Analgesic nephropathy

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

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.

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was first reported in German.^[1] In 1977, Australia was first to legally ban phenacetin.^[2] In 1983, phenacetin was withdrawn from the US markets.^[3]

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]

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]

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 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]

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

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]

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]

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]

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]

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]

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]

There are no ECG findings associated with analgesic nephropathy.

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

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 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]

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

There are no other imaging findings associated with analgesic nephropathy.

There are no other diagnostic studies associated with analgesic nephropathy.

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

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]

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

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]

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

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

Template:WH Template:WS

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

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

• In 1887, phenacetin was introduced as an analgesic which later became know that is metabolized to acetaminophen.^[1]
• In 1893, acetaminophen was introduced as an analgesic.^[1]
• In 1953, the association between analgesic drugs and chronic renal disease was first reported in German.^[2]
• In 1977, phenacetin became legally banned in Australia.^[3]  
• In 1978, phenacetin was withdrawn from the Canadian markets.^[4]
• In 1980, phenacetin was withdrawn from the markets in the United Kingdom.^[4]
• In 1983, phenacetin was withdrawn from the US markets.^[5]

Template:WH Template:WS

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

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. Renal ischemia and renal papillary necrosis may be result from the methemoglobinemia caused by phenacetin. 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. 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.

• There is a strong association between phenacetin and analgesic nephropathy.^[1]
• The classic analgesic nephropathy is disappearing after the removal of phenacetin from the markets over 30 years ago.^[2]
• 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.^[3][4]

• Toxic metabolites of phenacetin cause capillary sclerosis in the renal medulla, which result in renal papillary necrosis, tubulointerstitial nephropathy and cortical atrophy.^[5][2]
• Renal ischemia and renal papillary necrosis may be result from the methemoglobinemia caused by phenacetin.^[6]
• 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]
• Acetaminophen is a metabolite of phenacetin.^[8]

• In renal cells, acetaminophen is converted to N-acetyl-p-benzoquinoneimine (NAPQI) which depletes glutathione. With depletion of glutathione, the reactive metabolite of acetaminophen produces lipid peroxides and arylation of tissue proteins, which result in oxidative stress and renal papilliary necrosis.^[8]  

• NSAIDs and aspirin (ASA) inhibit the production of prostaglandin E2 (PGE2) in the kidneys (PGE2 regulates the renal blood flow).^[9]
• It has been reported that the concentration of salicylates is higher at the papillary compared to the cortex which is suggestive of direct damage to the renal papillary cells.^[10][7][9]

On gross pathology, the following findings are found in analgesic nephropathy:^[11]

• Decreased kidney size
• Adherent capsule and multiple cysts on the surface
• Scars on the surface (cortical atropy overlying papillary necrosis)
• Papillary necrosis (shrunken greyish black in appearance)

• Brownish-black papillae (due to products of phenacetin)
• Golden-brown streaks on the mucosal lining of the renal pelvis and the urinary tract

On microscopic histopathological analysis, the following are seen in analgesic nephropathy:^[11]

• Renal papillary necrosis
• Calcification in the necrotic medulla
• Chronic interstitial nephritis changes:
  • Tubular atrophy and dilatation  
  • Interstitial fibrosis 
  • Round cell infiltrate  
• Variable glomerular changes (normal to global sclerosis)
• Fibrosis of the periglomerular

On immunofluorescent microscopy, the following findings are seen:^[11]

• Segmental lesions show coarse blobs of C3
• Membranous lesions show granular deposits of IgG and C3 along glomerular capillary loops (epimembranous distribution)
• Arteries may be normal or show nephrosclerosis

Template:WH Template:WS

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

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. 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.

• There is a strong association between phenacetin and analgesic nephropathy.^[1]
• The classic analgesic nephropathy is disappearing after the removal of phenacetin from the markets over 30 years ago.^[2]

• Although non-phenacetin analgesics (such as NSAIDs, aspirin and acetaminophen) and 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.^[3][4]
• Further studies are required to assess renal injury and analgesic nephropathy caused by non-phenacetin analgesics .^[3]

Template:WH Template:WS

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

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.

Analgesic nephropathy should be differentiated with other disorders that cause renal papillary necrosis, such as:^[1][2][3]

• Diabetic nephropathy
• Renal crisis in sickle cell disease
• Pyelonephritis
• Obstructive uropathy
• Renal tuberculosis
• Alcohol-induced nephropathy
• Systemic vasculitis
• Renal vein thrombosis

Template:WH Template:WS

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

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. Most patients with analgesic nephropathy have been reported to be middle age or older with a history of chronic pain. Studies suggest that analgesic nephropathy is more conman in females than males.

• There is insufficient evidence about the incidence of analgesic nephropathy.
• However, the classic analgesic nephropathy is disappearing after the removal of phenacetin from the markets over 30 years ago.^[1]

• There is insufficient evidence about the prevalence of analgesic nephropathy.
• However, the classic analgesic nephropathy is disappearing after the removal of phenacetin from the markets over 30 years ago.^[1]

Most patients with analgesic nephropathy have been reported to be middle age or older with a history of chronic pain.^[2]  

There is insufficient evidence that suggests racial predilection in analgesic nephropathy.

Studies suggest that analgesic nephropathy is more conman in females than males. ^[3]

Template:WH Template:WS

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

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.

Risk factors for renal insufficiency from NSAIDs include:^[1]

• History of renal disorder
• Older age

• Congestive heart failure (CHF)
• Cirrhosis with ascites
• Nephrotic Syndrome

• Low salt dietary
• History of hemorrhage
• History of surgery
• Vomiting
• Diarrhea

Template:WH Template:WS

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

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

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

Template:WH Template:WS

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

The prognosis of analgesic nephropathy depends on the scarring and damage to the renal tissue. 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). Complications of analgesic nephropathy include: urinary tract infections, varying degrees of renal failure and End stage renal disease (ESRD).

• Renal function in most patients recovers to normal level after stopping the usage of analgesic drug if it is in the early stages of the disease.^[1]
• Depending on the scarring and damage to the renal tissue, some patients may progress to end stage renal disease (ESRD), even after stopping the usage of analgesic drug.^[1]

Complications associated with analgesic nephropathy include:^[2][3]

• Urinary tract infections
• Varying degrees of renal failure
• End stage renal disease (ESRD)^[1]
• Transitional cell tumours of the urothelium (in abuse of analgesics containing phenacetin)

The prognosis of analgesic nephropathy depends on the scarring and damage to the renal tissue. 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).^[1]

Some factors that contribute to poor outcome include:^[2]

• Malignant hypertension
• Persistent proteinuria
• Initial renal size and glomerular filtration rate (GFR)

Template:WH Template:WS