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Nephrotoxins and drugs in renal insufficiency
DRUGS AND THE KIDNEY
Renal disease may alter plasma protein binding (e.g. phenytoin), thereby increasing the fraction of the drug that is unbound and thus active. Drugs that act on the luminal side of the renal tubule (e.g. loop and thiazide diuretics, and antibiotics for urinary tract infections) reach their site of action by glomerular filtration, and higher doses may be required as GFR falls. In severe renal insufficiency (eGFR <25 ml/minute), thiazide diuretics are usually ineffective.
Nephrotoxins and drugs in renal insufficiency Caroline Ashley
Abstract Renal insufficiency induces profound pharmacokinetic and pharmacodynamic changes. The widespread reporting of estimated glomerular filtration rate (eGFR) has alerted clinicians to the incidence of renal insufficiency and the need for drug dose amendment. For drugs with a high therapeutic index, the eGFR can be used as a guide to dose adjustment. However, for drugs with a low therapeutic index, pending further experimental data relating drug excretion to the modification of diet in renal disease (MDRD) determination of eGFR, the Cockcroft and Gault equation using the patient’s ideal body weight is the most reliable way to determine dose adjustment.
Pharmacodynamic changes in renal disease The sensitivity of the brain to the effects of some psychoactive drugs is increased. Tissue sensitivity to the effects of some endogenous hormones (e.g. insulin, vitamin D analogues and growth hormone) is reduced. Sensitivity to the effects of acetylcholinesterase inhibitors is increased.
Keywords determination of renal function; drug dosing; loading dose; maintenance dose; pharmacodynamics; pharmacokinetics; renal insufficiency
Drug dosing regimens in renal insufficiency When initiating therapy, the usual approach is to start at the lower end of the recommended dosage range, monitor the response and, if the desired therapeutic effect is not achieved, increase the dosage gradually. If a drug is eliminated by metabolism in the liver, in general, standard therapeutic doses may be used. However, it is important to beware of pharmacologically active metabolites that are cleared by the kidney, as these may accumulate in patients with reduced kidney function and cause toxic effects. A typical example is morphine, which is metabolized by the liver to its 3- and 6-glucuronides. These metabolites are opioids in their own right, with greater potency than the parent drug, and are excreted via the kidneys.3 Thus, morphine should be used with great caution in those individuals with severe renal impairment, who are at greatly increased risk of central nervous system (CNS) and respiratory depression. The half-life (t½) of a drug determines the rate at which it will accumulate in the body during repeated dosing. With any given drug, it takes approximately four to five half-lives for the amount in the body, and the plasma concentration, to reach steady state, when the rate of drug elimination equates to the rate of drug intake. In patients with decreased renal function, any drug that is excreted via the kidneys will have an extended half-life, and take longer to reach steady state. For example, digoxin has a half-life of approximately 40 hours in someone with normal renal function, so it will take about 1 week to reach steady state. In someone with an eGFR of less then 15 ml/minute, the half-life of digoxin is increased to approximately 100 hours, and it will take nearly 1 month to reach steady state.
The widespread reporting of estimated glomerular filtration rates (eGFR) has brought greater awareness of the prevalence of renal insufficiency and thereby encouraged medical practitioners to take account of reduced renal function when prescribing. It is well recognized that serum creatinine (SCr) per se is a poor reflection of renal function but can be improved by incorporating SCr in one of several equations, the principal two being Cockcroft and Gault, and the modification of diet in renal disease (MDRD),1 to give estimates of creatinine clearance (CrCl) or GFR respectively. It is still a matter of debate as to which equation should be used with respect to drug dosing, owing principally to how pharmacodynamic data have been gathered in the past. The general consensus is that for drugs with a high therapeutic index (the ratio between the highest tolerated dosage and the lowest effective dosage), MDRD eGFR is sufficient. However, for those drugs with a low therapeutic index, where the dosing regimen needs to be adjusted more precisely in patients with renal dysfunction, the Cockcroft and Gault equation using the patient’s ideal body weight is more accurate.2
Pharmacokinetic changes to consider in renal disease For drugs that are excreted by the kidneys, reduced clearance in renal insufficiency will lead to a prolonged half-life and accumulation of the drug if the dose and/or dosing frequency are not amended. Reduced GFR will also have pharmacokinetic effects if a drug has active metabolites that are excreted in the urine. If a patient requires renal replacement therapy (RRT), the type of RRT used will determine the rate of elimination of a drug.
Loading dose If there is likely to be a delay in reaching steady state, a loading dose may be required. The plasma concentration of a drug that is excreted by the kidney will take longer to decay after a loading dose if GFR is reduced, but would also take longer than usual to reach steady state with repeated maintenance doses, so a therapeutic concentration is still achieved rapidly and maintained. In most cases, the size of the loading dose is not affected by the degree of renal insufficiency. For example, with teicoplanin, the
Caroline Ashley MSc BPharm FFRPS FRPharmS is Lead Pharmacist for Renal Services at the Royal Free London NHS Foundation Trust, London, UK. Competing interests: none declared.
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DRUGS AND THE KIDNEY
loading dose will still be 400 mg every 12 hours for three doses even if the patient has an eGFR less than 15 ml/minute. It may be necessary to reduce the loading dose if the volume of distribution of the drug is decreased. For example, in someone with severe renal insufficiency, digoxin tends to be displaced from its binding sites on cardiac muscle, which effectively reduces its volume of distribution. Hence, the total loading dose is often reduced from 1000e1500 micrograms down to 750e1000 micrograms.
