REVIEW
Antiviral Drug–Induced Nephrotoxicity Hassane Izzedine, MD, Vincent Launay-Vacher, PharmD, and Gilbert Deray, MD ● Drug-induced kidney injury is a major side effect in clinical practice, frequently leading to acute renal failure (ARF). It accounts for more than 2% to 15% of cases of ARF in patients admitted to the hospital or in the intensive care unit, respectively. The exact frequency of nephrotoxicity induced by antiviral drugs is difficult to determine. Antiviral drugs cause renal failure through a variety of mechanisms. Direct renal tubular toxicity has been described with a number of new medications with unique effects on epithelial cells of the kidney. These include cidofovir, adefovir dipivoxil, and tenofovir, as well as acyclovir. Additionally, crystal deposition in the kidney may promote the development of renal failure. Several different drugs have been described to induce crystal nephropathy, including acyclovir and the protease inhibitor indinavir. Renal injury associated with antiviral drugs involves diverse processes having effects on the renal transporters, as well as on tubule cells. In this article, we review the pathogenesis of antiviral drug–induced kidney injury, common nephrotoxic renal syndromes, and strategies for preventing kidney injury. Am J Kidney Dis 45:804-817. © 2005 by the National Kidney Foundation, Inc. INDEX WORDS: Tubular dysfunction; renal failure; nephrotoxicity; antiviral drugs.
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HE INTRODUCTION OF more effective and powerful antiviral drugs (eg, protease inhibitors [PIs], acyclic nucleotide phosphonate analogues) and the necessity to combine several potentially toxic drugs in complex patient groups (eg, human immunodeficiency virus [HIV]– infected patients, immunocompromised transplant recipients with cytomegalovirus [CMV] infection) are well-known causes of the additional increase in the incidence of antiviral drug nephrotoxicity. Because the kidney excretes many drugs, it is exposed routinely to high concentrations of these drugs, their metabolites, or both. Furthermore, the kidney has several features that allow nephrotoxins to accumulate.1 It is highly vascular, receiving approximately 25% of resting cardiac output. The proximal renal tubule presents a large area for nephrotoxin binding and transport into the renal epithelium. Reabsorption of the glomerular filtrate progressively increases intraluminal nephrotoxin concentrations, whereas From the Department of Nephrology, Pitie-Salpetriere Hospital, Paris, France. Received November 10, 2004; accepted in revised form February 2, 2005. Originally published online as doi:10.1053/j.ajkd.2005.02.010 on March 29, 2005. Address reprint requests to Hassane Izzedine, MD, at the Department of Nephrology, Pitie-Salpetriere Hospital 83, Blvd de l’Hopital, 75013, Paris, France. E-mail:
[email protected] © 2005 by the National Kidney Foundation, Inc. 0272-6386/05/4505-0003$30.00/0 doi:10.1053/j.ajkd.2005.02.010 804
specific transport pathways in the kidney may engender site-specific toxicity. Drug-induced kidney injury is a major side effect in clinical practice, frequently leading to acute renal failure (ARF). It accounts for more than 2%2 to 15%3 of the cases of ARF in patients admitted to the hospital or in the intensive care unit, respectively. The exact frequency of nephrotoxicity induced by antiviral drugs is difficult to determine. Discrepancies between animal and clinical studies, availability of only isolated case reports of toxicity when drugs are clinically introduced, clinical trials that are uncontrolled or poorly designed, and lack of uniformity in defining criteria for renal dysfunction are some of the important factors for the uncertainty about the frequency of a specific nephrotoxicity. In this article, we review the pathogenesis of antiviral drug– induced kidney injury, common nephrotoxic renal syndromes, and strategies for preventing kidney injury (Tables 1 and 2). PATHOGENESIS
Although tubule cell death (resulting in acute tubular necrosis) is a major component of toxicity related to many antiviral drugs (eg, foscarnet, acyclovir, interferon [IFN], and cidofovir), others may induce mild forms of injury without cellular necrosis or apoptosis, resulting in such isolated tubular defects as Fanconi-like syndrome (cidofovir, tenofovir), distal tubular acidosis (eg, acyclic nucleotide phosphonates, foscarnet), and nephrogenic diabetes insipidus (NDI;
American Journal of Kidney Diseases, Vol 45, No 5 (May), 2005: pp 804-817
