The Kidney and Analgesics NSAIDs Acetaminophen ASA Shiva

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The Kidney and Analgesics (NSAIDs, Acetaminophen, ASA) Shiva Seyrafian- IUMS 98/9/7___ 28/11/2019

The Kidney and Analgesics (NSAIDs, Acetaminophen, ASA) Shiva Seyrafian- IUMS 98/9/7___ 28/11/2019

Pharmacology and mechanism of action of NSAIDs • More than 20 different nonsteroidal antiinflammatory

Pharmacology and mechanism of action of NSAIDs • More than 20 different nonsteroidal antiinflammatory drugs (NSAIDs) are available. • Used worldwide for their analgesic, antipyretic and antiinflammatory effects. • inhibition of cyclooxygenase, impairing transformation of arachidonic acid to prostaglandins • Nonselective NSAIDs (ns. NSAIDs) that block both cyclooxygenase (COX)-1 and COX-2. NSAIDs and Kidney 2

Pharmacology and mechanism of action. . v. Hypoalbuminemia (ie; due to cirrhosis or active

Pharmacology and mechanism of action. . v. Hypoalbuminemia (ie; due to cirrhosis or active rheumatoid arthritis) may have a higher free serum concentration of the drug. v. Topical NSAIDs: limits systemic absorption and the associated side effects and drug interactions v. Aspirin (the only acetylated NSAID) NSAIDs and Kidney 3

Pharmacology and mechanism of action. . Half life < 6 hrs (short-acting) Half life

Pharmacology and mechanism of action. . Half life < 6 hrs (short-acting) Half life > 6 hrs (long-acting) Ibuprofen Naproxen Diclofenac Celecoxib Ketoprofen Meloxicam Indomethacin Piroxicam Nabumetone NSAIDs and Kidney 4

Renal syndromes associated with NSAID use AKI ( hemodynamically-mediated Hypertension /edema or ATN) Acute

Renal syndromes associated with NSAID use AKI ( hemodynamically-mediated Hypertension /edema or ATN) Acute interstitial nephritis Acute papillary necrosis Nephrotic syndrome (minimal change disease or membranous nephropathy) Chronic tubulointerstitial nephritis/ analgesic nephropathy Hyponatremia Uroepithelial malignancy Hyperkalemia/ type 4 RTA NSAIDs and Kidney 5

Acute kidney injury (acute renal failure) EPIDEMIOLOGY 1 to 5 percent of all patients

Acute kidney injury (acute renal failure) EPIDEMIOLOGY 1 to 5 percent of all patients using nonsteroidal antiinflammatory drugs (NSAIDs) Use of NSAIDs increases the risk of AKI by nearly twofold, and the risk diminishes after cessation of the drug. NSAIDs and Kidney 6

PGI 2/PGE 2 attenuate the vasoconstricting effect of Renin angiotensin system and sympathetic nervous

PGI 2/PGE 2 attenuate the vasoconstricting effect of Renin angiotensin system and sympathetic nervous system in: Decreased Intravascular Volume Diseases Comorbidities Sepsis CHF DM Haemorrhage Cirrhosis HTN Diuretic therapy Nephrotic Syndrome Nephrolithiasis J. Evid. Based Med. Healthc. , p. ISSN- 2349 -2562, e. ISSN- 2349 -2570/ Vol. 5/Issue 21/May 21, 2018 NSAIDs and Kidney 7

Acute kidney injury • AKI can occur with any class of traditional, nonselective NSAID

Acute kidney injury • AKI can occur with any class of traditional, nonselective NSAID or cyclooxygenase-2 (COX-2)-specific NSAIDs • Indomethacin and rofecoxib, celecoxib NSAIDs and Kidney 8

Acute kidney injury RISK FACTORS 1. Existing glomerular disease, 2. Chronic Kidney Disease 3.

Acute kidney injury RISK FACTORS 1. Existing glomerular disease, 2. Chronic Kidney Disease 3. Severe hypercalcemia, 4. Effective volume depletion (heart failure and cirrhosis, nephrotic syndrome) 5. True volume depletion (diarrhea, aggressive diuresis, vomiting). 6. Medications: diuretics, ACE inhibitors, ARBs, and calcineurin inhibitors (CNIs). 7. Dose and duration NSAIDs and Kidney 9

Acute kidney injury- PREVENTION Avoided chronic use of NSAIDs if possible • In e.

