How Antiviral Drugs Have Led to Acute Kidney Injury

Abstract

The introductions of more effective and powerful antiviral drugs are common cause drug-induced acute kidney injury (AKI). The exact prevalence of nephrotoxicity induced by antiviral drugs is difficult to determine. It causes AKI through a variety of mechanisms including acute tubular necrosis (ATN), allergic interstitial nephritis (AIN), and crystal nephropathy. ATN has been described with a number of antiviral drugs such as cidofovir, adefovir and tenofovir with unique effects on transporter defects, apoptosis, and mitochondrial injury. AIN from atazanavir is rapid onset of AKI and usually non-oliguric but dialytic therapy are needed because of severity.Additionally, crystal nephropathy from aciclovir, indinavir, and foscarnet can cause AKI due to intratubular obstruction. In this article, the pathogenesis of antiviral drug-induced AKIwas reviewed and strategies for preventing AKI were mentioned. Keywords:Antiviral drug, acute kidney injury (AKI), cidofovir, adefovir, tenofovir, atazanavir, aciclovir, indinavir, foscarnet.

Acute kidney injury (AKI) is commonly defined as an abrupt decrease in renal function, clinically manifesting as a reversible acute increase in nitrogen waste products over the course of hours to weeks, which encompasses both injury and impairment

1. It is a syndrome that rarely has a sole and distinct pathophysiology. Most of the patients with AKI have a mixed etiology such as septicemia, ischemia and nephrotoxicity from any course, and complicate recognition and treatment
2. Moreover, AKI is quite common among patients without critical illness and it is essential that health care professionals could detect it easily
3. The introduction of more effective and powerful antiviral drugs and the necessity to combine several potentially toxic drugs in complicated patient groups are common causes of the additional increase in the incidence of antiviral drug nephrotoxicity.

Because the kidney has several features that allow nephrotoxins to accumulate. It is highly blood supply and the proximal renal tubule presents a large area for nephrotoxins binding and transport into the renal epithelium. Furthermore, reabsorption of the glomerular filtrate progressively increases intraluminal nephrotoxins concentrations. Nephrotoxic agents have been implicated as etiologic factors in 17% - 26% of in-hospital AKI (4, 5). Drug-induced renal impairment involves many classes of drugs and includes prescription agents as well as commonly over-the-counter (OTC) drugs. There are drug-specific and patient-specific risk factors that influence the development of drug-related nephropathy. In this article, we will review only antiviral drugs associated with nephrotoxicity, especially AKI.

Acute Tubular Necrosis (ATN)Tubular cell death is a major component of toxicity related to many antiviral drugs but mild forms of injury without cellular necrosis or apoptosis, resulting in such isolated tubular defects, distal tubular acidosis and nephrogenic diabetes insipidus (NDI) could occur (6). There are 3 mechanisms of antiviral agents that could induce proximal tubule injury: 1. transporter defects, 2. apoptosis,and 3. mitochondrial injury.Genetic defects in transporters,as in human organic anion transporter 1 (hOAT-1), human organic cation transporter (hOCT), or multidrug resistance - associated protein type 2 (MRP-2), may promote renal insufficiency during treatment with antiviral drugs. The Intracellular concentration of drug is the major factor in its tubular cells toxicity. The pathophysiology is intracellular influx through hOAT-1 and a defect in luminal excretion through MRP-2 or both. Genetic defects in transporters,as in hOAT, hOCT, or MRP (7, 8). Renal function usually improves upon discontinuing antiviral nucleoside analogues (NA) however they can also lead to end stage renal diseases.

