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 Analgesics Analgesics are widely used self-medicated compounds (5.3% of the US population). Analgesic nephropathy is characterized by slowly progres- sive CKD and results from the da ily use over many years of analgesic mixtures containing phenacetin (in the past) or parace tamol (now) with salicylates and addictive sub- stances such as caffeine or codeine or both . Pathological changes in analgesic nephropathy include interstitial renal \201 brosis, p redominantly in the medulla, with papillary necrosis and subendothelial capillary sclerosis . In typical cases renal CT scan shows small kidneys, with irregular contours and papillary calci \201 cation. The risk of developing ESRD secondary to analgesic abuse (daily consum ption for years) has been calculated at 1.7 per 1000 per year. Analgesic nephrotoxicity re mains a matter for debate. In the past, there was little doubt that analgesic mixtures invo lving phenacetin were responsible for chronic intersti- tial nephritis and urothelial carci noma. Since phenacetin withdrawal, controversy persists about the relationship between nonp henacetin-containing analgesics and nephropathy. Some studies indicate that prolonged use o f analgesics, even acetaminophen alone, leads to CKD. Anticonvulsants Carbamazepine Diazepam Phenobarbital Phenytoin Valproate sodium From: Rossert (2001). Amphotericins Amphotericin B (AmB) is a polyene macrolide, largely used in critically ill a nd immunocompromised patients for severe fungal infections. AmB is associated with frequent and severe acute and chronic toxicity. Nephrotoxicity is its most restrictive adverse effe ct. Tubular (distal convoluted tubule and ascending limb of the loop) and glomerular damage has been reported resulting in: CHAPTER 18.2 Drug-induced nephropathies 701 Other studies fail to provide evidence for an increased risk of CKD in healthy subjects wit h chronic use (up to 14 years) of aspirin, acetaminophen and other NSAIDs. Despite the cont roversy, it is reasonable to discourage the prolonged used of analgesic mixtures, especiall y those containing caffeine and/or codeine, as these drugs seem to favor addiction. Moreove r, as exposure to analgesics (such as NSAIDs) may accelerate the progression of CKD, prolon ged use of analgesics should be avoided in cases of pre-existing renal disease. Tenofovir disoproxil fumarate A reverse-transcriptase inhibitor, rarely associated with pro ximal tubulopathy. Nephrogenic DI has been seen in patients concomitantly treated with teno fovir and ritonavir or lopinavir. Calcineurin inhibitors Ciclosporin A (CsA) and tacrolimus (FK 506) are immuno- suppressive drugs inhibiting calcineurin, a key enzyme involved in T-cell activation. Both are effectiv e in primary immunosuppressive regimens for solid organ and bone marrow transplantation (BM T) and in the treatment of nonimmune diseases (uveitis, psoriasis, rheumatoid arthri- tis). CsA is also used in steroid-resistant or relapsing neph- rotic syndrome and in some forms of GN. An improved bioavailability has been obtained with the development of self-emulsifyi ng formulations. Two distinct forms of renal injury may be attributed to cal- cineurin inhi bitors (CNIs): Antiviral therapy Aciclovir This may crystallize in renal tubules, mainly when adminis- tra ted as a rapid IV bolus and in the setting of intravascular volume depletion. AKI often dev elops within 24 \200\22348 h, and may be severe enough to warrant temporary dialysis. Often asymptomatic, abdominal pain may be observed. Urinalysis reveals hematuria, pyuria, and bi refringent nee- dle-shaped crystals with polarizing microscopy. Most cases recover to basel ine renal function after drug discontinua- tion and \202 uid infusion. Prophylactic measu res include slow infusion, induction of high urine output and dosage adapta- tion to renal function. Acute nephrotoxicity This is hemodynamically mediated and characterized by the absence of p ermanent structural changes and by reversibility on dose reduction or CNI discontinuation. Chronic nephrotoxicity Characterized by the insidious development of irreversible and progr essive renal interstitial \201 brosis, leading to a sig- ni \201 cant decrease in renal function and possible ESRD. Adefovir dipivoxil This analog of adenosine triphosphate induces mild \200\223 moderate pro ximal tubular toxicity (22 \200\22350% of patients) at a dose >60 mg/day. Renal injury may not resolve com- pletely in 15% of cases General prophylactic measures In all clinical situations, careful attention should be paid to concomitant administration of nephrotoxic drugs. CNIs are metabolized by the cytochrome P450 liver micro- somal enzyme system ; many drugs interfering with this pathway can cause signi \201 cant changes in CNI blood levels. Compounds inhibiting P450 enzymes increase CN I blood concentration: \200 Cidofovir This nucleotide analog has a dose-dependent nephro- toxicity leading to proteinur ia (50% of cases), elevated serum Cr (12%), Fanconi syndrome (1%), rarely chronic interstit ial nephritis and nephrogenic DI. Renal function generally returns to baseline levels after dosing adjustment or drug discontinuation. e.g. ketoconazole, erythromycin, and diltiazem. Compounds inducing these enzymes can lower CNI levels and impair immunosuppression: e.g. phenobarbital, carbamazepine and rifampicin. Didanosine Exceptionally this is associated with AKI and nephrogenic DI. Foscarnet This pyrophosphate analog frequently causes AKI which can be effectively prevente d by IV hydration. Nephrogenic DI has also been observed. Acute CsA nephrotoxicity There are four common presentations: Ganciclovir Like aciclovir, this may precipitate into the tubular lumen and cause AKI. Asymptomatic increase in serum creatinine The most frequent and dose-related presentation, even when CsA whole-blood trough levels are within the thera- peutic range. Distinction fro m kidney rejection may be dif \201 cult in kidney transplant recipients or from primary re nal disease progression in the case of GN treated with CsA. Renal histology is usually norm al or shows nonspeci \201 c tubular changes (vacuolization, giant mitochondria). Improveme nt in serum Cr is the rule after 1 week of drug discontinuation or dose reduction. Indinavir This is poorly soluble at urinary pH 5.5 \200\2237.0, and causes crystalluria and intrarenal tubular obstruction. Symptoms are classic renal colic, dysuria, back/ \202 ank pain or macro- scopic hematuria. Stone formation (radiolucent) may occur. Renal impairment is often moderate and reversible. However, severe AKI and CKD have also been reported. Hyd ration (at least 2 \200\2233 L of \202 uid) is the main prophylactic measure; urinary aci dification is generally not recom- mended. Nephrogenic DI has also been reported. Interfero n-A (INF-A) See below \200\230IV immunoglobulins, recombinant cytokines, interferon-A \200 \231. Ritonavir This can induce AKI, particularly in patients with pre-exist- ing renal ins uf \201 ciency. Renal impairment is reversible after drug withdrawal. Acute kidney injury This may be observed in 10 \200\22350% of patients in the postop- erati ve period of heart, liver or BMT. It is usually multifactorial: impaired pretransplant rena l function is frequent in cardiac transplant recipients; liver transplant patients frequent ly present with intravascular volume depletion, hypotension, coagulopathy and have a high r isk of sepsis; after BMT graft-versus-host disease, J. NORTIER, F. DEBELLE AND J.-L. VANHERWEGHEM 702 Clinical management of chronic CsA nephrotoxicity This remains a matter for debate. Some po tential diagnos- tic markers need to be validated (e.g. urinary enzymes or microproteins re \202 ecting structural vs functional defects of the proximal tubule). Preventive measures or treatment are speculative. In many cases, decreasing dosages or CsA withdrawal result i n renal function improvement but comparative renal biopsies to con \201 rm this improvemen t structurally are often lacking. veno-occlusive liver disease, infection and hemodynamic instability are not uncommon. Delayed graft function This can be seen after renal transplantation when high CsA doses are combined with prolonged ischemic times. Recurrent or de novo hemolytic uremic syndrome This is a rare, but severe cause of AKI due to endothelial cell injury. Most often it is seen in BMT and kidney trans- plantation (wher e it can mimic acute vascular rejection). Prognosis of the renal graft is very poor. Biolog ical param- eters and renal biopsy abnormalities classically found in thrombotic microangio pathy may be highly variable in severity. Acute and chronic tacrolimus (FK 506) nephrotoxicity Like CsA, tacrolimus induces acute and reversible func- tional changes in renal function, chronic renal lesions, elec- trolyte di sturbances, RTA and HUS. However, tacrolimus induces less hypertension but more glucose met abolic impairment than CsA. Tacrolimus trough levels correlate strongly with drug exposure and high trough levels are associated with epi- sodes of nephrotoxicity. Dose should be adj usted to obtain ef \201 cient immunosuppression with minimal nephrotoxicity (usually blood levels of 10 \200\22315 ng/mL). Chronic CsA nephrotoxicity This clinicopathologic entity associates some degree of renal dy sfunction with tubulointerstitial \201 brosis in a striped pattern from the medulla to th e medullary rays of the cor- tex, and degenerative hyaline changes in the afferent arte- ri ole. This arteriolar lesion, classically absent in acute renal graft rejection, is actually reversible after CsA discontinua- tion, whereas tubulointerstitial changes never regress. The contribution of chronic CsA nephrotoxicity to renal allograft survival is hard to delin eate, as many combined factors may contribute to progressive structural and func- tional im pairment. Therefore an improvement of renal function after CsA reduction or withdrawal occu rs in only a small proportion of patients with biopsy-proven chronic CsA nephropathy. In no nrenal solid organ transplantation, long-term use of CsA is associated with development of CKD. The fre- quency of ESRD after heart transplantation varies between 1 and 8%, with a me an time period to initiation of dialysis of 6 \200\2237 years. Chemotherapy in cancer (cisplatin and others) Chemotherapeutic agents may induce nephrotoxi city as a result of two principal processes: \200 a direct toxic cellular effect related to the pharmaco- logical properties of the anticance r drug, usually seen with drugs which have a narrow therapeutic index and prescribed at hig h dose; a disturbed pharmacokinetic profile as a result of pre-existing CKD, which requires an adaptation of the dosage. The frequency of renal disease in cancer patients is not well-de \201 ned despite the eval uation of renal function being mandatory before initiation of many chemotherapeutic treatme nts. Clinical syndromes include AKI and CKD, tubular disorders and thrombotic microangiopat hy. Proposed risk factors for end-stage renal failure: \200 \200 \200 \200 \200 \200 \200 individual susceptibility to CsA-induced injury; early decrease in GFR; CsA dose and length of exposure to CsA therapy; previous renal dysfunction; older age; hepatorenal syndrome in liver-transplanted patients; BMT. Predisposing factors \200 \200 Underlying renal disease (e.g. diabetic nephropathy). Prerenal failure (common due to poor intake, diarrhea, sepsis). Coadministration of nephrotoxic drugs. Cisplatin (and to a lesser extent carboplatin) This alkylating agent has a direct toxic eff ect on tubular cells. Renal manifestations are more frequent when treat- ment is prolonged and repeated, and often irreversible. Bone marrow transplantation High doses of CsA (10 \200\22312 mg/kg) are used for prevention of graft-versus-host disease for limited time periods (rang- ing from 6 to 18 months). Thi s may partially explain the high prevalence of chronic CsA nephrotoxicity. Other risk facto rs identi \201 ed are: long duration of CsA therapy; more severe renal dysfunction in the \201 rst trimester post transplant; and the use of total body irradiation. Tubular toxicity There may be severe hypomagnesemia (urinary waste of magnesium), which may be associated with hypocalcemia and tetany. About 50% of patients receiving 70 mg/m2 cispl atin every 3 weeks may present with hypomagnesemia, which is more pronounced when other nep hrotoxic agents are coadministered (e.g. aminoglycosides). CsA use in autoimmune diseases Chronic CsA nephrotoxicity may be detected even with low CsA doses (initial 5 mg/kg, tapered to 1 \200\2232 mg/kg). Histological lesions mainly consist of interstitial \201 brosis and tubular atrophy, arteriolopathy is rarely demonstrated. Onset of chronic injury and its severity appear to depend on individual susceptibility to C sA. No correlation has been found between structural injury, cumulative CsA dose, and durat ion of treatment or decrease in GFR. The best predictors for the presence of \201 brosis are the dura- tion of renal dysfunction and the lack of reversibility of functional impairm ent after CsA discontinuation. Proteinuria This re \202 ects defects in reabsorptive capacity of the tubular epithelium t owards low molecular weight proteins such as B2-microglobulin. Acute or progressive renal f ailure CKD is related to the total cumulative dose and the frequency of administration. Irr eversible tubulointerstitial lesions are commonly seen and may be worse in patients who hav e also received radiotherapy. CHAPTER 18.2 Drug-induced nephropathies 703 Thrombotic microangiopathy syndrome This has been described but is uncommon. corticomedullary junction. Histologic \201 ndings are mainly vacuolar changes in the prox imal convoluted tubular cells. Risk factors for RCIN are numerous and their effect addi- ti ve (presence of multiple risk factors in the same patient can create a high risk 50% for R CIN). Prophylactic measures \200 \200 \200 Hydration and vigorous diuresis with saline. Use daily doses for 5 days instead of single i nfusion. Aim for cumulative dose <120 mg/m2. Risk factors for RCIN \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Pre-existing CKD (eGFR <60 mL/min/1.73 m2). Diabetes. Periprocedural hemodynamic instabilit y. Volume depletion. Congestive heart failure. Older age (>75 years). Nephrotoxic drug use (NSAIDs). Anemia. Hypoalbuminemia. High volume and high osmolar contrast media. Cyclophosphamide and ifosfamide Oxazophosporines are known to induce hemorrhagic cys- titis , which may be prevented by aggressive hydration and Mesna \233\232. Both agents are tubulo toxic and Fanconi syn- drome may be observed. Reversible tubular lesions are re \202 ected by transient increase in proximal tubule enzymu- ria. Although severe toxicity of ifosfami de is uncommon, tubular lesions may be irreversible, resulting in progressive CKD. Dose fra ctionation is recommended to minimize complications. Streptozotocin This belongs to the nitrosourea group of drugs and may cause Fanconi syndrom e (severe hypophosphatemia) and glomerular toxicity. Long-term treatment with carmustine or >6 courses with the conventional dose of 200 mg/m2 are associated with a high risk of deve loping renal failure. Strategies to prevent RCIN All patients should be evaluated for their risk of RCIN (when se rum Cr is not available, medical history of the patient can identify those who require furt her assessment of renal function). Low osmolar contrast medium is recommended and the admin istered volume should be the minimum amount required for an interpretable study. Optimal vo lume status: outpatients are encouraged to drink water liberally in the 12 h before contras t exposure. Inpatients \200\230at risk \200\231 require IV volume expansion adapted to the patient characteristics (time available prior to contrast exposure, cardiac status). Isoto nic crystalloid (1.0 \200\2231.5 mL/ kg/h) \211 6 h before the procedure and continued at least 6 h afterward is generally recommended. IV sodium bicarbonate infusion is not recomme nded unless ef \201 cacy con \201 rmed by further trials. The risk/bene \201 t of discon tinuing drugs with nephrotoxic potential (ACEIs, ARBs diuretics) prior to contrast exposure should be evaluated. In stable patients with chronic therapy, these agents do not need to be withheld. Con \202 icting data regarding the ef \201 cacy of N-acetylcysteine (NAC) pr events a strong recommendation for the use of this drug for the prevention of RCIN. When gi ven at the discretion of the physician, the recommended dose is 600 \200\2231200 mg orally given twice on day before and day of procedure. When time available before procedure is sho rt, NAC may be given IV (150 mg/kg in 500 mL 0.9% saline before and 50 mg/kg in 500 mL 0.9% saline after procedure). Other prophylactic agents are ineffective (e.g. dopamine, fenoldo pam, calcium channel blockers) or deleterious (e.g. furosemide, mannitol, endothelin recept or antago- nist). Any potential bene \201 t of theophylline/aminophylline needs to be con \201 rmed in further clinical trials. Hemodialysis is not useful in lowering the risk for RCIN. Further trials are required before recommending hemo \201 l- tration as a prophylact ic measure for patients at high risk for RCIN. A follow-up serum Cr is necessary in all pat ients at high risk for RCIN. Methotrexate This antimetabolite has been associated with ATN and non- oliguric AKI, attrib uted to intrarenal obstructive uropathy (precipitation of intact methotrexate or metabolite s in distal tubules if dose >50 mg/m2). Enhanced toxicity has been reported when there has been previous treatment with cis- platin or NSAIDs. If dose >1 g/m2, a rapid and dose-relat ed fall in GFR is seen. Prevention of methotrexate nephro- toxicity is by urinary alkaliniz ation and hydration. In cases of severe renal toxicity, charcoal hemoperfusion and sequenti al hemodialysis (high \202 ux) has been shown to be effective. Mitomycin This antitumor antibiotic may induce HUS when high doses are used (>60 mg/m2). Es timated risk ranges from 2 to 10%. Onset is late, occurring after 3 \200\2234 cycles. No pr edic- tive marker known. In order to prevent HUS the cumula- tive dose should not exceed 40 mg/m2. Mithramycin A daily dose of 5 \200\22350 g/kg may result in ATN and tubular atrop hy in 40% of cases. Gemcitabine Thrombotic microangiopathy is a rare but serious compli- cation (incidence 0.01 5 \200\2231.4%); risk increases with a cumu- lative dose 20 000 mg/m2. Discontinuation of the drug is recommended in association with antihypertensive therapy where necessary. In se vere cases, plasma exchange or hemoperfusion should be considered. Radiocontrast-induced nephropathy (RCIN) RCIN is usually de \201 ned as otherwise unexplai ned AKI 48 \200\223 72 h after iodinated contrast agent administration (increase in serum C r of \211 25% or 0.5 mg/dL, or a reduction in GFR of >25% from the baseline value). RCIN i s the third commonest cause of hospital-acquired renal failure (incidence is variable, depe nding on the patient population studied and the de \201 nition used for RCIN), and is asso ciated with signi \201 cant patient morbidity and mortality. In general, RCIN is attribute d to a combination of direct tubular toxicity and sustained vasoconstriction at the Fibrates and statins Fibric acid derivatives ( \201 brates) and HMG-CoA reductase inhibito rs (statins) are lipid-lowering drugs associated J. NORTIER, F. DEBELLE AND J.-L. VANHERWEGHEM 704 with myotoxicity, which ranges in severity from myalgia to rhabdomyolysis resulting in AKI and death. Herbal nephrotoxicity falls into four main categories 1. Herbal plants may be properly iden ti \201 ed but may have unknown or underestimated toxicity. This is often the case for ATN secondary to some traditional African medicines, the mineralocorticoid activity of licoric e used in many herbal prescriptions and the adrenergic effect of ephedra-containing herbal preparations. Fibrates These are generally well-tolerated and are not generally associated with an increa sed risk of renal failure but may be associated with: \200 reversible increase in serum Cr (most likely due to an effect mediated by peroxisome prolif erator-activated receptor-A). higher risk of rhabdomyolysis-associated AKI when used in com bination with statins. 2. Herbal medicines may contain undisclosed drugs and heavy metals (up to 35%). Contaminati on by cadmium may result in Fanconi syndrome. Adulteration by NSAIDs has led to a chronic \200\230analgesic \200\231nephropathy. 3. Herbal plants may be incorrectly identi \201 ed, resulting in patients being given toxic compounds (or compounds with an underestimated tox icity) under the false assump- tion that they are harmless natural herbal remedies. Chronic interstitial \201 brosis (and urothelial carcinoma) secondary to the intake of medicinal herbs containing aristolochic acids is discussed in Chapter 6.6. Gemfibrozil should be avoided and fenofibrate is preferred (it is not associated with inhib ition of statin metabolism). Ezetimide alone or with a statin may cause myopathy. Serum Cr should be measured before \201 brate initiation and the dose adjusted according to renal function. Routine monitoring of serum Cr is not required but could be useful in situations of possible drug interactions and/or in patients with advanced CKD. 4. Herbal plants may interact with conventional drugs. Hypericum perforatum (St John \200 \231s wort) activates the hepatic cytochrome system and thus can decrease plasma levels of a wide range of prescribed drugs, with clinical consequences such as a renal allograft reje ction in patients treated by CsA or tacrolimus. Statins There is limited information available on the potential benefit of statins in CKD i n terms of reduction of cardiovascular morbidity and mortality. A beneficial effect on albu minuria has been proposed but is still contro- versial. Statins are safe and usually well-t olerated even in advanced CKD and ESRD. However, the following adverse events have been rep orted: For patients with ESRD, it must also be stressed that some herbal compounds contain signi \201 cant amounts of potassium and may induce hyperkalemia: alfala (Medicago sativa), dande lion (Taraxacum of \201 cinale), noni juice (Morinda of \201 cinalis). Intravenous immunoglobulin, recombinant cytokines, interferon-A High dose intravenous immun oglobulin (IVIG) IVIG is generally well-tolerated. However, cases of AKI have been reported secondary to the tubular toxic effects of sucrose, maltose, glucose, or glycine contained in IVIG formulations. Advanced age, diabetes mellitus and