Analgesic nephropathy

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Analgesic nephropathy
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Classically caused by mixed analgesics containing phenacetin, analgesic nephropathy was once a common cause of acute kidney injury.
Specialty Nephrology  OOjs UI icon edit-ltr-progressive.svg

Analgesic nephropathy is injury to the kidneys caused by analgesic medications such as aspirin, bucetin, phenacetin, and paracetamol. The term usually refers to damage induced by excessive use of combinations of these medications, especially combinations that include phenacetin. It may also be used to describe kidney injury from any single analgesic medication.

Contents

The specific kidney injuries induced by analgesics are renal papillary necrosis and chronic interstitial nephritis. They appear to result from decreased blood flow to the kidney, rapid consumption of antioxidants, and subsequent oxidative damage to the kidney. This kidney damage may lead to progressive chronic kidney failure, abnormal urinalysis results, high blood pressure, and anemia. A small proportion of individuals with analgesic nephropathy may develop end-stage kidney disease.

Analgesic nephropathy was once a common cause of kidney injury and end-stage kidney disease in parts of Europe, Australia, and the United States. In most areas, its incidence has declined sharply since the use of phenacetin fell in the 1970s and 1980s.[ citation needed ]

Presentation

Clinical findings in analgesic nephropathy [1]
FindingProportion affected
Headache35-100%
Pyuria50-100%
Anemia60-90%
Hypertension15-70%
Gastrointestinal symptoms40-60%
Urinary tract infection30-60%

Common findings in people with analgesic nephropathy include headache, anemia, high blood pressure (hypertension), and white blood cells in the urine (leucocyturia, pyuria). [1] Some individuals with analgesic nephropathy may also have protein in their urine (proteinuria). [2]

Complications

Complications of analgesic nephropathy include pyelonephritis [3] and end-stage kidney disease. [4] Risk factors for poor prognosis include recurrent urinary tract infection and persistently elevated blood pressure. [5] Analgesic nephropathy also appears to increase the risk of developing cancers of the urinary system. [6]

Pathophysiology

The scarring of the small blood vessels, called capillary sclerosis, is the initial lesion of analgesic nephropathy. [7] Found in the renal pelvis, ureter, and capillaries supplying the nephrons, capillary sclerosis is thought to lead to renal papillary necrosis and, in turn, chronic interstitial nephritis. [8] [7]

How phenacetin and other analgesics lead to this damage is incompletely understood. It is currently thought that the kidney toxicities of NSAIDs and the antipyretics phenacetin and paracetamol may combine to give rise to analgesic nephropathy. A committee of investigators reported in 2000 that there was insufficient evidence to suggest that non-phenacetin analgesics by themselves are associated with analgesic nephropathy. [9]

Aspirin and NSAIDs

Proper kidney function depends upon adequate blood flow to the kidney. Kidney blood flow is a complex, tightly regulated process that relies on a number of hormones and other small molecules, such as prostaglandins. Under normal circumstances, prostaglandin E2 (PGE2) produced by the kidney is necessary to support adequate blood flow to the kidney. Like all prostaglandins, PGE2 synthesis depends upon the cyclooxygenases.[ citation needed ]

Aspirin and other NSAIDs are inhibitors of the cyclooxygenases. In the kidney, this inhibition results in decreased PGE2 concentration causing a reduction in blood flow. Because blood flow to the kidney first reaches the renal cortex (outside) and then the renal medulla (inside), the deeper structures of the kidney are most sensitive to decreased blood flow. Thus the innermost structures of the kidney, known as the renal papillae, are especially dependent on prostaglandin synthesis to maintain adequate blood flow. Inhibition of cyclooxygenases therefore rather selectively damages the renal papillae, increasing the risk of renal papillary necrosis. [10]

NSAIDs caused no adverse effects on renal function in healthy dogs subjected to anesthesia. [11] [12] [13] Most healthy kidneys contain enough physiologic reserve to compensate for this NSAID-induced decrease in blood flow. However, those subjected to additional injury from phenacetin or paracetamol may progress to analgesic nephropathy.[ citation needed ]

Phenacetin and paracetamol

It is unclear how phenacetin induces injury to the kidney. [10] Bach and Hardy have proposed that phenacetin's metabolites lead to lipid peroxidation that damages cells of the kidney. [14]

