RENAL PRESENTATION GROUP C

1
RENAL PRESENTATIONGROUP C

• KIDNEY FUNCTION
• AND
• NSAIDS

2
Blood Urea Nitrogen (BUN)

• Urea is the end product of protein metabolism.
• Urea contains nitrogen which is eliminated from
  amino acids via the urea cycle in the liver.
• A very small amount of nitrogen is retained for
  acid base balance.

3
Urea Cycle

• Occurs in the liver
• Is only activated when there is nitrogen to be
  removed

4
Analysis of nitrogenous compounds

• Urea and uric acid are waste products containing
  nitrogen

urea
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Analysis of nitrogenous compounds (contd)

• Interferences in the conversion of urea to
  ammonia are measured by

6
Application of BUN

• Urea is freely filtered by the kidneys. It is
  also able to undergo reabsorption. BUN may
  therefore underestimate GFR.
• Normal physiological values 3.0 - 8.0 mmol/L
• gt8.0 mmol/L may indicate pre renal failure. I.e.
  the urea is unable to be filtered by the kidneys.
• lt3.0 mmol/L may indicate liver dysfunction as it
  may be compromised to conduct the urea cycle.

7
BUN variation

• BUN may change with medication use, e.g. NSAIDS,
  diuretics and antibiotics.
• Diet also influences BUN. An increase in protein
  intake will increase BUN.
• An increase in physical activity will also
  increase BUN.
• Physiological states may also affect BUN e.g.
  heart failure, dehydration and GIT bleeding.
• A decrease in GFR will also decrease BUN.
• Since BUN is affected by these diet, physical
  activity and drugs, it is not a very robust
  indicator of renal function.

8
Creatinine and urea ratio

• Both creatinine and urea are freely filtered.
  This ratio is used clinically to locate renal
  dysfunction.
• An elevation of both compounds with ratio 11
  indicate intra-renal failure. (cant filter it)
• A uc ratio of gt801 indicates pre-renal failure.
• A uc ratio of lt351 indicates hepatic failure.

9
NSAIDS and Renal Impairment

• Intra-renal circulation controlled by many
  factors including prostaglandins
  renin-angiotensin system
• These systems are particularly activated in
  disease states such as renal impairment
  abnormalities of cardiac output.
• Affected by drugs such as NSAIDS

10

• Risk factors for NSAID toxicity include old age,
  pre-existing renal dysfunction, hypertension and
  diabetes.

11

• NSAIDS can cause
• Acute renal failure
• In susceptible people a reduction in renal
  plasma flow glomerular filtration rate within
  hours
• An increase in serum creatinine and urea nitrogen
• Inhibition of renal prostaglandin synthesis,
  leading to intra renal vasoconstriction.
• A decrease in the glomerular filtration rate and
  salt and fluid retention

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Why Should NSAIDS be avoided in patients with
moderate-severe renal impairment?

• NSAIDS inhibit renal prostaglandin synthesis,
  leading to intra renal vasoconstriction.
• Vasoconstriction results in a reduction in the
  GFR and can lead to salt and fluid retention, by
  decreasing urine output.
• Consequently resulting in an increase in blood
  pressure and can manifest as heart failure.

13

• NSAIDS and Renal Haemodynamics
• NSAIDS have been associated with a number of
  renal abnormalities due to alteration in renal
  haemodynamics
• NSAIDS can cause sodium retention, hyperkalaemia
  and fluid retention. Hence NSAIDS should be
  avoided in moderate or severe renal impairment
• These effects are readily reversible upon
  discontinuation of NSAIDS

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• 1. Sodium retention
• In renal impairment sodium excretion decreases,
  thus excess sodium increases ECF volume which
  leads to oedema
• NSAIDS decrease sodium excretion and hence
  increase ECF volume

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NSAIDS and Electrolyte Balance (contd)

• 2. Hyperkalaemia
• In renal impairment, potassium excretion is
  decreased.
• NSAIDS also cause severe hyperkalaemia, by
  inhibiting renin release, reducing glomerular
  filtration and decreasing rate of distal tubular
  flow.

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NSAIDS and Electrolyte Balance (contd)

• 3. Fluid retention
• Kidneys function of regulating water is also
  compromised, which leads to increase to ECF
  volume and oedema
• NSAIDS also promote water retention by enhancing
  cellular response to antidiuretic hormone and
  increased interstitial osmotic agent

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• NSAIDS and Pharmacokinetics
• Alteration in PK of NSAIDS may contribute to
  nephrotoxicity
• Elderly patients have a decrease in total body
  water and a lower serum albumin, which increases
  the free NSAID serum concentration and possibly
  the drug effect
• Since up to 50 of unchanged drug and the
  metabolites are eliminated by kidney, in renal
  impairment the duration of the effect of active
  drug will be increased.

