DRUGS ANd THE KIdNEY

Drugs and toxins that damage the kidney

Matthew LP Howse Gordon M Bell

Illustrative examples of different drug-induced nephropathies

Mechanism of toxicity Glomerulonephritis Acute tubular necrosis Alteration in renal blood ow Intersitital nephritis Vasculitis Drugs Penicillamine, Gold Aminoglycosides RAAS inhibitors, NSAIDs Ciprooxacin Hydralazine, procainamide, isoniazid, propylthiouracil, phenytoin Ifosphamide, amphotericin

Abstract
A wide variety of pharmacological agents, drugs of misuse and environmental pollutants can cause an equally wide variety of renal disease. Consequently, the clinician should always consider these a potential cause for any newly diagnosed case of renal disease. In this contribution we describe some of the commoner and more important presentations.

Tubular toxicity (Fanconis syndrome or specic tubular decits) Obstruction

Keywords drugs of misuse; hydrocarbons; heavy metals; nephrotoxicity;

organic solvents; therapeutic drugs Table 1

Crystalluria (aciclovir, indinavir, methotrexate) Sloughing of papillae (analgesics) Retroperitoneal brosis (methysergide, bromocriptine)

In this section we present an overview of the commoner pharmacological and environmental nephrotoxins and also discuss the nephrotoxicity of drugs of misuse. A more comprehensive discussion of pharmacology in renal failure is presented elsewhere (pages 396398).

biphosphonates, are often not mentioned by patients. Patients may deliberately attempt to conceal overdose and substance abuse. In addition to information from the patient, history from the general practitioner, carer and community pharmacist and psychiatric nurse can be useful. Reninaldosteroneangiotensin system (RAAS) inhibitors RAAS inhibitors (angiotensin-converting enzyme inhibitors and angiotensin-II receptor antagonists) are valuable in the treatment of hypertension, cardiac failure and possibly proteinuric renal disease. The vasomotor tone of the efferent (post-glomerular) arteriole is exquisitely sensitive to angiotensin-II. In pre-renal failure, such as in hypotension, salt and water depletion and bilateral renal artery stenosis, glomerular pressure and glomerular ltration rate (GFR) is maintained by efferent artery angiotensin-II mediated vasoconstriction (Figure 1). RAAS inhibitors prevent the formation or action of angiotensin-II and abolish this protective mechanism; the efferent arteriole dilates; intraglomerular pressure and GFR fall.2 Nephrotoxicity is usually reversible on discontinuation of the drug. Non-steroidal anti-inammatory agents The tone of the afferent (pre-glomerular) arteriole is largely dependent on local prostaglandin synthesis. In pre-renal failure prostaglandin synthesis induced afferent arteriole vasodilatation maintains GFR. Non-steroidal anti-inammatory agents (NSAIDs) abolish this protective mechanism and predispose patients to develop acute renal failure (ARF). This is more likely to occur when a number of factors altering renal blood ow are also present intravascular volume depletion, hypotension, sepsis, radiological contrast, or RAAS inhibitors. The inuence of chronic NSAID usage on chronic kidney disease (CKD) is less clear. Available epidemiological studies are imperfect.3 Acutely, NSAIDs, cause a transient rise in blood pressure due to activation of RAAS. However, it is unclear whether
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Pharmacological agents
Innumerable therapeutic drugs can be nephrotoxic by a wide range of mechanisms as shown in Table 1. The most common and important of these are presented here. Particular care and vigilance should be taken when these are prescribed in combination. Whenever there is doubt, the prescriber should seek additional information from a renal physician or renal pharmacist. In the UK, the British National Formulary (BNF) and the Renal Drug Handbook1 are widely available and may also be consulted. There are a number of potential pitfalls in drug history taking. Many patients do not consider over the counter and complementary preparations as medicines or drugs. How ever, paracetamol may be nephrotoxic in overdose as are Chinese herbal medicines. Once-weekly prescriptions, such as for

Matthew LP Howse MRCP is a Consultant Nephrologist at the Royal Liverpool University Hospital, Liverpool, UK. He qualied at the University of Newcastle upon tyne and trained in Nephrology in Liverpool. His interests include the environmental risks for kidney disease. Competing interests: none declared. Gordon M Bell FRCP FRCPE is a Consultant Physician and Nephrologist at the Royal Liverpool University Hospital, Liverpool, UK. He obtained his medical training at Edinburgh University and the Renal Unit of the Royal Inrmary of Edinburgh. He is currently also Clinical Director of the Renal Unit at the Royal Liverpool University Hospital and a Member of the UK Renal Association Executive. Competing interests: none declared.

