Substance abuse has been increasing steadily in the UK and some other countries. Recent evidence suggests more than 40% of young people have tried illicit drugs at some time. There are numerous medical consequences to recreational drug use, and a physician should always consider substance abuse in any unexplained illness. The renal complications of drug abuse are also becoming more frequent, and may encompass a spectrum of glomerular, interstitial and vascular diseases. Although some substances are directly nephrotoxic, a number of other mechanisms are also involved. These effects are often chronic and irreversible, but occasionally acute with possible recovery. The rapid growth of illicit drug use is clearly a major public health problem. We review the commonly used substances of abuse and their associations with renal disease.
Man has used drugs for recreational purposes as long as history itself. Arabic traders smoked opium in the 3rd century BC, and the Aztecs enjoyed the effects of hallucinogenic mushrooms at a similar time. In the last 30 years, the number of people using recreational drugs appears to have increased.1 This may have accelerated since the advent of the club scene. By 1997, 25% of the population reported using illicit drugs at some point in their lives, and 10% within the last year.
Drugs users are more commonly in social class A B or C1, and young White males aged 25–29.2 Monozygotic twin studies have suggested some genetic predisposition to recreational drug abuse,1 but a specific premorbid ‘addictive personality’ is not yet defined.
There are numerous medical consequences to recreational drug use. Follow‐up studies of heroin addicts indicates an annual mortality of 4.8%.3 Thus, physicians should consider substance abuse in any unexplained illness. The majority of these drugs, or their metabolites, are excreted via the kidney. While some substances may be directly nephrotoxic, a number of other mechanisms are also involved. To achieve their recreational effects these drugs must cross the blood‐brain barrier and many are highly lipid‐soluble; this results in high volumes of distribution with dialysis of little benefit in overdose. This paper reviews the commonly used substances of abuse and their associations with renal pathology.
Heroin (diacetylmorphine, diamorphine) is the most commonly abused drug in this group. It can be sniffed (‘snorting’), eaten, smoked (‘chasing the dragon’), injected subcutaneously (‘skin popping’), or injected intravenously (‘mainlining’). It is often injected in combination with cocaine (‘speedballing’).4 Heroin has a half‐life of 3 min and is rapidly metabolized to morphine, which is mainly responsible for the pharmacological actions of heroin. Heroin is excreted in the urine as free and unconjugated morphine. There are several renal complications from its abuse.5 Coma from overdose or underestimated drug potency leads to pressure‐induced muscle damage and rhabdomyolysis. Hypotension, hypoxia, acidosis and dehydration may aggravate this. Others have demonstrated rhabdomyolysis in the absence of coma or evidence of muscle compression, and suggest this could be due to a direct toxic effect or an allergic response to heroin or the components in adulterated heroin.6
There is a high rate of viral, bacterial and fungal contamination associated with intravenous drug misuse, including heroin,7 and consequently users are at risk of a variety of infections. Glomerulonephritis (GN) may be associated with these chronic infections. Local pyogenic abscesses, due to Staphylococcus aureus, have been associated with GN, thought to be due to deposition of immune complexes formed in response to the organism. Bacterial and fungal8 endocarditis can also cause immune‐complex‐mediated GN. Hepatitis B has also been associated with GN, usually membranous and with polyarteritis nodosa. Hepatitis C causes mesangiocapillary GN with associated cryoglobulinaemia.
Secondary (AA) amyloidosis has increased in frequency as a cause of renal disease in chronic parenteral drug users, particularly among those who inject drugs subcutaneously (‘skin poppers’).9 With continued abuse, the majority progress to end‐stage renal failure. Various drug treatments have been tried but drug abstinence appears to be the most important factor in treatment. Complete resolution following abstinence from subcutaneous drug abuse has been reported.10
In the 1970s and 1980s, heroin‐associated nephropathy (HAN) was described, presenting as nephrotic syndrome and progressing rapidly to end‐stage renal failure. Occasionally the process reversed with abstinence from further heroin use.5 Renal biopsy usually showed a focal segmental glomerulosclerosis.11 The pathogenesis of this is unclear; earlier studies suggested that heroin, or one of its adulterants, acted as antigen leading to renal deposition of immune complexes in the kidney.5 More recent animal studies have shown that morphine may have a direct effect on the glomerulus, causing proliferation of fibroblasts and a decrease in degradation of type IV collagen.
In North America, a decrease in the incidence of HAN12 among intravenous heroin addicts has been described (Figure 1). ‘Street’ heroin has become increasingly pure, and addicts may be exposed to lower doses of the possibly nephrotoxic adulterants.