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Nephrotoxicity

• NSAID USE
• ?
• INH COX? ?PROSTAGLANDINS
• ?
• oedema
• hyperkalaemia
• ?
• ACUTE RENAL FAILURE
• Characterised by
• -mild-mod oliguria
• -low excretion Na
• Reversible on discontinuation of NSAID
• if advanced can lead to more serious renal
  dysfunction (next slide)

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Advanced acute renal failure

• ALTERED RENAL BLOOD FLOW
• ?
• ?filtered load,
• ?analgesic conc
• ?conc of glutathione
• ?
• PAPILLARY MEDULLARY NECROSIS
• Characterised by
• -sclerotic necrosis of kidney
• -calcification of kidney
• -metaplastic bone formation
• Irreversible depending on degreee of damage at
  time of diagnosis

• ? FREE RADICALS
• t-cell activation?lymphokine release?altered
  vascular permeability
• ?
• TUBULOINTERSTITIAL NEPHRITIS
• Characterised by
• -heavy proteinuria(foamy urine)
• -urine sediment with microscopic haematuria and
  pyuria
• Renal function improves on discontinuation of
  NSAID
• Recovery usually slow range 1 month-1 year

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Renal Adverse Effect Profile COX-1 Vs COX-2
Inhibitors

• THEORY
• COX-1 maintains the normal physiological
  functions of the kidney and that COX-2 is
  primarily involved in inflammatory processes
• EXPECTATION
• Coxibs would have less renal adverse effects
  associated with conventional (non-selective)
  NSAIDS

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• OVERSIMPLIFICATION!
• COX-1 may also contribute to inflammatory
  processes and COX-2 may have an important role in
  the synthesis of prostanoids (integral to the
  regulation of renal perfusion), salt and water
  handling, and renin release.
• However, normal regulation of renal blood flow
  does not depend on PGs

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Are Coxibs Any Better?

• GFR Effects
• Healthy subjects Coxibs show no significant
  interference but non-selective NSAIDS modestly
  reduce GFR
• Susceptible patients e.g. renal insufficiency,
  CHF, diabetes, old age, volume salt depleted
  Selective NSAIDS have similar risk profile to
  traditional NSAIDS, are able to reduce GFR to the
  same degree and acute renal failure may develop

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• Electrolyte and Fluid Effects
• Coxibs transiently reduce Na excretion rates
  similar to conventional NSAIDS
• Oedema in the lower extremities, is commonly
  reported in Coxib clinical studies as it is
  during therapy with traditional NSAIDS.
• It is dose dependant with selective COX
  inhibitors
• The risk of congestive heart failure (the most
  serious complication of fluid retention) is
  similar to conventional NSAIDS
• Similar nephrotic potential

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• Blood Pressure Effects
• Non-selective NSAIDS are well known to raise
  blood pressure and exacerbate hypertension in pxs
  on blood pressure lowering medications.
• NSAID induced increase in BP
• inhibition of PG synthesis at the renal level ?
  Na and water retention ? expands plasma volume
• inhibition of prostacyclin synthesis ? increased
  peripheral resistance because of vasodilator
  effect from prostacyclin has been lost
• PGs have inhibitory effects on the renal
  synthesis of endothelin-1 which may lead to Na
  and water retention ? increased peripheral
  vascular resistance
• BP effects expected due to Coxibs, and appears to
  be dose dependant.
• Pxs should be monitored in the initial phase of
  treatment

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Clinical Renal Syndromes Associated with COX
Inhibitors
26
Clinical Renal Syndromes Associated with COX
Inhibitors
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General Summary

• BUN is not an reliable independent indicator of
  renal function due to its variability, despite
  this, it is still used clinically.
• NSAIDS can cause an acute usually reversible
  deterioration in renal function, hence it should
  be avoided in moderate or severe impairment
• The effects of NSAIDS on fluid and electrolyte
  balance and levels of protective mechanisms can
  lead to acute renal failure and possibly more
  serious nephrotoxic syndromes
• Risk and severity of adverse renal effects due to
  selective COX-2 inhibitors are similar to
  conventional NSAIDS

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References

• Gambaro, A. Perazella, A. Adverse renal effects
  of anti-inflammatory agents evaluation of
  selective and nonselective cyclo-oxygenase
  inhibitors. Journal of Internal Medicine 2003
  253643-652
• Saker,B. Everyday drug therapies affecting the
  kidney. Australian prescriber 2000 2317-19
  www.australianprescriber.com
• Thatte,L Vaamonde, C.A. Drug-induced
  nephrotoxicity, the crucial role of risk factors
  Postgraduate Medicine 1996 10083-106
  http//www.postgradmed.com/issues/1996/12_96/thatt
  e.htm
• Tisher,C. Renal pathology with clinical and
  functional correlation. JB lippincoA company,
  Philadelphia 1989.
• Cham,J Gill, J. Kidney electrolyte disorders.
  Churchill living stone New York 1990