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DRUGS ANd THE KIdNEY

Schematic representation of glomerular pressure autoregulation in pre-renal failure and how this fails when the patient is taking NSAIDs and RAAS inhibitors
Afferent arteriole

amage from leukocyte-generated oxidants, has been proposed as d prophylaxis against CIN. The published controlled trials, whilst being generally positive, have been of heterogeneous design and variable quality and therefore, at present, acetylcysteine cannot be recommended as standard therapy.6 Because of the risk of precipitating acidosis during ARF, concurrent metformin therapy should be stopped prior to radiocontrast being administered.

Efferent arteriole Pre-renal failure Vasodilation Intra-glomerular pressure maintained Vasoconstriction Pre-renal failure plus NSAIDs and RAAS inhibitors Vasoconstriction Intra-glomerular pressure maintained Vasodilation

Other therapeutic drugs

Lithium (Li), used in the treatment of bipolar affective dis orders has a narrow therapeutic/toxic ratio. It is freely ltered at the glomerulus but approximately two-thirds is reabsorbed in the proximal tubule, where it inhibits the generation of cyclic AMP and the expression of aquaporin-2 (the cellular water channel). This leads to diabetes insipidus and less commonly renal tubular acidosis. Chronic Li therapy appears to be associated with a higher incidence of CKD compared to the general population. However, the incidence is comparable to patients with affective disorders who have not received Li treatment.7 Discontinuation of Li therapy does not appear to halt progression of CKD. Plasma lithium levels are increased by dietary sodium restriction and concomitant use of thiazide diuretics and NSAIDs. Patients receiving lithium therapy should be warned about potential drug interactions and to avoid dietary changes that may increase serum levels. Acute lithium intoxication may occur following deliberate overdose or following periods of dehydration with or without diuretic use. Toxicity may be asymptomatic or clinically manifest as ataxia, confusion and impaired consciousness with associated acute renal failure. When toxicity is manifest Li levels are usually in excess of 2.5 mmol/l. Rehydration and haemodialysis to remove Li are the mainstay of treatment. Li has a high volume of distribution and therefore prolonged and frequent dialysis sessions are required to achieve adequate clearances. Anti cancer drugs Ifosphamide, an alkalating agent related to cyclophosphamide, can cause hypophosphataemia, Fanconis syndrome (pages 368376) and a reduced GFR. In a prospective study of children and adolescents receiving the drug nephrotoxicity, graded as moderate or severe, occurred in 28% of patients, the biggest risk factor for which was total dose administered.8 Cisplatinum and other platinum-containing drugs are potent proximal tubular toxins. This may in part be due to direct binding and damage to tubular cell DNA leading to apoptosis and necrosis, and partly to induction of the inammatory cytokine TNF. Tubular damage may lead to hypomagnesaemia, renal tubular acidosis and acute renal failure. The latter is less likely if the patient is well hydrated, and is usually at least partially reversible. Chronic renal failure may follow repeated exposure. Antibiotics The nephrotoxicity of aminoglycosides is discussed above. The glycopeptide antibiotic vancomycin has earned a reputation of being a signicant nephrotoxin. Deterioration in renal function
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Figure 1

chronic NSAID use causes hypertension, although these drugs do appear to exacerbate pre-existing blood pressure disease.3 Aminoglycosides Aminoglycosides are almost exclusively excreted unchanged in the urine. Aminoglycosides are freely ltered at the glomerulus and taken up by proximal tubular cells where they bind to acidic phospholipids and megalin. This initiates functional and structural changes in these cells, leading to acute tubular necrosis.4 The risk of nephrotoxicity can be reduced by using a once-daily regimen, using estimated GFR (eGFR) to calculate the dose, using therapeutic drug-level monitoring and minimizing the duration of treatment. Radiocontrast agents The nephrotoxicity of hyperosmolar iodinated radiocontrast agents is well established with patients with pre-existing renal disease, diabetes mellitus, cardiac failure and hypotension at increased risk. The mechanism of contrast-induced nephro toxicity (CIN) is incompletely understood but appears to involve a combination of altered renal haemodynamics (vasoconstriction), increased blood viscosity, systemic hypoxia and increased tubular oxygen consumpution.5 Hypoxic injury triggers leucocyte recruitment that causes further tissue injury. CIN causes ARF that resolves spontaneously but is associated with increased mortality and morbidity. Treatment of CIN is supportive; research is focused on prevention. Use of the minimum volume of iso-osmolar contrast (rather than high-osmolar), reduces the frequency and severity of the condition. Pre-hydration with intravenous uids has also been shown to be benecial with one study suggesting that sodium bicarbonate may be the preferred uid.5 Acetylcysteine, which has anti-oxidant properties and so could ameliorate tissue

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DRUGS ANd THE KIdNEY

may in fact occur in only 5% of patients treated with the drug. However vancomycin appears to enhance the nephrotoxicity of aminoglycosides. When a glycopeptide is prescribed in combination with an aminoglycoside teicoplanin is therefore generally preferred.9 A variety of antibiotics may cause acute interstitial nephritis.