Dose reduced, dosing interval unchanged
Log plasma concentration
Teicoplanin 400 mg every 72 hours Teicoplanin 400 mg every 24 hours
Maintenance dose In order to prevent drug accumulation, or to avoid under-treating a patient, the general rule for maintenance dosing is to dose once every half-life. If a drug is excreted via the kidneys, the half-life is increased in renal insufficiency, so the dosing regimen will need to be amended to prevent toxicity. There are three main approaches to dosage alteration: increase the dosing interval, while leaving the dose unchanged decrease the dose while leaving the dosing interval unchanged decrease the dose and increase the dosing interval. Which ploy is used often depends on the desired therapeutic effect. For instance, with antibiotics, a reasonably high peak concentration is still required in order to combat the infection, so the first approach is employed. An example of this is teicoplanin, where the maintenance dose is reduced from 400 mg daily to 400 mg every 3 days in severe renal insufficiency (Figure 1).4 Another example is low-molecular-weight heparin, which is excreted via the kidneys and accumulates in severe renal impairment, potentially leading to haemorrhage; the dose of enoxaparin for the treatment of acute coronary syndrome should be 1 mg/kg once daily rather than twice daily, with close monitoring of anti-factor Xa concentration.5 In contrast, with digoxin, a high peak concentration is not required, so the second approach will suffice, and a typical dose of 62.5 micrograms instead of 250 micrograms daily will achieve an adequate plasma concentration4 (Figure 2). With some drugs, it is necessary to reduce the dose and increase the dosing interval in order to avoid toxicity. A prime example is gentamicin, where a typical dose in someone with an eGFR of less
0
than 15 ml/minute is 2 mg/kg three times a week, dependent on close monitoring of plasma concentration.4 Effects of drugs on renal function Medications cause renal failure by a variety of mechanisms. The kidneys provide the final common pathway for the excretion of many drugs and their metabolites, and therefore are frequently exposed to high concentrations of potentially toxic substances. Drugs and their metabolites are taken up selectively and concentrated by the renal tubular cells before excretion into the urine, so high intracellular concentrations are attained, particularly in the renal medulla, which is relatively avascular. As a result, direct toxic damage occurs, generally affecting the renal tubular cells and renal papillae. Nephrotoxicity of this type tends to be dose-dependent. Consequently, many groups of drugs can cause renal damage, and their effects are increased in the presence of pre-existing renal disease. There are various ways in which drugs can cause nephrotoxicity, but the main effects of drugs on the kidneys may be generally categorized as follows: pre-renal effects (e.g. water and electrolyte loss, increased catabolism, vascular occlusion, altered renal haemodynamics) obstructive uropathy allergic or immunological damage (i.e. hypersensitivity reactions resulting in vasculitis, interstitial nephritis, glomerulonephritis) direct nephrotoxicity (giving rise to acute tubular or interstitial damage and renal papillary necrosis). One of the most important principles in drug-induced renal disease is that chronic kidney disease (CKD), common in the elderly, increases the individual’s risk of acute kidney injury (AKI). Hence, particular care should be taken to avoid or limit the use of nephrotoxic drugs in such patients. Metformin is not itself nephrotoxic (a common misconception). However, the risk of lactic acidosis is increased in patients taking metformin who have severe renal insufficiency. Traditionally, the limit for using this drug is a GFR of 30 ml/minute/ 1.73 m2, although some recent data have suggested this adverse effect may be less common than previously thought.6
Log plasma concentration
2
3
Time (days) Figure 1
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Figure 2
Teicoplanin 400 mg every 72 hours Teicoplanin 400 mg every 24 hours
1
2
Time (days)
Dose constant, dosing interval increased
0
1
2
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DRUGS AND THE KIDNEY
Altered renal haemodynamics Some drugs have specific effects on renal haemodynamics. The renal vascular bed demonstrates a capacity to autoregulate blood flow across a range of systemic blood pressure. The balance between vasodilatation of the afferent arteriole and vasoconstriction of the efferent arteriole is at the heart of this mechanism. Non-steroidal anti-inflammatory drugs (NSAIDs) are a wellrecognized cause of drug-induced AKI. Even a short course of an NSAID (such as diclofenac) has been associated with AKI, especially in older patients. NSAIDs inhibit intrarenal prostaglandin synthesis, particularly prostaglandins E2, D2 and I2 (prostacyclin). These prostaglandins are all potent vasodilators having their predominant effect on the afferent arteriole, vasodilatation of which leads to an increase in blood flow to the glomerulus and the medulla. Thus, NSAIDs impair the ability of the renovasculature to adapt to a fall in perfusion pressure or to an increase in vasoconstrictor balance (as might be seen in scleroderma renal crisis).7,8 The selective cyclo-oxygenase 2 (COX2) inhibitors have the same effect on intrarenal haemodynamics as conventional NSAIDs.9 Similarly, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) may also reduce renal function by preventing the angiotensineIIemediated vasoconstriction of the efferent glomerular arteriole, vasoconstriction of which maintains the pressure gradient across the glomerulus. If renal perfusion pressure falls, reducing flow through the afferent arteriole, it is necessary to increase efferent arteriolar resistance in order to maintain intraglomerular pressure and GFR. NSAIDs, and ACE inhibitors and ARBs antagonize different arms of this vital autoregulatory system and thus predispose to the development of AKI, especially in the context of other physiological stressors; the combination of both is especially toxic. Other drugs affecting renal haemodynamics include the calcineurin inhibitors (ciclosporin and tacrolimus). High wholeblood concentrations of both ciclosporin and tacrolimus are associated with intense vasoconstriction of the renal microvasculature, resulting in reduced renal perfusion, a fall in GFR, and compensatory hypertension. Consequently, doses must be adjusted to maximize therapeutic effect while minimizing renal damage. A whole-blood ciclosporin concentration greater than 400 ng/ml is generally associated with tubular damage.
Haemoglobin: Drug-induced intravascular haemolysis can occur in patients with specific conditions, for example, glucose-6phosphate dehydrogenase deficiency. If such patients take drugs such as antimalarials, sulfonamides, co-trimoxazole, aspirin, paracetamol or, occasionally, rifampicin, they can experience drug-induced haemolysis. The resulting release of haemoglobin causes microtubular obstruction as well as direct oxidative injury to the tubules, resulting in AKI. Analogously, drugs that cause rhabdomyolysis can cause renal insufficiency via myoglobinuria. These include statins, particularly when used in combination with fibrates. The risk of rhabdomyolysis is also increased when statins are co-prescribed with ciclosporin. Allergic or immunological damage Acute interstitial nephritis is a hypersensitivity reaction, characterized by an acute fall in GFR within hours or days to months after exposure to a particular drug. Accompanying symptoms may include modest proteinuria and haematuria, plus fever, rash, arthralgia and abnormal liver function tests. Recovery of renal function usually occurs over 1e12 months after discontinuation of the drug, but permanent impairment can result. Corticosteroids may be helpful, although there is no conclusive evidence that they enhance the rate or degree of recovery from acute renal failure. It is important to identify the causative agent since kidney damage is potentially reversible. Many drugs have been reported to cause acute interstitial nephritis (Table 1). Proton pump inhibitors account for the largest number of cases of drug-induced tubulo-interstitial nephritis (TIN), owing to their high prescribing frequency, even though the likelihood of this adverse effect in the individual patient is small. Chronic interstitial nephritis, also known as analgesic nephropathy, occurs following excessive analgesic use. It is underdiagnosed since patients tend to under-report their use of analgesics, but is one of the most common forms of drug-induced renal failure. Analgesic combinations, particularly those containing salicylates, caffeine or paracetamol, seem to increase the risk of chronic tubular interstitial disease, suggesting a synergistic effect. Paracetamol can cause direct oxidative damage to renal tubular cells, and aspirin potentiates the damage by reducing renal blood flow, leading to ischaemia, as well as by
Tubular blockage Crystalluria: The formation of intra- or extrarenal crystals may result in microtubular or ureteric obstruction. During the treatment of myeloproliferative disorders with cytotoxic agents, tumour-lysis syndrome may occur, particularly if there is a large tumour burden. As a result, uric acid crystals may be deposited in the renal tubules to such an extent that the tubules become blocked, leading to the onset of AKI. The use of prophylactic allopurinol or rasburicase together with the maintenance of a high fluid intake is effective in preventing this phenomeno. The early sulfonamides such as sulfathiazole and sulfadiazine were relatively water insoluble and tended to crystallize in acidic urine. Even with modern sulfonamides, a high fluid intake should be maintained. Crystalluria has also been reported to occur after therapy with acetazolamide, high-dose mercaptopurine, methotrexate, cisplatin, probenecid, naftidrofuryl, aciclovir, indinavir, cidofovir and ganciclovir.
