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exacerbate indinavir crystal deposition within the kidney. [20]. In the presence of a distal renal tubular acidosis (RTA), which occurs in HIV-infected patients, the ...
Current Drug Safety, 2007, 2, 147-154

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Nephrotoxicity Associated with Antiretroviral Therapy in HIV-Infected Patients Mira Rho and Mark A. Perazella* Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, USA Abstract: Antiretroviral therapy (ART) has made a significant impact on the morbidity and mortality of patients with HIV infection. However, many of these agents have nephrotoxic potential and are implicated in causing both acute and chronic kidney disease. Safely employing these medications requires a thorough understanding of risk factors that predispose to kidney injury, which include both patient-related characteristics as well drug-related factors. Acute tubular toxicity, crystal nephropathy, and acute interstitial nephritis are among the common renal manifestations of these drugs. Adefovir and tenofovir are associated with tubular toxicity. Crystalluria, crystal nephropathy and nephrolithiasis have been established with indinavir. Acute interstitial nephritis, although not common among antiretroviral agents, is seen with indinavir and atazanavir in these immunocompromised patients. Rarely, enfuvirtide may promote a glomerulopathy. Frequent exposure to other nephrotoxic non-antiretroviral drugs also contributes to kidney disease. Identification and reversal of potentially modifiable risk factors prior to drug administration is important to limiting kidney injury. Recognition of drugrelated nephrotoxicity will promote earlier resolution of acute kidney injury and reduce the development of chronic kidney disease.

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Keywords: HIV, nephrotoxicity, antiretroviral therapy, HAART, acute kidney injury, chronic kidney disease.

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INTRODUCTION

Antiretroviral agents have been successfully used in managing HIV disease, however these therapeutic agents have been implicated in causing acute kidney injury (AKI). The kidney is responsible for excretion of many of these drugs and their metabolites, and given its high rate of blood flow, is at increased risk to develop drug toxicity. The proximal tubule is particularly susceptible to injury due to nephrotoxin uptake and transport through the intracellular compartments. Several different patterns of renal injury are seen depending on the underlying patient risk factors, the innate nephrotoxicity of the drug, the pharmacokinetics of the drug and the host immune (allergic) response to the administered agent. Understanding these aspects of drug handling and the mechanisms of renal injury are essential for appropriate preventive measures.

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Some drug-induced kidney injury is completely reversible, whereas other forms of toxic injury are irreversible and associated with progression to chronic kidney disease (CKD), especially if not detected early in the course of disease. This may account in part for the high prevalence of kidney disease (up to 30%) noted in HIV-infected patients [1]. However, the contribution of renal failure induced by antiretroviral drugs to this prevalence of kidney disease is not clearly known. Before highly active antiretroviral therapy (HAART) was available, AKI was most often associated with severe immunodeficiency, opportunistic infections and sepsis [2-6]. Although there has been significant improvement in morbidity and mortality among HIV patients on *Address correspondence to this author at the Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, FMP 107, 330 Cedar Street, P.O. Box 208029, New Haven, CT 06520-8029, USA; Tel: (203) 785-4184; Fax: (203) 785-7068; E-mail: [email protected] 1574-8863/07 $50.00+.00

HAART, AKI is still prevalent. This is likely due to the presence of numerous underlying co-morbidities (kidney disease, diabetes mellitus, hypertension, cardiac disease, etc) as well as extensive pharmacotherapy (with inherent nephrotoxic risks) that these patients receive. With this in mind, identifying both patient and drug-related risk factors that predispose to AKI is critical for prevention and preservation of renal function long term. This review will focus on the various risk factors associated with antiretroviral nephrotoxicity, as well as the common renal manifestations of currently used HIV medications. RISK FACTORS

Prior to subjecting a patient to a known nephrotoxic antiretroviral agent, correcting any modifiable risk factors is important to minimize kidney injury. As with nephrotoxicity from any pharmacologic agent, there are both patient-related and drug-related risk factors to consider with initiating antiviral therapy [7, 8]. Pre-emptive risk reduction is the first step in lowering the occurrence of drug-induced nephrotoxicity. Patient Related Risk Factors Drug pharmacogenetics – The role of pharmacogenetics is a potential explanation for the heterogeneous response of patients to xenobiotics as it relates to efficacy and toxicity [9-11]. The hepatic cytochrome P450 (CYP450) enzyme system has several CYP450 enzyme gene polymorphisms that are associated with reduced metabolism and subsequent end organ toxicity. The kidney also possesses CYP450 enzymes that participate in antiretroviral drug metabolism [911]. Gene polymorphisms within the renal system may reduce drug metabolism and potentially increase nephrotoxic risk. Polymorphisms of genes encoding proteins involved in the metabolism and subsequent renal elimination of drugs © 2007 Bentham Science Publishers Ltd.