ANTIVIRAL DRUG–INDUCED NEPHROTOXICITY
foscarnet).4,5 Intracellular drug concentration is the major actor in its tubular toxicity. Thus, renal toxicity might be explained in the case of many drugs by an increase in intracellular influx through human organic anion transporter (OAT) 1 (hOAT1)-controlled mechanisms, a defect in its luminal excretion through multidrug resistance– associated protein (MRP) type 2 (MRP2)-controlled mechanisms, or both. Intrarenal obstruction can occur when crystalline deposits form in the renal tubule in response to acyclovir, ganciclovir, and indinavir therapy.6 Finally, the glomerulus can be the target of the drug, resulting in proteinuria and, in some cases, nephrotic syndrome by immune-mediated complex (IFN)7,8 or crystal deposit (foscarnet).9,10 Target of Cell Injury At least 3 mechanisms explain antiviral agent– induced renal injury: transporter defects, apoptosis, and mitochondrial injury. Additionally, there may be crystal deposition and vascular injury (Fig 1). Drugs that affect transport proteins at the tubule membrane can promote electrolyte loss. This process causes tubular acidosis; however, little cell injury occurs (Fig 1A). Genetic defects in transporters, as in OAT, organic cation transporter (OCT), or MRP, may promote renal insufficiency during treatment with antiviral drugs. Nucleoside analogues enter the cell by the hOAT or human OCT (hOCT) system, although their active removal by MRP2,4 or P-glycoprotein may vary between cells and over time.11,12 Increased cellular uptake of acyclic nucleotide cidofovir or adefovir dipivoxil by the hOAT1 favors proximal tubular dysfunction13,14 (Fig 2). This was shown in an in vitro study for cidofovir and adefovir dipivoxil, but not for tenofovir.15 In addition, tenofovir and adefovir dipivoxil interact with hOAT1 and 3, whereas cidofovir interacts with hOAT1 only.16 Nucleoside analogues, including zidovudine, stavudine, didanosine, zalcitabine, and lamivudine, also are substrates of OAT1,12 but these agents have not been associated with tubular dysfunction. By using cells stably expressing OATs and OCTs, Takeda et al17 showed that hOAT1 and hOCT1 mediate renal acyclovir and ganciclovir transport. Unlike lamivudine,13 the nucleotide analogues tenofovir and adefovir dipivoxil are not substrates for renal organic cation transport systems. Because HIV protease inhibitors carry posi-
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tively charged amine moieties, they may interact with OCTs. In addition to being substrates of cytochrome P-450, PIs also are substrates and can act as inhibitors of P-glycoprotein, but only ritonavir inhibits the functional activity of MRP1. Moreover, PIs (especially saquinavir and ritonavir) may potently inhibit the transport of cationic drugs, which are substrates of hOCT1 and lead to potential drug-drug interactions. Of the 2 PIs, ritonavir was the most potent inhibitor of transport by a factor of at least 20. Recent studies have shown that adefovir dipivoxil may interact with MRP4.16,18,19 MRP4 has been shown to confer low-level resistance to adefovir dipivoxil.19 There are 2 implications of these findings: MRP4 overexpression thus may protect cells from the cytotoxic effects of adefovir dipivoxil and provide a protective sanctuary for the virus, and this correlates with both drug accumulation and an impaired ability to inhibit HIV replication because of decreased drug accumulation. The decrease in zidovudine monophosphate accumulation in cells that overexpressed MRP4 facilitated their survival, even in the presence of high concentrations of zidovudine. Thus, variations in MRP4 expression also may contribute to the differential sensitivity of cells to zidovudine by allowing different levels of zidovudine monophosphate to accumulate. Lamivudine renal tubular secretion and overall renal clearance are significantly reduced by trimethoprim in the isolated perfused rat kidney and in humans in a dose-dependent manner, suggesting that the 2 drugs may share a common organic cation transport.20 In addition, cells that overexpress MRP4 have decreased antiviral efficacy for lamivudine (3TC), a finding strongly suggesting MRP4 as a contributor to 3TC cellular resistance. Furthermore, 3TC metabolites also could be MRP4 substrate.21 An implication of these findings is that high active antiretroviral therapy, which uses combinations of highly cytotoxic antiretroviral drugs for long periods, may facilitate the survival of cells that overexpress MRP4, potentially causing antiretroviral drugs to fail to inhibit HIV replication in host cells.22 Finally, peptide transporters 1 and 2 mediate luminal uptake of such peptides as valaciclovir.23 Programmed cell death (apoptosis) can occur in concert with immune-mediated injury, destroying cells by way of the mitogen-activated protein kinase (MAPK) pathway (Fig 1D). For example, therapeutic administration of IFN often is accom-
