NSAIDs and the Kidney. Rania Derani Consultant Nephrologist Damascus-Syria

Transcription

1 NSAIDs and the Kidney Rania Derani Consultant Nephrologist Damascus-Syria

2 Physiologic Introduction

3 To function properly kidneys require: Normal renal blood flow Functioning glomeruli and tubules Clear urinary outflow tract

4 Renal Auto-regulation Autoregulation is the maintenance of a near normal intrarenal hemodynamic environment (RBF, RPF, and GFR) despite large changes in the systemic blood pressure RPF : Renal Plasma Flow RBF : Renal Blood Flow GFR : Glomerular Filtration Rate

5 Balance between vasoconstrictors and vasodilators involved in RBF and GFR Vasodilators PGs Kinins NO ANP Vasoconstrictors Renin Angiotensin II Endothelin ADH RBF GFR Figure : RBF / GFR is maintained by a balance between vasodilators and vasoconstrictors of Afferent and Efferent arterioles

6 Prostaglandins Prostaglandins are produced in the renal vasculature, collecting duct, and medullary and papillary interstitium. PGI2 and PGE2 act as vasodilators at the afferent arteriole and are particularly important in maintaining normal renal function

7 COX 1 and COX 2 Prostaglandins are synthesized from arachidonic acid in a pathway mediated by the Cyclooxygenase enzymes There are two forms of cyclooxygenase, COX1 (the predominant form) and COX2. The kidney contains COX1 and COX2.

8 Effect of Prostaglandins on Renal Function Maintain renal blood flow and GFR Antagonize systemic vasoconstriction Increase the secretion of renin Antagonize action of ADH Decreases Na+reabsorbtion

9 Role of Prostaglandins in the Kidney Arachidonic Acid COX-1, COX-2 PGE 2 PGI 2. Decreases Na + reabsorption GFR = glomerular filtration rate. Stimulates renin release secretion of aldosterone K + secretion Vasodilation - GFR - Renal blood flow

10 Prostaglandin Biosynthesis Membrane-bound phospholipids Arachidonic acid O 2 Phospholipase A 2 COX-1 COX-2 PGG 2 NSAIDs, ASA Coxibs PGH 2 Tissue-specific isomerases PGD 2 PGE 2 PGF 2 PGI 2 TxA 2 COX = cyclooxygenase; coxibs = COX-2 inhibitors; PG = prostaglandin; TxA 2 = thromboxane A 2 ; NSAID = nonsteroidal anti-inflammatory drug; ASA = aspirin.

11 Potential Effects of NSAIDs on Renal Physiology Arachidonic acid COX-1 NSAIDs COX-2 PGE 2 PGI 2 Sodium retention Peripheral edema Blood pressure Weight CHF (rarely) Hyperkalemia ARF CHF = congestive heart failure. COX = cyclooxygenase

12 Mechanism of Action of NSAIDs All NSAIDs inhibit the cyclooxygenase required for conversion of arachidonic acid to endoperoxide intermediate (PGG2 and PGH2). NSAIDs inhibit prostaglandin and thromboxane synthesis, they are potent inhibitors of cyclooxygenase and eliminate all prostaglandins and thromboxanes in every cell they reach.

13 Categories of NSAIDs There are two major categories for non-steroidal anti-inflammatory drugs. The first is non-selective anti-inflammatory drugs (COX-1 and COX-2 inhibitors). The second is selective anti-inflammatory drugs, COX-2 inhibitors. Non-selective and selective NSAIDs affect on renal functions

14 Type of non selective NSAIDs T1/2 (hr) dose/day (mg) short (1-8) indomethacin Ibuprofen * salicylate (low dose) 2-3 < 2500* diclofenac mefenamic acid (ponstan โ ) medium (10-20) naproxene sulindac salicylate (high dose) * long (24-36) nabumetone piroxicam very long (> 48) phenylbutazone tanoxicam

15 COX-2 Inhibitors Celecoxib, etoricoxib, valdecoxib selective COX-2 inhibitors. Have similar efficacies to that of the nonselective inhibitors, but the GIT side effects are decreasing by ~50%. But, no renal protection.

16 NSAIDs and the Kidney Non steroidal anti-inflammatory drugs (NSAIDs) are amongst the most commonly prescribed medication. Some are available over the counter(otc) and likely to be abused. Serious gastrointestinal side effects have been minimized with the advent of selective and specific COX-2 inhibitors and misoprostol. However, the newer NSAIDs continue to be nephrotoxic much like the conventional NSAIDs.

17 NSAIDs and the Kidney The spectrum of nephrotoxicity includes acute tubular necrosis, acute tubulointerstitial nephritis, glomerulonephritis, renal papillary necrosis, chronic renal failure, salt and water retention, hypertension, hyperkalaemia and hyporeninemic hypoaldosteronism (type IV renal tubular acidosis and hyperkalemia). There are reports of sub- clinical renal dysfunction due to NSAIDs.

18 Renal Complications of the use of NSAIDS Sodium Retention, Edema, Hypertension Hyperkalemia Papillary Necrosis Acute Kidney Injury Interstitial Nephritis Nephrotic Syndrome Chronic Kidney Disease Renal Dysgenesis Subclinical Renal Dysfunction

19 Sodium Retention, Edema, Hypertension PGE2 directly inhibits Na+ reabsorption in the thick ascending limb and collecting duct NSAIDs decrease renal PGE2 production and thereby may enhance renal sodium retention and promote the development of edema and hypertension.

20 Sodium Retention, Edema, Hypertension Usually edema occurs in susceptible individuals within the first week of therapy in up to 5% of patients. Patients with preexisting treated hypertension commonly experience hypertensive exacerbations with NSAIDs.

21 Hyperkalemia NSAIDs cause hyperkalemia due to suppression of the renin-aldosterone axis. Hyperkalemia is an unusual complication of NSAID therapy in healthy people but can occurs in up to 46% of high-risk individuals. Indomethacin appears to be the NSAID most frequently associated with the development of hyperkalemia.

22 Hyperkalemia Severe hyperkalemia has been reported in patients with mild renal insufficiency. Other predisposing factors for the development of NSAID-induced hyperkalemia include cardiac failure, diabetes, multiple myeloma, concurrent administration of potassium supplements or potassium sparing diuretics, and ACEIs.

23 Papillary Necrosis Both acute and subacute forms of papillary necrosis have been observed with NSAID use. Acute NSAID-associated renal papillary injury is more likely to occur in the setting of dehydration, which suggests a critical dependence of renal function on cyclooxygenase metabolism in this setting.

24 Papillary Necrosis Long-term use of NSAIDs has been associated with papillary necrosis and progressive renal structural and functional deterioration, much as in the syndrome of analgesic nephropathy observed with the use of acetaminophen, aspirin, and caffeine combinations. the development of analgesic nephropathy requires the regular ingestion of NSAIDs or analgesics over a period of years.

25 Acute Kidney Injury NSAIDs rank second to aminoglycosides as the most common cause of nephrotoxic AKI. Reversible renal insufficiency (haemodynamic AKI) is the most common renal complication of NSAIDs, It presents with rising BUN, creatinine and serum potassium, decreasing urine output and weight gain.

26 Acute Kidney Injury NSAID therapy may cause abrupt declines in RBF and GFR due to the vascular effects of PGE2 withdrawal. The balance between vasoconstriction and vasodilatation helps maintain RBF and GFR. When NSAIDs are used in these conditions, interruption of prostaglandin synthesis allows vasoconstriction to occur unopposed by vasodilatation.

27 Intrarenal Mechanisms for Autoregulation under decreased perfusion pressure MAP RBF Afferent Arteriole PGC Efferent Arteriole PGE Ang II Reff / Raff ratio = GFR. Figure: shows reduced perfusion pressure within the autoregulatory range. Normal glomerular capillary pressure is maintained by afferent vasodilatation and efferent vasoconstriction.

28 Reduced perfusion with NSAIDs Reff / Raff ratio RBF Θ PGE NSAID Afferent Arteriole PGC Efferent Arteriole Ang II GFR. Figure: Loss of vasodilatory PGs increases afferent resistance causing drop in the glomerular capillary pressure below normal values and the fall in GFR

29 Acute Kidney Injury Occurs in a significant proportion of patients with underlying volume depletion, renal insufficiency, congestive heart failure, diabetes, and advanced age. It is usually completely reversible within 24 hours of discontinuation of NSAID.

30 Acute Kidney Injury Continued therapy can result in acute kidney injury which may be due to ATN in some patients. Predisposing conditions include congestive heart failure, cirrhosis, overt renal disease like lupus nephritis or chronic renal failure, advanced age,atherosclerotic cardiovascular disease, diabetes mellitus,hypertension, and concurrent diuretic therapy, though it can occur even in the absence of any predisposing conditions.