CidofovirCidofovir is a monophosphate NA with inhibitory activity against human herpesvirus, adenovirus, polyomavirus, papillomavirus, and poxvirus. After undergoing cellular phosphorylation to its diphosphate form, it competitively inhibits the incorporation of deoxycytidine triphosphate into viral DNA. Incorporation of the drug disrupts further chain elongation (9, 10). Cidofovir has very low oral bioavailability. Penetration into the CSF is also low. Plasma levels after intravenous dosing decline in a biphasic pattern with a terminal t1/2 that averages 2.6 hr. The active form, cidofovir diphosphate, has a prolonged intracellular t1/2 and competitively inhibits CMV and HSV DNA polymerases at concentrations one-eighth to one six-hundredth of those required to inhibit human DNA polymerases. The prolonged intracellular t1/2 of cidofovir diphosphate allows infrequent dosing regimens. Cidofovir is cleared by the kidney via glomerular filtration and tubular secretion. Over 90% of the dose is recovered unchanged in the urine (11, 12). Intravenous cidofovir is approved for the treatment of CMV retinitis in HIV-infected patients. It also has been used for treating acyclovir-resistant mucocutaneous HSV infection, adenovirus disease in transplant recipients, and extensive molluscum contagiosum in HIV patients. Cidofovir causes proximal tubular cell injury andAKI in a dose-dependent manner.

Dose Dependent Nephrotoxicity requires dosing adjustment for discontinuation of the treatment if changes in renal function occur during therapy (13). Increased cellular uptake of acyclic nucleotide cidofovir by hOAT-1favors proximal tubular dysfunction. Ortiz reported that cidofovir induced apoptosis in primary cultures of human proximal tubular cells which the pattern of apoptosis consistent with that of clinical toxicity. These data suggested that apoptosis induction is a mechanism contributing to cidofovir nephrotoxicity (14).On maintenance doses of 5 mg/kg every 2 weeks, up to 50% of patients develop proteinuria, 10%–15% show an elevated serum creatinine concentration, and 15%–20% develop neutropenia. Anterior uveitis and cycloplegia occurs commonly, and low intraocular pressure occurs infrequently with intravenous cidofovir. Administration with food and pretreatment with anti-emetics, antihistamines, or acetaminophen may improve tolerance (13). Concurrent nephrotoxic agents are contraindicated, and at least 7 days should elapse before initiation of cidofovir treatment is recommended after prior exposure to aminoglycosides, intravenous pentamidine, amphotericin B, foscarnet, NSAID, or contrast media(15).Probenecid blocks tubular transport of cidofovir and reduces renal clearance and associated nephrotoxicity (16).AdefovirAdefovir dipivoxil is a ester prodrug of adefovir, an acyclic phosphonate NA of adenosine monophosphate. Adefovir dipivoxil enters cells and is de-esterified to adefovir. Adefovir is converted by cellular enzymes to the diphosphate, which acts as a competitive inhibitor of viral DNA polymerases and reverse transcriptases with respect to dATP and also serves as a chain terminator of viral DNA synthesis. The adefovir dipivoxil dose is 10 mg once daily but must be reduced for those with renal impairment (17). The parent compound has low oral bioavailability, whereas the dipivoxil prodrug is absorbed rapidly and hydrolyzed by esterases in the intestine, liver, and blood to adefovir, providing a bioavailability of about 30% - 60%. The drug is eliminated unchanged by the kidney through a combination of glomerular filtration and tubular secretion with secretion contributing about 60%. Dose reductions are recommended for creatinine clearance values below 50 mL/min (18).

Adefovir has a high affinity for substrates of hOAT-1, whereas they were found to be only marginally transported by hOAT-3 in some studies. The affinity forhOAT-3 is about 50-fold lower than for hOAT-1 (19, 20). Tanji and colleague described the main site of targeted nephron segment of adefovir appears to be proximal tubular cells. Adefovir-induced cellular damage has been attributed to mitochondrial injury, impaired ATP synthesis,and/or interference with ATP-dependent cellular mechanisms. Tanji also reported that upon ultrastructural examination, proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae (21). Functional histochemical stains for mitochondrial enzymes revealed focal tubular deficiency of cytochrome C oxidase with preservation of succinate dehydrogenase.This indicated that adefovir-induced nephrotoxicity is mediated by depletion of mtDNA from proximal tubular cells through inhibition ofmtDNA replication.

Adefovir dipivoxil causes dose-related nephrotoxicity and tubular dysfunction, manifested by azotemia and hypophosphatemia, acidosis, glycosuria, and proteinuria, which usually are reversible months after discontinuation. Adverse events lead to premature discontinuation in about 2% of patients. After 3 years of treatment, the risk of serum creatinine levels rising above 0.5 mg/dL is approximately 3% - 4% but is higher in those with pre-existing renal insufficiency (22).

