CHAPTER 18.1 Handling of drugs in kidney disease 691 Table 18.1.1 Mechanisms of altered pharmacokinetics in renal disease Pharmacokinetic phase Pharmacokinetic change Examples ferrous sulfate, folic acid aspirin, ferrous sulfate, cipro \202 oxacin Raised stomach pH can reduce absorption of some drugs. Phosphate-binding agents such as alu minum hydroxide may Absorption interfere with the absorption of other drug. Other factors in \202 uencing absorption: \200 prolonged gastric emptying \200 gut edema \200 nausea. reduced activity of intestinal drug transporters Protein concentration or protein binding reduced (more unbound (active) drug). warfarin, diazepam, phenytoin Distribution Fluid volume expansion (increased volume of distribution of water-soluble drugs). atenolol Tissue binding reduced (decreased volume of distribution). digoxin Reduced proportion of body fat (decreased volume of distribution of fat-soluble drugs). Reduced liver metabolism for many drugs due to: impaired transportation into hepatocytes im paired liver metabolic pathways. aciclovir, cimetidine, metoclopramide, codeine, imipenem Metabolism \200 Reduced renal metabolism. insulin Reduced GFR leading to the retention of: Renal excretion unaltered drug \200 active metabolites. digoxin, gentamicin, morphine-6-glucuronide Renal blood \202 ow Renal blood \202 ow can become an important independent in \202 ue nce on drug excretion when GFR has declined sig- ni \201 cantly. In these circumstances, d rug clearance may be adversely affected by hypovolemia or other drugs that impact on perfus ion, e.g. NSAIDs (impair cortical blood \202 ow by inter- fering with prostaglandin synth esis). All aspects of renal elimination including glomerular \201 ltration, reabsorption and sec retion are altered in renal failure. Nonpolar drugs easily diffuse across membranes while p olar ones do not. As the urine is progressively concentrated during its passage through the renal tubule, nonpolar drugs tend to be reabsorbed passively down their concentration grad ient while polar drugs or the polar derivatives of nonpolar drugs produced in the liver are not. Some polar drugs are actively excreted by the same mech- anisms as organic acids and bases: \200 Assessing renal function before prescribing The most important measure of renal function th at might in \202 uence prescribing is the GFR. Serum creatinine has been a widely used sur rogate of renal function but is dependent not only on GFR but also on creatinine production and may signi \201 cantly overestimate GFR in some groups (e.g. the elderly, those with l ow body mass). Estimation of GFR from single creatinine measurements can be made by adjustm ent for body weight, age and gender using mathematical formulas (e.g. the Cockcroft \200 \223Gault formula). The modi \201 ed MDRD formula is now commonly used to calculate \200 \230eGFR \200\231. The advantage is that it requires only the serum creatinine, age and gen der (not height or weight). However, when using eGFR to make assessments of renal function that may in \202 uence decisions about thera- peutic dose, there are important caveats: \200 organic acids (e.g. penicillins, cephalosporins, salicylates, furosemide and thiazides); or ganic bases (e.g. amiloride, procainamide and quinidine). Some drugs interfere with the excretion of others: \200 \200 \200 probenecid with penicillins; cephalosporins and furosemide; aspirin and paracetamol reduce the excretion of meth- otrexate. A low protein diet reduces the acidity of the urine which may alter the ionization of drugs . There is some evidence that \201 ltration and secretion of drugs may fall in parallel a nd in proportion to the GFR. Some drugs are eliminated unchanged by the kidneys and are par ticularly vulnerable to accumulation in renal disorders. More commonly drugs are cleared by transformation into more water-soluble metabolites that can be eliminated in the urine. Fo r most drugs the development of renal failure has a modest impact but, in some cases, the m etabolite retains much of the activity of the parent drug and has the potential to cause ad verse effects. the eGFR is increasingly unreliable at the extremes of body weight and might lead to overdo sing of small patients and underdosing of large patients; rises in serum creatinine (and he nce reductions in eGFR) may lag behind the actual deterioration of GFR in AKI which is espe cially important in the intensive care setting; it is not valid in pregnant women or in chi ldren. S. MAXWELL 692 Concentration \200\223time relationship Most drugs eliminated by the kidneys exhibit \201 rst-order kinetics, i.e. the rate of removal is proportionate to the drug concentration. U nder these circumstances a plot of concentration (C) versus time (t) displays an exponentia l decline (Fig. 18.1.1a) described by