although the kidney does enlarge, there is not an increase in nephrons or number of glomeruli after birth.

13.Functional recovery has been reported as long as 150 days following relief of unilateral ureteral obstruction.

14.Older age and decreased cortical thickness are predictors of diminished recovery following relief of obstruction.

15.Recovery of renal function following relief of obstruction is affected by the duration, the degree, the patient's age, baseline renal function, collecting system compliance, and infection.

16.Chronic ureteral obstruction leads to renal inflammation, increased extracellular matrix formation, tubulointerstitial fibrosis, and apoptosis of renal tubules, thus limiting the potential for return of renal function.

17.Ureteral obstruction may result in prolonged decreases in concentrating ability, urinary acidification, and electrolyte transport long after the obstruction is released.

18.A Whitaker test requires a fixed rate of infusion of 10 mL/min into the renal pelvis. A catheter is placed in the bladder. After equilibration, a renal pelvic pressure less than 15 cm of water is considered normal. A pressure greater than 22 cm of water is considered obstructed, and a pressure of 15 to 22 cm of water is equivocal.

19.For diuretic renograms, a half-time of less than 10 min is normal; a halftime greater than 20 min is obstructed, and between 10 and 20 min is equivocal.

20.Postobstructive diuresis is a result of (1) a physiologic diuresis that involves volume expansion and solute accumulation and (2) a pathologic diuresis that involves derangements of the medullary gradient and transport processes for solutes in the renal tubule.

21.Distended bladders should be expeditiously decompressed. There is no role for gradual decompression, because this does not limit hematuria or postobstructive diuresis.

22.Hypertension may occur with obstruction and is probably due to upregulation of the renin-angiotensin system.

23.The pathophysiology of obstruction-induced renal fibrosis involves an expansion in the number of matrix-producing fibroblasts.

24.By promoting dilation of the afferent arteriole and constriction of the efferent arteriole, atrial natriuretic peptide increases GFR. It also decreases the sensitivity of tubuloglomerular feedback, inhibits renin release, and increases the ultrafiltration coefficient.

25.Inflammatory cell infiltration occurs early in the course of obstruction

26.NSAIDs reduce the pain associated with renal colic by reducing collecting system pressure and distention. This effect appears to be primarily mediated by a reduction in renal blood flow, but NSAIDs may also reduce hydrostatic pressures in the collecting system by preventing the downregulation in aquaporin and major sodium channels in the renal tubule. Because NSAIDs reduce renal blood flow, they are contraindicated in patients with renal insufficiency.

* Sources referenced can be found in Campbell-Walsh Urology, 11th Edition, on the Expert Consult website.