Acute kidney injury- PREVENTION Avoided chronic use of NSAIDs if possible • In e. GFR <60 m. L/min/1. 73 m 2 and cautious use in e. GFR 60 to 89 m. L/min/1. 73 m 2 • Heart failure, • Cirrhosis, • Nephrotic syndrome • Hypercalcemia No "safe" dose or duration of NSAID has been defined NSAIDs and Kidney 10

Acute kidney injury- PREVENTION Patients with reduced e. GFR in whom limited NSAID use

Acute kidney injury- PREVENTION Patients with reduced e. GFR in whom limited NSAID use is unavoidable, 1. The patient should be advised of the risk, 2. The creatinine should be followed closely when receiving NSAIDs 3. Should not receive NSAIDs prior to procedures involving radiocontrast or other nephrotoxic drug administration. 4. Aware of medications that may increase the risk of hemodynamically mediated AKI NSAIDs and Kidney 11

Acute kidney injury-CLINICAL MANIFESTATIONS • Increase in the plasma creatinine • Urinalysis is usually

Acute kidney injury-CLINICAL MANIFESTATIONS • Increase in the plasma creatinine • Urinalysis is usually negative for hematuria and proteinuria, maybe low-level proteinuria (<500 mg/day) • Significant proteinuria (ie, >1 g/day): NSAID-induced glomerular lesion (minimal change disease or membranous nephropathy) • Hemodynamic AKI: hyaline casts • ATN: renal tubular epithelial cell casts, renal tubular epithelial cells, or granular casts. • AIN: White blood cells (WBCs) and WBC casts NSAIDs and Kidney 12

NSAIDs and Kidney 13

NSAIDs and Kidney 13

Acute kidney injury- DIAGNOSIS 1. History of recent NSAID use, 2. Absence of significant

Acute kidney injury- DIAGNOSIS 1. History of recent NSAID use, 2. Absence of significant proteinuria (<500 mg/day), and hematuria 3. The bland urine sediment. 4. Renal ultrasound to exclude possible obstruction. 5. If the history is overwhelmingly consistent with NSAID initiation or subacute or chronic use, avoid other costly tests as generally the diagnosis is made when recovery of kidney function occurs after the NSAID is discontinued. 6. Failure to recover or progression, biopsy within three to seven days NSAIDs and Kidney 14

Acute kidney injury- TREATMENT • No different than other forms of AKI. • Agent

Acute kidney injury- TREATMENT • No different than other forms of AKI. • Agent stopped immediately. • Volume resuscitation should be provided, based on blood pressure/pulse, urine output, and other parameters. • Renal replacement therapy rarely required but when severe AKI or serious electrolyte and acid-base disturbances. NSAIDs and Kidney 15

NSAIDs and Kidney 16

NSAIDs and Kidney 16

Definition of analgesic nephropathy A disease resulting from the habitual consumption over several years

Definition of analgesic nephropathy A disease resulting from the habitual consumption over several years of a mixture containing at least two anti-pyretic analgesics and usually codeine or caffeine. • It is characterized by kidney papillary necrosis and chronic interstitial nephritis that leads to insidious onset of progressive kidney failure. Kidney International (2007) 72, 517– 520 NSAIDs and Kidney 17

NSAIDs and Kidney 18

NSAIDs and Kidney 18

CASE PRESENTATION-1 • A 76–year-old male was referred to the chronic kidney disease clinic

CASE PRESENTATION-1 • A 76–year-old male was referred to the chronic kidney disease clinic for evaluation of his kidney impairment of longstanding duration. • He was asymptomatic at the time of presentation. • His serum creatinine was 2. 8 mg/dl and his estimated glomerular filtration rate (GFR) using the abbreviated modification of diet in renal disease study group (MDRD) equation was 24 -ml/min/1. 73 m 2. • The patient’s past medical history was remarkable for long-term ingestion of anacin (anacin comprised of phenacetin and acetyl salicylic acid), which he bought as an over-the-counter medication for recurrent headaches. NSAIDs and Kidney 19

CASE PRESENTATION-1. . • Anacin started during his college years and continued for several

CASE PRESENTATION-1. . • Anacin started during his college years and continued for several years (almost 20 years) because no other remedy was found for his recurrent headaches. • Although the patient could not recall precisely, he estimated that his average daily consumption of anacin was 2 g/day. • Over the past 20 years he had switched to acetaminophen – he estimated that he ingested 3– 4 tablets (1. 5– 2 g) of acetaminophen (single ingredient) each day. He was diagnosed with hypertension in 30 yrs ago and initiated on a thiazide diuretic. NSAIDs and Kidney 20

CASE PRESENTATION-1… • However, his gout got progressively worse to the extent of having

CASE PRESENTATION-1… • However, his gout got progressively worse to the extent of having an attack every 3 weeks and was successfully controlled with initiation of allopurinol 200 mg a day for 15 yrs. 13 yrs ago, he was also noted to have mild abnormal kidney function with a serum creatinine of 1. 5 mg/dl and an estimated GFR of 53 ml/min/1. 73 m 2. His kidney function remained relatively stable for almost a decade. • However, from 3 yrs ago his creatinine gradually rose from 1. 5 to 2. 8 mg/dl (corresponding to fall in estimated GFR from 53 to 23 ml/min/1. 73 m 2). NSAIDs and Kidney 21

Analgesic-related Chronic Kidney Disease • Clinical features: renal papillary necrosis and chronic interstitial nephritis

Analgesic-related Chronic Kidney Disease • Clinical features: renal papillary necrosis and chronic interstitial nephritis • Causes: prolonged and excessive consumption of analgesic mixtures containing aspirin or antipyrine, in combination with phenacetin, paracetamol, or salicylamide and caffeine and/or codeine • Pathogenesis: . Phenacetin is metabolized to acetaminophen and to reactive intermediates that can injure cells, • Damage to the vascular endothelial cells, focal segmental glomerulosclerosis and interstitial infiltration and fibrosis NSAIDs and Kidney 22

Analgesic-related Chronic Kidney Disease. . Aspirin potentiates the nephrotoxicity of both phenacetin and acetaminophen

Analgesic-related Chronic Kidney Disease. . Aspirin potentiates the nephrotoxicity of both phenacetin and acetaminophen Phenacetin-containing combination agents were almost certainly the most important cause of analgesic nephropathy. Analgesic nephropathy was common before phenacetin was removed from over-the-counter analgesics If acetaminophen is present alone, there is sufficient glutathione generated in the papillae to detoxify the reactive intermediate. If acetaminophen is ingested with aspirin, the aspirin is converted to salicylate, which becomes highly concentrated and depletes glutathione in both the cortex and papillae of the kidney. NSAIDs and Kidney 23

Analgesic-related Chronic Kidney Disease. . A 20 -year prospective of 7275 women showed an

Analgesic-related Chronic Kidney Disease. . A 20 -year prospective of 7275 women showed an increase in the risk of death from renal disease among phenacetin users compared with nonusers The nephrotoxicity of phenacetin is dose dependent. Decreased concentrating ability or a mild reduction in glomerular filtration rate (GFR). Renal disease requires a minimum intake of 2 to 3 kg each of phenacetin and aspirin. This requires six to eight years of a patient ingesting six to eight tablets (or approximately 1 gram) of phenacetin-containing compounds per day. NSAIDs and Kidney 24

NSAIDs and Kidney 25

NSAIDs and Kidney 25

Analgesic-related CKD- Aspirin • In most but not all studies, the long-term administration of

Analgesic-related CKD- Aspirin • In most but not all studies, the long-term administration of aspirin alone (in therapeutic doses) did not appear to induce renal injury. • Aspirin may potentiate the toxicity of phenacetin and acetaminophen NSAIDs and Kidney 26

Analgesic-related CKD-Acetaminophen • There is suggestive, but not definitive, evidence that chronic, especially daily,

Analgesic-related CKD-Acetaminophen • There is suggestive, but not definitive, evidence that chronic, especially daily, acetaminophen (paracetamol) use has dose-dependent, long-term nephrotoxicity • Small studies have suggested that acetaminophen alone is nephrotoxic, although the risk is less than that of phenacetin-aspirin combinations • Compared with those consuming <100 grams of acetaminophen, women consuming >3000 grams of acetaminophen had a multivariate OR of 2. 04 (95% CI 1. 28 -3. 24) for a decrease in glomerular filtration rate (GFR) of ≥ 30 m. L/min/1. 73 m 2 over an 11 -year period. NSAIDs and Kidney 27

Analgesic-related CKD- NSAIDs • Exposure to large quantities of NSAIDs can probably induce CKD

Analgesic-related CKD- NSAIDs • Exposure to large quantities of NSAIDs can probably induce CKD in some cases, although the percentage of patients affected is small relative to the number of prescriptions written • Large epidemiologic studies have failed to convincingly demonstrate an association between chronic NSAID use and CKD among initially healthy individuals NSAIDs and Kidney 28

NSAIDs and Kidney 29

NSAIDs and Kidney 29

Electrolyte complications • Hyperkalemia • Hyponatremia • Edema • Hypokalemia and renal tubular acidosis(ibuprofen)

Electrolyte complications • Hyperkalemia • Hyponatremia • Edema • Hypokalemia and renal tubular acidosis(ibuprofen) NSAIDs and Kidney 31

CHOICE OF NSAID • Renal prostaglandin synthesis may be relatively spared following therapy with

CHOICE OF NSAID • Renal prostaglandin synthesis may be relatively spared following therapy with sulindac or low-dose aspirin. • Indomethacin may be the most potent. NSAIDs and Kidney 32

Papillary calcifications in analgesic nephropathy. Non–contrast-enhanced CT scan of a patient with long-time analgesic

Papillary calcifications in analgesic nephropathy. Non–contrast-enhanced CT scan of a patient with long-time analgesic abuse showed thinning of the renal parenchyma and typical papillary calcifications (arrows). NSAIDs and Kidney 33

A, Macroscopic kidney specimen from a patient who developed ESRD as result of analgesic

A, Macroscopic kidney specimen from a patient who developed ESRD as result of analgesic nephropathy. B, Characteristic analgesic nephropathy features on CT scanning include reduced kidney size, irregular contours, and papillary calcifications. C, Noncontrast CT findings comparing a normal subject with two cases of analgesic nephropathy, with two distinct levels of reduced kidney function. Catherine M. Meyers, in National Kidney Foundation Primer on Kidney Diseases (Sixth Edition), 2014 NSAIDs and Kidney 34

Case 2 • Mrs MJ (83 years old) was referred for a routine visit.

Case 2 • Mrs MJ (83 years old) was referred for a routine visit. • Mrs MJ’s medical history included: atrial fibrillation, analgesic nephropathy (AN), chronic kidney disease (stage 3, estimated glomerular filtration rate 60 m. L/min/1. 73 m 2), gastroesophageal reflux disease, vitamin B 12 deficiency, hypertension, hypercholesterolemia, hypothyroidism, myocardial infarction (two), degenerative spondylolisthesis, and transient ischemic attack. NSAIDs and Kidney 35

medication profile Medication Dose and frequency Amlodipine 5 mg One tablet daily Irbesartan 300

medication profile Medication Dose and frequency Amlodipine 5 mg One tablet daily Irbesartan 300 mg One tablet daily Sotalol 80 mg Half a tablet twice daily Moxonidine 200 μg One tablet daily Simvastatin 40 mg One tablet at night Dabigatran 150 mg One tablet twice a day Calcium 600 mg One tablet daily Thyroxine 50 μg One tablet daily Pantoprazole 40 mg One tablet when required (usually once a week) Paracetamol SR 665 mg Not using (prescribed one tablet three times a day) Paracetamol 500 mg/codeine 30 mg One tablet at night Folic acid 0. 5 mg One tablet daily Vitamin B 6 240 mg One tablet daily Vitamin B 12 100 μg One tablet daily NSAIDs and Kidney 36

Case 2. . • At review, Mrs MJ described persistent back pain, but was

Case 2. . • At review, Mrs MJ described persistent back pain, but was reluctant to take paracetamol, due to her renal disease and previously documented analgesic -induced nephropathy. • The patient had been told to be careful with “some painkillers” to avoid further kidney damage, and subsequently had chosen to avoid paracetamol. • The patient had decided it would be prudent to avoid “all painkillers”, and she could not recall a health professional telling her paracetamol was safe. Further, it was documented that the patient had previously experienced acute renal failure from the use of an NSAID. • The patient was unsure which NSAID had caused her acute kidney failure, and it was not documented in her medical history. NSAIDs and Kidney 37

Case 2 • A case of a patient presented who was concerned about an

Case 2 • A case of a patient presented who was concerned about an adverse side effect of paracetamol that has not been clearly established in the literature. The patient was reassured that paracetamol was safe. • At follow-up, patient recommended to recommence paracetamol (665 mg three times a day), with improvement in back pain control without deterioration of renal function. NSAIDs and Kidney 38

NSAIDs and Kidney 39

NSAIDs and Kidney 39

Role of Acetaminophen With the currently available evidence acetaminophen remains the nonnarcotic analgesic of

Role of Acetaminophen With the currently available evidence acetaminophen remains the nonnarcotic analgesic of choice for occasional use in patients with underlying kidney disease. Kidney International (2007) 72, 517– 520 NSAIDs and Kidney 40

Role of aspirin Long-term aspirin monotherapy in therapeutic doses does not cause kidney injury

Role of aspirin Long-term aspirin monotherapy in therapeutic doses does not cause kidney injury in patients with normal kidney function. However, aspirin should be avoided in patients with: • Impaired kidney function • ‘at-risk groups’ such as those with volume deplete states, • glomerulonephritides, etc. There is no long-term adverse kidney risk with the lower doses of aspirin recommended for prevention of cardiovascular events and stroke. Kidney International (2007) 72, 517– 520 NSAIDs and Kidney 41

Role of NSAIDs The chronic use of NSAIDs in therapeutic doses is generally safe.

Role of NSAIDs The chronic use of NSAIDs in therapeutic doses is generally safe. kidney papillary necrosis and chronic kidney failure can occur in some patients. Exposure to a large cumulative dose of NSAID may lead to chronic kidney disease in some cases. The percentage of patients affected is small relative to the number of prescriptions written. Prolonged regular use of NSAIDS should be discouraged but if deemed necessary, it should be closely monitored. Kidney International (2007) 72, 517– 520 NSAIDs and Kidney 42

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