Paracetamol is the major metabolite of phenacetin and may contribute to kidney injury through a specific mechanism. In cells of the kidney, cyclooxygenases catalyse the conversion of paracetamol into N-acetyl-p-benzoquinoneimine (NAPQI). [15] NAPQI depletes glutathione via non-enzymatic conjugation with glutathione, a naturally occurring antioxidant. [16] With depletion of glutathione, cells of the kidney become particularly sensitive to oxidative damage.[ citation needed ]

Diagnosis

Diagnosis is traditionally based on the clinical findings above in combination with excessive analgesic use. Once suspected, analgesic nephropathy can be confirmed with relative accuracy using computed tomography (CT) imaging without contrast. [17] One trial demonstrated that the appearance of papillary calcifications on CT imaging was 92% sensitive and 100% specific for the diagnosis of analgesic nephropathy. [18]

Treatment

Treatment of analgesic nephropathy begins with the discontinuation of analgesics, which often halts the progression of the disease and may even result in normalization of kidney function. [5] In Stage 5 chronic kidney disease patients renal replacement therapy may become necessary.[ citation needed ]

History

Analgesics are a class of medications widely used in the treatment of pain. They include aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), [19] as well as the antipyretics paracetamol (known as acetaminophen in the United States) and phenacetin. Introduced in the late 19th century, phenacetin was once a common component of mixed analgesics in parts of Europe, Australia, and the United States. [20] These analgesics contained aspirin or other NSAIDs combined with phenacetin, paracetamol, or salicylamide, and caffeine or codeine. [10]

In the 1950s, Spühler and Zollinger reported an association between kidney injury and the chronic use of phenacetin. [21] They noted that chronic users of phenacetin had an increased risk of developing specific kidney injuries, namely renal papillary necrosis and chronic interstitial nephritis. This condition was dubbed analgesic nephropathy and was attributed to phenacetin, although no absolute causative role was demonstrated. With further reports of the increased risk of kidney injury with prolonged and excessive phenacetin use, however, phenacetin was banned in several countries between the 1960s and 1980s. [20]

As the use of phenacetin declined, so too did the prevalence of analgesic nephropathy as a cause of end-stage kidney disease. Data from Switzerland, for example, demonstrated a decline in the prevalence of analgesic nephropathy among people with end-stage kidney disease, from 28% in 1981 to 12% in 1990. [4] An autopsy study performed in Switzerland suggested that the prevalence of analgesic nephropathy in the general population has likewise decreased; the prevalence was 3% in 1980 and 0.2% in 2000. [8]

While these data demonstrate that analgesic nephropathy has been all but eliminated in some regions, in other regions the condition persists. Notably, in Belgium, the prevalence of analgesic nephropathy among people having dialysis was 17.9% in 1984 and 15.6% in 1990. [22] [23] Michielsen and de Schepper suggest that analgesic nephropathy persists among people in Belgium having dialysis not due to non-phenacetin analgesics, but because Belgium accepts a higher proportion of elderly people for dialysis. According to these authors, a greater proportion have analgesic nephropathy because a greater percentage of people in Belgium having dialysis have been exposed to long-term use of phenacetin. [24]

Terminology

The term analgesic nephropathy usually refers to damage induced by excessive use of combinations of these medications, specifically combinations that include phenacetin. For this reason, it is also called analgesic abuse nephropathy. Murray prefers the less judgmental analgesic-associated nephropathy. [1] Both terms are abbreviated to the acronym AAN, by which the condition is also commonly known.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Nonsteroidal anti-inflammatory drug</span> Class of therapeutic drug for relieving pain and inflammation

Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of use, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease.

An antipyretic is a substance that reduces fever. Antipyretics cause the hypothalamus to override a prostaglandin-induced increase in temperature. The body then works to lower the temperature, which results in a reduction in fever.

<span class="mw-page-title-main">Ibuprofen</span> Medication used for treating pain, fever, and inflammation

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arteriosus in a premature baby. It can be used orally or intravenously. It typically begins working within an hour.

<span class="mw-page-title-main">Phenacetin</span> Pharmaceutical drug

Phenacetin is a pain-relieving and fever-reducing drug, which was widely used following its introduction in 1887. It was withdrawn from medicinal use as dangerous from the 1970s.

