Glomerular Filtration, Renal Blood Flow, Collecting System Pressure

There are many functional changes in the kidney associated with obstructive nephropathy that affect renal hemodynamic variables and glomerular filtration. These are influenced by the extent and severity of obstruction, whether the obstruction is unilateral or bilateral, and whether the obstruction currently persists or has been relieved. A brief discussion of the determinants of glomerular filtration is in order to understand the interrelationships between changes in renal hemodynamics and alterations in the glomerular filtration rate (GFR) during and after obstruction. Factors influencing GFR are expressed in the following equation:

K_f is a glomerular ultrafiltration coefficient related to the surface area and permeability of the capillary membrane. P_GC is the glomerular capillary pressure, which is influenced by renal plasma flow and the resistances of the afferent and efferent arterioles. The hydraulic pressure driving fluid into Bowman space is resisted by the hydraulic pressure of fluid in the tubule (P_T), and also the increasing oncotic pressure (π) of the proteins remaining at higher concentrations in the late glomerular capillary and efferent arteriolar blood. Although filtered fluid is not completely free of small proteins, for practical purposes, its oncotic pressure is negligible. The net pressure determining glomerular filtration is referred to as the ultrafiltration pressure (P_UF) and is derived from (P_GC − P_T − π_GC). P_GC is also influenced by renal plasma flow (RPF). RPF depends upon the renal perfusion pressure and intrarenal resistance to flow, the latter primarily mediated by the resistances in the afferent and efferent arterioles. The aforementioned relationships are depicted in the following equation:

Thus constriction of the afferent or efferent arteriole or both would reduce RPF. Constriction of the afferent arteriole results in a decrease of P_GC and GFR, whereas an increase in efferent arteriolar resistance increases P_GC. Whole kidney GFR depends upon factors regulating perfusion of each glomerulus and also upon the percentage of glomeruli actually filtering. For each glomerulus, the single-nephron glomerular filtration rate (SNGFR) is determined by the previously mentioned GFR equation. Obstruction can transiently or permanently alter GFR and some or all of the determinants of GFR.

The results of animal experiments are used here to profile the hemodynamic, renal, and systemic responses of renal obstruction. The limitations of animal models including the potential for a species-specific response must be taken into consideration when making analogies or comparisons with humans.

Hemodynamic Changes with Unilateral Ureteral Occlusion

There are differences between unilateral ureteral obstruction (UUO) and bilateral obstruction (BUO) that have been characterized in animal models. These include hemodynamic patterns and other factors that influence GFR. Renal blood flow (RBF) was assessed in the classical studies characterizing hemodynamic differences. In some, RBF was measured directly with various types of flow probes, and in others it was determined indirectly by measuring RPF using secretory markers and indexing this to the hematocrit. A number of vasoactive substances are thought to play a role in the changes in RBF and GFR occurring with both models of obstruction. The timing of changes in intrarenal concentrations of vasoconstrictors and vasodilators during the course of obstruction and the release of obstruction is poorly understood. The varying hemodynamic patterns during the time course of obstruction may be due to a combination of vasoactive hormones synthesized and released at different rates, physical damage to glomerular and tubular units, and extrarenal compensatory mechanisms.

Animal experiments have demonstrated a triphasic pattern of RBF and ureteral pressure changes in UUO that differs from BUO or unilateral obstruction of a solitary kidney (Fig. 40–1). With UUO, RBF increases during the first 1 to 2 hours and is accompanied by a high P_T and collecting system pressure because of the obstruction. In a second phase lasting 3 to 4 hours, these pressure parameters remain elevated but RBF begins to decline. A third phase beginning about 5 hours after obstruction is characterized by a further decline in RBF, now paralleled by a decrease in P_T and collecting system pressure. These changes are explained by physical alterations in flow dynamics within the kidney and are modified by changes in the biochemical and hormonal milieu regulating renal resistance.

Figure 40–1 Triphasic relationship between ipsilateral renal blood flow and left ureteral pressure during 18 hours of left-sided occlusion. The three phases are designated by roman numerals and separated by vertical dashed lines. In phase I, renal blood flow and ureteral pressure rise together. In phase II, the left renal blood flow begins to decline and ureteral pressure remains elevated and, in fact, continues to rise. In phase III, the left renal blood flow and ureteral pressure decline together.