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Drugs that can cause interstitial nephritis C
C
Allopurinol Aminosalicylates Amlodipine Azathioprine Bumetanide Carbamazepine Cefalosporins Cimetidine Co-trimoxazole
C
Diltiazem
C
C C C C C C C C
C C C C C C C C
Erythromycin Furosemide Gentamicin Gold Interferon Isoniazid Lithium Mesalazine Non-steroidal anti-inflammatory drugs Penicillins
C C C C C C C C C
Phenobarbital Phenytoin Proton pump inhibitors Quinolones Ranitidine Rifampicin Sulfonamides Thiazides Vancomycin
Table 1
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inhibiting the enzyme systems involved in the defence of kidney against oxidative damage. Discontinuation of analgesics often results in stabilization or improvement of renal function. Drug-induced (secondary) glomerulonephritis is an immunemediated disease in which antigeneantibody complexes accumulate within the glomerulus, with the deposition of immunoglobulins and complement along the glomerular basement membrane and in blood vessels, precipitating an inflammatory response. Infection and numerous drugs are known to act as antigens or allergens in this situation. Drugs known to cause glomerulonephritis are listed in Table 2. Propylthiouracil is one of a handful of drugs that may be associated with the development of anti-neutrophil cytoplasmic antibodies (ANCA) and systemic vasculitis. Hydralazine, minocycline, and levamisole-adulterated cocaine have also been implicated. Lupus erythematosus: Three drugs in particular (hydralazine, procainamide and isoniazid) are associated with lupus erythematosus syndrome. Others reported to cause it include methyldopa, penicillamine, phenytoin and ethosuximide. The condition may be genetically determined, as it is more common in slow acetylators, and becomes more prevalent with prolonged treatment. It is characterized by depositions of immunoglobulin G (IgG) and C3 in the glomerular mesangium, but the effects are readily reversible and severe renal impairment seldom occurs.
Drugs that can cause acute tubular necrosis C C C C C C
C C C
C C
C C C C C
Allopurinol Dapsone Halothane Non-steroidal anti-inflammatory drugs Penicillins Probenecid Sulfonamides Tolbutamide Captopril
C C C C
C C C C C
Gold Hydralazine Penicillamine Phenindione Rifampicin Thiazide diuretics Procainamide Psoralen Levamisole
Table 2
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Ciclosporin Ethylene glycol Foscarnet
C
C C C C C
C C
Furosemide Gold Ifosfamide Lithium Mannitol Non-steroidal anti-inflammatory drugs Paracetamol Tacrolimus Vancomycin
mechanisms. They cause a direct cytotoxic effect on the renal proximal tubular cells, enhance cellular damage by reactive oxygen species, and increase resistance to renal blood flow. They also exacerbate renal vasoconstriction, particularly in the deeper portions of the outer medulla. This is especially important in patients with CKD, because their preexisting abnormal vascular pathobiology is made worse by the effects of CM. CM-mediated vasoconstriction is the result of a direct action of CM on vascular smooth muscle and of metabolites such as adenosine and endothelin. Additionally, the osmotic property of CM, especially in the tubular lumen, decreases water reabsorption, leading to a build-up of interstitial pressure. This, along with the increased salt and water load to the distal tubules, reduces GFR and causes local compression of the vasa recta. All these effects contribute to worsening medullary hypoxemia and renal vasoconstriction in patients who may already be volume depleted.10 Finally, CM also increase resistance to blood flow by increasing blood viscosity and by decreasing red cell deformability. This intravascular sludging generates local ischaemia and causes activation of reactive oxygen species that result in tubular damage at a cellular level. The risk factors for developing contrast-induced nephropathy CIN) include: age CKD diabetes mellitus hypertension metabolic syndrome anaemia multiple myeloma hypoalbuminaemia renal transplant hypovolaemia and decreased effective circulating volumes e as evidenced by congestive heart failure, an ejection fraction of less than 40%, hypotension, and intra-aortic balloon counterpulsation use. In general, the older ionic contrast media are far more nephrotoxic than their newer, non-ionic counterparts. Within the group of non-ionic contrast media, the extremely hyperosmolar agents (1500e1800 mOsm/kg) are associated with a greater toxic effect than the lower hyperosmolar agents (600e850 mOsm/kg). However, the newest iso-osmolar agents such as iodixanol appear to be the most ‘kidney-sparing’ with regard to the reported incidence of CIN.11 Manoeuvres such as the administration of
Drugs that can cause glomerulonephritis C
C
Table 3
Direct nephrotoxicity Acute tubular damage can occur with normal doses of certain drugs but is more often dose dependent, resulting from high-dose treatment or accumulation of a drug in a patient who is typically either dehydrated or has pre-existing impairment of renal function. Potentiation of the renal damage occurs with the coadministration of two or more nephrotoxic agents. Examples of drugs causing direct tubular damage are listed in Table 3 The immunosuppressant drugs ciclosporin and tacrolimus, in addition to their effects on intra-renal haemodynamics, also have a direct tubular toxic effect. Ciclosporin nephrotoxicity is potentiated by aminoglycosides, vancomycin, ciprofloxacin and NSAIDs. An unusual form of renal failure characterized by swollen, vacuolated proximal tubular cells can develop from hyperosmolar substances, such as intravenous immunoglobulin, mannitol and the plasma expander, hydroxyethyl starch. Radiological contrast media (CM) act on distinct anatomic sites within the kidney and exert adverse effects via multiple
C
Aciclovir Aminoglycosides Amphotericin Cefalosporins Cisplatin Contrast media
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both TIN and a glomerulopathy. Early manifestations of cadmium nephropathy are those of tubular dysfunction, including low-molecular-weight tubular proteinuria, aminoaciduria and glucosuria. A doseeresponse relationship is observed with more severe kidney damage resulting from prolonged and high-level exposure. This has been confirmed in studies of occupationally exposed workers. An excess risk of kidney stones, possibly related to an increased excretion of calcium in urine following the tubular damage, has been shown in several studies. Treatment requires elimination of cadmium exposure; chelation with Na calcium edetate (EDTA) may increase cadmium nephrotoxicity. Tubular proteinuria is usually irreversible. Mercury: Mercury-containing compounds bind to sulfhydryl groups of proteins and can therefore interfere with structural proteins, enzymes and transport processes. Extensive proximal tubular necrosis is seen with cast formation in the distal nephron. Exposure to mercuric chloride leads to calcification of the kidney, which tends to increase with increasing doses. Other heavy metals that are nephrotoxic include copper, gold, uranium, arsenic, iron, bismuth and chromium. All cause tubular damage and dysfunction (e.g. tubular proteinuria, aminoaciduria) as well as tubular necrosis, but glomerulopathies may predominate with some compounds (mercury, gold). Treatment involves removal of the patient from further exposure and either or both of the following: chelating agents (copper, arsenic, bismuth) dialysis (chromium, arsenic, bismuth) is often used when chelation fails or simultaneously with chelation for severe arsenic poisoning.
intravenous sodium chloride 0.9%, sodium bicarbonate and acetylcysteine have been shown to be beneficial in reducing the risk of developing CIN, although the literature is inconclusive on which is most effective. Gadolinium Nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy is a rare and serious syndrome that involves fibrosis of skin, joints, eyes and internal organs. Patients develop large areas of hardened skin with fibrotic nodules and plaques. NSF may also cause joint contractures resulting in joint pain and a restricted range of movement. In its most severe form, NSF may cause severe systemic fibrosis affecting internal organs including the lungs, heart and liver, and resembles systemic sclerosis. The first cases were identified in 1997 and its cause is not fully understood. However, evidence suggests that NSF is associated with exposure to gadolinium (principally in the form of contrast agents used for magnetic resonance imaging) in patients with CKD.12 As a result, gadolinium-containing contrast is now considered contraindicated in patients with an eGFR less than 60 ml/minute and especially if it is less than 30 ml/minute. Distal tubular damage Fluorinated anaesthetic agents have been reported to cause acute distal tubular damage, especially in obese patients, resulting in polyuria and hypernatraemia. Lithium salts can cause nephrogenic diabetes insipidus, resulting in the production of a large volume of dilute urine regardless of volume status. This may lead to hypernatraemia, and is unresponsive to vasopressin and aldosterone. The polyuria and dehydration with renal damage leads to increased plasma lithium concentration, thus exacerbating the effect. Both acute and chronic renal failure can occur, with scarring of the renal interstitium. Inappropriate secretion of antidiuretic hormone (ADH), the hormone responsible for controlling the rate at which kidneys excrete or retain free water, can result in hyponatraemia and water intoxication. Of the drugs associated with inappropriate ADH secretion, the most important are carbamazepine, vincristine and cyclophosphamide.