Environmental and occupational chemical exposure

Heavy metals Lead (Pb) nephropathy may be acute or chronic. Acute Pb poison ing usually occurs in children or the mentally ill with the deliberate ingestion of Pb-containing compounds such as paint from old buildings. In acute poisoning, encephalopathy and seizures predominate but the patient can also develop a partial or occasionally complete Fanconi syndrome. In acute Pb poisoning, chelation of Pb with 51(r-ethylenediaminetetraacetic acid EDTA) leads to an improvement in both the neurology and the renal effects. Chronic Pb exposure, which is usually occupational, causes gout, hypertension and chronic interstitial nephritis. The association between Pb exposure and chronic nephropathy has been questioned as in occupational studies subjects are exposed to a multitude of potentially toxic compounds simultaneously. However, chronic Pb nephropathy has been observed in drinkers of Pb-contaminated moonshine (illicit alcohol).10 Blood levels do not accurately reect body Pb burdens and Pb mobilization tests maybe required. X-ray uorescence can be used instead but cut-off values for excessive body Pb have not yet been dened and this technique is not generally available. Short-term studies of EDTA chelation have suggested this may improve renal function in patients with CKD and marginally raised body Pb burden but data on the long-term benets of this manoeuvre is lacking.11 Cadmium (Cd) is used widely in industry, including jewellery and battery manufacture, welding and smelting. However, the major sources of exposure in the general population are cigarette smoking and food.12 Cd binds to albumin in the blood and is consequently not ltered at the glomerulus. However, the metal is bound to metallothionein (MT) and the Cd-MT complexes are freely ltered. These complexes are taken up into the proximal tubules where Cd is released, causing toxicity. Cd exposure causes proximal tubular dysfunction, hypercalciuria, renal stones and chronic interstitial nephritis. Furthermore there is an increased incidence of end-stage renal disease in exposed subjects although epidemiological data suggests this is predominantly due to exacerbation of pre-existing renal disease.13 Workers at risk of Cd nephropathy may be monitored by measurement of urinary tubular proteins such as 2 microglobulin, although these are not specic for Cd nephropathy. Radionuclear scanning techniques can be used to measure body Cd content.14 Other than avoidance of further Cd exposure there is no specic treatment. Other heavy metals Mercury may exist elementally, as water-soluble inorganic salts, such as mercury dichloride (HgCl2) or as lipid-soluble organomercurials, such as methyl mercury, that are produced by microbial metabolism of Hg2+. Methyl Hg accumulates in the
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food chain, particularly sh. The other source of exposure is to dental staff, via dental amalgam.12 Methyl Hg, being lipid-soluble, causes neurotoxicity. Inorganic Hg salts cause proximal tubular nephrotoxicity by binding to sulphydryl groups in the tubular cells.9 This is reversible when exposure ceases. In rodents mercuric chloride causes an immune-complex mediated glomerulonephritis. Nephrotic syndrome has also been reported in humans following Hg expo sure but this is so uncommon that a causal relationship has not been established. The metal silicon (Si) exists as silicon dioxide, silica (SiO2), in nature. Miners and quarrymen are exposed occupationally. The commonest silica-related occupational disease is pulmonary brosis (silicosis). However case-control studies have shown that exposed individuals have increased rates of auto-immune and kidney disease15 including ANCA-associated vasculitis. The mechanism for these is unknown. Hydrocarbons and organic solvents The term hydrocarbons encompasses a wide variety of organic solvents used in manufacturing and the petrochemical industry. These include bromobenzene, used in motor oils, perchloroethylene, used as a solvent for dry cleaning and xylene used in adhesives and as a cleaning agent. These chemicals are both putative causes and exacerbators of kidney disease. Case-control and cohort studies have shown that individuals exposed to these chemicals have a higher incidence of membranous glomerulonephritis (GN), have higher serum creatinine level at presentation with GN, have a more rapid rise in serum creatinine following diagnosis of GN, and a higher incidence of early markers of renal disease such as tubular enzymuria.16 A recent review concluded that the Bradford-Hill criteria for causation of renal disease by hydrocarbon exposure had been satised.17 A wide variety of tubular and glomerular renal effects are thought to be secondary to occupational exposure to these chemicals Furthermore, a group of subjects exposed to hexachlorobutadiene (HCBD) in their homes were shown to have tubular proteinuria/enzymuria and this resolved after the subjects left their homes.18 The mechanisms by which hydrocarbons cause renal damage are incompletely understood and are likely to be as diverse as the chemicals themselves. However, both trichloroethylene (TCE) and HCBD are hepatically conjugated with glutathione and these metabolites are delivered to the kidney where, in the proximal tubule, they are converted to reactive electrophils by the enzyme -lyase.18 Other solvents may cause immune-mediated kidney damage.16

