Renal Functional Changes

During acute UUO, electrolyte and renal con­

centrating ability is altered. Obstruction results

Renal Growth/Counterbalance

in a significant decrease in sodium, potassium,

and solute excretion. This results in a decrease

Hinman initially described compensatory gro­

in urine sodium concentration and an increase

in urine osmolality.28

However, during chronic

wth of the

contralateral

kidney in

rats

with

UUO the literature is conflicting regarding the

UUO.16 Obstruction at a younger age is associ­

effects

on electrolyte

transport. With chronic

ated with a greater degree of ipsilateral growth

UUO, sodium, potassium, and osmotic excre­

impairment

and

contralateral

increased

tion can either increase or decrease depending

growth.17 It has also been demonstrated in neo­

upon the overall renal function and physiologic

natal rats that an increased duration of obstruc­

homeostasis.17,29­33

tion results in a greater degree of growth in the

Ureteral obstruction also results in decreased

contralateral

kidney.18

Compensatory

renal

renal concentrating ability and urinary acidifi­

growth has also been demonstrated in human

cation. The reduction in concentrating ability is

fetuses.19 A greater degree of contralateral com­

thought to be a result of medullary and inner

pensatory renal growth has been associated with

cortical

dysfunction

caused by decreased

a greater severity of obstruction in infants with

sodium absorption in the distal tubule and med­

ureteropelvic junction obstruction.20

ullary nephrons.28 Under normal conditions,

one of the major tasks of the renal proximal

Vascular Changes

tubule is acid secretion. The proximal tubule

reabsorbs up to 90% of the filtered bicarbonate

High renal vascular resistance in the fetus and

and can generate additional bicarbonate in

neonate is the result of activation of the renin­

order to regulate blood pH.34 Ureteral obstruc­

angiotensin system (RAS).21 Chronic UUO

tion causes urinary acidification dysfunction

results in increase of RAS activity and renal vas­

that may be secondary to alteration in the reab­

cular resistance, which resolves by relief of the

sorption of bicarbonate in the juxtamedullary

obstruction.22 Chronic UUO also results in vaso­

nephrons as well as decreased acid secretion in

dilatation of the contralateral kidney.23,24 The

the distal tubules.28

vasodilator nitric oxide plays a role in regulating

Inflammatory Mediators

renal vascular resistance.After UUO,nitric oxide

synthase activity is increased as a counterbal­

Interstitial inflammation is an early response to

ance to the increased renal vascular resistance

brought about by RAS activation.25

UUO.35 This inflammation can contribute to

tubular apoptosis and interstitial fibrosis.36

Changes to Electrolyte Transport/

Monocyte chemoattractant protein­1 (MCP­1) is

believed to be a mediator of the intrarenal inflam­

Renal Concentrating Ability

mation that occurs after obstruction.37 MCP­1 is

Normally, the proximal nephron is responsible

suppressed by heme oxygenase­1 (HO­1) that

provides negative feedback to this inflammatory

for reabsorption of 60–70% of the filtered

pathway.38

sodium and water and 90% of the filtered bicar­

After renal obstruction, the upregulated

bonate.26,27 The thick ascending loop of Henle

renin­angiotensin system acts to recruit inflam­

reabsorbs 20–30% of filtered sodium via

matory cells through activation of AT1 and AT2

sodium­chloride

­potassium cotransporters.

receptors and the NF­kBpathway.39 Angiotensin

Approximately, 5–10% of filtered sodium is

also increases production of TGF­1 and Smad3,

reabsorbed by the distal tubule through sodium

which cause apoptosis and interstitial fibrosis.40

chloride cotransport in the luminal membrane.