Solvents It has been shown that all solvent exposure is associated with the progression of primary glomerulonephritis to end-stage renal disease (ESRD), but little is known about the type of solvents that are high risk. A study in France looking at patients with biopsyproven primary glomerulonephritis showed that the highest risk of progression to ESRD was seen in exposed machinery fitters, machine assemblers and plumbers/welders, as well as those who had ever handled printing inks and petroleum products. Among solvents, the highest risks were found for toluene/xylene, gasoline, fuel and gas-oil, and ketones.15 Other studies have reinforced this finding, with organic solvent exposure being associated with progression of IgAN and FSGS.16
Effect of environmental chemicals on renal function Heavy metals Heavy metals (e.g. lead, cadmium, copper) and other toxins can cause a form of chronic TIN.13,14 Lead: Chronic TIN results as lead accumulates in proximal tubular cells. Short-term lead exposure causes proximal tubular dysfunction, including decreased urate secretion and hyperuricemia, aminoaciduria, and renal glucosuria. Chronic lead exposure (for 5 to 30 years) causes progressive tubular atrophy and interstitial fibrosis, with renal insufficiency, hypertension, gout and Fanconi’s syndrome. However, chronic low-level exposure may cause renal insufficiency and hypertension independent of TIN. Hyperuricaemia disproportionate to the degree of renal insufficiency and a bland urinary sediment are common. Treatment with chelation therapy can stabilize renal function, but recovery may be incomplete. Cadmium: Cadmium exposure following workplace exposure or as a result of contaminated water, food and tobacco can cause
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Herbal remedies Aristolochic acid nephropathy (AAN), a progressive renal interstitial fibrosis frequently associated with urothelial malignancies, was initially reported in a Belgian cohort of more than 100 patients after the intake of slimming pills containing a Chinese herb, Aristolochia fangchi.17 Although botanicals known or suspected to contain aristolochic acid (AA) are banned in many countries, cases of AAN continue to be regularly observed worldwide. The incidence of AAN is probably much higher than initially thought, especially in Asia and the Balkans. In Asian countries, where traditional medicines remain very popular, there is a high risk of AAN because of the frequent substitution of the botanical products of AA-containing herbs. In the Balkans, exposure to AA in flour obtained from wheat contaminated with seeds of Aristolochia clematitis could be responsible for so-called
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8 Huerta C, Castellsague J, Varas-Lorenzo C, Garcı´a Rodrı´guez LA. Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population. Am J Kidney Dis 2005; 45: 531. 9 Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343: 1520e8. for the VIGOR Study Group. 10 Jo SH, Youn TJ, Koo BK, et al. Renal toxicity evaluation and comparison between visipaque (iodixanol) and hexabrix (ioxaglate) in patients with renal insufficiency undergoing coronary angiography: the RECOVER study: a randomized controlled trial48: 924e30. J Am Coll Cardiol. 11 Maioli M, Toso A, Leoncini M, Gallopin M, Musilli N, Bellandi F. Persistent renal damage after contrast-induced acute kidney injury: incidence, evolution, risk factors, and prognosis. Circulation 2012; 125: 3099e107. 12 Thomsen HS. Nephrogenic systemic fibrosis: history and epidemiology. Radiol Clin North Am 2009; 47: 827e31. 13 Jarup L. Hazards of heavy metal contamination. Br Med Bull 2003; 68: 167e82. 14 O1 Barbier, Jacquillet G, Tauc M, Cougnon M, Poujeol P. Effect of heavy metals on, and handling by, the kidney. Nephron Physiol 2005; 99: p105e110. 15 Jacob S, Hery M, Protois JC, Rossert J, Stengel B. New insight into solvent-related end-stage renal disease: occupations, products and types of solvents at risk. Occup Environ Med 2007; 64: 843e8. 16 Jacob S, Hery M. Jean-claude Protois J-C, Jerome Rossert J, Stengel B. Effect of organic solvent exposure on chronic kidney disease progression: the GN-PROGRESS cohort study. J Am Soc Nephrol 2007; 18: 274e81. 17 Debelle FD, Vanherweghem JL, Nortier JL. Aristolochic acid nephropathy: a worldwide problem. Kidney Int 2008; 74: 158e69. 18 Gabardi S, Munz K, Ulbricht C. A review of dietary supplement einduced renal dysfunction. Clin J Am Soc Nephrol 2007; 2: 757e65.
Herbal compounds associated with renal toxicity Potential mechanism
CAM scientific name (common name)
COX inhibition (altered renal hemodynamics)
Curcuma longa (turmeric) Filipendula ulmaria (meadowsweet) Tanacetum parthenium (feverfew) Zingiber officinale (ginger) Boswellia serrata (frankincense) Camelia sinensis (green tea) Aesculus hippocastanum (horse chestnut) Rheum officinale (rhubarb) Rumex acetosa (sorrel) Rumex crispus (yellow dock) Cannabis sativa (marijuana) Colchicum autumnale (autumn crocus) Commiphora mukul (guggul) Coutarea latiflora (copalchi) Monascus purpureus (red yeast)
Nephrolithiasis
Rhabdomyolysis
Adapted from Gabardi S, Munz K, Ulbricht C. A Review of Dietary Supplement eInduced Renal Dysfunction. Clin J Am Soc Nephrol 2007; 2(4): 757e65
Table 4
Balkan endemic nephropathy. Finally, despite the Food and Drug Administration’s warnings concerning the safety of botanical remedies containing AA, these herbs continue to be sold via the Internet. In addition to aristolochic acid, a number of over-the-counter herbal remedies and dietary supplements have been associated with the development of renal dysfunction. These are detailed in Table 4.18 A
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FURTHER READING Aronson JK. Prescribing in renal insufficiency: principles and practice. In: Jamison RL, Wilkinson R, eds. Nephrology. London: Chapman& Hall, 1997 [Chapter 69]. Broe ME. Drug induced nephropathies. Oxford textbook of clinical nephrology. 3rd edn. Oxford Medical Publications, 2005; 2581e99. Kappel J, Calissi P. Nephrology: 3. Safe drug prescribing for patients with renal insufficiency. Can Med Assoc J 2002; 166: 473e7. Kidney Disease. Improving global outcomes (KDIGO) acute kidney injury Work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Inter Suppl 2012; 2: 1e138. Kidney Disease. Improving global outcomes (KDIGO) clinical practice guidelines for evaluation and management of chronic kidney disease. Kidney Inter Suppl 2013; 3: 1e150. Lee Anne, ed. Adverse Drug Reactions. Second edn. Pharmaceutical Press, 2009. Meyler’s Side Effects of Drugs. The international encyclopedia of adverse drug reactions and interactions. 15th edition, volume 1e6. Oxford: JK Aronson. Published by Elsevier, 2006. Pearson J. Drug-induced kidney disease. Introduction to Renal Therapeutics. In: Ashley C, Morlidge C, eds. London: Pharmaceutical Press, 2008. Renal Pharmacotherapy. Dosage adjustment of medications eliminated by the kidneys golightly LK. In: Teitelbaum I, Kiser T, eds. New York: Springer Publishing Co, 2013.
