Embed Size (px)
Citation preview
ABDULAZIZ M.BAKHSH
Pathophysiology of urinary tract obstruction
Hemodynamic changes
The changes influenced by the extent & the severity of the obstruction and wither the obstruction persist or has been relived .
what is the relation between the GFR & the renal hemodynamic ?
GFR= Kf (Pgc - Pt – gc ) .
Kf is the glomerular ultrafiltration coefficient .
Pgc is the glomerular capillary pressure , which influenced by renal plasma flow (RPF) & resistant of the afferent & efferent arterioles .
Pt is the pressure of fluid in the tubules , gc is the oncotic pressure in the late glomerular capillary & efferent arteriole .
Renal plasma flow (RPF) depend on the renal perfusion pressure & vascular resistant .
RPF = (aortic pressure – renal venous pressure ) / renal vascular resistant
What is the effect on the GFR in case of :Constriction of afferent arteriole ? Constriction of efferent arteriole ?
The whole kidney GFR depend on the renal perfusion & the percentage of the glomeruli actually filtering .
Obstruction can transiently or permanently change the GFR .
Hemodynamic Changes with Unilateral Ureteral obstruction :
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 .
With UUO, RBF increases during the first 1 to 2 hours and is accompanied by a high PT 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 .
The 3rd phase start 5 hours after obstruction its characterized by further decline in RBF in association with parallel with Pt and other 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 , that regulate the renal resistance .
In the 1st phase the increase in PT would lead to decrease the GFR logically .
But this is counterbalanced by an increase in RBF related to afferent arteriolar vasodilation ,this will limit the fall in GFR due the increase in Pgc .
Why ?
This hyperemic changes 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 .
As will as changes in interstitial pressure within the kidney , or the release of vasodilators such as prostanoids like prostaglandin E2 & NO .
There various of evidence that support the involvement of PGE2 , NO . Studies showed an increase in excretion of PGE2 in the urine of the contralaterall kidney .
increase in PGE2 and the vasodilation of the obstructed kidney could be blocked by a prostaglandin synthesis inhibitor .
Also iNO increase in the obstructed kidney .And administration of the NOS inhibitor
attenuated the early rise in RBF .
In the 2nd GFR and RBF progressively decline in UUO In contrast to the early rise in PT 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 (Raff) . 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 .
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 PGC but also to global reduction in filtration related to no perfusion or underperfusion of many glomeruli .
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 because during the first phase of UUO renal vein renin levels increase , Infusion of the angiotensin-converting enzyme (ACE) inhibitor captopril attenuates the declines in RBF and GFR in UUO .
Other vasoconstrictors is Thromboxane A2 (TXA2) , which 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 .
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
How the kidney will response to the release of the obstruction ?
The kidney's response to the release of UUO depends on the duration and extent of obstruction .
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. 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 .
Hemodynamic Changes with Bilateral Ureteral obstruction :
In contrast to the early robust renal vasodilation with UUO, there is a modest increase in RBF with BUO lasting approximately 90 minutes followed by a prolonged and profound decrease in RBF that is greater than that found with UUO .
Vasodilators : NO maintain renal hemodynamics in early
BUO .platelet-activating factor (paf) . Research
showed that PAF contribute to preservation of renal hemodynamic especially when vasoconstrictors like TXA2 were bloked .
Vasoconstrictors : TXA2 .Angiotensin II .Endotheline .All these mediators when blocked , GFR &
RPF decline stopped .
The intrarenal distribution of blood flow is different with BUO than with models of UUO .
A study showed he 55% of RBF reach the cortical nephrons while only 14 % reach the inner most zones .
Another study 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 with BUO.
Although in both cases ureteral and tubular pressure is increased for the first 4 to 5 hours , then in :
BUO it will remain at least 24h elevated , which will eventually decrease the SNGFR & the whole kidney GFR .
UUO it will return to preobstruction level by 24h .
Explanation : 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 UUO the initial preglomerular dilation and short-lived postglomerular vasoconstriction are followed by a more prolonged preglomerular vasoconstriction that stop the elevations in PGC and hence in PT.
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 as they would be excreted by the contralateral kidney. Atrial natriuretic peptide (ANP) appears to be one of these substances
Summary
both UUO and BUO involve increases in renal vascular resistances and increases in ureteral pressures.
the timing and regulation of these changes differ . 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 .
Egress of Urine from the Kidney :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 .
Extravasation of urine into the venous (pyelovenous) and lymphatic system (pyelolymphatic) may also occur in this setting especially in chronic obstruction .
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 .
Studies showed that The GFR in the obstructed kidney was significantly less than that in the nonobstructed kidney , and the urine osmolality, osmolar clearance, and fractional free water clearance were all significantly less in the postobstructed kidney .
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 back flux from the inner medullary collecting duct, and water permeability of the collecting duct mediated by vasopressin & aquaporin water channels .
The onset of concentration defects may develop soon after obstruction .
Jaenike and Bray demonstrated a concentrating defect in the unilaterally obstructed kidney after only 6 minutes of ureteral obstruction .
Why ? Strong hypothesis this is due to vasopressin resistance .Vascular changes may play a role. Even after only 18
hours of UUO, there is decrease in inner medullary plasma flow that increased when the occlusion was released , Necrosis of both the inner and outer medullae was present i.e ischemia may play a role .
Summary : 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 of obstructive nephropathy.
Sodium Transport :decrease in sodium transport in the nephron
appears to play an additional prominent role in the decreased ability of the postobstructed kidney to concentrate and dilute urine .