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Table 1. Antiviral Drug–Induced Kidney Injury Nephrotoxicity Drug
Treatment
Clinical Aspects
ARF Chronic renal disease Crystal nephropathy Proximal tubulopathy ARF
27-50 50
Cidofovir
High dose Bolus therapy (IV) Volume depletion High dose ⱖ 30 mg/d Renal impairment Preexisting tubular dysfunction Renal impairment
Fanconi syndrome ARF Chronic renal disease Diabetes insipidus
1 12-25 Unknown 1 case
Didanosine
Unknown
1 case
Foscarnet
Renal impairment
ARF with proximal tubulopathy and diabetes insipidus ARF Diabetes insipidus Chronic renal disease Crystalline GN Fanconi syndrome ARF
Acyclovir
Adefovir dipivoxil
Ganciclovir Indinavir
Volume depletion Alkaline urine Renal impairment
IFN
Renal impairment
Ritonavir
Renal impairment
Crystalluria Nephrolithiasis ARF Chronic renal disease Hypertension ARF Glomerulopathies TMA ARF
Incidence (%)
12-79 Unknown
27 4.3 Unknown 2 cases Unknown 20% in BMT recipients 20-30 8 13 Unknown Unknown 25 Unknown Unknown ⬍30 cases
Preventive
Supportive
Avoid rapid IV bolus Adjust dose for renal function Establish euvolemia before therapy Avoid preexisting tubulopathy Adjust dose for renal function Coadministration of L-carnitine
Discontinue or reduce dose Establish high urine flow Hemodialysis Discontinue
Avoid preexisting tubulopathy or proteinuria Avoid in patients with significant renal impairment Adjust dose for renal function The recommended dosage, frequency, and infusion rate should not be exceeded Intravascular volume expansion with IV fluids before drug initiation Coadministration of probenecid Any
Cidofovir dosing should be reduced or therapy stopped if renal function changes during therapy
Establish euvolemia before treatment Calcium channel blocker?
Discontinue Establish high urine flow
Establish euvolemia before treatment
Discontinue treatment
Establish euvolemia before treatment Establish high urine flow Acidify the urine? Calcium channel blocker?
Discontinue or reduce dose Volume resuscitate to euvolemia Establish high urine flow Alleviate urinary obstruction
Adjust dose for renal function
Discontinue or reduce dose
Unknown (Continued)
Discontinue
Discontinue
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Risk Factors
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Discontinue
Discontinue or reduce dose
Patient-related factors Age, sex, race Previous renal impairment Dehydration and volume depletion Acidosis and electrolyte depletion Hyperuricemia Renal transplantation Drug-related factors Inherent nephrotoxic potential Adapted dosage to renal function Duration, route of administration Combined diagnostic or therapeutic agents with potential nephrotoxic effects (eg, radiocontrast agents, aminoglycosides, nonsteroidal anti-inflammatory drugs, platin, angiotensin-converting enzyme inhibitors)
Valaciclovir
Abbreviations: IV, intravenous; GN, glomerulonephritis; BMT, bone marrow transplant.
Unknown 1 case
Adjust dose for renal function 0.02 4 cases
Fanconi syndrome ARF Diabetes insipidus TMA Renal impairment Ritonavir coadministration Any Tenofovir
Preventive Incidence (%) Clinical Aspects Risk Factors Drug
Nephrotoxicity
Table 1 (Cont’d). Antiviral Drug–Induced Kidney Injury
Treatment
Supportive
Table 2. Nephrotoxicity of Antiviral Drugs: Risk factors
panied by impaired renal function. The effect was reversible on removal of IFN. IFN can affect barrier function in renal epithelial cells through the MAPK activation pathway.24 Other pathways to injury may develop when drugs (eg, nucleoside reverse transcriptase inhibitors) damage mitochondria (Fig 1C). Antiviral nucleoside triphosphates present in the mitochondria can be derived from 2 sources. In the first, nucleosides may diffuse or be transported into the mitochondria, where, if the necessary enzymes are present, they will be phosphorylated (eg, zidovudine, stavudine) to triphosphates to produce their mitochondrial toxicity. Alternatively, when phosphorylating enzymes are present only in the cytosol (eg, deoxycytidine kinase for zalcitabine), antiviral nucleotides may be transported into the mitochondria25 (Fig 1C). Recently, the human equilibrative nucleoside transporter 