Analgesic nephropathy overview

Analgesic nephropathy Microchapters

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Overview

Historical Perspective

Pathophysiology

Differentiating Analgesic nephropathy from other Diseases

Epidemiology and Demographics

Risk Factors

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

Physical Examination

Laboratory Findings

Treatment

Medical Therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:  Shakiba Hassanzadeh, MD[2]

## Overview

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Analgesic nephropathy is a disorder caused by long-term use of analgesic drugs, mainly phenacetin and combinations containing phenacetin. This resulted in the withdrawal of phenacetin from most markets around the world since over 30 years ago, which has led to the disappearance of classic analgesic nephropathy caused by phenacetin. The main findings in analgesic nephropathy are renal papillary necrosis and chronic interstitial nephritis. The kidney injury may progress to end stage renal disease (ESRD). Although non-phenacetin analgesics (such as NSAIDs, aspirin and acetaminophen) or their combinations have been reported in some studies as causes to analgesic nephropathy, but there is insufficient evidence that suggests these drugs cause analgesic nephropathy.

## Historical Perspective

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In 1953, the association between analgesic drugs and chronic renal disease was first reported in German.[1] In 1977, Australia was first to legally ban phenacetin.[2] In 1983, phenacetin was withdrawn from the US markets.[3]

## Pathopysiology

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The pathogenesis of analgesic nephropathy caused by phenacetin may be due to several reasons. Toxic metabolites of phenacetin cause capillary sclerosis in the renal medulla, which results in renal papillary necrosis, tubulointerstitial nephropathy and cortical atrophy.[4][5] Renal ischemia and renal papillary necrosis may be result from the methemoglobinemia caused by phenacetin.[6] Additionally, It has been reported that the concentration of phenacetin is higher at the papillary which is suggestive of direct damage to the renal papillary cells.[7] Although non-phenacetin analgesics (such as NSAIDs, aspirin and acetaminophen) or their combinations have been reported in some studies as causes to analgesic nephropathy, but there is insufficient evidence that suggests these drugs cause analgesic nephropathy.[8][9]

## Causes

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There is a strong association between phenacetin and analgesic nephropathy which has led to the disappearing of classic analgesic nephropathy after the removal of phenacetin from the markets over 30 years ago.[10][5] Although non-phenacetin analgesics (such as NSAIDs, aspirin and acetaminophen) or their combinations have been reported in some studies as causes to analgesic nephropathy, but there is insufficient evidence that suggests these drugs cause analgesic nephropathy.[8][9]

## Differentiating Analgesic nephropathy from other Diseases

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Analgesic nephropathy should be differentiated with other disorders that cause renal papillary necrosis, such as: diabetic nephropathy, renal crisis in sickle cell disease, pyelonephritis, obstructive uropathy, renal tuberculosis, alcohol-induced nephropathy, systemic vasculitis and renal vein thrombosis.[11][12][13]

## Risk Factors

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Risk factors for renal insufficiency from NSAIDs include: history of renal disorder, older age, congestive heart failure (CHF), cirrhosis with ascites, nephrotic syndrome, history of hemorrhage or surgery, vomiting and diarrhea.[14]

## Screening

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There is insufficient evidence to recommend routine screening for analgesic nephropathy.

## Natural History, Complications and Prognosis

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The prognosis of analgesic nephropathy depends on the scarring and damage to the renal tissue.[11] Most patients in early stages recover to normal renal function after stopping the analgesic drug, however some may progress to end stage renal disease (ESRD).[11] Complications of analgesic nephropathy include: urinary tract infections, varying degrees of renal failure and end stage renal disease (ESRD).[15][16][11]

## Epidemiology and Demographics

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There is insufficient evidence about the incidence, prevalence and racial predilection of analgesic nephropathy. However, the classic analgesic nephropathy is disappearing after the removal of phenacetin from the markets over 30 years ago.[5] Most patients with analgesic nephropathy have been reported to be middle age or older with a history of chronic pain.[17] Studies suggest that analgesic nephropathy is more conman in females than males.[18]