After the release of an obstruction : UUO , urine volume is normal or slightly
increase , despite fractional excretion of sodium (FENa) in the previously obstructed kidney .
Why ?
BUO , sodium and water excretions may significantly increase after release of obstruction .
FENa may be increased up to 20 time the normal .
ANP play a significant role in this proces which it will appeare more in BUO than in UUO .
Intrarenal and extrarenal substances and hormones can also modulate sodium transport .
PGE2 secretion increased markedly in obstructed kidney , its known about PGE2 that it cause natriuresis .
A study showed that PGE2 inhipit Na reabsorbtion in MTAL & collecting duct , and its inhibitory effect on vasopressin by which increase free water loss
Extracellular fluid volume may be greatly expanded with BUO , as a result ANP level increase .
Atrial natriuretic peptide (ANP ) :GFR support .reduction of renin secretion & angiotensin effect .reduced aldosterone secretion .direct inhibition of Na transport in the collecting
duct . This explain post obstructive diuresis is more in
BUO.
Summary :major changes occur with the ability of the kidney to
concentrate the urine because of downregulation of transporters and aquaporin water channels .
Sodium excretion is greater after relief BUO because of ANP .
Potassium and phosphate excretions follow changes in sodium , increase with BUO & decrease in UUO due to altered transport & retention .
Obstruction causes a deficit in urinary acidification that has been demonstrated in humans and in animals.
Cellular and Molecular Mechanisms Leading to fibrosis & apoptosis :
Urinary tract obstruction leads to progressive and eventually permanent changes in the structure of the kidney including the development of tubulointerstitial fibrosis , tubular atrophy and apoptosis, and interstitial inflammation .
A Number of cytokines play role in these events which include TNF , TGF-B and Angiotensin II ,some of these are produced by the renal tubule & other produced by macrophages .
Tubulointerstitial fibrosis develops as a consequence of extracellular matrix being synthesized and deposited at a greater rate than it is degraded .
matrix metalloproteinases (MMP) responsible for degradation of fibrosis .
Obstruction increases the synthesis of tissue inhibitors of metalloproteinases (TIMPs) that reduce MMP activity, resulting in the accumulation of extracellular matrix.
The strongest fibrotic cytokines are TGFB & Angiotensin II .
ACE inhibitors or angiotensin receptor blockers diminish TGF-β1 expression and reduce tubulointerstitial fibrosis .
Summary :Although the events leading to fibrosis
are thought to be initiated by increased angiotensin II, other profibrotic factors appear to play a significant role because inhibition of angiotensin synthesis by ACE inhibitors or antagonism of the AT1 receptors blunts but does not completely abolish the fibrotic process .
Apoptosis : Renal obstruction produces atrophy and cell
death .Cysteinyl aspartate-specific proteinases
(caspases) are known to mediate apoptotic cell death in obstructed kidney , it’s a 12 enzymes family .
There are 2 pathway for caspases :1st pathway include binding of TNF to its
receptors which will activate cell membrane death .
2nd pathway involves intrinsic stress signals that result in mitochondrial release of proapoptotic proteins such as cytochrome c .
both pathways will activate effector caspases, resulting in condensation of nuclear material and cell death.
Compensatory Renal Growth :Compensatory renal growth of the
unobstructed kidney was first described by Hinman (1943) .
An increase in contralateral renal volume has been detected ultrasonographically when hydronephrosis or unilateral renal agenesis is present (Mandell et al, 1993 ) .
The mechanism is by several factors including :
Age .Degree of obstruction .Duration of obstruction .
Both hyperplastic and hypertrophic compensatory growth have been demonstrated (Dicker and Shirley, 1973; Castle and McDougal, 1984; Peters et al, 1993
Both hyperplastic and hypertrophic compensatory growth have been demonstrated (Dicker and Shirley, 1973; Castle and McDougal, 1984; Peters et al, 1993
While the kidney enlarges, an increase in the number of nephrons or glomeruli does not occur (Peters et al, 1993 ) .
But an increase in the length of the proximal tubule has been described (Moller, 1988 ) .
Studies of humans subjected to nephrectomy, a functional surrogate for obstruction, have demonstrated that a reduction in renal compensatory growth occurs with increasing age (Edgren et al, 1976) .
Insulin-like growth factor I (IGF-I) may play a role in the compensatory mechanism .
When acute, complete ureteral obstruction is promptly relieved, full recovery of global GFR can occur .
Several studies showed it will go back to baseline GFR within 14 days post release .
Longer periods of complete ureteral obstruction are associated with diminished return of GFR .
I
In BUO there are 2 phases of recovery :during the first 2 weeks after relief of
obstruction when tubular function improved.later phase occurring over the next 10 weeks
when GFR gradually improved .An assessment of functioning cortex with
such imaging is the best predictor .dimercaptosuccinic acid (DMSA) shown to
be superior to (DTPA) OR (MAG3) .
Postobstructive Diuresis
Following the relief of urinary tract obstruction postobstructive diuresis , a period if significant polyureia may occur .
The diuresis is a normal physiologic response to volume expansion & solutes accumulation occuring during obstruction .
After homeostasis of Na , urea & free water is achieved diuresis must stop .
Pathologic postobstructive diuresis is charactrized by inappropriate handling of water & solutes .
Mechanisms :Down regulation of Na transporters with
subsequent impaired Na reabsorbtion in thick ascending loop of henle .
Derangement of medullary solute gradient .Increase the production of ANP .
There is also poor responsive of the collecting duct to ADH . This because of down regulation of aquaporin water channels .