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have been described and are correlated with various levels of drug sensitivity. Specific to the discussion of nephrotoxicity, loss-of-function mutations in apical secretory transporters, and mutations in kinases that regulate drug carrier proteins can specifically impair some antiretroviral drug elimination and promote toxicity (elevated intracellular toxin concentrations) as these drugs are importantly handled by these pathways [10]. Underlying kidney disease – Acute or chronic kidney disease is a significant risk factor for development of acute kidney injury following exposure to most nephrotoxic substances. The reduced number of functioning nephrons is exposed to higher drug concentrations, enhancing potential nephrotoxicity. Patients may also receive excessive drug dosing if renal function is not in steady state at the time of glomerular filtration rate (GFR) calculation. Underlying impaired kidney function also slows the recovery rate and lengthens the recovery period from drug-induced nephrotoxicity [12-14]. Nephrotic syndrome, which may be present from direct HIV infection within the kidney (HIVAN), other viral infections (hepatitis B and C viruses), or heroin abuse (heroin nephropathy) raises risk through multiple mechanisms that include altered renal perfusion (reduced effective volume), hypoalbuminemia with increased free circulating drug, and unrecognized renal impairment [12, 15-17]. Through induction of renal hypoperfusion, nephrotic syndrome enhances nephrotoxicity of many drugs, in particular those excreted primarily by the kidney, those reabsorbed in the proximal tubule (increased intracellular concentration), and those which tend to be insoluble in the urine (crystal precipitation within distal tubular lumens with sluggish flow) [12, 15-17].

toxins [9-11]. There is significant heterogeneity in the response of patients to drugs and exogenous exposures. A heightened allergic response of some patients as compared with others is an example. Drug-induced stimulation of Tcell production and localization of these cells within the kidney to induce interstitial nephritis has been demonstrated. It is likely that differences in innate host immune response genes predispose certain patients to develop an allergic response to a substance. This translates into enhanced vulnerability to an allergic response in the kidney and development of an acute interstitial nephritis. DRUG-RELATED RISK FACTORS Renal handling of drug - Enhanced toxicity in proximal tubular cells occurs due to the extensive cellular uptake of potential toxins and drugs by both apical and basolateral transport systems. Apical uptake of substances occurs via endocytosis and other transport pathways [21-25]. Another pathway of proximal tubular cell toxin exposure occurs via basolateral delivery of endogenous and exogenous organic ions (anions and cations) by peritubular capillaries [24, 25]. Drug delivery via peritubular capillaries is followed by uptake into proximal tubular cells via a family of transporters, including human organic anion (HOAT) and cation (HOCT) transporters [24, 25] (Fig. 1). As an example, adefovir and tenofovir are transported via HOAT. Transport of these drugs into cells, followed by movement through the intracellular space via various regulated carrier proteins, and subsequent exit from the cells via apical transport proteins enhances toxicity in proximal tubular cells [24, 25]. Loss of function mutations in and competition for apical secretory transporters [25], which reduces toxin efflux from cell into urine, may promote accumulation of toxic substances within proximal tubular cell and cause cellular injury (apoptosis or necrosis). This extensive trafficking of substances increases exposure and risk for elevated concentration of toxin when other risk factors (as discussed) supervene.

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Intravascular volume depletion – This is a general risk factor for drug-related AKI. Use of potent diuretics in conjunction with nephrotoxins, through decreasing intravascular volume and sodium depletion, therefore predisposes to injury. Other states of volume depletion include chronic diarrhea, anorexia, active infections, adrenal insufficiency, and renal salt wasting [18, 19]. States of decreased effective circulating volume such as congestive heart failure, cirrhosis, and sepsis portend similar problems in renal hemodynamics. In these “true” or “effective” volume depleted states, renal hemodynamics are altered due to lower arterial blood pressure and production of renal arteriolar vasoconstricting substances, such as catecholamines, endothelin, vasopressin, angiotensin II, and aldosterone. The net result is renal hypoperfusion and prerenal azotemia. Intravascular volume depletion, through lower urine flow rates also enhances risk for indinavir crystal deposition within tubular lumens and nephrolithiasis. Adequate intravascular volume repletion and correction of the underlying disease state prior to these medications and during the course of treatment is essential to avoid prerenal azotemia and maintain high urine flow rates.