the equation Most drugs are given repeatedly at regular intervals and their concentration increases to r each a steady state (after \210 5 \227 t ) when the rate of intake matches the rate of e xcretion (Fig. 18.1.1b). Increases in the dose or frequency will result in a new, higher, s teady state concen- tration pro \201 le producing the required elimination rate. If renal function is impaired the clearance rate is reduced at any given concentration and the drug t is increased. If the dose and frequency remain the same, a higher steady state concentr ation (and hence drug exposure) will be required to produce the necessary elimination (Fig. 18.1.1b). The increased steady state plasma concentration and drug exposure can be avoided by either a reduction in the drug dose or frequency (dose interval). It should be noted th at these two strategies are not equivalent. C(t) = C0 e \200\223kt where C0 is the concentration at time zero and k is the elimination rate constant. Drugs that exhibit such kinetics can be described by their half-life (t ), the time taken for the concentration to halve (after absorption and distribution are comple te). This has a major in \202 uence on the best dosing interval, the time required to achi eve \200\230steady state \200\231 and the persistence of the drug effect after treatment i s stopped (all are proportional to t ). A constant fraction of drug is cleared in unit time \210\222kt C(t)= C0e C = drug concentration k = rate constant for elimination ) L / g m ( n o i t a r t n e c n o c t = 16 h Renal failure t = 8 h g u r D Normal 6 12 Time (h) 18 24 (a) Plasma drug concentration Repeat dosing Renal failure 97% Trough level 94% 87.5% 75% Normal 50% 1 2 Time (days) 3 (b) Fig. 18.1.1 Dose \200\223response curves following (a) single dose administration or (b) re peated dosing in the presence and absence of renal impairment. Note the effect of reduced r enal clearance on the half-life, time to steady state, and the steady state plasma concentr ation. CHAPTER 18.1 Handling of drugs in kidney disease 693 Dose reductions result in lower peak concentrations but maintained trough levels, which is ideal if a constant exposure is required. Increased dose intervals preserve peak concentrat ions but allow lower trough levels to be reached. The former strategy may be more suited to antihypertensive drugs while the latter is more suitable for aminoglycoside antibiotics wh ere high peak concentration is required for bactericidal activity with low troughs to help avoid toxicity. Single or \200\230loading \200\231 doses do not usually need to be altered in renal failure, even if the drug has a narrow therapeutic index. This is because, althou gh drug exposure time may be increased, accumulation to high concentration will not occur. The dose should take into account the diminished intrinsic renal function. Therapeutic drug monitoring Therapeutic drug monitoring describes the process of monitoring drug concentration or drug effect to tailor the drug regimen for individual patients (rath er than relying on dosing considered appropriate for the average patient). Monitoring is pa rticularly important for drugs with a nar- row therapeutic window (where there is a high ri sk of adverse effects) or in circumstances where pharmacoki- netics are disturbed (notably renal impairment). Drug concentrations are only helpful if there is an estab- lished relati onship between concentration and adverse or bene \201 cial effects. Plasma concentration s hould normally be interpreted once steady state has been reached (e.g. digoxin). However, p eak and trough levels after the \201 rst dose are important for some drugs (e.g. aminogly cosides). The timing of the peak is uncertain after oral dosing but measurement should be m ade 30 min after an IV dose. Clearance of drugs in hemodialysis and peritoneal dialysis Patients on dialysis will normal ly have a creatinine clear- ance/GFR of <10 mL/min. Some drugs are actively removed from th e circulation dur- ing dialysis, and this needs to be considered when deciding on the timin g of administration as well as the dosage. No form of dialysis is as effective as the norma l kidney and the doses required will never be larger than those recom- mended in normal ren al function. Clearance by hemodialysis (HD) and hemo \201 ltration (HF) follows \201 rst order kinetics. Factors in \202 uencing clearance include: \200 Notes on speci \201 c drugs When a drug with signi \201 cant renal excretion is prescribe d in renal impairment the dosing regimen can be adjusted in three ways: \200 \200 \200 dose reduction; extending the dose interval; a combination of both. properties of the drug (e.g. molecular weight, protein binding and volume of distribution); delivery of drug to the \201 lter (dependent on the blood \202 ow through the \201 