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RENAL PRESENTATION GROUP C

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Physiological states may also affect BUN e.g. heart failure, dehydration and GIT ... COX-1 maintains the normal physiological functions of the kidney and that COX-2 ... – PowerPoint PPT presentation

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Title: 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
5
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

12
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

14
  • 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

15
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.

16
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

17
  • 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.

18
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)

19
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

20
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

21
  • 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

22
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

23
  • 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

24
  • 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

25
Clinical Renal Syndromes Associated with COX
Inhibitors
26
Clinical Renal Syndromes Associated with COX
Inhibitors
27
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

28
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
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