Metabolic abnormalities – Acid-base disturbances can exacerbate indinavir crystal deposition within the kidney [20]. In the presence of a distal renal tubular acidosis (RTA), which occurs in HIV-infected patients, the associated alkaline will increase precipitation of indinavir crystals within tubular lumens and frank stone formation. Immune response – The underlying genetic makeup of the host can enhance renal vulnerability to potential nephro-

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Biotransformation of drugs by multiple renal enzyme systems, including CYP450 and flavin-containing monooxygenases favors the formation of toxic metabolites and reactive oxygen species [26-28]. The presence of these byproducts of metabolism tilts the balance in favor of oxidative stress, which outstrips natural antioxidants and increases renal injury via nucleic acid alkylation or oxidation, protein damage, lipid peroxidation and DNA strand breaks [26-28]. Nephrotoxic potential – The potential for drug-specific nephrotoxicity is important to keep in mind. Not all antiretroviral agents have an adverse effect on the kidneys (Table 1). The underlying characteristics of the offending agent play an important role in the development of nephrotoxicity. From a practical standpoint, prolonged therapy at high doses with toxic substances enhances renal injury based on excessive renal exposure in the absence of other risks. Several drugs maintain extensive toxic potential that enhances renal injury, even with brief exposure. One such example is the antiretroviral agent, adefovir [8, 29]. Tenofovir, on the other hand, requires more prolonged exposure to induce renal injury. These drugs enter the cell via basolateral HOAT-1 and promote cellular injury through multiple mechanisms. Mitochondrial injury (as manifested by mitochondrial enlargement, clumped cristae, and convoluted contours) occurs with

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Fig. (1). Mechanism of tubular secretion of antiretroviral agents. Antiretroviral drugs as either organic anions and organic cations are delivered from the peritubular capillaries into the renal proximal tubular cell via the basolateral membrane transporters, HOAT1, HOAT3, and HOCT. Organic anions consist of agents such as acyclic nucleotide phosphonates, nucleoside reverse transcriptase inhibitors. Organic cations include protease inhibitors. These agents are transported through the cell and exit the cell via apical membrane efflux transporters (MRP2 and MRP4) into the urinary space. The transport of drugs into the intracellular space enhances toxicity in proximal tubular cells. Functional loss of apical secretory transporters increases intracellular concentrations of the drug, potentiating cell injury such as apoptosis and necrosis.

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adefovir through inhibition of DNA polymerase gamma, which is the sole DNA polymerase in mitochondria [8, 29]. Although currently unknown, tenofovir may impair cellular energetics through mitochondrial disruption or some other intracellular process [8, 29]. Another antiretroviral drug factor to be considered in the risk of nephrotoxicity is the effect of these drugs (protease inhibitors, nucleoside transcriptase inhibitors) to induce endothelial dysfunction, as reflected by increased endothelin-1 (ET-1) levels [30]. Endothelial dysfunction, probably occurring through antiretroviral druginduced impairment of mitochondrial function and induction of oxidative stress is associated with renal arteriolar vasoTable 1.

constriction, vascular smooth muscle proliferation and renal cell dysfunction [30]. These effects enhance drug-induced nephrotoxicity. Dose and Duration– With certain agents, the degree of nephrotoxicity is highly dependent on the dose of the drug administered. This is related to high concentrations of drug delivered to the proximal tubules causing direct tubular injury, as well as increasing potential for crystal deposition with indinavir [31]. The duration of drug administration has been shown to correlate with increased nephrotoxicity in certain cases.

Renal Abnormalities by Class of Antiretroviral Agent Protease Inhibitors

Nucleoside RTI

AKI - Acute tubular necrosis

Nucleotide RTI

Fusion Inhibitor

Tenofovir

AKI - Acute interstitial nephritis

Atazanavir Indinavir

AKI - Tubulointerstitial nephritis with crystals

Indinavir

Proximal tubular dysfunction (Fanconi syndrome)

Didanosine

Nephrolithiasis

Indinavir Saquinavir, Nelfinavir

Papillary necrosis

Indinavir

Leukocyturia

Indinavir

Nephrogenic DI Membranoproliferative glomerulonephritis Abbreviations: RTI, reverse transcriptase inhibitor; AKI, acute kidney injury; DI, diabetes insipidus. References: [39, 40, 42-45, 53-56, 61-64, 66-68, 70-73].