In parallel with the declining incidence of HAN, HIV‐associated nephropathy (HIVAN) is being diagnosed more frequently among heroin addicts with HIV infection.13 HIVAN also presents with nephrotic syndrome and rapidly progressing renal failure, and in some inner‐city communities of the USA, it can cause up 38% of end‐stage renal failure.14 Renal biopsy usually reveals characteristic collapsing glomerular tuft15 with epithelial cell prominence (Figure 2). Localized segmental sclerosis of the tuft can also occur. A recent report of a case of clinical and histological resolution of HIVAN following treatment with triple antiretroviral therapy and reduction in viral load, supports the hypothesis that the virus has a direct cytopathic effect on the kidney.16
A post‐mortem study from the Institute of Forensic Medicine, University of Bonn, reviewed 179 renal specimens from autopsies of persons known to be intravenous drug addicts,17 105 specimens (61.7%) showed a mono‐lymphocytic membranoproliferative glomerulonephritis and 48 specimens (45.7%) deposits of IgM. No cases with focal segmental glomerulosclerosis as reported in male African‐American intravenous drug addicts were found.
Cocaine is an alkaloid extracted from a shrub (Erythroxylon coca) which grows in the Andes mountains.18 Cocaine can be absorbed through any mucous membrane, smoked or injected intravenously or intramuscularly. It has an estimated half‐life of 30 to 90 min. Eighty to 90% of cocaine is metabolized, while the remainder is excreted unchanged in the urine where its metabolites can be detected for 36 to 48 h.18
The euphoria of cocaine is caused by blocking the reuptake of dopamine, while the hypertensive effects are caused by inhibition of reuptake of noradrenaline. It also acts as a local anaesthetic by blocking sodium channels in sensory neurones thereby impairing nerve impulses.18
A wide spectrum of renal complications can occur with both acute and chronic use of cocaine. Acute renal failure can occur as a result of rhabdomyolysis.19 In one series 24% of patients seen in an emergency department with cocaine‐associated complaints presented with concentrations of creatine kinase of more than 1000U/l.20 Up to one third of such patients develop acute renal failure.19
Muscle ischaemia caused through prolonged vasoconstriction of intramuscular arteries, generalized seizures, coma with secondary muscle compression, or direct myofibrillar damage are different mechanisms of cocaine‐induced rhabdomyolysis. Cocaine may be contaminated with arsenic, strychnine, amphetamine and phencyclidine, which may also cause seizures and rhabdomyolysis.
The syndrome of cocaine‐induced premature coronary artery disease is well described. Less well known is that cocaine can cause renal infarction21 and atherosclerosis of the kidney.22,23 Of increasing concern is the growing numbers of inner‐city African‐Americans developing hypertensive end‐stage renal failure.24 Some 44% of such patients have a history of substance abuse, compared with 5% of diabetics and 11% of patients with other causes of renal disease. However, a recent study of 301 chronic cocaine users showed no association with chronic hypertension or the development of microalbuminuria.25 There may be perhaps a propensity for cocaine to exacerbate pre‐existing renal disease rather than cause de novo disease. While controlled studies of such patients are difficult, a syndrome of accelerated hypertension and progressive renal failure has been described.26
Immunologically, cocaine has been shown to cause mesangial proliferation by increasing the release of interleukin‐6 by macrophages, which may be a cause of focal segmental glomerulosclerosis.27 Associations of cocaine abuse with renal scleroderma28 and Henoch‐Schönlein purpura29 have also been described.
Ecstasy and other amphetamines
Ecstasy (MDMA: 3,4‐methylenedioxymethamphetamine), originally patented in 1914 as an appetite suppressant, is now a commonly used recreational drug in the UK club scene. Since 1977, it has been listed as a class A drug in the UK under the Misuse of Drugs Act, 1971.
MDMA is rapidly absorbed, reaching plasma peak levels in approximately 2 h.30 It is metabolized by the liver and excreted by the kidney.
In Europe, MDMA and amphetamines are generally taken by mouth during prolonged group dancing while attending ‘rave’ parties or clubs. The increased physical activity, overheated environments and dehydration can result in hyperthermia. In experimental animals, MDMA has been shown to cause fever even in the absence of strenuous exercise. Unwanted effects may be minor—loss of appetite, nausea, vomiting, headaches, trismus and cramps, or serious—convulsions, hyperpyrexia, hepatic dysfunction, rhabdomyolysis, disseminated intravascular coagulation31 and acute renal failure.32 The patient with rhabdomyolysis typically presents with muscle pain and tenderness, and is found to be in acute renal failure with hyperkalaemia, hyperphosphataemia, and raised creatine kinase. Myoglobin and granular casts are found in the urine.
With press coverage, drug abusers are becoming aware of the risk of dehydration and often drink large quantities of water after taking ecstasy to try to prevent this. As a consequence, cases of hyponatraemia, catatonic states and cerebral oedema have occurred.33 The dilutional hyponatraemia, due to excessive fluid ingestion, may involve inappropriate antidiuretic hormone secretion.34 ‘Chill out’ rooms are now provided in an attempt to prevent hyperthermia. In the USA, ecstasy has not been taken as a dance drug and consequently the spectrum of unwanted effects is different, with cardiac arrhythmias being more common.35
As ecstasy has marked sympathomimetic effects, it is not surprising that cases of accelerated hypertension with associated acute renal failure36 have been described. Similarly, urinary retention due to bladder neck closure37 has been associated with its use.