l ter); \201 lter properties (e.g. pore size, surface area and duration of use). For drugs with a narrow therapeutic index or serious adverse effects, monitoring plasma dru g concentrations will be an important guide. It should be noted that steady state concentra tion will only be reached after 5 \227 t and these may be longer in the presence of rena l impairment. Dose adjustment is normally only required when the cre- atinine clearance is <60 mL/min. People who have been taking a drug for many years may need a dose adjustment as they age. Some basic guiding principles are set out in Table 18.1.2. HD drug clearance is based on diffusion down a concentration gradient from plasma to dialys ate while hemo \201 ltration clearance relies on convection only. In the case of low molec ular weight drugs, HD provides more ef \201 cient clearance. With a pore size of only 0.00 1 m, HD membranes will only clear molecules smaller than 500 Da. Hemo \201 lters have po re sizes of 0.01 m and may clear mol- ecules up to 5000 Da. Peritoneal dialysis clears dr ugs much less ef \201 ciently than either HD or HF. Although most antimicrobials are effec tively cleared by HD, some important molecules such as vancomycin (1800 Da), amphotericin ( 960 Da) and erythromycin (734 Da) are retained. Heavily protein-bound drugs such as propran olol (259 Da) are not successfully \201 ltered even though they have a low molecular mass . Water-soluble drugs pass through \201 lters more readily than those that are lipid solu ble. Drugs with large volumes of distribution tend to have low plasma concentrations and so are less readily available for \201 ltration (e.g. digoxin and antidepressants). HD is n ormally performed for short periods every two or three days. Drugs that are cleared by HD a re usually given after the session to avoid early postdose clearance. Antimicrobials Many antimicrobial drugs depend on renal excretion. Most have a wide therape utic index and dose reductions are only required when GFR is <20 mL/min but gentamicin and vancomycin are notable exceptions. Cephalosporins require dose reductions in more severe re nal impairment. Cefotaxime, cephalexin and cephradrin can be used in normal doses until GFR is <10 mL/min but ceftazidime requires earlier dose reductions. Cephalosporins should be u sed cautiously when combined with loop diuretics. Penicillins (e.g. amoxycillin, benzylpeni cillin, co-amoxiclav), cefotaxime, ceftazidime, ciprofloxacin, clarythromycin, meropenem, m etronidazole and trimethoprim are cleared by HD and should be given after the session. B-La ctam accumulation signi \201 cantly increases the risk of seizures when high doses are use d in patients with renal impairment. Aminoglycosides have the potential to cause severe nep h- rotoxocity and irreversible ototoxicity if they accumulate. Dose adjustment is required, even in mild renal failure. S. MAXWELL 694 (measured at 2 h) should be 20 \200\22330 mg/L while the trough should be <10 mg/L. Neither gentamicin or vancomycin is effectively cleared by dialysis and doses are often days apart . Teicoplanin is a glycopeptide related to vancomycin but with an increased half-life. Anti microbials that do not require dose adjustment include macrolides, metronidazole, cloxacill in and clindamycin. Table 18.1.2 Issues for prescribers to consider in relation to renal impairment Clinical issue Comment Age Renal excretion of drugs is age dependent. Weight Drug dose may be calculated in mg/kg. Renal function May be assessed by measured creatinine clearance or estimated, e.g. eGFR. Antivirals Many antivirals, including those used for treating herpes simplex, herpes zoster and cytomegalovirus infections (e.g. aciclovir, famciclovir, valganciclovir and ganciclovi r), depend on renal clearance and tend to accumulate. Even normal doses may precipitate neu rological signs such as dizziness, confusion, hallucinations, somnolence and convulsions, a s well as (more rarely) tremor, ataxia, dysarthria, seizures and encephalopathy. These effe cts are dose-related and reversible, and more elderly patients and those taking other neuro toxic drugs are most at risk. Lower doses are necessary when the GFR is <50 mL/min. The dos e of lamivudine should be reduced in mild renal impairment. Acute or chronic renal impairment Estimated renal function may be misleading if there are rapid changes. Timing of drug clearance by dialysis needs to be taken into account Is the patient being dialysed? If so, how? Clearance varies with mode of dialysis. Indication for the drug Is the drug justi \201 ed in the face of increased hazards? Always consider the risk \200\223bene \201 t balance. Some drugs cause serious adverse effects in patients with renal failure, e.g. sedation with morphine, lactic acidosis with metformin. Others rarely cause harm even with