pre- existing renal failure are r isk factors. Slow rate of infusion and nonsucrose formulations may prevent renal complica- tions. IVIG can also inhibit tubular secretion of Cr and, thus, may cause a \200\230false \200\231 renal failure. Interferon-A (INF-A) This is frequently used as an antiviral agent, immunomodu- lator and anticancer therapy. Administration may lead to mild \200\223moderate proteinuria (25%) and an increase in serum Cr (10%), mostly in patients with hematological malignan- cies or hepatitis. Renal biopsies reveal minimal change dis- ease, focal segment al hyalinosis or crescentic glomerulonephritis. Thrombotic microangiopathy has also been ob served with INF-A. Interleukin-2 (IL-2) IL-2 is used in certain forms of renal carcinoma. T he admin- istration of IL-2 may result in a capillary leak syndrome with proteinuria and pr erenal AKI secondary to an ineffective circulating blood volume. Muscle pain or weakness Seen in fewer than 1 in 10 000 patients on standard doses. Risk var ies with statin, and increases with higher doses and interacting drugs. Drug discontinuatio n reverses these side-effects. Potentiation of myotoxicity may be observed when atorv- asta tin is used with colchicine or quinine because of modi- \201 cations of the pharmacokinet ic pro \201 le of atorvastatin (colchicine is a P-glycoprotein inhibitor and quinine inhib its cytochrome P450 isoenzyme 3A4). Acute hepatic injury and AKI secondary to rhabdomyolysis This has been reported in patients receiving gem \201 brozil and \202 uvastatin. Cerivastatin was banned after similar fat al cases. Rhabdomyolysis with cardiac involvement and AKI This has been reported with rosuvastatin co mbined with feno \201 brate. Tubular proteinuria Rosuvastatin ( \211 40 mg/day) may cause a mild form of tubular protein uria without an increased risk of renal failure. Thus it is recommended that statins are us ed carefully in CKD. Herbal medicine Herbal medicines are used by 75% of the world \200\231s popula- tion, mostl y in the developing countries. Herbal medicine is also popular in the West with 15% of the population consulting a herbal medicine provider each year. Herbal products may contain nep hrotoxic compounds and, therefore, may be responsible for various renal syndromes (Table 18 .2.4). Lithium In Western countries 1 in 1000 individuals is given lithium for the treatment of u ni- or bipolar affective disorders. Lithium is eliminated by the kidney (glomerular \201 ltration and proximal tubular reabsorption) and may accumulate in distal tubular cells. Aft er long-term exposure, tubular cysts as well as tubular atrophy and interstitial \201 bro sis and some- times glomerular sclerosis may develop. CHAPTER 18.2 Drug-induced nephropathies 705 Renal side-effects of lithium include: \200 \200 \200 \200 \200 and resistance to diuretics have been related to the use of NSAIDs. The long-term (>2 years ) daily use of NSAIDs has been associated with an increased risk for developing CKD sec- on dary to chronic interstitial nephritis. Episodes of papillary necrosis have been reported w ith ibuprofen, indomethacin, phenylbutazone, fenoprofen and mefenamic acid. Suprofen may gi ve rise to AKI with unilateral or bilateral \202 ank pain ( \200\230suprofen nephropathy \200\231). This syndrome is prob- ably due to the uricosuric properties of NSAIDs leading t o an acute uric acid nephropathy. Among all NSAIDs, aspirin is the only one that is clearly associated with a low risk of renal side-effects (with the exception of lupus nephropathy) . Claims regarding the renal-sparing properties of particular NSAIDs (sulindac, nabumetone) lack convincing evidence. Thus caution must be applied when using NSAIDs (including select ive COX-2 inhibitors) chronically or in situations associated with renal hemodynamic stress . AKI (prerenal type); CKD (secondary to interstitial renal \201 brosis); nephrogenic DI (m ost frequently); incomplete distal RTA (rare, no clinical consequence); nephrotic syndrome (rare, due to FSGS). Lithium may also induce hypothyroidism and hyperparathy- roidism. The latter is responsible for hypercalcemia (in 35% of the patients) which can aggravate renal lesions. Nephrogenic diabetes insipidus Lithium induces resistance to ADH: 50% of patients will have impaired urine concentration ability and 20% develop polyuria and polydypsia. In view of t he ef \201 cacy of lithium therapy polyuria is commonly accepted as a side-effect. Treatme nt with amiloride (10 \200\22320 mg/day) can signi \201 cantly reduce daily urine