<span class="mw-page-title-main">Kidney disease</span> Damage to or disease of a kidney

Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can be diagnosed by blood tests. Nephrosis is non-inflammatory kidney disease. Nephritis and nephrosis can give rise to nephritic syndrome and nephrotic syndrome respectively. Kidney disease usually causes a loss of kidney function to some degree and can result in kidney failure, the complete loss of kidney function. Kidney failure is known as the end-stage of kidney disease, where dialysis or a kidney transplant is the only treatment option.

<span class="mw-page-title-main">Acute kidney injury</span> Medical condition

Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both.

<span class="mw-page-title-main">IgA nephropathy</span> Disease of the kidney

IgA nephropathy (IgAN), also known as Berger's disease, or synpharyngitic glomerulonephritis, is a disease of the kidney and the immune system; specifically it is a form of glomerulonephritis or an inflammation of the glomeruli of the kidney. Aggressive Berger's disease can attack other major organs, such as the liver, skin and heart.

Anti-inflammatory or antiphlogistic is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as opposed to opioids, which affect the central nervous system to block pain signaling to the brain.

<span class="mw-page-title-main">Indometacin</span> Anti-inflammatory drug

Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of prostaglandins, endogenous signaling molecules known to cause these symptoms. It does this by inhibiting cyclooxygenase, an enzyme that catalyzes the production of prostaglandins.

Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxins are substances displaying nephrotoxicity.

COX-3 is an enzyme that is encoded by the PTGS1 (COX1) gene, but is not functional in humans. COX-3 is the third and most recently discovered cyclooxygenase (COX3050) isozyme, while the first two to be discovered were COX-1 and COX-2. The COX-3 isozyme is encoded by the same gene as COX-1, with the difference that COX-3 retains an intron that is not retained in COX-1.

Thin basement membrane disease is, along with IgA nephropathy, the most common cause of hematuria without other symptoms. The only abnormal finding in this disease is a thinning of the basement membrane of the glomeruli in the kidneys. Its importance lies in the fact that it has a benign prognosis, with patients maintaining a normal kidney function throughout their lives.

<span class="mw-page-title-main">Interstitial nephritis</span> Medical condition

Interstitial nephritis, also known as tubulointerstitial nephritis, is inflammation of the area of the kidney known as the renal interstitium, which consists of a collection of cells, extracellular matrix, and fluid surrounding the renal tubules. It is also known as intestinal nephritis because the clinical picture may include mesenteric lymphadenitis in some cases of acute pyelonephritis. More specifically, in case of recurrent urinary tract infection, secondary infection can spread to adjacent intestine. In addition to providing a scaffolding support for the tubular architecture, the interstitium has been shown to participate in the fluid and electrolyte exchange as well as endocrine functions of the kidney.

Phosphate nephropathy or nephrocalcinosis is an adverse renal condition that arises with a formation of phosphate crystals within the kidney's tubules. This renal insufficiency is associated with the use of oral sodium phosphate (OSP) such as C.B. Fleet's Phospho soda and Salix's Visocol, for bowel cleansing prior to a colonoscopy.   

<span class="mw-page-title-main">Balkan endemic nephropathy</span> Medical condition

Balkan endemic nephropathy (BEN) is a form of interstitial nephritis causing kidney failure. It was first identified in the 1920s among several small, discrete communities along the Danube River and its major tributaries, in the modern countries of Croatia, Bosnia and Herzegovina, Serbia, Kosovo, Romania, and Bulgaria. It is caused by small long-term doses of aristolochic acid in the diet. The disease primarily affects people 30 to 60 years of age. Doses of the toxin are usually low and people moving to endemic areas typically develop the condition only when they have lived there for 10–20 years. People taking higher doses of aristolochic acid have developed kidney failure after shorter durations of exposure.

<span class="mw-page-title-main">Renal papillary necrosis</span> Medical condition

Renal papillary necrosis is a form of nephropathy involving the necrosis of the renal papilla. Lesions that characterize renal papillary necrosis come from an impairment of the blood supply and from subsequent ischemic necrosis that is diffuse.

A prostaglandin antagonist is a hormone antagonist acting upon one or more prostaglandins, a subclass of eicosanoid compounds which function as signaling molecules in numerous types of animal tissues.