(From Moody TE, Vaughn ED Jr, Gillenwater JY. Relationship between renal blood flow and ureteral pressure during 18 hours of total unilateral ureteral occlusion. Implications for changing sites of increased renal resistance. Invest Urol 1975;13:246–51.)

In the first phase of UUO, the increase in P_T would logically be expected to reduce GFR greatly. However, this is counterbalanced by an increase in RBF related to afferent arteriolar vasodilation (Vaughan et al, 1970), which limits the fall in GFR because P_GC rises. This hyperemic response has been attributed to stimulation of the tubuloglomerular feedback mechanism that relaxes the afferent arterioles as a consequence of decreased sodium delivery to the macula densa (Wright and Briggs, 1979), changes in interstitial pressure within the kidney (Vaughan et al, 1971; Francisco et al, 1980), or the release of vasodilators such as prostanoids like prostaglandin E₂ (PGE₂) (Allen et al, 1978). There are various lines of evidence supporting the role of prostaglandin involvement. Frøkiær and Sørensen (1995) demonstrated an increase in PGE₂ excretion in the urine from the contralateral kidney after UUO. In addition, studies have shown that the increase in PGE₂ and the vasodilation of the obstructed kidney could be blocked by indomethacin, a prostaglandin synthesis inhibitor (Allen et al, 1978; Blackshear and Wathen, 1978; Gaudio et al, 1980). Nitric oxide (NO) may also contribute to the early renal vasodilation in UUO. The kidney contains nitric oxide synthases (NOS) that are both constitutive (endothelial and neuronal isoforms) and inducible (iNOS). In obstructed kidneys from rabbits and rodents, iNOS increases (Salvemini et al, 1994; Miyajima et al, 2001). Furthermore, Lanzone and colleagues (1995) showed that administration of the NOS inhibitor N^G-monomethyl-L-arginine (L-NMMA) before UUO attenuated the early rise in RBF, and that the renal vasodilation returned when L-NMMA was discontinued. Thus it is likely that both PGE₂ and NO contribute to the net renal vasodilation that occurs early following UUO.

After this initial phase of several hours, GFR and RBF progressively decline in UUO (Jaenike, 1972; Harris and Yarger, 1974; Dal Canton et al, 1980). In contrast to the early rise in P_T in the initial phases of UUO, this parameter and RBF both decline 12 to 24 hours after obstruction. This is best explained by an increase in afferent arteriolar resistance (R_aff) that occurs. At this time, there are also shifts in regional blood flow in the kidney, with large portions of the cortical vascular bed not perfused or underperfused (Harris and Yarger, 1974; Gaudio et al, 1980). A shift in RBF from the outer cortex to more juxtamedullary regions was reported by Yarger and Griffith (1974) in dogs with UUO. Thus reduced whole kidney GFR at this stage of obstruction is due not only to reduced perfusion of individual glomeruli, related to afferent vasoconstriction and reduced P_GC, but also to global reduction in filtration related to no perfusion or underperfusion of many glomeruli (Arendshorst et al, 1974).

Vasoconstrictors appear to play a role in the reduction in RBF after UUO. There is evidence that the renin-angiotensin system is activated during UUO, that is, during the first phase of UUO renal vein renin levels increase (Moody et al, 1975; Yarger et al, 1980) even though there is a net renal vasodilation at this time. Infusion of the angiotensin-converting enzyme (ACE) inhibitor captopril attenuates the declines in RBF and GFR in UUO, suggesting that angiotensin II is an important mediator of the preglomerular vasoconstriction occurring during the second and third phases of UUO (Ichikawa et al, 1985).

Other vasoconstrictors also appear to be involved in the reduction of RBF with UUO. Thromboxane A₂ (TXA₂) is also thought to be an influential postobstructive vasoconstrictor that contributes to the continued reduction in GFR and RBF. Administration of TXA₂ synthesis inhibitors to the obstructed kidney limits the reduction in RBF and GFR (Klotman et al, 1986; Loo et al, 1987; Purkerson and Klahr, 1989). TXA₂ may be generated in the kidney itself, perhaps in glomeruli (Yanagisawa et al, 1990), but synthesis from macrophages migrating to the kidney during obstruction is another potential source of this vasoconstrictor (Schreiner et al, 1988; Harris et al, 1989).