Tenofovir

Tenofovir disoproxil fumarate (TDF) is a nucleotide analogue reverse-transcriptase inhibitor (NtRTI). TDF is used to treat chronic hepatitis B and to prevent and treat HIV/AIDS (23, 24). With TDF, cellular esterases cleave the diester, yielding tenofovir in plasma, which enters cells and is subsequently phosphorylated by cellular kinases to tenofovir diphosphate.Tenofovir is not metabolized by CYP enzymes and tenofovir pharmacokinetics is not altered in hepatic impairment patients. The t1/2 of tenofovir in plasma is 17 hr, and the t1/2 of the active form of the drug, tenofovir diphosphate, is 6-days and 17 days in peripheral blood and red blood cells, respectively (24). Tenofovir is eliminated unchanged in the urine by a combination of glomerular filtration and proximal tubular secretion, and 20% - 30% of the drug is actively transported into renal proximal-tubule cells by hOAT-1.

TDF is also a substrate for permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and thus tenofovir may be affected by drugs that inhibit or induce these transporters. Kidney Toxicity may lead to AKI,chronic kidney disease (CKD), and features of proximal tubular injury, including Fanconi syndrome,isolated hypophosphatemia, and decreased bone mineral density.Fernandez-Fernandez Demonstrated tubular dysfunction with tenofovirin 17% - 22% of tenofovir-treated patients (25).Tenofovir is taken up by hOAT-1 and hOAT-3 and efflux into urine byMRP-4 in proximal-tubule cells. When there is reduced apical efflux transport out of the cell (MRP-4 transporter mutation or drug competition), tenofovir will injure cells primarily by inducing mitochondrial dysfunction. The renal biopsy finding is varying degrees of chronic tubule-interstitial scarring with tubular atrophy and interstitial fibrosis. A large-scaled population-based study of 53,500 ChineseCHB subjects showed that NA treatment in general did not increase the risk of hard renal events including renal failure and renal replacement therapy (RRT); these events happened in 1.4% and 0.7%,respectively, in NA-treated patients at a median follow-up of4.9 years (26). The renal safety profile was further demonstrated by another 2cohort studies from Europe and USA (27, 28). It implies that with monitoring adequately of renal function with proper adjustment of dosages of NA, NA can be used without increasing significant renal events in CHB patients.Allergic Interstitial Nephritis (AIN)Idiosyncratic or allergic reaction leading to inflammation and infiltration of immune cells leading to injury to the renal tubules and interstitium could occur from antiviral drugs. The hallmark of classic AIN is rapid onset of AKI after the initiation of a suspect drug.

Renal injury is usually non-oliguric but severe AKI and dialytic therapy are needed.Renal dysfunction in druginducedAIN is believed to be the cause of AKI in 3% -15%of all cases (29). The onset may range from 3 to 20 days and may be accelerated following re-challenge. In general the clinical presentation includes, fever, rash and eosinophilia. However this triad only occurs in one third of the patient who actually has the disease. In addition AIN is often accompanied by low grade proteinuria and biopsy findings consistent with interstitial infiltration of immune cells.Diagnosis is based on clinical evidence. The ultrasound or CT scanning may show renal enlargement (30).AtazanavirAtazanavir is an azapeptide protease inhibitor (PI) that is active against both HIV-1 and HIV-2. Atazanavir, with or without ritonavir, is approved for treatment of adults and pediatric patients more than 3 months of age and weighing at least 5 kg. Atazanavir is absorbed rapidly after oral administration and should be administered with food. Absorption is pH dependent, and proton pump inhibitors or other acid-reducing agents substantially reduce atazanavir concentrations after oral dosing.

The mean elimination t1/2 of atazanavir increases with dose, from 7 hr. at the standard 400-mg once-daily dose to nearly 10 hr. at a dose of 600 mg. The atazanavir dose is 400 mg once daily in adults if given without a pharmacokinetic enhancer (ritonavir or cobicistat) and 300 mg if given with ritonavir 100 mg or cobicistat 150 mg (31). The drug is present in CSF at less than 3% of plasma concentrations but has excellent penetration into seminal fluid. Brewster and Perazellafirst described PAIN associated with atazanavir in 2004. They speculated that a hypersensitivity type reaction may be the underlying mechanism in the relationship between atazanavir and tubulointerstitial nephritis, lacking the granuloma formation (32). Atazanavir and it metabolites that are insoluble in urine frequently cause renal injury. In addition to drug characteristics that induce insolubility, factors such as urine pH, slow urine flow rates, and rapid parenteral administration enhance risk for precipitation and crystal formation in distal tubular lumens.There are many cases showing an association between atazanavir use and AIN including granulomatous interstitial nephritis(GIN).Schmid et al. also suggested that the intrarenal activation of cytotoxic T cells may be one of the pathomechanisms of interstitial nephritis. The patients clinically manifested AKI in 4–16 weeks after the administration of atazanavir/ritonavir, and showed no granuloma formation (33).There are eight case reports, showing an association between atazanavir/ritonavir use and tubulointerstitial nephritis including GIN.

Three cases were reversible. However, renal biopsy has confirmed crystal-associated chronic GIN in a few patients. The clinical course was of progressive CKD with frequent crystalluria, hematuria and proteinuria in. Withdrawal of atazanavir does not lead to recovery of renal function (34). Therefore, periodic careful monitoring about hematuria and renal function tests is the most important in early identification of AIN or GIN. Dose reduction should be considered in particular when hematuria is sustained concurrently with crystalluria.Crystal NephropathyDeposition of crystals within the kidney can promote acute and chronic kidney injury. A variety of drugs can cause crystalluria, whereas massive amounts of crystals within the renal tubules can cause acute kidney injury (AKI) due to intratubular obstruction. Renal dysfunction most commonly occurs owing to precipitation of crystals in distal tubular lumens. Several routinely prescribed medications can cause crystal-induced AKI termed “crystal nephropathy” (35).Predisposing factors are the degree of supersaturation of constituent molecules, urine pH, and the presence or absence of inhibitors of crystallization,severe volume depletion,underlying renal impairment, excessive drug dosing, and metabolic perturbations such as systemic metabolic acidosis or alkalosis or renal tubular acidosis may exacerbate intra-renal crystal deposition (36). AciclovirAciclovir was the first antiviral drug with selective toxicity. It inhibits the replication of certain viruses while exhibiting virtually no toxic side effects on host cells. Structurally, it is acyclo-guanosine, an analogue of the purine nucleoside, guanosine.

Aciclovir itself is inactive; it must be phosphorylated on the 5ʹ-hydroxyl group to the triphosphate form within the infected cells. Renal excretion of unchanged drug accounts for 62% - 91% of acyclovir. Acyclovir is relatively insoluble in urine.This low urine solubility and the low urine output occurring with volume contraction may favor drug crystallization in distal tubules (37). Rapidintravenous bolus administration of acyclovir contributes to intratubular precipitation of crystals. Obstructive tubulopathy developed and drug crystals were observed in the collecting ducts. Crystal nephropathy often develops within 24 to 48 hours of acyclovir administration. The mechanisms of acyclovir-induced nephrotoxicity has been believed its crystallization in tubular lumen leading obstructive nephropathy.Sawyer reported on four patients with a chronic fatigue syndrome who experienced five episodes of acute renal insufficiency associated with high dose intravenous acyclovir administered (38).Nephrotoxicity developed despite precautions to avoid volume contraction. Examination of the urinary sediment of three patients by polarizing microscopy showed bi-refringent needle shaped crystals within leukocytes. In the most severely affected patient, a serum creatinine concentration of 8.6 mg/dl developed, and the patient underwent percutaneous renal biopsy that revealed foci of interstitial inflammation without tubular necrosis (39). Urine, blood, and renal tissue levels of acyclovir were high. They concluded that combined data from these patients support crystalluria and obstructive nephropathy as a mechanism of acyclovir-induced renal failure. It is very important to maintain adequate hydration during high-dose acyclovir therapy (40).

