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.
- The second form is typically an acute kidney injury (AKI) associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs).
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 injruy may result. NSAIDs also produce interstitial nephritis with or without nephrotic syndrome secondary to minimal change disease. Although this presents as AKI, vhronic use of NSAIDs may result in chronic kidney disease (CKD).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).
Analgesic nephropathy occurs in about 4 out of 100,000 people - mostly women aged over 30.In an Australasian study, of 31,654 renal replacement therapy patients, 10.2% had analgesic nephropathy. 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. 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.
- Use of OTC analgesics containing more than one active ingredient.
- Chronic headache.
- Chronic backache or musculoskeletal pain.
- 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).
- In the early stages of the disease, the clinical symptoms are limited to polyuria, sometimes associated with sterile pyuria.
- 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.
- In moderate-to-advanced disease - commonly, hypertension and anaemia.
- Proteinuria is found with worsening renal function.
- 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.
- 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.
- 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.
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.
Further reading and references
Waddington F, Naunton M, Thomas J; Paracetamol and analgesic nephropathy: Are you kidneying me? Int Med Case Rep J. 2014 Dec 158:1-5. doi: 10.2147/IMCRJ.S71471. eCollection 2015.
Hur E, Duman E, Bozkurt D, et al; Non steroidal antiinflammatory drugs may be harmful to normal kidneys: experimental surgery model*. Hippokratia. 2012 Apr16(2):160-5.
More on NSAID adverse effects; Bandolier, Sept 2000
Sutariya HC, Pandya VK; Renal Papillary Necrosis: Role of Radiology. J Clin Diagn Res. 2016 Jan10(1):TD10-2. doi: 10.7860/JCDR/2016/15092.7091. Epub 2016 Jan 1.
Ungprasert P, Cheungpasitporn W, Crowson CS, et al; Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies. Eur J Intern Med. 2015 May26(4):285-91. doi: 10.1016/j.ejim.2015.03.008. Epub 2015 Apr 8.
Vuckovic S, Vujovic KS, Medic B, et al; Prevention of renal complications induced by non-steroidal anti-inflammatory drugs. Curr Med Chem. 2016 Feb 10.
Turner N et al; Oxford Textbook of Clinical Nephrology, 2015.
Chang SH, Mathew TH, McDonald SP; Analgesic nephropathy and renal replacement therapy in Australia: trends, comorbidities and outcomes. Clin J Am Soc Nephrol. 2008 May3(3):768-76. Epub 2008 Feb 13.
Mihatsch MJ, Khanlari B, Brunner FP; Obituary to analgesic nephropathy - an autopsy study. Nephrol Dial Transplant. 2006 Nov21(11):3139-45. Epub 2006 Aug 5.
Pazhayattil GS, Shirali AC; Drug-induced impairment of renal function. Int J Nephrol Renovasc Dis. 2014 Dec 127:457-68. doi: 10.2147/IJNRD.S39747. eCollection 2014.
Wise GJ, Schlegel PN; Sterile pyuria. N Engl J Med. 2015 Mar 12372(11):1048-54. doi: 10.1056/NEJMra1410052.
De Broe ME, Elseviers MM; Over-the-counter analgesic use. J Am Soc Nephrol. 2009 Oct20(10):2098-103. doi: 10.1681/ASN.2008101097. Epub 2009 May 7.