Endothelin is another endogenous vasoconstrictor thought to participate in these events, although perhaps later in the established phase of UUO and after release of the obstruction. Administration of endothelin antagonists limits the reduction of RBF and GFR in rats during and after release of UUO (Bhangdia et al, 1998; Syed et al, 1998; Colon et al, 2000). Furthermore, endothelin excretion is increased in the targeted kidney after release of UUO in swine but not in the contralateral renal unit (Kelleher et al, 1992).

The kidney’s response to the release of UUO depends on the duration and extent of obstruction and is also species specific. Many models of UUO use complete obstruction of the ureter for 24 hours before release. After release of 24-hour UUO, the GFR is initially 50% of normal in dogs and less than 25% of normal in rats, accompanied by greatly reduced RBF. There are also regional differences within the kidney. Harris and Yarger (1974) showed a marked decrease in perfusion of the superficial cortex accompanied by an increase in juxtamedullary glomerular perfusion after release of 24 hours of UUO in rats. Tubuloglomerular feedback may play a role in these responses (Tanner, 1985). Some of the mediators of the hemodynamic changes in the kidney following release of the obstruction may be different from those involved in the earlier phases.

Hemodynamic Changes with Bilateral Ureteral Occlusion

The changes with BUO or obstruction of a solitary kidney are different. In contrast to the early robust renal vasodilation with UUO, there is a modest increase in RBF with BUO that lasts approximately 90 minutes, followed by a prolonged and profound decrease in RBF that is greater than found with UUO (Gulmi et al, 1995). Reyes and Klahr (1992) found that an NO synthesis antagonist caused a further decline in RBF and GFR compared with control values, suggesting that NO helps maintain renal hemodynamics in early BUO. Other potential vasodilators, such as platelet-activating factor (PAF), have been postulated to contribute to renal hemodynamic changes with BUO. Reyes and Klahr (1991) showed, in rats, that when vasoconstrictors such as TXA₂ were blocked, endogenous or exogenous intrarenal PAF-mediated vasodilation contributed to the preservation of RBF and GFR. The earlier and more profound decrease in RBF with BUO may be contributed to by increased renal nerve stimulation that initiates vasoconstriction related to increased renorenal reflex activity (Francisco et al, 1980; Ma et al, 2002). Endothelin may also contribute to these responses in BUO. The administration of an endothelin antibody to rats with BUO was reported to attenuate the decreases in GFR and RPF (Reyes and Klahr, 1992). Angiotensin II and TXA₂ are also probably involved in the changes occurring with BUO. The administration of inhibitors of either of these vasoconstrictors to rats, prior to BUO, resulted in improved postobstructive GFR and RPF compared with their administration at the time of release of obstruction (Purkerson and Klahr, 1989).

The intrarenal distribution of blood flow is quite different with BUO than with models of UUO. Jaenike (1972) used microspheres to show that 55% of the RBF perfused the cortical nephrons, while the innermost zones received only 14% of the flow in rats after BUO. Similarly, Solez and associates (1976) showed a 92% decrease in inner medullary plasma flow with 18 hours of BUO in rats. Thus the shift seen with UUO of blood flow from outer to inner cortex is the opposite of that with BUO.