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Renal disease may alter plasma protein binding (e.g. phenytoin), thereby increasing the fraction of the drug that is unbound and thus active. Drugs that act on the luminal side of the renal tubule (e.g. loop and thiazide diuretics, and antibiotics for urinary tract infections) reach their site of action by glomerular filtration, and higher doses may be required as GFR falls. In severe renal insufficiency (eGFR <25 ml/minute), thiazide diuretics are usually ineffective.
Nephrotoxins and drugs in renal insufficiency Caroline Ashley
Abstract Renal insufficiency induces profound pharmacokinetic and pharmacodynamic changes. The widespread reporting of estimated glomerular filtration rate (eGFR) has alerted clinicians to the incidence of renal insufficiency and the need for drug dose amendment. For drugs with a high therapeutic index, the eGFR can be used as a guide to dose adjustment. However, for drugs with a low therapeutic index, pending further experimental data relating drug excretion to the modification of diet in renal disease (MDRD) determination of eGFR, the Cockcroft and Gault equation using the patient’s ideal body weight is the most reliable way to determine dose adjustment.
Pharmacodynamic changes in renal disease The sensitivity of the brain to the effects of some psychoactive drugs is increased. Tissue sensitivity to the effects of some endogenous hormones (e.g. insulin, vitamin D analogues and growth hormone) is reduced. Sensitivity to the effects of acetylcholinesterase inhibitors is increased.
Keywords determination of renal function; drug dosing; loading dose; maintenance dose; pharmacodynamics; pharmacokinetics; renal insufficiency
Drug dosing regimens in renal insufficiency When initiating therapy, the usual approach is to start at the lower end of the recommended dosage range, monitor the response and, if the desired therapeutic effect is not achieved, increase the dosage gradually. If a drug is eliminated by metabolism in the liver, in general, standard therapeutic doses may be used. However, it is important to beware of pharmacologically active metabolites that are cleared by the kidney, as these may accumulate in patients with reduced kidney function and cause toxic effects. A typical example is morphine, which is metabolized by the liver to its 3- and 6-glucuronides. These metabolites are opioids in their own right, with greater potency than the parent drug, and are excreted via the kidneys.3 Thus, morphine should be used with great caution in those individuals with severe renal impairment, who are at greatly increased risk of central nervous system (CNS) and respiratory depression. The half-life (t½) of a drug determines the rate at which it will accumulate in the body during repeated dosing. With any given drug, it takes approximately four to five half-lives for the amount in the body, and the plasma concentration, to reach steady state, when the rate of drug elimination equates to the rate of drug intake. In patients with decreased renal function, any drug that is excreted via the kidneys will have an extended half-life, and take longer to reach steady state. For example, digoxin has a half-life of approximately 40 hours in someone with normal renal function, so it will take about 1 week to reach steady state. In someone with an eGFR of less then 15 ml/minute, the half-life of digoxin is increased to approximately 100 hours, and it will take nearly 1 month to reach steady state.
The widespread reporting of estimated glomerular filtration rates (eGFR) has brought greater awareness of the prevalence of renal insufficiency and thereby encouraged medical practitioners to take account of reduced renal function when prescribing. It is well recognized that serum creatinine (SCr) per se is a poor reflection of renal function but can be improved by incorporating SCr in one of several equations, the principal two being Cockcroft and Gault, and the modification of diet in renal disease (MDRD),1 to give estimates of creatinine clearance (CrCl) or GFR respectively. It is still a matter of debate as to which equation should be used with respect to drug dosing, owing principally to how pharmacodynamic data have been gathered in the past. The general consensus is that for drugs with a high therapeutic index (the ratio between the highest tolerated dosage and the lowest effective dosage), MDRD eGFR is sufficient. However, for those drugs with a low therapeutic index, where the dosing regimen needs to be adjusted more precisely in patients with renal dysfunction, the Cockcroft and Gault equation using the patient’s ideal body weight is more accurate.2
Pharmacokinetic changes to consider in renal disease For drugs that are excreted by the kidneys, reduced clearance in renal insufficiency will lead to a prolonged half-life and accumulation of the drug if the dose and/or dosing frequency are not amended. Reduced GFR will also have pharmacokinetic effects if a drug has active metabolites that are excreted in the urine. If a patient requires renal replacement therapy (RRT), the type of RRT used will determine the rate of elimination of a drug.
Loading dose If there is likely to be a delay in reaching steady state, a loading dose may be required. The plasma concentration of a drug that is excreted by the kidney will take longer to decay after a loading dose if GFR is reduced, but would also take longer than usual to reach steady state with repeated maintenance doses, so a therapeutic concentration is still achieved rapidly and maintained. In most cases, the size of the loading dose is not affected by the degree of renal insufficiency. For example, with teicoplanin, the
Caroline Ashley MSc BPharm FFRPS FRPharmS is Lead Pharmacist for Renal Services at the Royal Free London NHS Foundation Trust, London, UK. Competing interests: none declared.
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DRUGS AND THE KIDNEY
loading dose will still be 400 mg every 12 hours for three doses even if the patient has an eGFR less than 15 ml/minute. It may be necessary to reduce the loading dose if the volume of distribution of the drug is decreased. For example, in someone with severe renal insufficiency, digoxin tends to be displaced from its binding sites on cardiac muscle, which effectively reduces its volume of distribution. Hence, the total loading dose is often reduced from 1000e1500 micrograms down to 750e1000 micrograms.