Abacavir

Tenofovir

Tenofovir Tenofovir Enfuvirtide

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Drug combinations – These are important to consider especially with HAART, where several of these classes of medications can interact with various other drugs, synergistically worsening renal failure. The mode of drug metabolism is important to keep in mind, as involvement of the p450 system can cause elevated levels of certain drugs that may be nephrotoxic. Elevated levels of tenofovir are commonly seen with the concomitant use of ritonavir-lopinavir [32]. Concomitant administration of trimethoprim-sulfamethoxazole and indinavir increases development of crystal nephropathy [33]. Other nephrotoxins – The concomitant use of other nephrotoxic drugs certainly potentiates the risk for AKI from various antiretroviral agents (Table 2). Medications that should be avoided (when possible) include nonsteroidal antiinflammatory drugs (NSAIDS), aminoglycosides, amphotericin B (including liposomal compounds), foscarnet, acyclovir, pentamidine, intravenous radiocontrast, and ciprofloxacin [34]. ACE-inhibitors and angiotensin-receptor blockers (ARBs) may further enhance risk in the volumedepleted subject getting a nephrotoxic antiretroviral agent. Table 2.

Nephrotoxicity Associated with Non-ART Medications Commonly Administered to HIV Patients

Aminoglycosides

Risk Factor

Cidofovir

Underlying kidney disease is major risk for all these drugs

Foscarnet

Volume depletion

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Ganciclovir (rare)

With ganciclovir - 20% in bone marrow transplant

Acyclovir

Rapid high dose IV infusion

Sulfadiazine

Volume depletion

Tubular toxicity

Amphotericin

Underlying kidney disease

Cidofovir

Foscarnet

Interstitial nephritis

Hyperkalemia

Reduced GFR

Tenofovir, an acyclic nucleoside phosphonate, is a nucleoside reverse transcriptase inhibitor (NRTI) that has known proximal renal tubule toxicity and can present with Fanconi syndrome, manifested by glucosuria, low-grade proteinuria, hypokalemia and hypophosphatemia. When the distal tubule is involved, however, it presents as nephrogenic diabetes insipidus. Although the incidence of renal failure associated with tenofovir is low (0.5-1.5%), the development of acute kidney injury, which is generally reversible if the medication is stopped early, can lead to chronic kidney disease [37, 38].

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Beta-lactams

Beta-lactam allergy

Sulfonamides

Sulfa allergy

Ciprofloxacin

Quinolone allergy

Pentamadine

Underlying kidney disease

Trimethoprim

Volume depletion

Pentamidine

Underlying kidney disease

Abbreviations: IV, intravenous; GFR, glomerular filtration rate. References: [7, 13, 14, 34, 35, 74, 75].

ACUTE TUBULAR TOXICITY Adefovir, a nucleotide analog of adenine, was the first drug developed in the class of nucleotide reverse transcriptase inhibitors. Its nephrotoxic effects relate to direct cytotoxicity at the proximal tubule as well as disruption of ATP-dependent processes involved in intracellular transport at the level of the mitochondria [35]. Prior studies have shown this nephrotoxicity as the most important doselimiting toxicity for adefovir therapy. Adefovir administered

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Tenofovir-associated AKI occurs with prolonged exposure in patients with prior normal baseline renal function and underlying renal insufficiency. In one of the initial case reports, a patient with stable CKD developed acute tubular necrosis after 6 weeks of tenofovir (300 mg per day) [39]. Serum creatinine concentration increased to a peak of 6.2 mg/dl from a baseline of 1.8-2.0 mg/dl. Five weeks after discontinuation of tenofovir, serum creatinine concentration stabilized at 2.0 mg/dl. A recent report examined five patients with normal baseline renal function, which progressed to AKI secondary to acute tubular necrosis in four of the patients, with peak serum creatinine concentration ranging from 1.8 – 7.4mg/dl [32]. In three patients, renal function did not resolve to baseline function (1.4-2.6mg/dl). These patients received tenofovir 300mg/day for 12-29 months and after discontinuation of therapy, the recovery period varied from 7 weeks to 20 months. Another report reviewed five patients on tenofovir with normal baseline renal function (1.0-1.3mg/dl) [40]. In this series, patients were on tenofovir for 7 to 18 months prior to developing acute kidney injury with peak serum creatinine concentration noted at 1.6-2.6 mg/dl. Four of these patients developed Fanconi syndrome, manifesting with glucosuria, acidosis, low-grade proteinuria, hypokalemia, and hypophosphatemia. With discontinuation of tenofovir, renal dysfunction resolved within a period of 1 to 3 months, even with reinstitution of other antiretroviral agents. Fanconi syndrome, in addition to acute tubular necrosis, is well-documented in association with tenofovir use [32, 40-46]. One report described 5 cases of Fanconi syndrome after tenofovir treatment for 5 to 64 weeks [44]. Resolution of proximal tubulopathy occurred 2 to 4 months after stopping this agent. All patients had normal baseline kidney function prior to initiating therapy. These cases suggest that patients with a higher baseline renal function prior to tenofovir-induced AKI fare better. Both shorter recovery time (3 months vs 9-20 months) and higher residual renal function at resolution (GFR, 51-74 ml/min vs 19-37 ml/min; serum creatinine concentration, 1.4-2.6mg/dl vs 0.8-1.7mg/dl) are noted [32, 42, 44]. Importantly, many develop permanent CKD.