Ureteral pressure is higher with BUO than with UUO. Although in both cases ureteral and tubular pressures are increased for the first 4 to 5 hours, the ureteral pressure remains elevated for at least 24 hours with BUO, whereas it begins to decline and approaches preocclusion pressures by 24 hours with UUO. The prolonged elevation in intratubular pressure contributes to the profound decrease in SNGFR and whole kidney GFR. Micropuncture studies (Yarger et al, 1972; Dal Canton et al, 1980) in which intratubular pressure is measured directly have demonstrated that it remains elevated in rats after 24 hours of BUO in comparison with pressure normalization in animals after 24 hours of UUO. Ureteral pressure remains high because BUO passes through a phase of preglomerular vasodilation and then a prolonged postglomerular vasoconstriction. This explains the persistent elevation in ureteral pressure in spite of a decrease in RBF and increase in renal resistance. In contrast, in UUO the initial preglomerular dilation and short-lived postglomerular vasoconstriction are followed by a more prolonged preglomerular vasoconstriction that tempers elevations in P_GC and hence in P_T. This difference between the two pathophysiologic conditions has been hypothesized to be due to an accumulation of vasoactive substances in BUO that could contribute to preglomerular vasodilation and postglomerular vasoconstriction. Such substances would not accumulate in UUO because they would be excreted by the contralateral kidney. Atrial natriuretic peptide (ANP) appears to be one of these substances (Purkerson et al, 1989). With excretory ability abrogated, BUO increases intravascular volume, as evidenced by an increase in pulmonary capillary wedge pressure and body weight, which serves as the stimulus for secretion of ANP. ANP increases afferent arteriolar dilation and efferent arteriolar vasoconstriction, thus increasing P_GC. It also decreases the sensitivity of tubuloglomerular feedback, inhibits release of renin, and increases K_f (Fried et al, 1987; Brenner et al, 1990; Cogan, 1990). In addition, changes within the renal unit may contribute to elevated pelvic pressure. In both rats and humans, ureteral obstruction increases COX-2 in the proximal dilated ureter but not in the distal nondilated ureter. When the obstruction was released, the urinary concentration of PGE₂ was elevated. Furthermore, a COX-2 selective inhibitor reduced pelvic pressure. Thus intrarenal PGE₂ acting on ureteral smooth muscle may contribute directly to increased pelvic pressure after obstruction (Nørregaard et al, 2006). Glomerular filtration and RBF remain depressed after release of BUO. This is due to persistent vasoconstriction of the afferent arteriole (Jaenike, 1972; Moody et al, 1977). The decrease in RBF in the renal medulla remains more prominent than in the cortex (Solez et al, 1976). Tubuloglomerular feedback does not appear to contribute to this response as it does with UUO (Tanner, 1985). Urine flow and sodium excretion are increased after release of BUO. ANP appears to play a prominent role in this response based on its natriuretic properties and those previously reviewed. It may also have a protective effect. Ryndin and associates (2005) reported that the administration of ANP or phosphoramidon, an inhibitor of ANP degradation, to rats with BUO resulted in improved GFR and a more brisk diuresis and natriuresis after release of obstruction.

In summary, both UUO and BUO involve increases in renal vascular resistances and increases in ureteral pressures. However, the timing and regulation of these changes differ (Fig. 40–2). With UUO, early renal vasodilation primarily mediated by prostaglandins and NO is followed by prolonged vasoconstriction and normalization of intratubular-ureteral pressure as the contralateral kidney contributes to fluid balance. With BUO, little early vasodilation is seen, and vasoconstriction is more profound. When the obstruction is released, the postobstructive diuresis is much greater with BUO because volume expansion, urea and other osmolytes, and secreted ANP contribute to a profound diuresis and natriuresis.

Figure 40–2 Summary of the functional changes during and following ureteral obstruction. Symbols and abbreviations indicate ↑↓, increases and decreases; ~, little change; angII, angiotensin II; ANP, atrial natriuretic peptide; AQP, aquaporin; ECV, extracellular volume; ET, endothelin; FE, fractional excretion; NO, nitric oxide; P_GC, glomerular capillary hydraulic pressure; P_T, proximal tubular hydraulic pressure; PGE₂, prostaglandin E₂; R_aff, afferent arteriolar resistance; R_eff, efferent arteriolar resistance; RBF, renal blood flow; TG feedback, tubuloglomerular feedback; TXA₂, thromboxane A₂.

Partial Ureteral Occlusion

Although most models of urinary tract obstruction study complete obstruction over a fixed time interval, such as 24 hours, many clinical conditions involve partial obstruction over varying times. Partial obstruction models often involve perinatal obstruction where renal growth and differentiation may be affected, as well as hemodynamics and excretion. In many cases, the changes in renal hemodynamics and in tubular function are similar to those induced by more acute, complete models of obstruction but develop more slowly. In other cases, such as perinatal models of obstruction either before or shortly after birth, an animal such as a rat is still in a period of nephrogenesis. Consequently, formation of glomeruli and tubules may be compromised so that irreversible changes occur without total loss of kidney function.