Dose reduced, dosing interval unchanged
Log plasma concentration
Teicoplanin 400 mg every 72 hours Teicoplanin 400 mg every 24 hours
Maintenance dose In order to prevent drug accumulation, or to avoid under-treating a patient, the general rule for maintenance dosing is to dose once every half-life. If a drug is excreted via the kidneys, the half-life is increased in renal insufficiency, so the dosing regimen will need to be amended to prevent toxicity. There are three main approaches to dosage alteration: increase the dosing interval, while leaving the dose unchanged decrease the dose while leaving the dosing interval unchanged decrease the dose and increase the dosing interval. Which ploy is used often depends on the desired therapeutic effect. For instance, with antibiotics, a reasonably high peak concentration is still required in order to combat the infection, so the first approach is employed. An example of this is teicoplanin, where the maintenance dose is reduced from 400 mg daily to 400 mg every 3 days in severe renal insufficiency (Figure 1).4 Another example is low-molecular-weight heparin, which is excreted via the kidneys and accumulates in severe renal impairment, potentially leading to haemorrhage; the dose of enoxaparin for the treatment of acute coronary syndrome should be 1 mg/kg once daily rather than twice daily, with close monitoring of anti-factor Xa concentration.5 In contrast, with digoxin, a high peak concentration is not required, so the second approach will suffice, and a typical dose of 62.5 micrograms instead of 250 micrograms daily will achieve an adequate plasma concentration4 (Figure 2). With some drugs, it is necessary to reduce the dose and increase the dosing interval in order to avoid toxicity. A prime example is gentamicin, where a typical dose in someone with an eGFR of less
0
than 15 ml/minute is 2 mg/kg three times a week, dependent on close monitoring of plasma concentration.4 Effects of drugs on renal function Medications cause renal failure by a variety of mechanisms. The kidneys provide the final common pathway for the excretion of many drugs and their metabolites, and therefore are frequently exposed to high concentrations of potentially toxic substances. Drugs and their metabolites are taken up selectively and concentrated by the renal tubular cells before excretion into the urine, so high intracellular concentrations are attained, particularly in the renal medulla, which is relatively avascular. As a result, direct toxic damage occurs, generally affecting the renal tubular cells and renal papillae. Nephrotoxicity of this type tends to be dose-dependent. Consequently, many groups of drugs can cause renal damage, and their effects are increased in the presence of pre-existing renal disease. There are various ways in which drugs can cause nephrotoxicity, but the main effects of drugs on the kidneys may be generally categorized as follows: pre-renal effects (e.g. water and electrolyte loss, increased catabolism, vascular occlusion, altered renal haemodynamics) obstructive uropathy allergic or immunological damage (i.e. hypersensitivity reactions resulting in vasculitis, interstitial nephritis, glomerulonephritis) direct nephrotoxicity (giving rise to acute tubular or interstitial damage and renal papillary necrosis). One of the most important principles in drug-induced renal disease is that chronic kidney disease (CKD), common in the elderly, increases the individual’s risk of acute kidney injury (AKI). Hence, particular care should be taken to avoid or limit the use of nephrotoxic drugs in such patients. Metformin is not itself nephrotoxic (a common misconception). However, the risk of lactic acidosis is increased in patients taking metformin who have severe renal insufficiency. Traditionally, the limit for using this drug is a GFR of 30 ml/minute/ 1.73 m2, although some recent data have suggested this adverse effect may be less common than previously thought.6
Log plasma concentration
2
3
Time (days) Figure 1
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Figure 2
Teicoplanin 400 mg every 72 hours Teicoplanin 400 mg every 24 hours
1
2
Time (days)
Dose constant, dosing interval increased
0
1
2
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DRUGS AND THE KIDNEY
Altered renal haemodynamics Some drugs have specific effects on renal haemodynamics. The renal vascular bed demonstrates a capacity to autoregulate blood flow across a range of systemic blood pressure. The balance between vasodilatation of the afferent arteriole and vasoconstriction of the efferent arteriole is at the heart of this mechanism. Non-steroidal anti-inflammatory drugs (NSAIDs) are a wellrecognized cause of drug-induced AKI. Even a short course of an NSAID (such as diclofenac) has been associated with AKI, especially in older patients. NSAIDs inhibit intrarenal prostaglandin synthesis, particularly prostaglandins E2, D2 and I2 (prostacyclin). These prostaglandins are all potent vasodilators having their predominant effect on the afferent arteriole, vasodilatation of which leads to an increase in blood flow to the glomerulus and the medulla. Thus, NSAIDs impair the ability of the renovasculature to adapt to a fall in perfusion pressure or to an increase in vasoconstrictor balance (as might be seen in scleroderma renal crisis).7,8 The selective cyclo-oxygenase 2 (COX2) inhibitors have the same effect on intrarenal haemodynamics as conventional NSAIDs.9 Similarly, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) may also reduce renal function by preventing the angiotensineIIemediated vasoconstriction of the efferent glomerular arteriole, vasoconstriction of which maintains the pressure gradient across the glomerulus. If renal perfusion pressure falls, reducing flow through the afferent arteriole, it is necessary to increase efferent arteriolar resistance in order to maintain intraglomerular pressure and GFR. NSAIDs, and ACE inhibitors and ARBs antagonize different arms of this vital autoregulatory system and thus predispose to the development of AKI, especially in the context of other physiological stressors; the combination of both is especially toxic. Other drugs affecting renal haemodynamics include the calcineurin inhibitors (ciclosporin and tacrolimus). High wholeblood concentrations of both ciclosporin and tacrolimus are associated with intense vasoconstriction of the renal microvasculature, resulting in reduced renal perfusion, a fall in GFR, and compensatory hypertension. Consequently, doses must be adjusted to maximize therapeutic effect while minimizing renal damage. A whole-blood ciclosporin concentration greater than 400 ng/ml is generally associated with tubular damage.
Haemoglobin: Drug-induced intravascular haemolysis can occur in patients with specific conditions, for example, glucose-6phosphate dehydrogenase deficiency. If such patients take drugs such as antimalarials, sulfonamides, co-trimoxazole, aspirin, paracetamol or, occasionally, rifampicin, they can experience drug-induced haemolysis. The resulting release of haemoglobin causes microtubular obstruction as well as direct oxidative injury to the tubules, resulting in AKI. Analogously, drugs that cause rhabdomyolysis can cause renal insufficiency via myoglobinuria. These include statins, particularly when used in combination with fibrates. The risk of rhabdomyolysis is also increased when statins are co-prescribed with ciclosporin. Allergic or immunological damage Acute interstitial nephritis is a hypersensitivity reaction, characterized by an acute fall in GFR within hours or days to months after exposure to a particular drug. Accompanying symptoms may include modest proteinuria and haematuria, plus fever, rash, arthralgia and abnormal liver function tests. Recovery of renal function usually occurs over 1e12 months after discontinuation of the drug, but permanent impairment can result. Corticosteroids may be helpful, although there is no conclusive evidence that they enhance the rate or degree of recovery from acute renal failure. It is important to identify the causative agent since kidney damage is potentially reversible. Many drugs have been reported to cause acute interstitial nephritis (Table 1). Proton pump inhibitors account for the largest number of cases of drug-induced tubulo-interstitial nephritis (TIN), owing to their high prescribing frequency, even though the likelihood of this adverse effect in the individual patient is small. Chronic interstitial nephritis, also known as analgesic nephropathy, occurs following excessive analgesic use. It is underdiagnosed since patients tend to under-report their use of analgesics, but is one of the most common forms of drug-induced renal failure. Analgesic combinations, particularly those containing salicylates, caffeine or paracetamol, seem to increase the risk of chronic tubular interstitial disease, suggesting a synergistic effect. Paracetamol can cause direct oxidative damage to renal tubular cells, and aspirin potentiates the damage by reducing renal blood flow, leading to ischaemia, as well as by
Tubular blockage Crystalluria: The formation of intra- or extrarenal crystals may result in microtubular or ureteric obstruction. During the treatment of myeloproliferative disorders with cytotoxic agents, tumour-lysis syndrome may occur, particularly if there is a large tumour burden. As a result, uric acid crystals may be deposited in the renal tubules to such an extent that the tubules become blocked, leading to the onset of AKI. The use of prophylactic allopurinol or rasburicase together with the maintenance of a high fluid intake is effective in preventing this phenomeno. The early sulfonamides such as sulfathiazole and sulfadiazine were relatively water insoluble and tended to crystallize in acidic urine. Even with modern sulfonamides, a high fluid intake should be maintained. Crystalluria has also been reported to occur after therapy with acetazolamide, high-dose mercaptopurine, methotrexate, cisplatin, probenecid, naftidrofuryl, aciclovir, indinavir, cidofovir and ganciclovir.
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Drugs that can cause interstitial nephritis C
C
Allopurinol Aminosalicylates Amlodipine Azathioprine Bumetanide Carbamazepine Cefalosporins Cimetidine Co-trimoxazole
C
Diltiazem
C
C C C C C C C C
C C C C C C C C
Erythromycin Furosemide Gentamicin Gold Interferon Isoniazid Lithium Mesalazine Non-steroidal anti-inflammatory drugs Penicillins
C C C C C C C C C
Phenobarbital Phenytoin Proton pump inhibitors Quinolones Ranitidine Rifampicin Sulfonamides Thiazides Vancomycin
Table 1
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inhibiting the enzyme systems involved in the defence of kidney against oxidative damage. Discontinuation of analgesics often results in stabilization or improvement of renal function. Drug-induced (secondary) glomerulonephritis is an immunemediated disease in which antigeneantibody complexes accumulate within the glomerulus, with the deposition of immunoglobulins and complement along the glomerular basement membrane and in blood vessels, precipitating an inflammatory response. Infection and numerous drugs are known to act as antigens or allergens in this situation. Drugs known to cause glomerulonephritis are listed in Table 2. Propylthiouracil is one of a handful of drugs that may be associated with the development of anti-neutrophil cytoplasmic antibodies (ANCA) and systemic vasculitis. Hydralazine, minocycline, and levamisole-adulterated cocaine have also been implicated. Lupus erythematosus: Three drugs in particular (hydralazine, procainamide and isoniazid) are associated with lupus erythematosus syndrome. Others reported to cause it include methyldopa, penicillamine, phenytoin and ethosuximide. The condition may be genetically determined, as it is more common in slow acetylators, and becomes more prevalent with prolonged treatment. It is characterized by depositions of immunoglobulin G (IgG) and C3 in the glomerular mesangium, but the effects are readily reversible and severe renal impairment seldom occurs.