Over-the-counter medicines and traditional/complementary medicines

A wide variety of herbal medicines may cause an equally wide variety of nephrotoxic affects.19 Herbal medicines may be contaminated with other drugs, hormones or heavy metals such as cadmium (see above). In Europe and North America in the last decade, signicant numbers of female patients have been noted with advanced renal failure associated with use of the Chinese slimming medicine Boui-ougi-tou. The culprit nephrotoxin may be aristoloic acid.

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St Johns wort is widely purchased over-the-counter and used for mild psychiatric symptoms. It induces cytochrome P450 and so interacts with a wide variety of drugs including the calcineurin inhibitors. Thus, renal transplant patients should be warned that use of this remedy may lower the levels of their anti-rejection drugs.19 The more mainstream over-the-counter medicines, salicylates and paracetamol may give rise to acute renal failure in acute overdose.20,21 Balkan nephropathy is thought to be an environmentally induced disease possibly in a population that is genetically susceptible, although the culprit nephrotoxin is yet to be identied.

Other misused substances Benzodiazepines may be injected. If this is done intra-arterially, muscle necrosis and rhabdomyolysis may result. Magic mush rooms, containing psilocybe, are not nephrotoxic but may be confused with cortinarius, some of which contain the powerful nephrotoxin orellanine.

Drugs of misuse
Drug misuse is a relatively common problem although the incidence of kidney damage following this behaviour is likely to be less well known. Heroin Street heroin contains large amounts of adulterants, which may be nephrotoxic, and intravenous use poses an infection risk. Acute renal failure following heroin misuse may occur secondary to rhabdomyolysis. This can be traumatic muscle necrosis following a prolonged period of unconsciousness or atraumatic. The pathogenesis of atraumatic heroin-induced rhabdomyolysis is not known, but a primary myopathy must be considered. Chronic heroin misuse can cause a glomerulopathy. This may be a direct result of heroin use or its adulterants (heroin-associated nephropathy, HAN) or secondary to concomitant HIV infection. In North America, HAN presents as heavy proteinuria followed by a progressive renal failure. Renal biopsy usually shows focal segmental glomerulosclerosis (FSGS).22 However, in Europe, a different pattern of disease is more common, with a more indolent membranoproliferative GN and a less rapid deterioration in renal function often in association with hepatitis C infection.23 Heroin can cause chronic skin infections leading to renal amyloidosis, and endocarditis causing an immune-complex-mediated GN.24 Cocaine Cocaine is a powerful vasoconstrictor causing extreme hyper tension during episodes of use. Acute renal failure can be caused by rhabdomyolysis due to seizures, vasoconstriction of intra muscular arteries and possibly a direct effect on myocytes. When severe, it can be accompanied by disseminated intravascular coagulation (DIC) and multiorgan failure. Cocaine-induced hypertension may cause, or at least severely exacerbate, chronic renal failure.25 Ecstasy and other amphetamines Ecstasy misuse causes malignant hyperpyrexia, partly by increasing physical activity through dancing in hot overcrowded rooms, but possibly also through a direct effect on thermoregulation. This can cause rhabdomyolysis and acute renal failure.24 Dantrolene has been suggested as a possible treatment for Ecstasyinduced hyperpyrexia, but there is no consensus, or clinical trials at present.26 Ecstasy users try to avoid hyperpyrexia by drinking large volumes of uids. This together with a putative SIADH effect of the drug can lead to water intoxication and profound hyponatraemia.
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References 1 Ashley C, Currie A. The renal drug handbook. Oxford: Radcliffe Medical, 2004. 2 Silas JH, Klenka Z, Solomon SA, Bone JM. Captopril induced reversible renal failure: a marker of renal artery stenosis affecting a solitary kidney. BMJ (Clin Res Ed) 1983; 286: 17023. 3 Gaziano JM. Nonnarcotic analgesics and hypertension; clinical implications of concomitant nonopioid analgesia in patients with or at risk for cardiovascular disease. Am J Cardio 2006; 97(suppl 1): 1016. 4 Nagai J, Takano M. Molecular aspects of renal handling of aminoglycosides and strategies for preventing the nephrotoxicity. Drug Metab Pharmacokinet 2004; 19: 15970. 5  Lameire NH. Contrast-induced nephropathy - prevention and risk reduction. Nephrol Dial Transplant 2006; 21(suppl 1): i1123. 6 Kshirsagar AV, Poole C, Mottl A, et al. N-acetylcysteine for the prevention of radiocontrast induced nephropathy: a meta-analysis of prospective controlled trials. J Am Soc Nephrol 2004; 15: 76169. 7  Walker RG. Lithium nephrotoxicity. Kidney Int Suppl 1993; 42: S9398. 8 Skinner R, Cotterill SJ, Stevens MC. Risk factors for nephrotoxicity after ifosfamide treatment in children: a UKCCSG Late Effects Group study. United Kingdom Childrens Cancer Study Group. Br J Cancer 2000; 82: 163645. 9  Wilson AP. Comparative safety of teicoplanin and vancomycin. Int J Antimicrob Agents 1998; 10: 14352. 10  Loghman-Adham M. Renal effects of environmental and occupational lead exposure. Environ Health Perspect 1997; 105: 92839. 11  Lin J-L, Ho H-H, Yu C-C. Chelation therapy for patients with elevated body lead burden and progressive renal insufciency: a randomized, controlled trial. Ann Intern Med 1999; 130: 713. 12  Jarup L. Hazards of heavy metal contamination. Br Med Bull 2003; 68: 16782. 13 Hellstrom L, Elinder CG, Dahlberg B, et al. Cadmium exposure and end-stage renal disease. Am J Kidney Dis 2001; 38: 10018. 14  Wittman R, Hu H. Cadmium exposure and nephropathy in a 28-year-old female metals worker. Environ Health Perspect 2002; 110: 126166. 15 Steenland K, Sanderson W, Calvert GM. Kidney disease and arthritis in a cohort study of workers exposed to silica. Epidemiology 2001; 12: 40512. 16  Bell GM, Howse MLP. Substance misuse, organic solvents and kidney disease. In: van Ypersele C, ed. Oxford textbook of clinical nephrology, 3rd edn. Oxford: Oxford University Press, 2005. 17 Ravnskov U. Hydrocarbon exposure may cause glomerulonephritis and worsen renal function: evidence based on Hills criteria for causality. Q JM 2000; 93: 55156. 18 Staples B, Howse ML, Mason H, Bell GM. Land contamination and urinary abnormalities: cause for concern? Occup Environ Med 2003; 60: 46367.