Recovery of renal function in adult animals with partial obstruction has been studied as a potential guideline for clinical treatment. Leahy and coworkers (1989) studied dogs in which partial UUO with stents was studied for up to 60 days. Reversibility of renal function was estimated by creatinine clearance. Renal function became normal in dogs partially obstructed for 14 days. Animals partially obstructed for 28 days recovered 31% of function, and those partially obstructed for 60 days recovered only 8% of function. Casts of the microvasculature showed arteriolar constriction, supporting the concept that postobstructive renal dysfunction is influenced by vascular responses.

Much less is known about the roles of vasoactive or inflammatory mediators in the partial ureteral obstruction model. As with acute occlusive models, administration of indomethacin or meclofenamate, both prostaglandin synthetase inhibitors, decreases GFR and increases arteriolar resistance (Ichikawa and Brenner, 1979) so that changes in eicosanoids are implicated in partial obstruction responses. Several investigators have shown that the renin-angiotensin-aldosterone axis is activated with partial obstruction, including studies in the fetus. Gobet and colleagues (1999) studied fetal sheep in utero and showed that partial obstruction of the bladder outlet increased renin messenger RNA (mRNA) after 2 weeks and increased the expression of renal AT2 receptors as well as the mRNA for transforming growth factor beta (TGF-β), a mediator of fibrosis.

One could hypothesize that changes in angiotensin II may be responsible for much of the hemodynamic, fibrotic, and apoptotic changes in neonatal animals with partial obstruction, as has been shown in more acute models. Beharrie and coworkers (2004) examined weanling male rats that had been subjected to a partial UUO. The partial obstruction led to proteinuria, hyperuricemia, and increased solute excretion primarily from the unaffected contralateral kidney. A parallel group of rats treated with the ACE inhibitor enalapril was protected from these changes. This suggests that angiotensin is involved with functional tubular changes as well. Eskild-Jensen and colleagues (2002) examined partial UUO for up to 24 weeks in young, postnatal pigs. The number of glomeruli was 28% less in the obstructed kidney, yet function was just transiently reduced by the occlusion. Thus partial neonatal obstruction can impair nephrogenesis independently of renal functional decline, and these changes may depend upon species, stage of renal development, or degree of occlusion. More work is needed to define the variables.

Various methods have been used to create partial obstruction. The models for preparing partial ureteral occlusions fall into three main categories. Intraluminal stents or catheters of varying sizes have been placed in the ureters of sheep (Abu-Zidan et al, 1999) and in dogs (Ryan and Fitzpatrick, 1987; Leahy et al, 1989) to restrict flow. In rats, or in growing animals, many investigators have used the technique of Ulm and Miller (1962), which involves splitting the psoas muscle longitudinally to form a groove into which the ureter is placed. This method has a potential advantage of increased constriction in proportion to the growth of the animal. Beharrie and colleagues (2004) used such a technique in young male weanling rats. A major problem with studies involving partial obstruction is the inability to determine reproducibly and accurately the degree of obstruction induced with these techniques. Thornhill and associates (2005) devised a method in neonatal rat pups of ligating a ureter along with a wire of a calibrated diameter that was then removed to make a partial and graded constriction of one ureter. When ureteral diameter was reduced by 70% to 75%, renal growth and number of glomeruli were reduced and fibrosis and pelvic dilation were proportionately increased. GFR was reduced by 80% after 28 days of partial UUO. Such models may offer new opportunities to model the clinical condition reproducibly.

Egress of Urine from the Kidney

Although the normal flow of urine from the kidney through the urinary tract is compromised with obstruction, urine may still egress from the kidney. An example of this is extravasation at the calyceal fornix (pyelosinus) that occurs with acute obstruction, typically ureteral stones (Stenberg et al, 1988). Extravasation of urine into the venous (pyelovenous) and lymphatic system (pyelolymphatic) may also occur in this setting. In chronic obstruction, fluid is thought to exit into the renal venous system.

Effects of Obstruction on Tubular Function

Obstruction of one or both kidneys can have profound effects on sodium, potassium, and hydrogen excretion and mechanisms of urinary concentration and dilution. In the case of UUO, relatively normal function of the nonobstructed kidney partially offsets the reduced ability of the postobstructive kidney to reabsorb solutes and water. Postobstructive diuresis, something that is commonly encountered after reversal of BUO, occurs uncommonly after release of UUO, probably as a consequence of the contralateral renal unit’s functional capacities that are enhanced by an upregulation of ion transporters (Li et al, 2007). The eventual correction of abnormal renal excretory function depends upon the degree and duration of obstruction.

