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. Ox de-am Trans-am 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 (cont’d) • 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 • >8.0 mmol/L may indicate pre renal failure. I.e. the urea is unable to be filtered by the kidneys. • <3.0 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 1:1 indicate intra-renal failure. (can’t filter it) • A u:c ratio of >80:1 indicates pre-renal failure. • A u:c ratio of <35:1 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 (cont’d) 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 (cont’d) 3. Fluid retention: • Kidney’s 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. 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 Advanced acute renal failure

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; 253:643-652 • Saker,B. Everyday drug therapies affecting the kidney. Australian prescriber 2000; 23:17-19 www.australianprescriber.com • Thatte,L; Vaamonde, C.A. Drug-induced nephrotoxicity, the crucial role of risk factors Postgraduate Medicine 1996; 100:83-106http://www.postgradmed.com/issues/1996/12_96/thatte.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