RENAL PRESENTATION GROUP C KIDNEY FUNCTION AND NSAIDS

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.

Urea Cycle Occurs in the liver Is only activated when there is nitrogen to be removed Trans-am Ox de-am

Analysis of nitrogenous compounds Urea and uric acid are waste products containing nitrogen urea

Analysis of nitrogenous compounds (cont’d) Interferences in the conversion of urea to ammonia are measured by:

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.

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.

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.

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

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

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

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.

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

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

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.

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

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.

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)

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

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

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

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

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

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

Clinical Renal Syndromes Associated with COX Inhibitors

Clinical Renal Syndromes Associated with COX Inhibitors

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

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; 100:83-106 http://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