Changes in tubule function after correction of UUO related to ureteropelvic junction or ureteral obstruction were characterized in 10 patients by Gillenwater and colleagues (1975). The mean period of obstruction in these cases was 12 months, and the range was from days to years. Functions of the normal and obstructed kidney were evaluated 1 week after relief of the obstruction. The GFR in the obstructed kidney was significantly less than that in the non-obstructed kidney (24 vs. 60 mL/min), and the urine osmolality and osmolar clearance were all significantly less in the postobstructed kidney. The similar osmolar clearances (volume of urine required to excrete urinary solute isosmotically) relative to GFR of the previously obstructed and unobstructed kidneys indicate that there is a true concentrating defect in the obstructed kidneys 1 week after relief of obstruction.

Urinary Concentrating Ability

Normal urine concentrating ability requires a hypertonic medullary interstitial gradient because of active salt reabsorption from the thick ascending limb of Henle, urea back flux from the inner medullary collecting duct, and water permeability of the collecting duct mediated by vasopressin and aquaporin water channels. Obstructive nephropathy can disrupt some or all of these mechanisms and lead to deficits in urinary concentration. A brief review of the normal concentrating mechanisms is provided to facilitate understanding the effects of obstruction.

In normal physiology, arginine vasopressin (AVP) is secreted into the bloodstream from the posterior pituitary gland in response to increased serum osmolality or a reduction in effective circulating volume. AVP binds to the V2 vasopressin receptor located on the basolateral surfaces of the collecting duct cells. This promotes G protein signaling, resulting in generation of cyclic adenosine monophosphate (cAMP). Generation of cAMP in turn activates protein kinase A, which stimulates the fusion of cytoplasmic vesicles containing aquaporin 2 (AQP2) with the apical membranes of the collecting duct cells. The fusion causes the normally watertight membrane to become water permeable. This promotes transcellular absorption of water through the AQP2 channels, which is transported through aquaporin 3 (AQP3) and aquaporin 4 (AQP4) channels located in the basolateral cell membrane into the interstitium. This sequence of events is driven by the osmotic gradient of sodium (Knoers, 2005). Another aquaporin, aquaporin 1 (AQP1), is abundant in renal proximal tubules, the thin descending limb of Henle, and the descending vasa recta in the kidney. It promotes urinary concentration through the countercurrent multiplier by facilitating water transport from the descending limb of Henle into the interstitium (King et al, 2001).

The onset of concentration defects may develop soon after obstruction. Jaenike and Bray (1960) demonstrated a concentrating defect in the unilaterally obstructed kidney after only 6 minutes of ureteral obstruction. Development of vasopressin resistance has been hypothesized as a mechanism of this occurrence. However, various studies have demonstrated conflicting results concerning whether vasopressin resistance is present. Vascular changes may play a role. Even after only 18 hours of UUO, Solez and colleagues (1976) found a decrease in inner medullary plasma flow that increased when the occlusion was released. Necrosis of both the inner and outer medullae was present, indicating that ischemia may contribute to the development of a concentrating defect.

Evidence from Li and coworkers (2001) demonstrated that the polyuria following the release of BUO correlates with a decreased expression of the aquaporin water channels AQP1, AQP2, and AQP3 in rats. Release of obstruction resulted in polyuria that gradually decreased over a 30-day period, even though urinary concentrating capacity remained significantly impaired. Expression of AQP2 and AQP3 became normal by 30 days after release, but the expression of AQP1 remained decreased.

Jensen and coworkers (2006) examined changes in water channels after bilateral ureteral obstruction in rats. As expected, postobstructive polyuria with reduced urine osmolality was accompanied by decreased expressions of AQP1, AQP2, and AQP3 compared with control rats. The AT1 antagonist candesartan attenuated reductions in GFR, urine output, and AQP suppression, as well as COX-2 induction in the inner medulla. These findings suggest that angiotensin II influences, directly or indirectly, the postobstructive diuresis of BUO.

Thus dysregulation of aquaporin water channels in the proximal tubule, thin descending loop, and collecting duct may contribute to the long-term polyuria and impaired concentrating capacity caused by obstructive nephropathy. Increases in angiotensin II may be a mediator of these changes.