Drugs that can cause acute tubular necrosis C C C C C C
C C C
C C
C C C C C
Allopurinol Dapsone Halothane Non-steroidal anti-inflammatory drugs Penicillins Probenecid Sulfonamides Tolbutamide Captopril
C C C C
C C C C C
Gold Hydralazine Penicillamine Phenindione Rifampicin Thiazide diuretics Procainamide Psoralen Levamisole
Table 2
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Ciclosporin Ethylene glycol Foscarnet
C
C C C C C
C C
Furosemide Gold Ifosfamide Lithium Mannitol Non-steroidal anti-inflammatory drugs Paracetamol Tacrolimus Vancomycin
mechanisms. They cause a direct cytotoxic effect on the renal proximal tubular cells, enhance cellular damage by reactive oxygen species, and increase resistance to renal blood flow. They also exacerbate renal vasoconstriction, particularly in the deeper portions of the outer medulla. This is especially important in patients with CKD, because their preexisting abnormal vascular pathobiology is made worse by the effects of CM. CM-mediated vasoconstriction is the result of a direct action of CM on vascular smooth muscle and of metabolites such as adenosine and endothelin. Additionally, the osmotic property of CM, especially in the tubular lumen, decreases water reabsorption, leading to a build-up of interstitial pressure. This, along with the increased salt and water load to the distal tubules, reduces GFR and causes local compression of the vasa recta. All these effects contribute to worsening medullary hypoxemia and renal vasoconstriction in patients who may already be volume depleted.10 Finally, CM also increase resistance to blood flow by increasing blood viscosity and by decreasing red cell deformability. This intravascular sludging generates local ischaemia and causes activation of reactive oxygen species that result in tubular damage at a cellular level. The risk factors for developing contrast-induced nephropathy CIN) include: age CKD diabetes mellitus hypertension metabolic syndrome anaemia multiple myeloma hypoalbuminaemia renal transplant hypovolaemia and decreased effective circulating volumes e as evidenced by congestive heart failure, an ejection fraction of less than 40%, hypotension, and intra-aortic balloon counterpulsation use. In general, the older ionic contrast media are far more nephrotoxic than their newer, non-ionic counterparts. Within the group of non-ionic contrast media, the extremely hyperosmolar agents (1500e1800 mOsm/kg) are associated with a greater toxic effect than the lower hyperosmolar agents (600e850 mOsm/kg). However, the newest iso-osmolar agents such as iodixanol appear to be the most ‘kidney-sparing’ with regard to the reported incidence of CIN.11 Manoeuvres such as the administration of
Drugs that can cause glomerulonephritis C
C
Table 3
Direct nephrotoxicity Acute tubular damage can occur with normal doses of certain drugs but is more often dose dependent, resulting from high-dose treatment or accumulation of a drug in a patient who is typically either dehydrated or has pre-existing impairment of renal function. Potentiation of the renal damage occurs with the coadministration of two or more nephrotoxic agents. Examples of drugs causing direct tubular damage are listed in Table 3 The immunosuppressant drugs ciclosporin and tacrolimus, in addition to their effects on intra-renal haemodynamics, also have a direct tubular toxic effect. Ciclosporin nephrotoxicity is potentiated by aminoglycosides, vancomycin, ciprofloxacin and NSAIDs. An unusual form of renal failure characterized by swollen, vacuolated proximal tubular cells can develop from hyperosmolar substances, such as intravenous immunoglobulin, mannitol and the plasma expander, hydroxyethyl starch. Radiological contrast media (CM) act on distinct anatomic sites within the kidney and exert adverse effects via multiple
C
Aciclovir Aminoglycosides Amphotericin Cefalosporins Cisplatin Contrast media
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both TIN and a glomerulopathy. Early manifestations of cadmium nephropathy are those of tubular dysfunction, including low-molecular-weight tubular proteinuria, aminoaciduria and glucosuria. A doseeresponse relationship is observed with more severe kidney damage resulting from prolonged and high-level exposure. This has been confirmed in studies of occupationally exposed workers. An excess risk of kidney stones, possibly related to an increased excretion of calcium in urine following the tubular damage, has been shown in several studies. Treatment requires elimination of cadmium exposure; chelation with Na calcium edetate (EDTA) may increase cadmium nephrotoxicity. Tubular proteinuria is usually irreversible. Mercury: Mercury-containing compounds bind to sulfhydryl groups of proteins and can therefore interfere with structural proteins, enzymes and transport processes. Extensive proximal tubular necrosis is seen with cast formation in the distal nephron. Exposure to mercuric chloride leads to calcification of the kidney, which tends to increase with increasing doses. Other heavy metals that are nephrotoxic include copper, gold, uranium, arsenic, iron, bismuth and chromium. All cause tubular damage and dysfunction (e.g. tubular proteinuria, aminoaciduria) as well as tubular necrosis, but glomerulopathies may predominate with some compounds (mercury, gold). Treatment involves removal of the patient from further exposure and either or both of the following: chelating agents (copper, arsenic, bismuth) dialysis (chromium, arsenic, bismuth) is often used when chelation fails or simultaneously with chelation for severe arsenic poisoning.
intravenous sodium chloride 0.9%, sodium bicarbonate and acetylcysteine have been shown to be beneficial in reducing the risk of developing CIN, although the literature is inconclusive on which is most effective. Gadolinium Nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy is a rare and serious syndrome that involves fibrosis of skin, joints, eyes and internal organs. Patients develop large areas of hardened skin with fibrotic nodules and plaques. NSF may also cause joint contractures resulting in joint pain and a restricted range of movement. In its most severe form, NSF may cause severe systemic fibrosis affecting internal organs including the lungs, heart and liver, and resembles systemic sclerosis. The first cases were identified in 1997 and its cause is not fully understood. However, evidence suggests that NSF is associated with exposure to gadolinium (principally in the form of contrast agents used for magnetic resonance imaging) in patients with CKD.12 As a result, gadolinium-containing contrast is now considered contraindicated in patients with an eGFR less than 60 ml/minute and especially if it is less than 30 ml/minute. Distal tubular damage Fluorinated anaesthetic agents have been reported to cause acute distal tubular damage, especially in obese patients, resulting in polyuria and hypernatraemia. Lithium salts can cause nephrogenic diabetes insipidus, resulting in the production of a large volume of dilute urine regardless of volume status. This may lead to hypernatraemia, and is unresponsive to vasopressin and aldosterone. The polyuria and dehydration with renal damage leads to increased plasma lithium concentration, thus exacerbating the effect. Both acute and chronic renal failure can occur, with scarring of the renal interstitium. Inappropriate secretion of antidiuretic hormone (ADH), the hormone responsible for controlling the rate at which kidneys excrete or retain free water, can result in hyponatraemia and water intoxication. Of the drugs associated with inappropriate ADH secretion, the most important are carbamazepine, vincristine and cyclophosphamide.