## Diagnosis

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### Diagnostic Study of Choice

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Renal biopsy is the diagnostic study of choice, however, since it is an invasive procedure, CT scan without contrast of the abdomen is usually preferred.[19][20]

### History and Symptoms

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Common findings in patients with analgesic nephropathy include: headache, upper gastrointestinal disease (such as peptic ulcer), anemia, urinary tract infections, pyuria and hypertension.[15][16]

### Physical Examination

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In physical examination of patients with analgesic nephropathy checking for the followings should be considered: headache, upper gastrointestinal disease (such as peptic ulcer), anemia, urinary tract infections, and hypertension.[15][16]

### Laboratory Findings

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The laboratory tests and findings in analgesic nephropathy may include: urinary examination (sterile pyuria, hematuria, proteinuria and bacteriuria) and blood tests (anemia and renal failure).[15][16][11]

### Electrocardiogram

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There are no ECG findings associated with analgesic nephropathy.

### X-ray

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A pyelogram is not helpful in the diagnosis of analgesic nephropathy and may worsen the renal injury due to contrast utilization.[19]

### Ultrasound

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There are no ultrasound findings associated with analgesic nephropathy. However, ultrasound of the abdomen, kidneys and the urinary bladder could be helpful in ruling out other causes of nephropathy (obstruction or infection).[11]

### CT Scan

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CT scan without contrast of the abdomen is usually preferred for diagnosing analgesic nephropathy, the findings include: decrease in renal size, irregular contours and papillary calcifications.[20]

### MRI

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There is insufficient evidence suggesting MRI findings associated with analgesic nephropathy.

### Other Imaging Findings

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There are no other imaging findings associated with analgesic nephropathy.

### Other Diagnostic studies

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There are no other diagnostic studies associated with analgesic nephropathy.

## Treatment

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### Medical therapy

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Medical treatment of analgesic nephropathy may include: discontinuation of analgesics, adequate hydration with normal saline and treatment of infections with antibiotics.[15][11]

### Interventions

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Patients with analgesic nephropathy that present with acute renal failure or progression to end stage renal disease (ESRD) may require renal replacement therapy with dialysis.[21][15]

### Surgery

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Patients with analgesic nephropathy that progress to end stage renal disease (ESRD) may require renal replacement therapy with renal transplantation.[21]

### Prevention

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It has been suggested that in clinical practice, non-opioid analgesics, when possible, should be avoided for long-term use due to their nephrotoxicity.[17]

### Cost-Effectiveness of Therapy

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There is insufficient evidence about the cost-effectiveness of therapy in analgesic nephropathy.

### Future or Investigational Therapies

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No further or investigational therapies have been suggested in analgesic nephropathy.