31 Acute Kidney Injury All groups of NSAIDs have been implicated (indomethacin being the most commonly incriminated). Agents with short half lives (e.g. ibuprofen) reach steady state early and manifest nephrotoxic effects sooner than NSAIDs with longer half lives (e.g. piroxicam, sulindac). The deterioration in renal function appears to be related to dose and duration of exposure to NSAID.

32 Acute Kidney Injury Rechange with even half the therapeutic dose can induce AKI especially in patients with mild asymptomatic renal failure at baseline. Even substituting one NSAID for another in a patient at risk of, or who has already demonstrated haemodynamic renal failure is likely to result in recurrence of this complication. Concomitant use of diuretic increases the risk of renal failure.

33 Risk factors for development of NSAID-Associated AKI Congestive heart failure Hepatic cirrhosis Nephrotic syndrome Hemorrhage Diuretic therapy Hypoalbuminemia Hepatic failure with ascites Hypertension Sepsis Anesthesia Diabetes mellitus Volume depletion due to diuretics or extra-renal fluid loss

34 Interstitial Nephritis Can occur within 1 week of NSAID administration but more often occurs several months to a year after the start of NSAID therapy Less commonly, the interstitial nephritis and renal failure may be fulminant. The clinical picture is typically much less dramatic than the allergic interstitial nephritis associated with β-lactam antibiotics, lacking fever or rash. Clinical symptoms of NSAID-induced interstitial nephritis also include edema, oliguria,haematuria, proteinuria and flank pain.

35 Interstitial Nephritis Interstitial nephritis is not related to the dose of NSAID used and does not appear to be directly related to inhibition of prostaglandin synthesis Typically resolve rapidly following discontinuation of the NSAID but may persist for 1 to 3 months Fenoprofen has been associated with interstitial nephritis more frequently than other traditional NSAIDs.

36 Nephrotic Syndrome Typically occurs in patients ingesting any one of NSAIDs over a course of months. The renal pathology is usually consistent with that of minimal change disease or membranous nephropathy. Typically, nephrotic syndrome occurs together with interstitial nephritis. Usually nephrotic syndrome resolves following discontinuation of the NSAID.

37 Chronic Kidney Disease From the preceding, it is evident that most forms of NSAID induce AKI, but it can progress in some cases to CKD. The underlying pathology is chronic papillary necrosis or chronic interstitial nephritis. Non immunologic and immunologic mechanisms may be involved. Medullary ischaemia seems to be the initiating event.

38 Chronic Kidney Disease NSAIDs, by inhibiting prostaglandin synthesis reduce medullary blood flow, suggesting that in this setting impaired medullary circulation may play a critical role in inducing papillary necrosis and chronic kidney disease. Hypertension may act as an aggravating factor.

39 Chronic Kidney Disease Immunological reactions that develop during the acute phase may continue to operate after the injury. Growth factors,(like TGF-β), and cytokines can induce both interstitial fibrosis and hypertrophy of the cells of the interstitium.

40 Renal Dysgenesis Reports of renal dysgenesis and oligohydramnios in offspring of women administered NSAIDs during the third trimester of pregnancy. So the Prostaglandins have a role in the process of normal renal development.

41 Subclinical Renal Dysfunction Although most of the literature on renal dysfunction due to NSAIDs pertains to clinically evident acute or chronic renal failure, there have been a few reports describing subclinical renal dysfunction in the form of functional abnormalities. In patients on long term NSAIDs without acute or chronic kidney injury, subclinical renal dysfunction such as reduced creatinine clearance and impaired urine concentrating ability has been shown to be present.

42 Subclinical Renal Dysfunction Although this sub-clinical dysfunction is reversible on withdrawal of NSAIDs, some reports have suggested a persistent residual dysfunction. Even with a wide range of NSAIDs at our disposal, a renal safe NSAID is yet to be discovered.

43 Recommendations Low-dose aspirin, low-dose over-the-counter ibuprofen, and sulindac appear to be safer. ketorolac might have greater nephrotoxic potential than other NSAIDs. avoid longt1/2. avoid Indomethacin.

44 Recommendations Low effective dose should be used initially Avoid NSAIDs use in Pregnant women Avoid continuous combination therapy One week of treatment to determine effect / side effect - if effective > continue / reducing dose / stop - if ineffective > try another NSAID

45 Thank you