1 (at the basolateral membrane) and the human concentrative nucleoside transporter 1 (at the apical pole) were localized to the mitochondria.25,26 These transporters are important in mediating the transport of nucleoside and nucleotide drugs (eg, antiviral and anticancer drugs) across cell membranes.27 Didanosine, zalcitabine, stavudine, and zidovudine are substrates of human equilibrative nucleoside transporter. To produce their mitochondrial toxicity, nucleoside drugs first must be transported into the cytosol or diffused into cells. Except for the few moderately lipophilic nucleoside drugs, such as zidovudine, other nucleoside drugs that cause mitochondrial toxicity are too hydrophilic to diffuse into
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Fig 1. Mechanisms of kidney injury induced by antiviral drugs. The normal nephron may be affected in at least (A-C) 3 ways. (A) Overexpression or competitive inhibition of such transport pumps as the hOAT family or MRP2 or 4 (MRP2,4) prevent or lead to tubular cell toxicity (expressed as tubular acidosis) for such drugs as acyclic nucleotide phosphonates.13,14 (B) Activation of the mitogen-activated protein kinase (MAPK) pathway can affect barrier function in renal epithelial cell cascade, which results in programmed cell death.15 (C) Other pathways to injury may develop when drugs damage mitochondria, disrupting fatty-acid oxidation and energy production. When drugs bind to or otherwise disable respiratory-chain enzymes or mitochondrial DNA, oxidative stress results, with ensuing anaerobic metabolism, lactic acidosis, and triglyceride accumulation (microvesicular fat within cells). The presence of reactive oxygen species may further disrupt mitochondrial DNA. This pattern of injury is characteristic of a variety of agents, including NRTIs, which bind directly to mitochondrial DNA. Furthermore, it was suggested that previous mitochondrial damage, caused by the use of NRTIs or any other condition, may be a prerequisite for conditions that allow tenofovir-induced tubular damage.15,109,110
cells in appreciable quantity. Thus, it is very likely that they are transported into cells by the nucleoside transporter. CLINICAL CONSEQUENCES
Acute Tubular Toxicity Direct tubular toxicity may cause ARF and tubular dysfunction. Direct injury to the renal tubular epithelia causes tubular cell degeneration and sloughing, appearing as dark brown, fine, or granulated tubular casts in the spun urinary. This injury may result from acyclic nucleotide phosphonates, acyclovir, and other antiviral agents (Table 1). A spectrum of injury ranging from isolated proximal tubular defects (Fanconi-like
syndrome) to severe acute tubular necrosis requiring renal replacement therapy has been described with acyclic nucleoside phosphonate analogues.28-33 These occurred in patients with underlying renal disease or those administered concomitant nephrotoxic agents (Table 2). Cidofovir. Cidofovir, a nucleotide analogue with potent activity against CMV, is 10-fold more potent than ganciclovir in vitro.30 Nephrotoxic effects are dose dependent, related to renal proximal tubular cell dysfunction. Cidofovir nephrotoxicity leads to proteinuria (protein ⬎ 100 mg/dL) in 50% of reported cases, increased serum creatinine levels (ⱖ0.4 mg/dL [ⱖ35 mol/L]) in 12% of cidofovir-treated pa-
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Fig 2. Pathways for the active renal tubular excretion of antiviral drugs. Uptake of organic anions (OA; such as NRTIs, acyclic nucleotide phosphonates [ANPs]) across the basolateral membrane (BLM) is mediated by the classic sodium-dependent OAT system, which includes alpha-ketoglutarate (KG2)/OA exchange through the OAT1 and sodium-ketoglutarate cotransport through the Naⴙ/dicarboxylate cotransporter. Once these agents accumulate in tubular cells, they interfere with various cell processes and are secreted into tubular lumen through apical membrane carriers or channels.111,112 The apical (brush-border) membrane (BBM) contains various transport systems for efflux of OA (such as ANPs, PIs) into the lumen or reabsorption from the lumen into the cell. The multidrug resistance transporter MRP mediates primary active luminal secretion. It is this pathway of drug elimination by the kidney that fosters proximal tubular injury. Cellular uptake of organic cation (OC) across the BLM is mediated by OCTs. Exit of cellular OC across the BBM is mediated by P-glycoprotein (Pgp). PEPT, peptide transporters; NNRTI, non-nucleoside reverse transcriptase inhibitors.