## References

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1. ↑ Spühler O, Zollinger HU (1953). "Die chronisch-interstitielle Nephritis". Z Klin Med (in German). 151 (1): 1–50. PMID 13137299.CS1 maint: Unrecognized language (link)
2. ↑ Michielsen P, de Schepper P (2001). "Trends of analgesic nephropathy in two high-endemic regions with different legislation". J Am Soc Nephrol. 12 (3): 550–6. PMID 11181803.
3. ↑ "List of drug products that have been withdrawn or removed from the market for reasons of safety or effectiveness. Food and Drug Administration, HHS. Final rule". Fed Regist. 64 (44): 10944–7. 1999. PMID 10557618.
4. ↑ Mihatsch MJ, Hofer HO, Gudat F, Knüsli C, Torhorst J, Zollinger HU (1983). "Capillary sclerosis of the urinary tract and analgesic nephropathy". Clin Nephrol. 20 (6): 285–301. PMID 6641031.CS1 maint: Multiple names: authors list (link)
5. ↑ 5.0 5.1 5.2 Mihatsch MJ, Khanlari B, Brunner FP (2006). "Obituary to analgesic nephropathy--an autopsy study". Nephrol Dial Transplant. 21 (11): 3139–45. doi:10.1093/ndt/gfl390. PMID 16891638.CS1 maint: Multiple names: authors list (link)
6. ↑ Gault MH, Shahidi NT, Barber VE (1974). "Methemoglobin formation in analgesic nephropathy". Clin Pharmacol Ther. 15 (5): 521–7. doi:10.1002/cpt1974155521. PMID 4827469.CS1 maint: Multiple names: authors list (link)
7. ↑ Bluemle LW, Goldberg M (1969). "Renal accumulation of salicylate and phenacetin: possible mechanisms in the nephropathy of analgesic abuse". J Clin Invest. 47 (11): 2507–14. doi:10.1172/JCI105932. PMC 297415. PMID 5813230.
8. ↑ 8.0 8.1 Feinstein AR, Heinemann LA, Curhan GC, Delzell E, Deschepper PJ, Fox JM; et al. (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.CS1 maint: Multiple names: authors list (link)
9. ↑ 9.0 9.1 Delzell E, Shapiro S (1998). "A review of epidemiologic studies of nonnarcotic analgesics and chronic renal disease". Medicine (Baltimore). 77 (2): 102–21. doi:10.1097/00005792-199803000-00003. PMID 9556702.
10. ↑ Yaxley J (2016). "Common Analgesic Agents and Their Roles in Analgesic Nephropathy: A Commentary on the Evidence". Korean J Fam Med. 37 (6): 310–316. doi:10.4082/kjfm.2016.37.6.310. PMC 5122661. PMID 27900067.
11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 "StatPearls". 2020. PMID 31082145.
12. ↑ Chalhoub NE, Riley K, Siddiqui N, Assaly R, Shahrour K, Booth R; et al. (2015). "Renal Papillary Necrosis Due to Invasive Candida Infection in a Morbidly Obese Patient". J Urol. 194 (4): 1107–8. doi:10.1016/j.juro.2015.07.036. PMID 26184064.CS1 maint: Multiple names: authors list (link)
13. ↑ Kawaguchi Y, Mori H, Izumi Y, Ito M (2018). "Renal Papillary Necrosis with Diabetes and Urinary Tract Infection". Intern Med. 57 (22): 3343. doi:10.2169/internalmedicine.0858-18. PMC 6288002. PMID 29984778.CS1 maint: Multiple names: authors list (link)
14. ↑ Henrich WL (1998). "Analgesic nephropathy". Trans Am Clin Climatol Assoc. 109: 147–58, discussion 158-9. PMC 2194329. PMID 9601134.
15. ↑ 15.0 15.1 15.2 15.3 15.4 15.5 Nanra RS (1980). "Clinical and pathological aspects of analgesic nephropathy". Br J Clin Pharmacol. 10 Suppl 2: 359S–368S. doi:10.1111/j.1365-2125.1980.tb01824.x. PMC 1430193. PMID 7002190.
16. ↑ 16.0 16.1 16.2 16.3 Nanra RS, Stuart-Taylor J, de Leon AH, White KH (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.CS1 maint: Multiple names: authors list (link)
17. ↑ 17.0 17.1 Yaxley J (2016). "Common analgesic agents and their role in analgesic nephropathy: A commentary of the evidence". Int J Risk Saf Med. 28 (4): 189–196. doi:10.3233/JRS-170735. PMID 28582877.
18. ↑ Gault MH, Wilson DR (1978). "Analgesic nephropathy in Canada: clinical syndrome, management, and outcome". Kidney Int. 13 (1): 58–63. doi:10.1038/ki.1978.8. PMID 713269.
19. ↑ 19.0 19.1 "Analgesic Nephropathy - StatPearls - NCBI Bookshelf".
20. ↑ 20.0 20.1 de Broe ME, Elseviers MM (1998). "Analgesic nephropathy". N. Engl. J. Med. 338 (7): 446–52. PMID 9459649. Unknown parameter `|month=` ignored (help)
21. ↑ 21.0 21.1 Linton AL (1972). "Renal disease due to analgesics. I. Recognition of the problem of analgesic nephropathy". Can Med Assoc J. 107 (8): 749–51. PMC 1941002. PMID 4638849. Unknown parameter `|month=` ignored (help)

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