Analgesic Nephropathy

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

• One is 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 renal failure associated with the use of nonsteroidal anti-inflammatory drugs.

Analgesic nephropathy is a common cause of chronic renal failure in Europe.² Acute renal failure associated with non-steroidal anti-inflammatory drug (NSAID) use has been reported to account for up to 15.6% of cases of drug-induced renal failure.³

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 renal failure.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.⁵

Analgesic nephropathy occurs in about 4 out of 100,000 people, mostly women over 30.⁶
In an Australasian study, of 31,654 renal replacement therapy patients, 10.2% had analgesic nephropathy.⁷
The rate has decreased significantly since phenacetin is no longer widely 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
• Pain with menstrual periods
• 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)

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.
• There may also have a history of peptic ulcer disease or symptoms.

Signs

• In moderate to advanced disease - commonly hypertension and anaemia
• Proteinuria that can be <3.5g/day

• Urine toxicology screen may show salicylates
• Urinalysis shows blood and white cells
• Full blood count 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 size of kidneys, irregular contours to kidneys, calcification of papillae⁹

• Stop all suspect analgesics, 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.

• Acute renal failure
• Chronic renal failure
• Hypertension

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

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 and use it, and more susceptible to its adverse effects.
The prolonged, regular use of NSAIDs should be discouraged.