dose accumulation. Use nephrotoxic drugs with caution in lowest possible doses. Analgesics NSAIDs should generally be avoided in signi \201 cant renal impairment, though in mild/moderate CKD they can be used after discussion and with monitoring if alternatives are much less effective. Avoidance is not essential for dialysis patients although the risk of upper GI bleeding is increased. The effects of opioid analgesics are often prolonged in renal failure because of the tendency of the parent drug and some active metabolites to ac cumulate. Morphine and diamorphine are metabolized to morphine- 3-glucuronide (M-3-G), morp hine-6-glucuronide (M-6-G) and normorphine. M-6-G is a potent analgesic and CNS depressant and, like morphine, accumulates in renal impairment. Fentanyl is metabolized to inactive an d nontoxic metabo- lites and may be a safer alternative. All strong opioids should be used cautiously, with dose reduction and increased dosing interval. Comorbidities These may also in \202 uence selection and dose, e.g. hepatic failure. Other drugs The drug effects may be additive, e.g. the patient may be taking several nephrotoxic or sed ative drugs. Active metabolites Are there known metabolites that may have adverse effects? Restrictions on \202 uid or sodium intake These may in \202 uence drug selection. How much data is available? In many instances there may not be \201 rm evidence to guide drug or dose selection and p rescribing should be based on understanding of the principles involved. Several factors increase the risk, including: \200 \200 \200 \200 \200 \200 prolonged treatment; dehydration; combination with diuretics; hypokalemia; hypomagnesemia; obstructive jaundice. Gastrointestinal system Aluminum or bismuth-containing compounds should be avoided in renal impairment because of the potential for accumulation and neurotoxicity. Cimetidine should be avoided in favor of ranitidine or other H2-blockers. Proton pump inhibitors do not requi re dose reductions. Dose adjustment is aimed at continuing to achieve bacteri- cidal plasma levels but allowing subsequent clearance to reach a low trough level. This is monitored by measuring the peak plasma concentration (1 h post injection) and the trough (immediately before subsequent dos e). For gentamicin an adequate loading dose (1 \200\2231.5 mg/kg) is essential and the peak should be 8 \200\22312 mg/L while the trough should be <2 mg/L. Gentamicin is now com- mon ly administered as a single daily dose of 5 mg/kg followed by a trough level at 24 h that c an be used to predict the subsequent doses. Continued monitoring is necessary. Vancomycin i s widely used for staphylococcal infec- tions including PD peritonitis and line sepsis. The peak Anticoagulants Patients with renal impairment already exhibit some degree of bleeding tende ncy and the decision to use anti- coagulants should take this into account. Low molecular w eight heparins are renally excreted and their action is unpredictably prolonged, which may be haz- ardous when combined with a uremic bleeding tendency. They should not be used above prophylactic doses and the use of unfractionated heparin is still recommended for full ant icoagulation. CHAPTER 18.1 Handling of drugs in kidney disease 695 A bolus of IV heparin (5000 U) is typically followed by an IV infusion at 1250 U/h. Anticoa gulation should be regularly checked by aPTT ratio, the normal therapeutic range being 1.5 \200\2232.5. Warfarin is metabolized in the liver and the anticoagulant effect depends only to a minor extent on renal function. No dose adjustment is necessary for patients with ren al failure. Anticonvulsants Phenytoin protein binding is reduced and its volume of distribution is sign i \201 cantly increased in renal failure. The proportion of the reported total plasma conc entra- tion that is unbound, and therefore active, is likely to be increased. For this reas on a low plasma level may not necessarily be subtherapeutic. Cardiovascular drugs ACEIs and ARBs reduce proteinuria and improve outcome in many patients with renal disease but need to be used with care because of the risks of hyperkalemia and renal function decline. Those at greatest risk are: \200 \200 Allopurinol Allopurinol and its active principal metabolite, oxypurinol, are mainly excrete d in the urine. The dose should be reduced in patients with poor renal function to avoid ac cumulation. Treatment is normally initiated at a dose of 100 mg/day and increased only if t he serum or urinary urate is not satisfac- torily controlled. The frequency of hypersensiti vity reactions (fever, chills, leukopenia, eosinophilia, arthralgia, and rash) is probably increased in patients with renal impairment, and in those who are concomitantly taking allo purinol and a thiazide diuretic. Caution is advised when using this combination in renal im pairment. The dose of colchicine should be halved for patients with GFR <10 mL/min. the elderly; those taking other high risk drugs (NSAIDs, spironolactone, loop diuretics); p atients with diabetes (increased risk of renal artery stenosis). A check of renal function is required after 3 \200\2234 days and again 7 \200\22310 days fo llowing introduction, dose titration or introduction of another interacting drug. A small r ise in creatinine is normal but a rise in creatinine of 20 \200\22330% should be regarded a s signi \201 cant. Calcium channel blockers, nitrates, amiodarone and A-blockers do not no rmally require dose adjustments. Statins and \201 bric acid derivatives are more likely t o cause myopathy in patients with renal failure and their doses should be reduced. Hypoglycemic drugs Metformin is occasionally associated with fatal lactic acido- sis when i t accumulates and the risk is increased when clearance is reduced by renal impairment. Naus ea is a common dose-related adverse effect that is more frequent in renal impairment. Metfo rmin should ideally be avoided in patients with a cre- atinine clearance of <30 mL/min and should be used with caution, at a reduced maximum daily dose of 1 g, in patients with a cre atinine clearance of 30 \200\22360 mL/min. For those patients with a creatinine clearance o f 60 \200\22390 mL/min, the recommended maximum daily dose is 2 g. Metformin should also be withdrawn in patients undergo- ing surgery, suffering from dehydration, trauma or serious infections, or undergoing procedures likely to affect renal function (for example, contrast studies). Sulfonylureas with more prolonged effects (e.g. glibencla- mide and glimepiride) are known to increase the risk of hypoglycemia and this risk is even greater in patients w ith renal impairment. Gliclazide or glipizide have a shorter action and are a safer choice but should be introduced cautiously. Insulin depends on renal clearance for up to half of i ts elimination. Dose requirements are often reduced and may reduce further if renal failure progresses. Diabetic neph- ropathy is often accompanied by unrecognized gastropare- sis wh ich delays food absorption, increasing the likelihood of insulin-induced hypoglycemia. Diuretics Potassium-sparing diuretics such as spironolactone, amilo- ride and triamterene o r potassium supplements are more likely to cause signi \201 cant hyperkalemia in patients with renal failure and should be avoided unless there is continu- ing hypokalemia. Further factors that may contribute to the risk of hyper- kalemia in patients with renal impairment are age, higher doses, diabetes mellitus, and concomitant use of NSAIDs. Frequent monitori ng of serum potassium, creatinine and urea is essential, especially when starting spironola ctone for heart failure. Most diuretics are organic acids and have to compete with retained metabolites to reach their active site in the tubular lumen. Consequently higher doses are normally required. Thiazide diuretics are ineffective in advanced renal impairment when hi gher doses of loop diuretics are required. Diuretics should be carefully monitored since ex cessive volume contraction might further reduce GFR. Digoxin Digoxin is excreted by the kidneys and accumulates even in mild degrees of renal im pairment necessitating reduced dose. Digitoxin has been proposed as an alternative cardiac glycoside because it is cleared by the liver but its longer half-life increases the risk of toxicity. Monitoring of digoxin levels helps to guide maintenance treatment. Psychoactive drugs Benzodiazepines are metabolized in the liver but a number of active pola r metabolites depend on renal clearance and have the potential to cause prolonged sedation. Chronic use should be avoided. Lithium carbonate is excreted by the kidney and careful dos e reduction and monitoring of plasma levels are required. S. MAXWELL 696 Antipsychotic drugs should be introduced cautiously at low dose. Tricyclic antidepressants are more likely to produce sedation and anticholinergic effects. The doses of selective- se rotonin reuptake inhibitors should also be reduced. Faull R. Prescribing in renal disease. Aust Prescriber 2007; 30: 17 \200\22320. Kappel J, C alissi P. Safe drug prescribing for patients with renal insuf \201 ciency. Can Med Assoc J 2002; 166: 474 \200\223477. Lam FYW, Banerji S, Hat \201 eld C, Talbert RL. Principles of drug administration in renal insuf \201 ciency. Clin Pharmacokinet 1997: 32: 30 \200\22357. Other drugs The following drugs require dose reductions even in mild renal impairment (crea tinine clearance 20 \200\22350 mL/min): \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Matzke GR, Frye RF. Drug administration in patients with renal insuf \201 ciency: minimizi ng renal and extrarenal toxicity. Drug Safety 1997: 16: 205 \200\223231. baclofen \200 capecitabine \200 chloroquine \200 duanorubicin \200 ethambutol \200 \202 uconazole \200 gabapentin \200 levetiracetam \200 moxonidine \200 pentamid ine \200 proguanil \200 terbina \201 ne atenolol buspirone carboplatin cimetidine disopyramide \202 ecainide \202 udarabine ima tinib methotrexate penicillamine procainamide rizatriptan tretinoin. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function \200\223 measured and estimated glomerular \201 ltration rate. N Engl J Med 2006; 354: 2473 \200\2232483. Internet resources Nephrology Drugstore Associates: http://www.nephrologypharmacy.com/index.html GlobalRPh.com. Guidelines for prescribing drug s in adults with impaired renal function: http://www.globalrph.com/renaldosing2.htm Joint Formulary Committee. British national formu lary. 53rd ed. London: British Medical Association and Royal Pharmaceutical Society of Grea t Britain, 2007: The following drugs are best avoided: \200 \200 \200 \200 \200 \200 http://www.bnf.org/bnf/ UK Medicines Information. Specialist Services. Drugs in renal failu re: acamprosate acetazolamide acitretin alendronate amphotericin cisplatin. http://www.ukmi.nhs.uk/activities/ specialistServices/default.asp?pageRef=5 South West Medi cines Information Center (UK). Drugs in renal failure: Further reading Ashley C, Currie A (eds), The Renal Drug Handbook, 2nd edn. http://www.swmit.nhs.uk/renal.htm University of Pennsylvania Medical Center Guidelines for Antibiotic Use: Oxford: Radcliffe Medical Press; 2004. Bakris GL, Talbert R. Drug dosing in patients with renal insuf \201 ciency. http://www.uphs.upenn.edu/bugdrug/antibiotic_ manual/renal.htm Royal In \201 rmary of Edin burgh Renal Unit: Postgrad Med 1993; 94: 153 \200\223164. Brier ME, Aronoff GR (eds), Drug prescribing in renal failure: dosing guidelines for adults and children, 5th edn. Philadelphia: American College of Physicians; 2007. http://renux.dmed.ed.ac.uk/edren/index.html Davies JG, Kingswood JC, Sharpstone P, Street MK. Drug removal in continuous haemofiltratio n and haemodialysis. Br J Hosp Med1995; 54: 524 \200\223528. See also Drug-induced nephropathies, p. 698 Clinical use of diuretics, p. 703 DeBellis RJ, Smith BS, Cawley PA, Burniske GM. Drug dosing in critically ill patients with renal failure: a pharmacokinetic approach. J Intensive Care Med 2000; 15: 273 \200\223313. Elliott R (ed.), Critical care therapeutics. London: Pharmaceutical Press; 1999. This page intentionally left blank J. NORTIER, F. DEBELLE AND J.-L. VANHERWEGHEM 698 Drug-induced nephropathies \200 Introduction The kidneys are particularly vulnerable to drug-related toxicity: They are the principal organ of excretion for many drugs or their water-soluble metabolites. High renal blood \202 ow (25% of cardiac output) results in a high rate of drug delivery to the kid neys. Some drugs are present in the tubular \202 uid at very high concentration (1000 tim es the plasma concentration). Drug concentrations in the medullary interstitium are several times higher than in other tissues. The thick ascending limb of Henle is highly sensitive to oxygen deprivation and/or decreased renal blood \202 ow due to the local low partial p ressure of oxygen. General symptoms (40%): fever, cutaneous rash, arthralgia. Eosinophilia (40%). The sensitivity and speci \201 city of noninvasive procedures (eosinophiluria and gallium scanning) is poor, so the diag- nosis can only be con \201 rmed by renal biopsy. Typical r enal biopsy \201 ndings are interstitial edema and in \201 l- tration by T-cells, monocy tes \200\223macrophages, plasma cells and eosinophils. Sometimes, in \201 ltrating cells f orm non- necrotic granulomas with few giant cells (granulomatous interstitial nephritis). N ormal renal function is not always restored after AIN: CKD can be observed in 40% of these patients. Treatment of drug-related AIN remains a matter of debate. The most important meas ure is the removal of the culprit drug. There is no evidence for the use of prolonged treat - ment with steroids. However, if there is no spontaneous recovery after 15 days, a brief c ourse of pulse methylpred- nisolone (60 mg/day for 3 days) seems to quicken recovery. Drug-induced renal syndromes A variety of renal syndromes may be attributable to drug admin istration (Table 18.2.1). Given the diversity of drug- related renal syndromes clinicians s hould always conduct a comprehensive inquiry into all drugs taken by the patient, used or m isused, prescribed or obtained over-the-counter, regular or alternative. Chronic kidney disease CKD occurs secondary to chronic interstitial nephritis and may be a consequence of prolonged use of some drugs (calcineurin inhibitors, lithium) or of the misu se of others (analgesics, herbal medicine containing aristolochic