Sickle cell nephropathy is a type of nephropathy associated with sickle cell disease which causes kidney complications as a result of sickling of red blood cells in the small blood vessels. The hypertonic and relatively hypoxic environment of the renal medulla, coupled with the slow blood flow in the vasa recta, favors sickling of red blood cells, with resultant local infarction. Functional tubule defects in patients with sickle cell disease are likely the result of partial ischemic injury to the renal tubules.

Aspirin/paracetamol/caffeine is a combination drug for the treatment of pain, especially tension headache and migraine. It contains aspirin, a non-steroidal anti-inflammatory drug; paracetamol (acetaminophen), an analgesic; and caffeine, a stimulant.

Prostaglandin inhibitors are drugs that inhibit the synthesis of prostaglandin in human body. There are various types of prostaglandins responsible for different physiological reactions such as maintaining the blood flow in stomach and kidney, regulating the contraction of involuntary muscles and blood vessels, and act as a mediator of inflammation and pain. Cyclooxygenase (COX) and Phospholipase A2 are the major enzymes involved in prostaglandin production, and they are the drug targets for prostaglandin inhibitors. There are mainly 2 classes of prostaglandin inhibitors, namely non- steroidal anti- inflammatory drugs (NSAIDs) and glucocorticoids. In the following sections, the medical uses, side effects, contraindications, toxicity and the pharmacology of these prostaglandin inhibitors will be discussed.