Abused temazepam and diazepam usually originate from legal prescriptions or thefts from pharmacies. Temazepam is now a controlled drug and may be taken alone or as part of a ‘cocktail’ of drugs. Approximately 70% of injecting drug users have used temazepam at some time.38 Acute renal failure has been described following inadvertent intra‐arterial temazepam injection. This provokes limb ischaemia as a result of particulate embolization and subsequent rhabdomolysis and myoglobinuria.39 Severe but temporary dialysis‐dependent renal failure was present in 20% of patients in one series.40
The liquid contents of the original gelatin capsule were reformulated to a hard gel to make temazepam more resistant to misuse. Despite this, misusers were still able to inject the gel by pre‐warming it a microwave oven. Temazepam is now only available in tablet form, so some of the worst complications of its injection can now be prevented.
The mushroom species Panaeolus muscaria and Psilocybe (including Psilocybe Semilanceata— ‘liberty cap’; ‘magic mushrooms’) are hallucinogenic when ingested.41 In the UK it is legal to pick and eat these mushrooms but not to prepare them in any way.1 They are not themselves nephrotoxic, however correct mushroom identification is difficult and inadvertent ingestion of poisonous species is not uncommon. Cortinarius mushrooms which contain the nephrotoxic substance orellanine can also masquerade as ‘magic mushrooms’.42 Oliguric renal failure may develop over 5 to 12 days after ingestion of Cortinarius. In some patients the renal failure is transient43 but in others it may be irreversible.44
Tobacco smoking and cannabis
The prevalence of tobacco smoking in the UK has steadily declined in recent decades. In 1972 46% of the population smoked; this figure had fallen to 30% by 1990. Unfortunately throughout this period, 25% of 15‐year‐olds continued to take up the habit. There is evidence that smoking hastens the progression of renal disease associated with both diabetes and hypertension.45 Smokers are more frequently found to be hypertensive, and in hypertensive subjects, smoking is an independent predictor of the development of microalbuminuria. Microalbuminuria is also more common amongst insulin‐dependent diabetics who smoke. Smoking also aggravates glomerular hyperfiltration which is considered to be the first stage in the development of diabetic nephropathy. In addition, smoking is associated with progression of renal lupus,46 renal artery stenosis,47 pulmonary haemorrhage in anti‐GBM disease48 and renal tubular dysfunction.49
Renal complications are rare following cannabis abuse, but one case of renal infarction has been reported in a heavy cannabis smoker.50 The combination of peripheral vasodilatation (from tetrahydrocannabinol), functional anaemia and an adrenergic effect may have all contributed.
The deliberate inhalation of volatile solvents (‘glue sniffing’) first emerged as a form of substance abuse in the early 1960s with the inhalation of model aeroplane glues. The practice has diversified to include the use of adhesive cements, aerosol paints, lacquer thinners, typewriter correction fluids and fuels.51 These products contain a number of volatile substances including toluene, n‐hexane, methyl ketones, chlorohydrocarbons and benzene. The ‘high’ from solvent inhalation is similar to alcohol intoxication. In addition, solvents can rapidly cause hallucinations52 of short duration (15 to 30 min). Serious cardiac, pulmonary, hepatic, neurological and renal complications may develop, as well as sudden death.53
The nephrotoxic insult of volatile glues appears to be due principally to toluene.54 Various renal lesions have been associated with its abuse: microhaematuria, pyuria and proteinuria,55 distal renal tubular acidosis and Fanconi's syndrome, urinary calculi,56 glomerulonephritis,57 Goodpasture's syndrome,58 acute tubular necrosis,59 hepatorenal syndrome60 and acute61 and chronic62 interstitial nephritis. Toluene is thought to cause renal tubular acidosis by inducing permeability changes in the nephron allowing backwards leakage of secreted acid. Chronic acid retention causes titration of alkaline bone salts leading to calcium mobilization, hypercalcuria and hence urinary calculi.56
In post‐mortem studies 50–100% of patients with hepatic cirrhosis due to alcohol have an associated glomerulopathy, histologically identical to IgA nephropathy.63 In life, the disease is characterized by microhaematuria and proteinuria, but tends to remain clinically silent. Macrohaematuria and renal insufficiency are rare. Increased levels of serum polymeric IgA and IgA immune complexes are found in patients with alcoholic cirrhosis. It is thought that portacaval shunting enables bacterial and food antigens to bypass hepatic Kupffer cells, leading to circulating immune complexes. The diseased liver is unable to catabolize these or transfer them into bile, and so they are deposited in the glomeruli.
Heavy alcohol consumption has also been associated with hypomagnesaemia. This is multifactorial in origin, but is at least in part due to a defect in renal tubular function.
The abuse of substances both causes, and exacerbates, a wide spectrum of kidney disease. This spectrum will hopefully change as users modify their behaviour as a result of fashion and health consciousness in the face of health promotion messages. Increasingly, and unfortunately, drug abuse now must be considered in the differential diagnosis of any patient with unexplained renal pathology. Provision of dialysis for both acute and chronic renal failure is extremely costly, and this adds extra impetus to educational measures which serve to reduce substance abuse in the community.
Address correspondence to Dr G.M. Bell, The Renal Unit, 6C Link, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP