There are at least two distinct forms of analgesic nephropathy:¹

• The classical analgesic nephropathy associated with regular use of predominantly combination analgesic products:
  • This disease takes many years to develop and is characterised by a dense interstitial fibrosis and the insidious development of renal failure.
  • Renal papillary necrosis had been classically associated with this illness.
• The second form is typically an acute kidney injury associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs).

Analgesic nephropathy is a common cause of chronic kidney disease in Europe.² Acute kidney injury associated with NSAID use has been reported to account for up to 15.6% of cases of drug-induced renal failure.³

Pathogenesis

Analgesic nephropathy produces renal papillary necrosis as a result of long-term excessive use of aspirin in combination with phenacetin (no longer available) and also paracetamol. The ingestion may have been excessive - about 3 pills per day for 6 years.

Despite the well-characterised acute biological effects of NSAIDs on the kidney, there is only limited evidence that they are associated with an increased risk of chronic kidney disease.⁴
Renal damage is most apparent in the medulla, starting as prominent thickening of the vasa recta capillaries with patchy areas of tubular necrosis. This is followed by papillary necrosis and secondary injury to the cortex with focal and segmental glomerulosclerosis, interstitial infiltration and fibrosis. There is associated inflammation around tubules and blood vessels with degeneration of tubular cells (chronic interstitial nephritis).

The mechanism of action is related to the metabolism of phenacetin/paracetamol to reactive intermediates. They accumulate in the renal medulla at high concentrations. This occurs principally at the papillary tip, where they are able to damage the cells lining the duct, by oxidation. Aspirin exacerbates this by depleting glutathione that would detoxify the reactive intermediates. It also reduces renal blood flow by inhibiting prostaglandins.

Epidemiology

Analgesic nephropathy occurs in about 4 out of 100,000 people - mostly women aged over 30.⁵
In an Australasian study, of 31,654 renal replacement therapy patients, 10.2% had analgesic nephropathy.⁶ In contrast, a Swiss study found the prevalence had decreased from 4% of autopsy cases between 1978 and 1980, to the single case in the report at the end of 2000.⁷ The rate has decreased significantly in the 20 years that phenacetin has no longer been available in over-the-counter (OTC) preparations.

Risk factors

• Use of OTC analgesics containing more than one active ingredient.
• Chronic headache.
• Chronic backache or musculoskeletal pain.
• Dysmenorrhoea.
• Emotional and/or behavioural changes.
• History of dependent behaviours, including smoking, alcoholism and excessive use of tranquilisers.

There may also have been a history of the following conditions:

• Urinary tract infections.
• Interstitial nephritis.
• Renal calculi.
• Congestive heart failure.
• Blood volume depletion (such as dehydration).

Presentation

Symptoms

• In the early stages of the disease, the clinical symptoms are limited to polyuria, sometimes associated with sterile pyuria.⁸
• Often there are no symptoms directly attributable to the urinary tract but, there may be flank pain (renal colic) and haematuria in later (often obstructive) stages of the process.
• Diagnosis suggested by patients aged 30-70 years, who admit long-term analgesic use for chronic headaches, low back pain or somatic complaints such as malaise and weakness.
• They may also have a history of peptic ulcer disease or symptoms.

Signs

• In moderate-to-advanced disease - commonly, hypertension and anaemia.
• Proteinuria is found with worsening renal function.

Investigations

• Urine toxicology screen may show salicylates.
• Urinalysis shows blood and white cells.
• FBC may show anaemia and histology of urinary sediment may show necrotic papillary tissue.
• Intravenous pyelogram may show papillary necrosis (tissue death) or sloughed papillae in the renal pelvis or ureter.
• CT scan shows reduction in the size of the kidneys, irregular contours to kidneys, and calcification of papillae.⁹

Treatment

• Stop all suspect analgesia, particularly OTC medications containing 2 analgesic compounds in combination with potentially addictive substances, e.g. caffeine and/or codeine.
• The aims of treatment are to prevent further damage and to treat any existing kidney failure, e.g. with dietary changes, fluid restriction, dialysis or kidney transplant.
• Counselling and/or behavioural modification may help and may provide other methods of chronic pain control.

Complications

• Acute kidney injury
• Chronic kidney disease
• Hypertension

Prognosis

• In early cases renal function stabilises or improves slightly on discontinuation of analgesia.
• In advanced disease it may continue to progress due to secondary changes associated with loss of nephrons.

Prevention

Analgesic toxicity can be prevented by limiting the availability of over-the-counter analgesia.
Particular attention should be given to monitoring the elderly. They are both more likely to need analgesia and to use it. They are also more susceptible to its adverse effects.

The prolonged, regular use of NSAIDs should be discouraged.

Document references

1. Henrich WL; Analgesic nephropathy. Trans Am Clin Climatol Assoc. 1998;109:147-58; discussion 158-9. [abstract]
2. Alexopoulos E; Drug-induced acute interstitial nephritis. Ren Fail. 1998 Nov;20(6):809-19. [abstract]
3. Delmas PD; Non-steroidal anti-inflammatory drugs and renal function. Br J Rheumatol. 1995 Apr;34 Suppl 1:25-8. [abstract]
4. Elseviers MM, De Broe ME; Analgesic abuse in the elderly. Renal sequelae and management. Drugs Aging. 1998 May;12(5):391-400. [abstract]
5. Analgesic nephropathy, MedlinePlus Medical Encyclopedia
6. Chang SH, Mathew TH, McDonald SP; Analgesic nephropathy and renal replacement therapy in Australia: trends, comorbidities and outcomes. Clin J Am Soc Nephrol. 2008 May;3(3):768-76. Epub 2008 Feb 13. [abstract]
7. Mihatsch MJ, Khanlari B, Brunner FP; Obituary to analgesic nephropathy--an autopsy study. Nephrol Dial Transplant. 2006 Nov;21(11):3139-45. Epub 2006 Aug 5. [abstract]
8. De Broe ME, Elseviers MM; Analgesic nephropathy. N Engl J Med. 1998 Feb 12;338(7):446-52.
9. Elseviers MM, Waller I, Nenoy D, et al; Evaluation of diagnostic criteria for analgesic nephropathy in patients with end-stage renal failure: results of the ANNE study. Analgesic Nephropathy Network of Europe. Nephrol Dial Transplant. 1995;10(6):808-14. [abstract]

Internet and further reading

• Nawaz Khan A et al; Papillary Necrosis, eMedicine, Dec 2008; (Good images)
• More on NSAID adverse effects, Bandolier, Sept 2000

Acknowledgements