tients29 and 25% of stem-cell transplant recipients,34 proximal tubular dysfunction (Fanconi syndrome observed in 1% of patients),35-37 and, rarely, chronic interstitial nephritis38 and NDI.5 Changes in renal function parameters after cidofovir therapy were reported to return toward baseline after discontinuation of the drug.35 Dosedependent nephrotoxicity requires dosing adjustment or discontinuation of the treatment if changes in renal function occur during therapy.39 Cidofovir therapy at the usual doses for treatment of CMV-related diseases should not be started if the patient has a serum creatinine concentration greater than 1.5 mg/dL (⬎133 mol/L], creatinine clearance less than 55 mL/ min (⬍0.92 mL/s), urine protein concentration greater than 100 mg/dL, ⫹⫹ proteinuria, or
glycosuria. When possible, cidofovir should not be administered within the 7 days after the administration of any potentially nephrotoxic drug, such as foscarnet, amphotericin B, aminoglycosides, nonsteroidal anti-inflammatory drugs, or N-pentamidine. Adefovir dipivoxil. Adefovir dipivoxil is an analogue of adenosine triphosphate and therefore may interfere with a range of energydependent processes.14 Previous studies indicated that nephrotoxicity was the most important dose-limiting toxicity of adefovir dipivoxil therapy observed when studied in patients with HIV type 1 (HIV-1) infection at doses of 60 and 120 mg/d. Proximal tubular toxicity was documented in 22% to 50% of patients treated with adefovir dipivoxil at greater than 30 mg/d for 72
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weeks.32,40 These changes usually are mild to moderate in severity and can be accompanied by changes in serum potassium, bicarbonate, and uric acid levels; glycosuria; and proteinuria. Time to onset of these changes appeared to be independent of dosage. However, the incidence of these changes appeared to be dose related. Analyses of these changes in HIV-infected patients treated with adefovir dipivoxil, 120 mg/d, showed that a confirmed increase in serum creatinine level of 0.5 mg/dL or greater (ⱖ44 mol/L) from baseline or a confirmed decrease in serum phosphorus level to less than 1.5 mg/dL (⬍0.48 mmol/L) was the most sensitive and specific indicator of adefovir dipivoxil–related nephrotoxicity. Proximal renal tubular toxicity was documented in 22% to 32% of patients treated with adefovir dipivoxil, 120 mg, for 48 weeks.32,40 Median time to resolution of proximal renal tubular dysfunction was 15 weeks among patients assigned to adefovir dipivoxil, and proximal renal tubular dysfunction did not resolve completely in 16% of patients 41 weeks after the onset of nephrotoxicity.41 We previously showed in an uncontrolled study of patients with HIV-1 infection and coinfection with hepatitis B virus that adefovir dipivoxil is not nephrotoxic at a dose of 10 mg/d.42,43 We further analyzed renal data from 2 randomized placebo-controlled trials and confirmed that adefovir dipivoxil nephrotoxicity is dose related. Mild nephrotoxicity was shown with a dose of 30 mg/d, but not in patients treated with adefovir dipivoxil, 10 mg, for a median follow-up of approximately 144 weeks.44 It is plausible that the dual effects of adefovir dipivoxil on mitochondria (carnitine depletion and greater adefovir dipivoxil intracellular concentration on DNA polymerase ␥)45 and renal tubular transporter (Fig 2) may be involved in the nephrotoxicity. Tenofovir disoproxil fumarate. Tenofovir disoproxil fumarate is a reverse-transcriptase inhibitor recently approved to treat HIV infection.46,47 Based on results of clinical trials to date, tenofovir disoproxil fumarate appears to have low nephrotoxic potential. Gallant et al48 reported in a 3-year randomized trial (tenofovir versus stavudine) in antiretroviral-naive patients, through 144 weeks, that the renal safety profile (serum creatinine level elevation, serum phosphorous level decrease) was similar between the 2 groups. No patient experienced grade 4 (phos-
IZZEDINE, LAUNAY-VACHER, AND DERAY
phate ⬍ 1.0 mg/dL [⬍0.32 mmol/L]) hypophosphatemia or (creatinine ⬎ 6 mg/dL [⬎530 mol/ L]) serum creatinine level elevations. The incidence of proteinuria and/or glycosuria was similar between the 2 groups. No patient developed Fanconi syndrome or discontinued from the study because of tenofovir disoproxil fumarate– related renal abnormalities.49 However, several observations of tenofovir-induced proximal tubulopathies have since been published. From our 19 cases, we suggest that normoglycemic glycosuria, mild proteinuria, and hypophosphoremia seem to be early and effective signs of proximal tubulopathy induced by tenofovir.33 Tenofovirrelated nephrotoxicity is manifest primarily after 20 weeks or more of therapy. Median time to resolution of proximal renal tubular dysfunction was 4.7 ⫾ 2.94 weeks (range, 1 to 10 weeks) after drug discontinuation.33 Renal biopsies available from some case reports of tenofovir-induced nephrotoxicity showed that glomeruli were always entirely normal, but there was marked proximal tubular damage. Based on these data, renal injury can be avoided or reduced by using the following guidelines: proper drug dosing for the prevailing level of renal function, avoidance in patients with significant renal impairment, and intravascular volume expansion with intravenous fluids before drug initiation will reduce ARF. Renal tubular transporters hOAT1 and 3 mediate active tubular excretion of tenofovir and adefovir dipivoxil by acting in concert with such apical efflux pumps as MRP4 (Fig 2).50 In this regard, it should be emphasized that 82% of our patients were administered both ritonavir and tenofovir. Although ritonavir is known to inhibit MRP2 activity,51 no data are available on ritonavir-inhibited MRP4 activity. However, we speculate that ritonavir-MRP4 interaction may interfere with tenofovir exit and lead to tubular cell accumulation and toxicity. Foscarnet. Foscarnet is a pyrophosphate analogue commonly used in the treatment of patients with CMV infection. It inhibits herpes virus DNA polymerase and retroviral reverse transcriptase. Various degrees of renal impairment occur in most foscarnet-treated patients. Systematic intravenous hydration has drastically reduced the incidence of foscarnet-induced renal failure from 60% to 10% to 20%.52 Renal failure
ANTIVIRAL DRUG–INDUCED NEPHROTOXICITY
may occur at any time and usually is reversible within the week that follows dosing adjustment or withdrawal of treatment. However, several patients died of foscarnet-induced renal failure within 4 weeks after discontinuation of therapy.53 Cumulative data from US studies conducted in patients with CMV retinitis indicate that abnormal renal function, including ARF, occurred in 27% of 189 patients treated with foscarnet.54 In a large multicenter trial in which patients with CMV retinitis were randomized to the administration of either ganciclovir or foscarnet (60 mg/kg every 8 hours for 2 weeks, followed by 90 mg/kg/d), the adjusted relative risk for developing a serum creatinine level of 2.9 mg/dL or greater (ⱖ743 mol/L) was nearly 3 times greater in the foscarnet group.55,56 Conversely, in a controlled trial comparing foscarnet with vidarabine in a similar group of patients, acute therapy with foscarnet, 40 mg/kg, every 8 hours produced no dose-limiting toxicity, with a serum creatinine level 1.1 times or more the upper limit of normal observed in only 3 of 24 patients.57 Others. Only 1 case of ARF with NDI and proximal tubular dysfunction related to didanosine has been published.58 Furthermore, it was suggested that overdosage of didanosine contributed to Fanconi syndrome and NDI in patients treated with tenofovir.59 Tubular dysfunction may lead to mitochondrial dysfunction, inducing depletion of mitochondrial DNA in renal tubular cells, as reported with stavudine or lamivudine.60 Crystal Nephropathy Deposition of crystals in the kidney can cause renal failure.61 The renal injury occurs from crystals that, because of their relative insolubility in human urine, tend to precipitate in distal tubular lumens.62 A number of routinely prescribed antiviral drugs cause crystal nephropathy.63 Importantly, characteristics common to patients administered these medications seem to predispose to the development of intratubular crystal deposition and tubular obstruction.6 Among factors that increase the likelihood of renal crystal deposition, severe volume depletion, underlying renal impairment, excessive drug dosing, and metabolic perturbations are the most important risk factors6,64 (Table 2).
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Acyclovir. Acyclovir is an antiviral agent shown to be a potent inhibitor of replication of the herpesvirus group. Renal excretion of unchanged drug accounts for approximately 62% to 91% of acyclovir elimination.65,66 Acyclovir is relatively insoluble in urine, with a maximum solubility of 2.5 mg/mL at physiological pH.65,66 This low urine solubility and the low urine output occurring with volume contraction may favor drug crystallization in kidney tubules. Rapid intravenous bolus administration of acyclovir (500 mg/m2) contributes to intratubular precipitation of crystals.65-69 Obstructive tubulopathy developed and drug crystals were observed in the collecting ducts. Conversely, low-dose intravenous and oral acyclovir therapy generally are well tolerated; however, they also can cause ARF in the setting of severe volume depletion.68-70 Asymptomatic renal insufficiency is most common, but flank or abdominal pains occasionally accompany renal failure. Crystal nephropathy often develops within 24 to 48 hours of acyclovir administration. Three large series observed a 12% to 48% incidence of acyclovir-associated renal failure. In 38% to 50% of those cases, serum creatinine levels returned to normal without discontinuation of treatment.65,66,70 Urinalysis usually shows both hematuria and pyuria, whereas birefringent needle-shaped acyclovir crystals also can be seen in urine sediment with polarizing microscopy.65,66,71 Although some patients require temporary dialysis therapy, most recover renal function with discontinuation of acyclovir therapy and volume resuscitation.70 Prevention of acyclovir deposition in the kidneys can be accomplished by avoiding rapid bolus infusion of acyclovir and infusing the drug slowly.65-67,69-71 Volume repletion and induction of high urinary flow rates (100 to 150 mL/h) before drug administration also will prevent crystal precipitation and tubular obstruction.65-67,69-71 Importantly, reduction in acyclovir dose is critical in patients with underlying renal insufficiency. Hemodialysis, which removes significant amounts of acyclovir (40% to 60%), may be indicated when renal failure is severe.72 Indinavir. Indinavir has been noted to cause crystal nephropathy, crystalluria, and nephrolithiasis.73-79 Approximately 20% of the administered drug is cleared by the kidneys, of which 11% is parent compound and the rest is a variety