output. Lithium-induced chronic kidney disease Evidence exists that lithium is responsible for chro nic interstitial nephritis sometimes leading to ESRD: \200 Development and progression of CKD are related to the average serum lithium level and the cumulative lith- ium dose. Ther efore, it is recommended to maintain a lithium serum concentration at the lowest level (if pos- sible between 0.4 and 0.8 mmol/l) to adequately control affective symptoms. Sulphasalazines (5-amino salicylic acid, 5-ASA) Sulphazalazine is effective in the treatmen t of patients with in \202 ammatory bowel disease (IBD). Second generation sul- phasalazin es (mesalazine, olsazazine, balsalazine) free of sulphapyridine were developed in order to avoid the hematological side-effects of sulphazalazine. 5-ASA therapy in chronic IBD has be en associated with renal impairment in 1.3 to 3.3 per 1000 patients. Treatment with mesalaz ine and olsalazine has been reported to induce biopsy-proven AIN. In several cases, recover y of renal function did not occur. Current recommendations are to monitor renal function in patients on 5-ASA derivatives every 3 months. If there is renal failure, a renal biopsy is required to con \201 rm the diag- nosis as patients with chronic IBD are at risk of diver se nephropathies (immune glomerulopathies, amyloidosis, oxalate stones). Once CKD is present, withdrawal of lithium after long-term use does not guarantee the stabi lization of renal function and progressive evolution to ESRD is still the rule. NSAIDs (including selective cyclo-oxygenase 2 inhibitors) NSAIDs are inhibitors of cyclo-ox ygenases (COX), which catalyze the production of prostaglandins (PG). Two COX isoforms have been isolated: COX-1 and COX-2. Selective COX-2 inhibitors are associated with fewer gastr ointesti- nal adverse effects than nonselective NSAIDs. Many of the renal effects of NSAIDs appear to be mediated by COX-2 inhibition rather than COX-1 inhibition. COX-2 inhibition d ecreases urinary PG excretion and may result in decreased GFR and sodium retention. This is particularly the case when renal PG secretion is required for the preservation of renal he modynamics: \200 \200 \200 Oral sodium phosphate solution (acute phosphate nephropathy) Oral sodium phosphate solution (OSPS; Fleet Phospho soda), widely used for bowel cleansing, may lead to acute phosphate nephropathy and AKI with a high risk of CKD. While the incidence is low this entity is pro bably under- recognized. Histologic \201 ndings are characterized by the presence of abun dant calcium phosphate crystals in renal tubules. Factors predisposing patients to acute ph osphate neph- ropathy after OSPS are: \200 volume depletion; \200 older age; \200 gen der (female); \200 hypertension; \200 concurrent therapy with diuretics, NSAIDs, ACEIs or ARBs. OSPS is contraindicated in CKD and should be used with caution in elderly patients and in patients with electrolyte disturbances. volume depletion; reduced renal blood \202 ow (cardiac failure); ineffective circulating blood volume (sepsis, cirrhosis, nephrotic syndrome); toxic injury (CsA, tacrolimus); advan ced age; pre-existing renal failure. \200 \200 In normal conditions, temporary use of NSAIDs produces negligible effects on renal hemodyna mics. In the conditions mentioned above, NSAIDs may induce prerenal AKI or ATN. Observation al studies have shown that NSAIDs were responsible for 36% of in-hospital AKI. All NSAIDs, including selective COX-2 inhibitors, may also induce AKI secondary to AIN. Most cases of N SAID-related AIN are associated with nephrotic syndrome (minimal change disease, rarely FSG S, membranous nephropathy). Various \202 uid and electrolyte disorders (hyponatremia, hyp er- kalemia, acidosis, \202 uid retention) as well as hypertension Further reading de Mattos A, Olyaei A, Bennett W. Nephrotoxicity of immunosup- pressive dru gs: long-term consequences and challenges for the future. Am J Kidney Dis 2000; 35: 333 \200\223346. J. NORTIER, F. DEBELLE AND J.-L. VANHERWEGHEM 706 Domenica D, Gehr T. 3-Hydroxy-3-methylglutaryl coenzyme A reduct- ase inhibitors and rhabdo myolysis: considerations in the renal failure patient. Curr Opin Nephrol Hypertens 2002; 11 : 123 \200\223133. Table 18.2.4 Renal syndromes related to herbal medicine Glycyrrhiza spp. (Chinese herbal teas, gancao, Boui-ougi-tou) Ephedra spp. (ma huang) Hypertension Isnard Bagnis C, Deray G, et al. Herbs and the kidney. Am J Kidney Dis 2004; 44: 1 \200\22311. Izzedine H, Launay-Vacher V, Deray G. Antiviral drug-induced neph-