References

  1. 1 2 3 Murray TG, Goldberg M (January 1978). "Analgesic-associated nephropathy in the U.S.A.: epidemiologic, clinical and pathogenetic features". Kidney Int. 13 (1): 64–71. doi: 10.1038/ki.1978.9 . PMID   713270.
  2. ↑ Nanra RS, Stuart-Taylor J, de Leon AH, White KH (January 1978). "Analgesic nephropathy: etiology, clinical syndrome, and clinicopathologic correlations in Australia". Kidney Int. 13 (1): 79–92. doi: 10.1038/ki.1978.11 . PMID   362034.
  3. ↑ Maisonneuve P, Agodoa L, Gellert R, et al. (January 2000). "Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: results from an international comparative study". Am. J. Kidney Dis. 35 (1): 157–65. doi:10.1016/S0272-6386(00)70316-7. PMID   10620560.
  4. 1 2 Brunner FP, Selwood NH (1994). "End-stage renal failure due to analgesic nephropathy, its changing pattern and cardiovascular mortality. EDTA-ERA Registry Committee" (PDF). Nephrol. Dial. Transplant. 9 (10): 1371–6. doi:10.1093/ndt/9.10.1371. PMID   7816247.
  5. 1 2 Linton AL (October 1972). "I. Recognition of the problem of analgesic nephropathy". Can Med Assoc J. 107 (8): 749–51. PMC   1941002 . PMID   4638849.
  6. ↑ Blohmé I, Johansson S (November 1981). "Renal pelvic neoplasms and atypical urothelium in patients with end-stage analgesic nephropathy". Kidney Int. 20 (5): 671–5. doi: 10.1038/ki.1981.192 . PMID   7045494.
  7. 1 2 Mihatsch MJ, Hofer HO, Gudat F, Knüsli C, Torhorst J, Zollinger HU (December 1983). "Capillary sclerosis of the urinary tract and analgesic nephropathy". Clin. Nephrol. 20 (6): 285–301. PMID   6641031.
  8. 1 2 Mihatsch MJ, Khanlari B, Brunner FP (November 2006). "Obituary to analgesic nephropathy--an autopsy study". Nephrol. Dial. Transplant. 21 (11): 3139–45. doi: 10.1093/ndt/gfl390 . PMID   16891638.
  9. ↑ Feinstein AR, Heinemann LA, Curhan GC, et al. (December 2000). "Relationship between nonphenacetin combined analgesics and nephropathy: a review. Ad Hoc Committee of the International Study Group on Analgesics and Nephropathy". Kidney Int. 58 (6): 2259–64. doi: 10.1046/j.1523-1755.2000.00410.x . PMID   11115060.
  10. 1 2 3 de Broe, Marc E (2008). "Analgesic nephropathy". In Curhan, Gary C (ed.). UpToDate. Waltham, MA.{{cite book}}: CS1 maint: location missing publisher (link)
  11. ↑ Boström, IM; Nyman, G; Hoppe, A; Lord, P (January 2006). "Effects of meloxicam on renal function in dogs with hypotension during anaesthesia". Veterinary Anaesthesia and Analgesia. 33 (1): 62–9. doi:10.1111/j.1467-2995.2005.00208.x. PMID   16412133.
  12. ↑ Frendin, JH; Boström, IM; Kampa, N; Eksell, P; Häggström, JU; Nyman, GC (December 2006). "Effects of carprofen on renal function during medetomidine-propofol-isoflurane anesthesia in dogs". American Journal of Veterinary Research. 67 (12): 1967–73. doi: 10.2460/ajvr.67.12.1967 . PMID   17144795.
  13. ↑ Boström, IM; Nyman, GC; Lord, PE; Häggström, J; Jones, BE; Bohlin, HP (May 2002). "Effects of carprofen on renal function and results of serum biochemical and hematologic analyses in anesthetized dogs that had low blood pressure during anesthesia". American Journal of Veterinary Research. 63 (5): 712–21. doi: 10.2460/ajvr.2002.63.712 . PMID   12013473.
  14. ↑ Bach PH, Hardy TL (October 1985). "Relevance of animal models to analgesic-associated renal papillary necrosis in humans". Kidney Int. 28 (4): 605–13. doi: 10.1038/ki.1985.172 . PMID   3910912.
  15. ↑ Mohandas J, Duggin GG, Horvath JS, Tiller DJ (November 1981). "Metabolic oxidation of acetaminophen (paracetamol) mediated by cytochrome P-450 mixed-function oxidase and prostaglandin endoperoxide synthetase in rabbit kidney". Toxicol. Appl. Pharmacol. 61 (2): 252–9. doi:10.1016/0041-008X(81)90415-4. PMID   6798713.
  16. ↑ Duggin GG (July 1996). "Combination analgesic-induced kidney disease: the Australian experience". Am. J. Kidney Dis. 28 (1 Suppl 1): S39–47. doi:10.1016/S0272-6386(96)90568-5. PMID   8669429.
  17. ↑ de Broe ME, Elseviers MM (February 1998). "Analgesic nephropathy". N. Engl. J. Med. 338 (7): 446–52. doi:10.1056/NEJM199802123380707. PMID   9459649.
  18. ↑ Elseviers MM, De Schepper A, Corthouts R, et al. (October 1995). "High diagnostic performance of CT scan for analgesic nephropathy in patients with incipient to severe renal failure". Kidney Int. 48 (4): 1316–23. doi: 10.1038/ki.1995.416 . PMID   8569094.
  19. ↑ Buer JK (Oct 2014). "Origins and impact of the term 'NSAID'". Inflammopharmacology. 22 (5): 263–7. doi:10.1007/s10787-014-0211-2. hdl: 10852/45403 . PMID   25064056. S2CID   16777111.
  20. 1 2 McLaughlin JK, Lipworth L, Chow WH, Blot WJ (September 1998). "Analgesic use and chronic renal failure: a critical review of the epidemiologic literature". Kidney Int. 54 (3): 679–86. doi: 10.1046/j.1523-1755.1998.00043.x . PMID   9734593.
  21. ↑ Spühler O, Zollinger HU (1953). "Die chronisch-interstitielle Nephritis". Z Klin Med (in German). 151 (1): 1–50. PMID   13137299.
  22. ↑ Elseviers MM, de Broe ME (1994). "Analgesic nephropathy in Belgium is related to the sales of particular analgesic mixtures". Nephrol. Dial. Transplant. 9 (1): 41–6. PMID   8177475.
  23. ↑ Noels LM, Elseviers MM, de Broe ME (1995). "Impact of legislative measures on the sales of analgesics and the subsequent prevalence of analgesic nephropathy: a comparative study in France, Sweden and Belgium". Nephrol. Dial. Transplant. 10 (2): 167–74. PMID   7753450.
  24. ↑ Michielsen P, de Schepper P (March 2001). "Trends of analgesic nephropathy in two high-endemic regions with different legislation". J. Am. Soc. Nephrol. 12 (3): 550–6. doi: 10.1681/ASN.V123550 . PMID   11181803.
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