ACETAMINOPHEN USE AND RENAL FAILURE

Deepkamal Kaur, MDRenal Fellow

Paracelsus

• “All things are poison, and

nothing is without poison. The right

dose differentiates a poison from a

remedy”

Facts

• Synthesized in 1877 in U.S.• Extensive use began around 1947• Initially prescription only in the U.S.• OTC status gained in 1960Toxic effects first noted in U.S. in

1971 About 150 deaths in US/yr by accidental

acetaminophen intake-CDC Acetaminophen has a narrow safety margin

Acetaminophen is Everywhere!Found in over 200 products

Tylenol Anacin 3 Tempra

Tylenol cold Goody’s Comtrex multi sx

Contac Severe Cold Junior Strength Tylenol Vicks Nyquil

Sinutab Sinus Theraflu Sine-offSinarest Robitussin Cold PanadolMidol PMS Sudafed Sinus VanquishVicks 44M Unisom SingletPyrroxate Midol teen

CoricidinDimetapp allergy Drixoral Cold Alka Seltzer

PlusActifed Sinus Benadryl allergy Panex

McNeil; Johnson & Johnson

Current use of APAP in US

Relatively little is known about its renal effects

Metabolism of Acetaminophen

Liver: CYP450: 1A2, 2E1 substrate

Excretion: Urine (5-10% unchanged); half-life: 2-4 hours

Proposed Mechanisms of Renal Injury

1. Acute Tubular Necrosis: Mouse models suggest a possible role of acetaminophen induced endoplasmic reticulum stress with subsequent renal epithelial cell apoptosis.

*Paracetamol-Induced Renal Tubular Injury: A Role for ER Stress; Lorz et al; JASN

February 1, 2004 vol. 15 no. 2 380-389

Proposed Mechanisms of Renal Injury

• Paracetamol-induced apoptosis is a caspase-dependent process that involves activation Caspase-9 and Caspase-3 in the absence of cytosolic cytochrome c or Smac/DIABLO.

• Induction of endoplasmic reticulum (ER) stress, characterized by GADD153 upregulation and translocation to the nucleus, as well as caspase-12 cleavage

Caspases: Lethal intracellular proteins

Proposed Mechanisms of Renal Injury

2. Analgesic nephropathy – One of the many causes of chronic interstitial nephritis

Chronic exposure to at least two anti-pyretic analgesics (one of which is acetaminophen) along with caffeine or codeine. On CT the kidneys often have a characteristic shrunken bumpy appearance with accompanying papillary calcifications.

Diagnostic criteria of analgesic nephropathy. (A) Macroscopic aspect of an AN kidney from a patient with ESRD. (B) Diagnostic criteria used. (C) CT scans without contrast material of an individual with normal kidneys and patients with AN and with stage 3 CKD and ESRD. Adapted from De Broe and Elseviers

Proposed Mechanisms of Renal Injury

3. Metabolic gap acidosis secondary to 5-Oxoproline accumulation

Another rare but underdiagnosed cause of severe, high anion gap metabolic acidosis in adults is that due to accumulation of 5-oxoproline (pyroglutamic acid)

*Increased Anion Gap Metabolic Acidosis as a Result of 5-Oxoproline (Pyroglutamic Acid): A Role for

Acetaminophen; Fenves et al; CJASN May 2006 vol. 1 no. 3 441-447

Increased Anion Gap Metabolic Acidosis as a Result of 5-Oxoproline (Pyroglutamic Acid): A Role for Acetaminophen; Andrew J. Fenves et al; CJASN May 2006 vol. 1 no. 3 441-447

Nephrotoxicity without Hepatotoxicity

American Journal of Medicine1987 Jun;82(6):1280-1.Acute renal failure due to acetaminophen ingestion without concurrent hepatotoxicity.Kher K et al.

On the Contrary

• Acetaminophen inhibits hemoprotein-catalyzed lipid peroxidation and attenuates rhabdomyolysis-induced renal failure (rat models-at therapeutic concentrations)

* Boutaud et al, PNAS, 2010 (Proceedings of the National Academy of Sciences of

USA)

Current use of APAP in United States

Treatment

• Unlike liver injury, there is no evidence that N-Acetylcysteine attenuates renal injury!

*Standard of Care may not Protect against Acetaminophen-Induced Nephrotoxicity

Slitt et al; Basic & Clinical Pharmacology & Toxicology; Volume 95, Issue 5, pages 247–248, November 2004

• Wait and watch!

Treatment• Erdosteine, a mucolytic agent having antioxidant

properties via its active metabolites. Protective role on APAP induced renal damage in rats

• Erdosteine treated APAP groups showed milder tubular degeneration, epithelial vacuolization in the proximal tubules, lesser cellular desquamation and better morphology when compared with APAP groups.

Erdosteine against acetaminophen induced renal toxicity; Isik B et al, Department of Family Medicine, Division of Nephrology, Fatih University, Ankara, Turkey. Mol Cell Biochem. 2006 Jul;287(1-2):185-91. Epub 2006 Mar 11

Key Issues

• Need more studies on acetaminophen and renal dysfunction

• Need guidelines for acetaminophen dose use in kidney patients as well

• Should we take its “unknown safety” for kidneys for granted?

• Patient education to avoid unintentional overdose

Questions? Concerns?