Solvents It has been shown that all solvent exposure is associated with the progression of primary glomerulonephritis to end-stage renal disease (ESRD), but little is known about the type of solvents that are high risk. A study in France looking at patients with biopsyproven primary glomerulonephritis showed that the highest risk of progression to ESRD was seen in exposed machinery fitters, machine assemblers and plumbers/welders, as well as those who had ever handled printing inks and petroleum products. Among solvents, the highest risks were found for toluene/xylene, gasoline, fuel and gas-oil, and ketones.15 Other studies have reinforced this finding, with organic solvent exposure being associated with progression of IgAN and FSGS.16
Effect of environmental chemicals on renal function Heavy metals Heavy metals (e.g. lead, cadmium, copper) and other toxins can cause a form of chronic TIN.13,14 Lead: Chronic TIN results as lead accumulates in proximal tubular cells. Short-term lead exposure causes proximal tubular dysfunction, including decreased urate secretion and hyperuricemia, aminoaciduria, and renal glucosuria. Chronic lead exposure (for 5 to 30 years) causes progressive tubular atrophy and interstitial fibrosis, with renal insufficiency, hypertension, gout and Fanconi’s syndrome. However, chronic low-level exposure may cause renal insufficiency and hypertension independent of TIN. Hyperuricaemia disproportionate to the degree of renal insufficiency and a bland urinary sediment are common. Treatment with chelation therapy can stabilize renal function, but recovery may be incomplete. Cadmium: Cadmium exposure following workplace exposure or as a result of contaminated water, food and tobacco can cause
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Herbal remedies Aristolochic acid nephropathy (AAN), a progressive renal interstitial fibrosis frequently associated with urothelial malignancies, was initially reported in a Belgian cohort of more than 100 patients after the intake of slimming pills containing a Chinese herb, Aristolochia fangchi.17 Although botanicals known or suspected to contain aristolochic acid (AA) are banned in many countries, cases of AAN continue to be regularly observed worldwide. The incidence of AAN is probably much higher than initially thought, especially in Asia and the Balkans. In Asian countries, where traditional medicines remain very popular, there is a high risk of AAN because of the frequent substitution of the botanical products of AA-containing herbs. In the Balkans, exposure to AA in flour obtained from wheat contaminated with seeds of Aristolochia clematitis could be responsible for so-called
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8 Huerta C, Castellsague J, Varas-Lorenzo C, Garcı´a Rodrı´guez LA. Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population. Am J Kidney Dis 2005; 45: 531. 9 Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343: 1520e8. for the VIGOR Study Group. 10 Jo SH, Youn TJ, Koo BK, et al. Renal toxicity evaluation and comparison between visipaque (iodixanol) and hexabrix (ioxaglate) in patients with renal insufficiency undergoing coronary angiography: the RECOVER study: a randomized controlled trial48: 924e30. J Am Coll Cardiol. 11 Maioli M, Toso A, Leoncini M, Gallopin M, Musilli N, Bellandi F. Persistent renal damage after contrast-induced acute kidney injury: incidence, evolution, risk factors, and prognosis. Circulation 2012; 125: 3099e107. 12 Thomsen HS. Nephrogenic systemic fibrosis: history and epidemiology. Radiol Clin North Am 2009; 47: 827e31. 13 Jarup L. Hazards of heavy metal contamination. Br Med Bull 2003; 68: 167e82. 14 O1 Barbier, Jacquillet G, Tauc M, Cougnon M, Poujeol P. Effect of heavy metals on, and handling by, the kidney. Nephron Physiol 2005; 99: p105e110. 15 Jacob S, Hery M, Protois JC, Rossert J, Stengel B. New insight into solvent-related end-stage renal disease: occupations, products and types of solvents at risk. Occup Environ Med 2007; 64: 843e8. 16 Jacob S, Hery M. Jean-claude Protois J-C, Jerome Rossert J, Stengel B. Effect of organic solvent exposure on chronic kidney disease progression: the GN-PROGRESS cohort study. J Am Soc Nephrol 2007; 18: 274e81. 17 Debelle FD, Vanherweghem JL, Nortier JL. Aristolochic acid nephropathy: a worldwide problem. Kidney Int 2008; 74: 158e69. 18 Gabardi S, Munz K, Ulbricht C. A review of dietary supplement einduced renal dysfunction. Clin J Am Soc Nephrol 2007; 2: 757e65.
Herbal compounds associated with renal toxicity Potential mechanism
CAM scientific name (common name)
COX inhibition (altered renal hemodynamics)
Curcuma longa (turmeric) Filipendula ulmaria (meadowsweet) Tanacetum parthenium (feverfew) Zingiber officinale (ginger) Boswellia serrata (frankincense) Camelia sinensis (green tea) Aesculus hippocastanum (horse chestnut) Rheum officinale (rhubarb) Rumex acetosa (sorrel) Rumex crispus (yellow dock) Cannabis sativa (marijuana) Colchicum autumnale (autumn crocus) Commiphora mukul (guggul) Coutarea latiflora (copalchi) Monascus purpureus (red yeast)
Nephrolithiasis
Rhabdomyolysis
Adapted from Gabardi S, Munz K, Ulbricht C. A Review of Dietary Supplement eInduced Renal Dysfunction. Clin J Am Soc Nephrol 2007; 2(4): 757e65
Table 4
Balkan endemic nephropathy. Finally, despite the Food and Drug Administration’s warnings concerning the safety of botanical remedies containing AA, these herbs continue to be sold via the Internet. In addition to aristolochic acid, a number of over-the-counter herbal remedies and dietary supplements have been associated with the development of renal dysfunction. These are detailed in Table 4.18 A
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FURTHER READING Aronson JK. Prescribing in renal insufficiency: principles and practice. In: Jamison RL, Wilkinson R, eds. Nephrology. London: Chapman& Hall, 1997 [Chapter 69]. Broe ME. Drug induced nephropathies. Oxford textbook of clinical nephrology. 3rd edn. Oxford Medical Publications, 2005; 2581e99. Kappel J, Calissi P. Nephrology: 3. Safe drug prescribing for patients with renal insufficiency. Can Med Assoc J 2002; 166: 473e7. Kidney Disease. Improving global outcomes (KDIGO) acute kidney injury Work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Inter Suppl 2012; 2: 1e138. Kidney Disease. Improving global outcomes (KDIGO) clinical practice guidelines for evaluation and management of chronic kidney disease. Kidney Inter Suppl 2013; 3: 1e150. Lee Anne, ed. Adverse Drug Reactions. Second edn. Pharmaceutical Press, 2009. Meyler’s Side Effects of Drugs. The international encyclopedia of adverse drug reactions and interactions. 15th edition, volume 1e6. Oxford: JK Aronson. Published by Elsevier, 2006. Pearson J. Drug-induced kidney disease. Introduction to Renal Therapeutics. In: Ashley C, Morlidge C, eds. London: Pharmaceutical Press, 2008. Renal Pharmacotherapy. Dosage adjustment of medications eliminated by the kidneys golightly LK. In: Teitelbaum I, Kiser T, eds. New York: Springer Publishing Co, 2013.
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Please cite this article in press as: Ashley C, Nephrotoxins and drugs in renal insufficiency, Medicine (2015), http://dx.doi.org/10.1016/ j.mpmed.2015.04.010