Nefropatía por analgésicos

What is analgesic nephropathy?

There are at least two distinct forms of analgesic nephropathy:

• 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 chronic kidney disease.

  • Renal papillary necrosis had been classically associated with this illness.¹

• The second form is typically an acute kidney injury (AKI) associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs).²

Patogénesis

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 not have been excessive but is likely to have occurred over a prolonged period of time - about three pills per day for six years.

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.

Prostaglandin synthesis inhibition also features in the pathophysiology of AKI related to NSAIDs. This results in vasoconstriction and reversible mild renal impairment in volume contracted states. In due course, acute tubular necrosis and acute kidney injury may result. NSAIDs also produce interstitial nephritis with or without nephrotic syndrome secondary to minimal change disease. Although this presents as AKI, chronic use of NSAIDs may result in chronic kidney disease (CKD).³ 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).

How common is analgesic nephropathy? (Epidemiology)

Analgesic nephropathy occurs in about 4 out of 100,000 people - mostly women aged over 30.⁴ In an Australian study, of 31,654 renal replacement therapy patients, 10.2% had analgesic nephropathy.⁵ 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 2000.⁶ The rate has decreased significantly since phenacetin was withdrawn as an over-the-counter (OTC) preparation in 1980. Renal side-effects are seen in 1-5% of people taking NSAIDs worldwide.⁷

Factores de riesgo

• 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.

• Apéndicolito.

• Insuficiencia cardíaca congestiva.

• Blood volume depletion (such as dehydration).

Presentation of analgesic nephropathy

Síntomas

• 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.

Signos

• In moderate-to-advanced disease - commonly, hypertension and anaemia.

• Proteinuria is found with worsening renal function.

Investigaciones

• Urine toxicology screen may show salicylates.

• Urinalysis may show blood and white cells.

• FBC may show anaemia.

• 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 for analgesic nephropathy

• Stop all suspect analgesia, particularly OTC medications containing two analgesic compounds in combination with potentially addictive substances - eg, caffeine and/or codeine.

• The aims of treatment are to prevent further damage and to treat any existing kidney failure - eg, 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 of analgesic nephropathy

• IRA.

• ERC.

• Hipertensión.

Pronóstico

• 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.

Prevención

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

The prolonged, regular use of NSAIDs should be discouraged.