As for water, the collecting duct can reabsorb

10–15% of that filtered. Under normal condi­

Glomerular Development Changes

tions, urinary excretion of sodium and water

can range from 0.1% to 3%, and 0.3 to 15% of

There is irreversible nephron loss that occurs

the filtered load, respectively.26

with UUO in the developing kidney. Chronic

200

Practical Urology: EssEntial PrinciPlEs and PracticE

UUO impairs nephrogenesis and glomerular

UUO. In addition, fractional potassium excre­

development in both animals and humans.41

tion is also increased after release of BUO but

Nephron number is decreased in fetal rabbits

significantly decreased after release of UUO.28

and pigs that experience chronic UUO.42,43 Relief

Figure 15.1 summarizes the differential

of obstruction does not result in subsequent

effects on renal blood flow and glomerular fil­

increased nephron development in the obs­

tration rate in unilateral and bilateral ureteral

tructed kidney, but rather hyperfiltration in the

obstruction.

remaining nephrons.44 Hyperfiltration can result

in injury to the remaining nephrons and future

Limitations of Animal Models

glomerular sclerosis even in the presence of a

normal contralateral kidney.41,45,46

Much of the knowledge on the pathophysiology

of renal obstruction is derived from animal

Mechanical Stretch of Renal Tubules

models. Although animal models have greatly

enhanced the understanding of renal injury,

Mechanical stretching of renal tubules is a sig­

they have limitations.52 Effective treatment of

nificant step in the progression of obstructive

acute renal failure in animal models has not

nephropathy.47 Integrins are cell surface recep­

translated to successful outcomes in human.53

tors that can sense extracellular mechanical sig­

This may be secondary to the variations in

nals and transmit them across the cell

pathophysiology between humans and animals.

membrane.48,49 After mechanical stretch occurs,

For instance, in acute tubular necrosis, animals

cation channels are activated with leads to Ca2+

have different locations of necrosis as compared

influx.47 Increased calcium levels result in the

to humans.52 Overall, animal models of obstruc­

activation of several pathways that lead to

tion and / or renal damage that are more trans­

increased TGF­b1 expression and induction of

latable to the human condition are needed. To

oxidative stress, which ultimately results in renal

better assess the applicability of a particular

inflammation and fibrosis.47

animal model of renal injury, applications such

as the quantitation of excreted proteins or the

Unilateral Versus Bilateral

assessment of renal oxygenation by radiographic

imaging techniques may be utilized to test the

There are major differences in renal function

efficacy of the animal model.52

before and after release of UUO and bilateral

ureteral obstruction (BUO).28 During UUO and

Future Research

BUO,GFR decline occurs secondary to a decrease

in intraglomerular capillary pressure. However,

Current and future research efforts continue to

with BUO a persistent elevation in intratubular

focus on understanding the basic pathophysiol­

pressure occurs that also contributes to GFR

ogy of UUO in an attempt to identify potential

decline.50 Although kidneys with both forms of

new therapeutic targets to protect or improve

obstruction experience an initial increase in

renal function. For example, it was believed that

intratubular pressure, kidneys with UUO expe­

the antioxidant therapies had limited effect on

rience a return to baseline intratubular pressure

mitochondria, the primary source of intracellu­

within 24 h. However, BUO kidneys have persis­

lar reactive oxygen species, and previous

tently elevated intratubular pressure even after

attempts at using antioxidant therapies to miti­

24 h.50 Another difference with BUO is that

gate the effects of UUO have had disappointing

intravascular increases of atrial natriuretic pep­

outcomes. However, recently, Mizuguchi et al.

tide and prostyacyclin occur that do not occur

demonstrated that peptides,which protect mito­

with UUO.51

chondria in vitro can provide protection from

After the release of obstruction, kidneys

renal damage in a UUO model.54 This and other

with BUO experience a postobstructive diure­

research are encouraging and will hopefully

sis and natriuresis that does not typically occur

identify new pathways of investigation.

with UUO. Urinary concentrating ability is

Other research efforts on UUO have focused

decreased and fractional sodium excretion is

on identifying new biomarkers of renal obstruc­

increased with release of BUO versus release of

tion to help guide therapy and potentially