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of metabolites.76 Indinavir is very soluble at urine pH of 3.5 (100 mg/mL), but relatively insoluble at higher levels of urinary pH (0.35 mg/mL at pH 6.0; 0.02 mg/mL at pH 7.0).74,76 Not unexpectedly, precipitation of indinavir crystals occurs in tubular lumina from the very low solubility of this drug in human urine at a pH range of 5.5 to 7.0. Consequently, intrarenal tubular obstruction can cause ARF or chronic renal failure.73-79 Indinavir therapy is associated with classic renal colic, dysuria, back/flank pain, or gross hematuria in HIV-infected patients that leads to discontinuation of treatment in 0.5% of patients.76 Urological symptoms developed in 8% of patients treated with indinavir.76 Urinary crystals were detected in 20% of patients with HIV infection treated with indinavir, whereas no patient not administered indinavir had similar crystals. Stone formation may occur at any time during treatment, and stones are easily friable and composed solely of indinavir sulfate, which is radiolucent. However, some stones may have associated calcium, rendering them radio-opaque. Crystals of varying shapes are visualized on examination of urine by using a lambda plate and/or polarizing light microscopy.76 Indinavir stones may be passed spontaneously or removed by urological procedures to control pain or relieve urinary obstruction.76,78 Chemical analysis of stones shows a composition consisting of a mixture of indinavir and their metabolites.75,76,78 Most cases of renal failure with indinavir therapy have been mild and reversible; however, more severe renal failure from obstructing indinavir calculi and chronic kidney disease also have been reported.73-79 In addition, interstitial fibrosis and obstructing indinavir calculi can promote impaired renal function.73,78,80 Indinavir therapy should be accompanied by the daily intake of at least 2 to 3 L of fluid by patients to maintain high urinary flow rates and prevent crystal deposition in the kidneys.73-79 Acidification of urine (pH of 3.5 to 4.5) will improve indinavir solubility, but is extremely difficult to achieve and potentially harmful. Therefore, this form of therapy is not recommended. Volume expansion allows therapy with indinavir to continue safely in approximately 75% of patients.76
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Ganciclovir. Intratubular precipitations of ganciclovir associated with serum creatinine level elevation have been reported.81 Schmidt et al82 reported that 20% of bone marrow transplant recipients administered a 120-day course of intravenous ganciclovir had increases in serum creatinine levels to more than 2.5 mg/dL (⬎221 mol/L). This increase in serum creatinine level also might be caused by other comorbidities prevalent in this patient population. Glomerulopathy Glomerular diseases have been noted with both IFN and foscarnet therapies. Approximately 25% of patients treated with IFN-␣ developed mild to moderate proteinuria, and 10% developed an increase in serum creatinine level.7,8,83 Most of these cases occurred in patients with hematologic malignancies or hepatitis. Dialysis was required in some cases. Furthermore, in patients treated with IFN, renal biopsy specimens have shown minimal change disease,84 focal segmental hyalinosis with glomerular visceral epithelial hyperplasia,7,8,85 and crescentic glomerulonephritis.86 Furthermore, Beaufils et al9 reported trisodium foscarnet crystals within the glomerular capillary lumen in several patients experiencing renal dysfunction during foscarnet treatment. Thrombotic Microangiopathy The term thrombotic microangiopathy (TMA) describes syndromes characterized by microangiopathic hemolytic anemia, thrombocytopenia, and variable signs of organ damage caused by platelet thrombi in the microcirculation. Although drug-induced TMA is a rare condition, it causes significant morbidity and mortality. Most cases reported are associated with antineoplastic, immunosuppressant, and only 2 antiviral drugs: IFN and valacyclovir. TMA has been observed in patients treated with IFN for chronic myelogenous leukemia, hairy cell leukemia, and hepatitis C.87 How IFN may induce TMA has not been clarified. The mechanism probably is immunologic; IFN may enhance cellular immunity88 and stimulate HLA-DR antigen expression on glomerular and tubular cells with subsequent attack by activated lymphocytes.89 Moreover, IFN-␣ may induce the production of autoantibodies,90 and the pres-