acids). \200\230False \200\231 renal failure Seen with drugs inhibiting tubular Cr secretion such as cimetidine and trimethoprim. Urinary tract syndromes These include urinary retention (atropine), papillary necro- sis (a nalgesics), stones formed by the drug itself (ephe- drine, methotrexate, indinavir) or by t he uricosuric properties of the drug (some NSAIDs), oxalate (vitamin C, cranberry juice) or xanthine (allopurinol). Nephrotic syndrome Nonsteroidal anti-in \202 ammatory drugs (NSAIDs) can cause minimal cha nge disease, focal glomerulosclerosis, membra- nous nephropathy. Gold therapy or penicillam ine for rheu- matoid arthritis can cause membranous nephropathy. Renal tract tumors Some drugs are carcinogenic and may be responsible for urothelial carcin oma (analgesics, herbal medicine contain- ing aristolochic acids). Tubulopathies A variety of drugs may be associated with the development of tubular injury ( Table 18.2.2). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) F unctional acute kidney injury An intact renin \200\223angiotensin system (RAS) is required for maintenance of GFR when renal perfusion pressure decreases. An acute and pronounced fal l in GFR may be seen after blocking the RAS with ACEI or ARB, speci \201 cally in patients with: \200 \200 Acute kidney injury Drugs are an important etiologic factor for hospital- acquired AKI. AKI may be due to prerenal reduction in renal blood supply, to direct acute tubular toxicity a nd tubular necrosis as well as to immunoallergic acute interstitial nephritis. 18 \200\2233 3% of in-hospital AKI may be attributed to drugs. The most frequently involved drugs are an tibiotics, analgesics, NSAIDs, angiotensin-converting enzyme inhibitors (ACEIs) and contras t media. Risk factors for drug-related AKI include congestive heart failure, severe liver d isease, pre-existing renal failure, elderly population and dehydration. In 20% of AKI, som e degree of renal impairment persists, especially in cases of NSAID-induced acute interstit ial nephritis. bilateral renal artery stenosis; renal artery stenosis in a solitary kidney (e.g. renal all ograft); congestive heart failure; advanced CKD. \200 In any of these settings a fall in GFR is made more likely with volume depletion (e.g. diur etic therapy). Prophylactic measures For patients at risk, different measures are required: \200 \200 \200 \200 \200 Acute interstitial nephritis (AIN) All drugs can cause AIN. The mechanism is immune-mediate d. AIN occurs in only a small percentage of individuals receiving the drug and is independe nt of the dosage. Drugs commonly associated with AIN are listed in Table 18.2.3. Clinical p resentation \200 \200 \200 use of a short-acting drug; adaptation of dose to the renal function; start drug at a low d ose with gradual titration; correction of volume depletion; temporary withdrawal of diureti cs. Renal failure (100%). Dialysis-dependent renal failure (40%). Hematuria (50%), proteinuria (60%). Combination with NSAIDs should be avoided (risk of severe hyperkalemia). CHAPTER 18.2 Drug-induced nephropathies 699 Table 18.2.1 Drug-induced renal syndromes Renal syndrome Mechanism/presentation Drugs Interference with creatinine tubular secretion Creatine, \201 brates, IV immunoglobulins, trimethoprim, cimetidine \200\230False \200\231 renal failure NSAIDs, gold, penicillamine, INF-A Ciclosporin, oral contraceptives, mitomycin C, quinine Nephrotic syndrome Glomerular syndromes Nephritic syndrome (microangiopathy) Fanconi syndrome Old tetracyclines, streptozotocin, cisplatin, ifosfamide, adefovir, cidofovir, valproate, 6 -mercaptopurine, herbal medicines Tubular syndromes Proximal tubular acidosis Acetazolamide Hypokalemia (urinary wasting) Amphotericin B, herbal medicines B-Blockers, NSAIDs, ACEIs, ARBs Hyperkalemia (hyporeninemia/ hypoaldosteronism syndromes) Hypomagnesemia (urinary wasting) Amphotericin B, cisplatin Distal renal tubular acidosis Amphotericin B Diabetes insipidus Lithium, demeclocycline, amphotericin B, cidofovir, didanoside, foscarnet NSAIDs, ACEIs, ARBs, diuretics, contrast media, cyclosporin, interleukins Prerenal (reduced renal perfusion) Acute kidney injury See Table 18.2.2 See Table 18.2.3 Acute tubular toxicity Acute interstitial nephritis (including granulomatous nephritis) Chronic interstitial nephritis Analgesics, NSAIDs, herbal medicine (Table 18.2.4), indinavir, lithium, ciclosporin, tacrol imus, aminosalicylic acid Chronic kidney disease Urinary retention Atropine and related Urinary tract syndromes Papillary necrosis Analgesics, NSAIDs Stones Drug itself Sulfonamides, glafenine, ephedrine (including herbal medicines) indinavir, methotrexate, ac iclovir, ganciclovir Allopurinol (xanthine) Suprofene, phenylbutazone Vitamin C, herbal med icine (Table 18.2.4) Metabolite Uric acid Oxalate Urinary tract