Sodium Transport

A decrease in sodium transport in the nephron appears to play an additional prominent role in the decreased ability of the postobstructed kidney to concentrate urine. When UUO is released after an occlusion period of 24 hours, total urine excretion is normal to modestly increased despite increased fractional excretion of sodium (FE_Na) in the previously obstructed kidney. This is attributed to the contralateral kidney compensating for the sodium losses of its mate. However, with BUO, sodium and water excretions may be quite robust after release of obstruction. The FE_Na may be increased to as much as 20 times normal in this setting (Zeidel and Pirtskhalaishvili, 2004). Although ANP appears to play a role in sodium diuresis after release of BUO, it is unlikely to affect sodium transport defects associated with UUO. The latter is most likely due to selective cell membrane changes in the nephron that reduce the number and effectiveness of sodium transporters. Such changes may also occur with BUO.

In spite of differential quantitative responses between UUO and BUO after release of the obstruction, the reabsorption defects in segmental nephron Na⁺ transport are similar. Micropuncture studies of kidneys from animals have been undertaken to assess these responses. These studies demonstrate normal to modestly enhanced isotonic volume flux (J_v) in superficial proximal convoluted tubules after release of UUO or BUO. On the other hand, sodium delivery to the loop of Henle in juxtamedullary nephrons, and to the first accessible portion of the inner medullary collecting duct, is substantially increased after release of both UUO and BUO, indicative of reduced sodium transport. Sonnenberg and Wilson (1976) even found evidence for net influx of sodium throughout the medullary collecting duct, which further contributed to an increased FE_Na. However, this was more prominent with BUO in their rat model.

Studies in isolated perfused nephron segments have also provided knowledge about the impact of obstruction at the level of the nephron. They have shown normal isotonic reabsorption in the superficial proximal convoluted tubules from animals with either UUO or BUO, whereas J_v in proximal straight tubules from juxtamedullary nephrons was demonstrated to be impaired (Hanley and Davidson, 1982). Similarly, chloride reabsorption and transport-dependent oxygen consumption (QO₂) from the medullary thick ascending limb of the Henle loop (MTAL) were severely impaired (Hanley and Davidson, 1982; Hwang et al, 1993b).

Cell suspensions from nephron segments have been used to assess the effects of obstruction at a cellular level. Active transport of Na⁺ across cell membranes requires apical entry through selective Na⁺ transporters or channels and basolateral exit driven by sodium-potassium adenosine triphosphatase (Na⁺,K⁺-ATPase). Furthermore, adequate adenosine triphosphate (ATP) must be generated to drive these primary transport steps. Hwang and associates showed that the amount and activity of the apical Na⁺,K⁺,2Cl⁻ cotransporter and bumetanide binding sites were reduced in cells isolated from the MTAL derived from obstructed rabbit kidneys. Basolateral transport is also affected in that ouabain-sensitive oxygen consumption, an index of Na⁺,K⁺-ATPase activity, has been shown to be reduced in cell suspensions from obstructed kidneys (Hwang et al, 1993a). A marked decrease in amiloride-sensitive oxygen consumption and Na⁺ entry in isolated cells from the inner medullary collecting ducts of obstructed rabbit kidneys reflects reduced activity of the apical Na channel (ENaC). In addition, ouabain-sensitive transport as measured by oxygen consumption and ATPase activity was shown to be reduced in cells from this portion of the nephron harvested from obstructed kidneys (Hwang et al, 1993a). Because cell suspension studies indicate that ATP generation is not the rate-limiting step underlying sodium transport dysfunction in this setting, the evidence points to downregulation of sodium transporters. This may be due to translational factors (reduction in mRNA for transporter synthesis) or post-translational processing of receptor proteins (Hwang et al, 1993a).