ANTIVIRAL DRUG–INDUCED NEPHROTOXICITY
ence of antiphospholipids also was reported in patients with IFN-associated TMA.91 Finally, a direct nephrotoxic effect has been proposed.83 In the 12 cases of IFN-associated TMA described in the literature, renal involvement was common and only 1 patient died of TMA. However, kidney prognosis was poor because 5 patients needed long-term dialysis therapy and 2 patients experienced persistent renal failure; 4 patients had normal laboratory values. Some patients received only supportive care, whereas others were treated with plasmapheresis and/or corticosteroids and vincristine.87 Only 1 case of TMA associated with ARF has been reported in an immunocompromised patient treated with valacyclovir.92 Nephrogenic Diabetes Insipidus Drug-induced diabetes insipidus is always of the nephrogenic type, ie, unresponsiveness of the kidney to the action of antidiuretic hormone. NDI is characterized by polyuria, which often is severe and causes thirst and polydipsia. This condition is diagnosed easily by measuring urinary concentrating capacity during a thirst test or by administration of a modified antidiuretic hormone, desmopressin, to show the renal unresponsiveness. A search of the World Health Organization’s adverse-effect database showed 359 reports of drug-induced NDI. Lithium was the most common cause (159 reports), followed by foscarnet (15 cases).93 Foscarnet can affect the vasopressin-responsiveness of the collecting duct and interfere with the kidney’s ability to concentrate urine, leading to a state of NDI4,94 by downregulating the vasopressin-regulated water channel aquaporin-2, which normally is expressed in the apical membrane of the collecting duct. Other antiviral drugs, such as indinavir,95 cidofovir,5 tenofovir,59,96,97 and didanosine,58 may induce NDI. In tenofovir-related cases, all patients were administered ritonavir or lopinavir concomitantly. MRP1 is expressed at the basolateral membrane of cells of Henle’s loop and in the cortical collecting duct98,99 (Fig 2). Inhibition of MRP1 leads to reduced renal tubular responsiveness to vasopressin and may cause, at least in part, NDI.97,98,100,101 Furthermore, it is known that ritonavir inhibits MRP1.101 Thus, we hypoth-
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esize that tenofovir-ritonavir association may induce NDI in some patients. Undetermined ARF Twenty-two observations of ritonavir-induced ARF (with or without saquinavir) have been reported102-104 at a median delay of 2 to 21 days after starting treatment, with a return to normal level within a week after ritonavir withdrawal. Ritonavir reintroduction was associated with a marked increase in serum creatinine level, with a return to normal level in a same delay after ritonavir withdrawal. Witzke et al105 reported 17 observations of renal impairment of 28 HIVpositive patients who were treated with ritonavir in combination with saquinavir. Creatinine levels increased from 0.95 ⫾ 0.19 mg/dL (84 ⫾ 17 mol/L) to 1.18 ⫾ 0.36 mg/dL (104 ⫾ 32 mol/L) with ritonavir treatment. In 9 patients (8 of these patients also were being treated with saquinavir), serum creatinine levels increased (ⱖ0.3 mg/dL [ⱖ27 mol/L] over baseline) within the first week and returned to baseline despite ongoing therapy in 6 patients. Significant renal impairment (increase in serum creatinine ⱖ 0.5 mg/dL [ⱖ44 mol/L]) directly related to the introduction of ritonavir was observed in 3 patients. All patients were concomitantly treated with saquinavir, and 2 patients, with foscarnet also. Renal function was stable under foscarnet therapy in both patients before the introduction of ritonavir and decreased immediately thereafter.105 Bochet et al104 reported a significant (⬎50%) increase in serum creatinine levels in 12 of 87 patients treated with ritonavir. In those patients, median glomerular filtration rates were 116 and 45 mL/min at baseline and a median delay of 112 days of treatment, respectively.104 There were no reported histological data for all those patients. In addition, Stricker et al106 described 2 cases of pancreatorenal syndrome with ritonavir-saquinavir combination and saquinavir alone. In the first patient, dialysis therapy was necessary for 16 days, and the patient gradually improved and was discharged 6 months later with normal renal function. These results imply that ritonavir-treated patients, especially those with other risk factors for renal dysfunction, such as preexisting renal insufficiency, should have their renal function moni-
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tored closely. However, ritonavir nephrotoxicity mechanisms remain unclear. Chronic Renal Failure Antiviral drugs may produce chronic renal failure. It has been reported that long-term treatment with indinavir107 or cidofovir38 may cause chronic renal impairment. Furthermore, renal atrophy has been associated with long-term treatment with indinavir,107 and in another case, atrophy of the kidney was associated with severe hypertension.108 No patient with indinavirinduced renal failure required dialysis. CONCLUSION
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