carcinoma Analgesics, herbal medicine (Table 18.2.4) Aminoglycosides Aminoglycosides (AmGs) are \201 ltered by the glomerulus and reabsorbed b y the S1/S2 proximal convoluted tubules via megalin-mediated endocytosis. AmGs can accumula te in lysosomes and induce tubular apoptosis and necrosis. Incidence of nephrotoxicity (gen erally manifesting as nono- liguric AKI) ranges from 5 to 25%. Membranous glomerulopathy This has been reported in patients with pre-existing renal diseas e treated with high doses of captopril (a sulfhydryl- containing ACEIs). Acute interstitial nephritis This has been seen during treatment with captopril in a few ca ses. Risk factors for nephrotoxicity \200 \200 \200 \200 \200 \200 \200 \200 Table 18.2.2 Drug-induced acute tubular toxicity Older age. Pre-existing renal disease. Female gender. Low intravascular volume. Hypokalemia and hypomagnesemia. Liver disease. Sepsis. Coadministration of other nephrotoxic drugs. Class of drug Typical examples Aminoglycosides, cephaloridine, cephalothin, amphotericin B, rifampicin, vancomycin, pentam idine Antibiotics NSAIDs and analgesics Diclofenac, indomethacin, glafenine, acetaminophen Diatrizoate, iothalamate, metrizoate Iodinated contrast media agents Prophylactic measures \200 \200 \200 Use least toxic AmG (amikacin < gentamicin). Limit duration of treatment. Adapt dose to ren al function. Ciclosporin, tacrolimus Calcineurin inhibitors Cisplatin IFN-A, foscarnet IFN-A, IV immunoglobulins Atorvastatin, simvastatin Antineoplastic drugs Antiviral drugs Trough serum levels do not predict the risk of nephrotoxicity. Immunomodulators Statins J. NORTIER, F. DEBELLE AND J.-L. VANHERWEGHEM 700 Table 18.2.3 Drug-induced acute interstitial nephritis Acute kidney injury Generally limited to the duration of treatment, rarely causes CKD. Inci dence varies between 50 and 90%. Risk factors are cumulative dose, rate of infusion (contin uous infusion is less toxic), pre-existing renal disease, older age, and diuretic use (lead ing to electrolyte imbalance). NSAIDs including salicylates Aclofenac Azapropazone Aspirin Benoxaprofen Diclofenac Di \202 unisal Fenclofenac Fenoprofen Flurbiprofen Ibuprofen Indomethacin Ketoprofen Mefenamic acid Meloxicam Mesalazine (5-ASA) Naproxen Ni \202 umic acid Phenazone Phenylbutazone Pir oxicam Pirprofen Sulfasalazine Sulindac Suprofen Tolementin Zomepirac Diuretics Chlorthalidone Ethacrynic acid Furosemide Hydrochlorothiazide Indapamide Tienilic acid Triamterene Antimicrobial agents Acyclovir Ampicillin Amoxicillin Aztreonam Carbenicillin Cefaclor Cefa mandole Cefazolin Cephalexin Cephaloridine Cephalothin Cephapirin Cephradine Ce \201 xitin Cefotetan Cefotaxime Cipro \202 oxacin Cloxacillin Colistin Cotrimoxazole Erythromycin Et hambutol Foscarnet Gentamicin Indinavir Interferon Isoniazid Gold salts Lincomycin Methicil lin Mezlocillin Minocycline Nafcillin Nitrofurantoin Nor \202 oxacin Oxacillin Penicillin G Piperacillin Piromidic acid Polymyxin acid Quinine Rifampicin Spiramycine Sulfonamides Te icoplanin Tetracycline Vancomycin Distal renal tubular acidosis Secondary to increased passive permeability of the luminal me mbrane to H+ and impaired secretion of titratable acids. Occurs after a cumulative dose >50 0 mg of AmB. Reversible after therapy discontinuation. Others Allopurinol A-Methyldopa Azathioprine Bethanidine Bismuth salts Captopril Carbimazol e Chlorpropamide Cyclosporine Cimetidine Clo \201 brate Clozapine Cyamethazine D-Penicilla mine Feno \201 brate Griseofulvin Interferon Interleukin-2 Omeprazole Phenindione Phenothi azine Phenylpropanolamine Probenecid Propranolol Propylthiouracil Ranitidine Streptokinase Sulphinpyrazone Warfarin Loss of concentrating ability of the kidney Occurs early (1 \200\2232 weeks) from direct tu bular toxicity (ADH hyporesponsiveness in the medullary collecting tubule). Renal wasting of potassium and magnesium Pathogenic mechanisms are unclear. Partial role of distal RTA (see above). Hypokalemia occurs in 75% of patients and may require up to 300 m mol of KCl supplementation per day (close monitoring necessary). Hypomagnesemia generally d evelops after a cumulative dose of 500 mg of AmB and is fully reversible. Prophylactic measures \200 \200 \200 Use of a 24 h infusion of AmB. Suf \201 cient hydration. Supplementation with sodium (150 mmol/day above the normal intake), potassium and magnesium. Frequent evaluation of serum electrolytes, serum Cr and hydration status are mandatory. The lower nephrotoxicity of liposomal formulations remains unproven (for equally therapeutic d oses to con- ventional AmB) and their use is often limited to patients with renal impairmen t, contraindications to sodium sup- plementation or to children. Analgesics Aminopyrine Antipyrine Antrafenin Clometacin Floctafenin Glafenin Metamizol Nora midopyrine