Title: RENAL PRESENTATION GROUP C
1RENAL PRESENTATIONGROUP C
- KIDNEY FUNCTION
- AND
- NSAIDS
2Blood 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.
3Urea Cycle
- Occurs in the liver
- Is only activated when there is nitrogen to be
removed
4Analysis of nitrogenous compounds
- Urea and uric acid are waste products containing
nitrogen
urea
5Analysis of nitrogenous compounds (contd)
- Interferences in the conversion of urea to
ammonia are measured by
6Application 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.
7BUN 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.
8Creatinine 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.
9NSAIDS 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
12Why 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
15NSAIDS 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.
16NSAIDS 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.
18Nephrotoxicity
- 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)
19Advanced 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
20Renal 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
22Are 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
25Clinical Renal Syndromes Associated with COX
Inhibitors
26Clinical Renal Syndromes Associated with COX
Inhibitors
27General 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
28References
- 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