Indinavir

Indinavir is a protease inhibitor used in the treatment of HIV infection. Approximately 20 % of the drug is cleared by kidney. Indinavir has low solubility at a pH of 6.0 but is quite soluble at a pH of 3.5.

This has important clinical implications as precipitation of indinavir crystals occurs within the tubular lumens in human urine at a pH of 5.5 – 7.0. Consequently, intra-renal tubular obstruction can cause acute or CKD (41). In addition, interstitial fibrosis and obstructing calculi can lead to renal dysfunction. Pharmacokinetic interactions between indinavir and other drugs, such as trimethoprim-sulfamethoxazole, and underlying liver disease may lead to increased blood concentrations of indinavir, with increased urinary excretion of crystals and a greater risk of renal injury.

Crystalluria, crystal nephropathy, nephrolithiasis, interstitial nephritis, and lower urinary tract inflammation have all been described in association with indinavir dosage. The nephrotoxicity of indinavir has two syndromes, one a syndrome of acute nephrolithiasis and the other of chronic indolent renal impairment. The pathogenesis of both has been difficult to determine. However, the evidence supports that indinavir can cause nephrolithiasis and renal impairment as a result of crystallization in the urinary tract. Studies have suggested that cofactors such as the administration of concomitant cotrimoxazole and aciclovir as well as low weight, low lean body mass, and ambient temperature may all increase the risk of indinavir-associated nephrolithiasis (42).

Renal colic, dysuria, back or flank pain,and gross hematuria has been described in HIV-infected patients treated with indinavir. In asymptomatic patients, elevated serum creatinine concentrations or abnormal urinalysis may be the only clue to renal injury. Microscopy of the urine sediment reveals crystals of varying shapes, including plate-like rectangles, fan-shaped crystals, and star bust forms. Chemical analysis of stones reveals a mixture of indinavir and its metabolites. However, more severe kidney failure from obstructing indinavir calculi as well as CKD has also been reported (43).Prevention of crystal deposition in the kidneys mandates that patients ingest at least 2 – 3 l of fluid per day. Most cases of indinavir-associated AKI are mild and reversible. Discontinuation of indinavir generally reverses nephrotoxicity. However, CKD from interstitial fibrosis has been noted with late recognition of drug nephrotoxicity.As indinavir is metabolized primarily in the liver through the P450, patients with hepatic dysfunction should have a dose reduction (44). FoscarnetFoscarnet is an inorganic pyrophosphate analog that inhibits herpesvirus DNA polymerase, RNA polymerase,and HIV reverse transcriptase directly. Foscarnet blocks the pyrophosphate binding site of these enzymes and inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates. Foscarnet is available in an intravenous formulation only because of poor oral bioavailability and gastrointestinal intolerance. Clearance of foscarnet is primarily renal and is directly proportional to creatinine clearance. Serum drug concentrations are reduced 50% by hemodialysis (45). Potential adverse effects of foscarnet include crystal nephropathy, hypo- or hypercalcemia, hypo- or hyperphosphatemia, hypokalemia, and hypomagnesemia. Foscarnet crystals have been observed in early segments of the nephron and within glomerulus of patients who developed renal insufficiency following repeated infusion of high doses for cytomegalovirus infection.

The crystals were identified as calcium and/or sodium salts of foscarnet (46). Saline preloading helps prevent nephrotoxicity and avoidance of concomitant administration of drugs with nephrotoxic potential. Foscarnet-induced renal impairment is almost always reversible on cessation of the drug (47). More recent studies have shown that foscarnet inhibits the membrane-associated carbonic anhydrase (hCA) IV, which is highly abundant in the kidneys. The authors hypothesized that inhibition of this enzyme might explain some of the renal adverse effects of foscarnet (48). Cidofovir is delivered to the basolateral membrane, transported into the cell via the human organic anion transporter-1 (OAT-1), and excreted into the urinary space. MRP-4 transporter mutation or drug competition will induce accumulation of tenofovir and damaged mitochondria of proximal tubular cells.