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19 Isnard Bagnis C, Deray G, Baumelou A, Le Quintrec M, VanherweghemJL. Herbs and the kidney. Am J Kidney Dis 2004; 44: 111. 20  Vale A. Salicylates. Medicine 2003; 31(10): 7273. 21  Vale A. Paracetamol (Acetaminophen). Medicine 2003; 31(10): 6768. 22  Cunningham EE, Brentjens JR, Zielezny MA, Andres GA, Venuto RC. Heroin nephropathy. A clinicopathologic and epidemiologic study. Am J Med 1980; 68: 4753. 23  Dettmeyer RB, Preuss J, Wollersen H, Madea B. Heroin-associated nephropathy. Expert Opin Drug Saf 2005; 4: 1928. 24  Crowe AV, Howse M, Bell GM, Henry JA. Substance abuse and the kidney. OJM 2000; 93: 14752. 25 Nzerue CM, Hewan-Lowe K, Riley Jr LJ. Cocaine and the kidney: a synthesis of pathophysiologic and clinical perspectives. Am J Kidney Dis 2000; 35: 78395.

26 Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F. Dantrolene - a review of its pharmacology, therapeutic use and new developments. Anaesthesia 2004; 59: 36473.

FUrther readinG Bell GM, Howse MLP. Substance misuse, organic solvents and kidney disease. In: Davison AM, Cameron JS, Grunfel JP, et al, eds. Oxford textbook of clinical nephrology, 3rd edn. Oxford: Oxford University Press, 2005. De Droe ME. Drug-induced nephropathies. In: Davison AM, Cameron JS, Grunfel JP, et al, eds. Oxford textbook of clinical nephrology, 3rd edn. Oxford: Oxford University Press, 2005. Wedeen RP, De Droe ME. Nephrotoxic metals. In: Davison AM, Cameron JS, Grunfel JP, et al, eds. Oxford textbook of clinical nephrology, 3rd edn. Oxford: Oxford University Press, 2005.

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