management of POD in patients with AUR

1. Pathophysiology of Urinary tract obstruction
&
Postobstructive diuresis

2. • Filtration
• Reabsorption
• Secretion

8. Introduction
• Obstructive uropathy refers to the functional or anatomic obstruction of
urinary flow at any level of the urinary tract.
• Obstructive Nephropathy is present when the obstruction causes functional
or anatomic renal damage.
• Hydronephrosis is the dilatation of the renal pelvis or calyces.
It may or may not be associated with obstruction but may be present in the
absence of obstruction.

9. Urinary tract Obstruction
 tubular pressure changes, renal blood flow, and glomerular filtration rate
affecting the excretion function and renal homeostasis
 irreversible renal impairment

10. Causes

13. Symptoms
Depends on
• Acute / Chronic
• Unilateral / Bilateral
• Extrinsic vs Intrinsic cause of obstruction
• Complete vs Partial
• Presence or absence of infection
• Compliance of collecting system

14. Pathophysiologic changes
UUO vs BUO
A. RBF,GFR, and Ureteral Pressure
B. Tubular Function in Ureteric Obstruction

15. Unilateral ureteric Obstruction

16. A. RBF,GFR, and Ureteral Pressure
Pre-glomerular vasodilatation
Phase I (0-90 mins)
- Increased RBF in response to increased ureteral pressure.
- Due to preglomerular vasodilatation, a compensatory response intended to
increase capillary hydrostatic pressure and thus GFR.
- Vascular mediators thought to play major role:
Eicosanoids
Nitric Oxide

17. Post-glomerular vasoconstriction, then pre- and post-glomerular vasoconstriction
• Phase II (90 mins – 4/5 hours) characterised by a fall in RBF with a continued rise
in ureteral pressure. Due to post-glomerular vasoconstriction. Further attempt by
kidney to maintain GFR.
• Phase III (5 hours+) associated with concomitant falls in RBF and ureteral pressure.
Further fall in RBF due to pre-glomerular vasoconstriction. By 24 hours tubular
pressure and ureteral pressure fall to 30% and 50% of control values respectively.
• Vaso-constrictive mediators in Phase II and III:
-Eicosanoids
-Thromboxanes
-Renin/ Angiotensin II
-Endothelin

18. • Triphasic relationship between ipsilateral renal blood flow (RBF) and ureteral
pressure during 18 hours of Unilateral ureteral obstruction.

19. • Decreased GFR due to
o Reduced single-nephron renal blood flow
o Shunting of blood from outer to inner cortex, decreasing the total number
of perfused glomeruli. ? Mechanism of shunting. Increased production of renin
witnessed in outer vs. inner cortex.
• Fall in ureteral pressure due to
o Reduced GFR
o Pelvicalyceal dilatation
o Pyelolymphatic and pyelovenous backflow

20. Functional changes during ureteral obstruction

21. B. Tubular Function in Unilateral Ureteric Obstruction
• GFR markedly reduced following release of obstruction, but total excretion from
post-obstructed kidney is normal/ slightly elevated, due to ineffective Na
reabsorption and water retention in the tubules, leading to impaired concentrating
ability.
• Active transport markedly impaired. Selective down-regulation of both transporter
activity and transporter protein synthesis after 24 hours of obstruction.
• Proximal tubule relatively spared, but marked failure of active transport mechanisms
from loop of Henle to collecting duct. Reduced reabsorption of sodium in ascending
limb, leads to a reduction in interstitial hypertonicity. Combined with insensitivity to
ADH in collecting duct, results in impaired concentrating ability.
• Potassium excretion falls proportionate to fall in GFR, due to defective distal tubular
secretion.
• Failed active transport also leads to an inability to acidify urine

22. • Urine
o Normal/ mildly elevated excretion of filtered load
o Low osmolality
o Normal/ high pH
o High sodium content (increased filtered fraction)
o Low potassium content
o Low phosphate content

23. Bilateral Ureteric Obstruction (Obstructed
Solitary Kidney)

24. A. Changes in RBF, GFR and Ureteric Pressure
• No triphasic patternBiphasic pattern
o Initial short-lived rise in RBF as in UUO, due to pre-glomerular vasodilatation
o Marked fall in RBF, associated with a persistently elevated ureteric pressure > 24
hours. Associated with post-glomerular vasoconstriction.
o NO pre-glomerular vasoconstriction seen in late-stage BUO. ? accumulation of a
‘substance’ which prevents preglomerular vasoconstriction.
GFR preservation, diuresis and natriuresis in UUO with contralateral nephrectomy,
and with contralateral urine perfusion of obstructed kidney, but not in UUO with
normal contrateral kidney. Substance believed to be Atrial Natriuretic Peptide

25. Atrial Natriuretic Peptide
• Released by cardiac atrium in response to increased intravascular volume
• Effects designed to maximise diuresis and natriuresis
o Increased GFR through pre-glomerular vasodilatation and postglomerular
vasoconstriction
o Increased glomerular capillary ultrafiltration co-efficient (leakier
membrane)
o Direct inhibition of tubuloglomerular feedback mechanism (renin/AII)
o Specific inhibition of NaCl co-transport in ascending limb of loop of Henle
o Blocks vasopressin-mediated osmotic water permeability
• Elevated in BUO but not in UUO in rats

26. Functional changes during ureteral obstruction

27. B. Tubular Function in Bilateral Ureteric Obstruction
• Similar tubular defects as seen in UUO, but exacerbated due to activity of ANP
• Marked post-obstructive diuresis and natriuresis may be seen
• A marked increase in Na delivery to the distal nephron, combined with elevated serum
potassium, results in an increased filtration fraction of potassium
• Urine
o Significantly increased total excretion of filtered load
o Low osmolality (lower cf. UUO)
o Normal/ High pH
o High sodium content
o High potassium content

28. Renal Function after Release of Ureteric Obstruction

29. A. Unilateral Ureteric Obstruction
Different durations of acute UUO
o If reversed within 2 weeks = full recovery of function
o After 14 days ~ up to 70% return of function
o No functional recovery after 6 weeks
o Continued improvement up to 6 months following obstruction
o Anecdotal reports of total return to function after as long as 6 months
o ? due to multi-calyceal kidney or pyelolymphatic ‘escape’

30. B.Bilateral Ureteric Obstruction
• No clear relationship between the duration of obstruction and recoverability of
function. Furthermore no pre-release chemistry which can predict recoverability.
• 2 phases of recovery of function:
An initial ‘tubular’ phase associated with improvements in creatinine clearance
and fractional excretion of sodium.
A further ‘glomerular’ phase associated with a gradual improvement in GFR
over approximately 3 months.

32. Effect of obstruction on tubular function
• Urinary Concentrating Ability
Normally it 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,
– 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

33. • Sodium Transport
- Active transport of Na+ across cell membranes requires apical entry through
selective Na+ transporters or channels and basolateral exit driven by Na+-K+-ATPase
and adequate ATP must be generated to drive these primary transport steps.
In obstruction there is reduced activity of the apical Na channel (ENaC) and also
decreased ATPase activity.
• Hydrogen Ion Transport and Urinary Acidification
- Major acidification defect is in the distal nephron, related to defective H+ secretion
in the distal tubule and collecting duct and/or decreased bicarbonate reabsorption in
the juxtamedullary nephron.
Obstruction causes a deficit in urinary acidification
• Insensitivity to ADH
- 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.

34. • Obstruction has an effect on other cation transport as well
• In UUO, potassium secretion is decreased in proportion to the decrease in GFR
after release of a 24-hour period of UUO. (due to reduced delivery of sodium to the
distal nephron and a low flow state, along with intrinsic defect in potassium
secretion)
• In contrast, potassium excretion increases in parallel with sodium excretion after
relief of BUO, and it appears that proximal reabsorption of potassium remains
unchanged whereas its secretion in the collecting duct is increased after relief of
obstruction. (related to increased water and sodium delivery to the collecting duct
and to the presence of high levels of ANP that can stimulate potassium secretion in
the distal nephron.)
• Magnesium excretion is also markedly increased
• Effect on phosphate reabsorption,
• In BUO after relieving the obstruction , accumulated phosphate is
rapidly excreted in proportion to sodium,
• Whereas, in UUO a decrease in phosphate excretion and a net
retention occur with release.

35. Pathological changes of obstruction

36. Gross Pathologic Findings
Renal Pelvis Dilates
-Generally assumed to occur in the first few days after ureteral obstruction
-Extrarenal pelvis dilatation>>intrarenal dilatation.
-Increased intrarenal pelvic pressure results in papillary compression and
thinning, with eventual septation and production of a ‘rim’ of functioning
cortex.
Initial Increase in Mean Kidney Weight
-Oedema > atrophy in first three months.
Pigmentation, Focal Ischaemia and Necrosis
-Focal necrosis and haemorrhage of papilla and fornix in particular

37. Microscopic Pathologic Findings
Tubular Apoptosis
-Initial dilatation and thinning of epithelium
-Apoptosis within 30 mins in animal models
-Dysregulation of proliferation and apoptosis
-Disappearance of recognisable tubular subunits within 21 days.
Glomerular Sparing
-Slight thickening of GBM with loss of filtration slits.
-Hyalinisation reported but not until ~ 6-9 months following obstruction, and then
only in a relatively small number of glomeruli.

38. • Inflammatory Infiltrate.
- Influx of predominantly macrophages but a few T-cells after 3-4 hours
- Associated conversion of fibroblasts to myofibroblasts.
- Production of mediators (TXA2, PAF and TGFB), leading to tubuloinsterstitial
fibrosis (TGF beta major is determinant)
• Tubulointerstitial fibrosis
- Thought to be major determinant of deranged renal function and failed
recovery following release of obstruction

39. Tubulointerstitial fibrosis
• Inflammatory Cell Infiltration
• Fibroblasts and Extracellular Matrix Production
• Epithelial-to-Mesenchymal Transition
• Cytokines and Vasoactive Mediators of Fibrosis
Transforming Growth Factor-β
Tumor Necrosis Factor-α
Interleukin-18
Angiotensin II
Apoptosis

40. Mechanisms of tubulointerstitial fibrosis during renal
obstruction.

41. • After infiltration of the interstitial space by activated macrophages,
inflammatory mediators are released,
• TGF-β1, TNF-α, and IL-18 trigger renal tubular cell apoptosis, the
transformation of renal tubular cells into matrix-producing
fibroblasts, and further inflammatory cell infiltration.
• Additional fibroblasts are recruited from the bone marrow, and
resident fibroblasts in the interstitial space are stimulated to secrete
extracellular matrix.
• Angiotensin II is produced in response to the decreased RBF
associated with obstruction, and it further stimulates macrophage
infiltration and cytokine production (TNF-α and TGF-β1).
• The resulting imbalance in ECM deposition results in expansion of the
interstitial space and increasing tubulointerstitial fibrosis.

42. Clinical impact of Obstruction
• Hypertension
• Increased ANP levels and intravascular volume
• A volume-mediated mechanism for hypertension
• BUO>UUO
• Compensatory Renal Growth
• Contralateral renal growth is influenced by age and the degree and duration
of obstruction
• While the kidney enlarges, an increase in the number of nephrons or
glomeruli does not occur, indicating that the increase in renal volume is
primarily a consequence of cellular hypertrophy rather than hyperplasia.

43. Post obstructive Diuresis

44. • Post-obstructive diuresis refers to the polyuria that may be encountered after
release of urinary obstruction as the body attempts to restore fluid and solute
homeostasis.
• Definition: Urine production exceeding 200 mL per hour for 2 consecutive hours
or producing greater than 3 L of urine in 24 hours is diagnostic of POD

45. • Factors necessary are
- Accumulation of total body water, Sodium and urea
- Impairment of Tubular re-absorptive capabilities. (in pathological POD)
• Clinical scenarios with significant POD
> Prior bilateral
> Ureteral obstruction
> Unilateral obstruction of a solitary functioning kidney
>Uncommon following UUO due to compensation by normally functioning
contralateral kidney.

46. • PHYSIOLOGICAL POD: Self limiting, generally lasts 24 hours– As a response to
simple solute and water overload. Stops after return to euvolemic state
• PATHOLOGICAL POD: Generally lasts longer than 48 hours and can be
exacerbated with excessive intravenous fluid replacement. Inappropriate diuresis
of water beyond euvolemic state.

47. Contributing factors after the release of obstruction
➢ Physiological
1. Excess Na and water retention
2. Retention of urea and non reabsorbable solutes
3. Accumulation of ANP
➢ Pathological
1. Concentration defect
2. Decreased tubular reabsorption of Na
3. Insensitivity to ADH
4. Increased tubular flow reducing equilibration time for reabsorption of Na and
water

48. ETIOLOGY
• The location of obstruction: Anywhere from meatus to the PUJ
• Common situations resulting in POD :
1) Infravesical obstructions-BPH,
CAP, NB,BT,urethral
strictures, meatal stenosis,
phimosis, CA penis
2) Bilateral ureteric obstructions-
Calculi, papilla, strictures,
PUJ obstructions, IRPF, RP tumors,
Abdominal aortic aneurysm
3) Unilateral obstruction in solitary
kidney-
Calculi, papilla, strictures

49. CLINICAL FEATURES/MONITORING
• Depend on duration and severity of obstruction- Asymptomatic to critically ill
• In POD following acute obstructions- Rapid to start, short plateau and rapid
normalisation of urinary volumes. Usually physiological POD.
• In POD following chronic obstruction (CRF)- Slow to start, longer plateau and
slow normalisation. This is the extended time taken for the concentrating
mechanisms to repair themselves.-Pathological POD)

50. Clues to possible pathological diuresis:
1)High degree of derangement of renal parameters.
2)Painless B/L HDUN/ unilateral in solitary kidney-Chronic
3)Hematuria following catheterisation-
Chronic obstruction - decompression hematuria
Slow decompression no longer advised.

51. During POD- Watch for
-Urine output recorded every hour initially and vital signs checked every 6 to 8 hours.
- Serum electrolyte (especially potassium), magnesium, phosphate, urea, and
creatinine levels should be checked every 12 to 24 hours and corrected if necessary.
-The intensity of monitoring depends on presence of risk factors for POD and the
subject's mental status, renal function, and electrolyte status.
-A urine sample should be collected for urinary sodium and potassium levels and urine
osmolality to determine if it is a salt or urea type of diuresis.
Urea diuresis is generally self-limiting,
Salt diuresis can convert to pathologic POD and requires careful monitoring of serum
electrolyte levels and hydration status.

52. • A simple method to estimate urine osmolality, if an automated
method is not available, is to assess the urine specific gravity.
A specific gravity of 1.010 is iso-osmotic with serum osmolality, indicating that the
kidneys do not need to concentrate the urine. This is consistent with physiologic
POD and is generally self-limiting.
A specific gravity of 1.020 demonstrates that the kidneys are concentrating the urine
and POD has resolved or has nearly resolved.
However, a specific gravity of 1.000 is hypo-osmotic with serum osmolality, indicating
the kidneys’ inability to concentrate the urine. This is consistent with pathologic
salt-wasting POD and should alert the health care team to monitor the patient
closely

53. MANAGEMENT
• Physiological POD: Basic monitoring and oral fluids regulated by thirst.
• Pathological POD: -Sequential monitoring
- Oral fluids + IV replacement depending on
volume of diuresis and ability of the patient to
take adequate oral fluids
- If Sodium is high- 0.45% saline. If Normal- 0.9%
saline
- Slightly under-hydrate to avoid iatrogenic
propagation of the diuretic phase and allow ADH
mechanisms to act on the tubules. (50-70-%
replacement is generally accepted)
- Correct hypokalemia that can be threatening.

54. • In the first 24 hours, urine output should be checked hourly.
➢ If it is over 200 mL/hour, then 80% (50% at CMCH) of the hourly output should be
replaced intravenously with 0.45% saline. Alternatively the same volume of water
may be consumed orally.
• After 24 hours of persistent diuresis,
➢ total fluids infused should be about 1 L less (or <75%) than the previous day's
output, provided the patient is hemodynamically stable.
- Once the urine output </- 3 L per day, oral fluids should suffice.
- If there are signs of hypovolemia, then total fluids replaced should be about 0.5 L
less, instead of 1 L, than the last 24 hours' output.

55. Pharmacological treatments
• Aquaporin expression was improved by administration of COX2 inhibitors and
associated with reduced urine output in the acute phase of POD but not after
24hours.
• PDIE -5 inhibtors has been shown to induce aquaporin membrane insertion
• Some interventions focus on preventing the long term consequences of
obstruction, such as fibrosis. For example, in rodent UUO models treatment with
statins, erythropoietin or rotenone decreased renal fibrosis.
• However, definitive human data are lacking to support routine pharmacological
intervention for POD at this time.