The signals responsible for downregulation of transporter activity with obstruction have not been clearly defined, but a number have been hypothesized. Stasis of tubular fluid flow may be one of the signals. When urine flow is obstructed, upstream Na⁺ delivery to apical cell membranes slows so that the transmembrane gradient is reduced. This could then serve as the signal for the downregulation of transporter activity or expression resulting in reduced active Na⁺ transport across the basolateral cell membrane (Zeidel, 1993). Several studies indicate that this is a feasible mechanism. For example, ouabain-sensitive Na⁺,K⁺-ATPase activity is reduced in MTAL and collecting duct cells when mineralocorticoid activity is controlled and chronic furosemide or amiloride is given to reduce Na⁺ entry into tubule cells (Petty et al, 1981; Grossman and Hebert, 1988). Additional studies have explored this concept in established cell lines. When A6 cells, an established line of collecting duct cells, are grown on a permeable substrate, Na⁺ influx across the apical membrane through the ENaC Na⁺ channel occurs. When Na⁺ entry was blocked, this induced a decreased expression of β-subunit of the epithelial sodium channel in the apical membrane (Rokaw et al, 1996). Ischemia has also been proposed as a signal in this setting, where ischemia that accompanies the reduced perfusion of the kidney with obstruction can also be a mediator of reduced transporter expression. The reduction in major renal sodium transporters reported with ischemic models of renal failure supports this concept (Kwon et al, 2000). Other proposed downstream signals include changes in renal interstitial pressure and local generation of natriuretic substances. Thus substrate delivery may be a regulatory step in the expression of sodium and possibly other transporters.

Intrarenal and extrarenal substances and hormones can also modulate sodium transport. The milieu of influential hormones may be substantially different between UUO and BUO. A number of investigators have shown that obstruction markedly increases the endogenous production of PGE₂ in the renal medulla. Furthermore, supraphysiologic concentrations of PGE₂ are well known to produce natriuresis (Strandhoy et al, 1974), and studies in isolated tubules and cell suspensions show that PGE₂ inhibits Na reabsorption in the MTAL and throughout the collecting duct (CD). One mechanism of this natriuretic response may be that PGE₂ reduces the amount of Na⁺,K⁺-ATPase at the basolateral membrane (Marver and Bernabe, 1992). PGE₂ can also inhibit the tubular effects of vasopressin (Zook and Strandhoy, 1980), thereby contributing to the free water loss from the post-UUO kidney. The influence of other substances and hormones in the postobstructed UUO kidney is counterbalanced or minimized by the contralateral renal unit.

Li and coworkers (2007) found that BUO caused a persistent decrease in the alpha and beta subunits of the epithelial Na channel (ENaC) three days after relief of obstruction. Similar changes in ENaC occurred following UUO but only in the obstructed kidney. The contralateral control kidney showed no changes in ENaC expression. Furthermore, Jensen and coworkers (2006) showed in rats that at 2 days following BUO there was reduced expressions of the Na phosphate cotransporter (NaPi-2), the loop Na⁺,K,2Cl⁻ cotransporter (NKCC2) and the Na⁺/H⁺ exchanger (NHE3). These decreases in Na transporters were consistent with the postobstructive natriuresis. Candesartan partially reduced these changes and attenuated the natriuresis.

Extracellular fluid volume may be greatly expanded with BUO. When the BUO is relieved, both intrarenal and extrarenal factors greatly enhance salt and water excretion so that a postobstructive diuresis is often seen. The normal physiologic consequences of extracellular fluid volume expansion ensue. These include a downregulation of sympathetic tone and the secretion of aldosterone and manifestation of the effects of ANP and probably other natriuretic factors. Levels of ANP are significantly elevated following BUO but not UUO (Purkerson and Klahr, 1989). The direct and indirect consequences of increased ANP levels include partial support of glomerular filtration, reduction of renin secretion and effects of angiotensin on transport, reduced aldosterone secretion, and direct inhibition of Na transport in the collecting duct (Brenner et al, 1990). Furthermore, BUO results in the accumulation of osmotic substances such as urea that can contribute to salt and water loss when the obstruction is relieved (Harris and Yarger, 1975, 1977). The FE_Na following relief of BUO is typically greater than that after UUO because BUO causes retention of Na, water, urea nitrogen, and other osmolar substances and increased production of ANP, all of which stimulate a profound natriuresis. Although Na transporters are similarly downregulated in the affected kidney in UUO, the contralateral kidney adequately compensates to maintain Na balance.

Potassium Transport

Obstruction has a complex impact on renal potassium handling, depending upon the type of obstruction. Harris and Yarger (1975) reported that there is a decrease in K⁺ excretion, in proportion to the decrease in GFR, after release of a 24-hour period of UUO. This may be partially due to reduced delivery of Na⁺ to the distal nephron and a low volume flow rate that would minimize the transmembrane gradient for K⁺

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