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Medication Acute kidney injury

at 10mg has not been shown to be nephrotoxic, however doses over 30mg demonstrated proximal renal tubular dysfunction and renal failure [36]. In this study, the incidence of changes in serum potassium, bicarbonate, uric acid, glycosuria, and proteinuria appeared to be dose related, although the time to onset of these changes were independent of the dose. Lack of power in the studies is likely important in explaining some of the absence of adefovir-associated nephrotoxicity. This medication is no longer employed as antiretroviral therapy.

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In contrast, randomized, double-blinded trials have not demonstrated severe nephrotoxicity with tenofovir. In fact, the renal safety profile of tenofovir is similar to other combination antiretroviral therapy. One study evaluated 552 stable HIV patients who were randomly assigned to receive either placebo or tenofovir 300mg/day for 24 weeks [47]. After 24 weeks, all patients received tenofovir for the remainder of the 48-week study. Overall, there was no difference in the incidence of elevated serum creatinine concentration (>2.0 mg/dl) or hypophosphatemia (6, high concentrations of indinavir >2g/day, concurrent use of trimethoprim-sulfamethoxazole or acyclovir, co-infection with hepatitis B or hepatitis C, and environmental factors such as a warm, humid climate [57-60]. Diagnostically, urinalysis can be obtained to assess for the presence of crystals and pyuria. Since the stones are composed of radiolucent, indinavir sulfate, and would not appear on routine roentgenogram, a noncontrast CT scan is required. Indinavir stones mixed with calcium are radioopaque and easily seen on plain abdominal radiograph. Generally, cases of AKI associated with indinavir are mild and reverse with discontinuation of the medication. However irreversible damage can occur and biopsies have shown interstitial nephritis, interstitial fibrosis and renal atrophy [61, 62].

may be bland and acellular in a significant percentage of cases. In a review of 60 renal biopsies in HIV patients with acute kidney injury, only 2 had drug-related interstitial nephritis [65]. Indinavir is noted to cause acute interstitial nephritis along with crystal deposition within tubules [66]. Atazanavir, a protease inhibitor favorable for its once daily dosing and lipid profile, has been documented in one case to cause acute interstitial nephritis [67]. The patient developed acute kidney injury, which improved after withdrawal of the medication and without steroid therapy. Recognition that these medications can cause AIN will promote early identification and preservation of kidney function when acute kidney injury develops following exposure to these medications. GLOMERULAR DISEASE Membranoproliferative Nephritis Enfuvirtide, a fusion inhibitor, is among the newer agents designed for treatment of multi-drug resistant HIV disease. In a randomized, open-label phase 3 study of enfuvirtide, 501 patients were randomly assigned in a 2:1 ratio to receive enfuvirtide or placebo for evaluation of HIV-1 RNA level from baseline to 24 weeks of therapy [68]. This study reported one patient who developed systemic hypersensitivity reaction and membranoproliferative glomerulonephritis from enfuvirtide after 57 days of therapy. This patient also had risk factors for underlying kidney disease, including diabetes mellitus, proteinuria and hematuria, further predisposing to renal injury. There are no other reports of this glomerulonephritis with enfuvirtide. Based on available data, dose adjustment for the fusion inhibitor does not appear necessary [69]. One report of a patient who initiated enfuvirtide 90mg bid developed an increase in creatinine on day 13 of therapy, however he was also concurrently taking tenofovir, didanosine, lopinavir/ritonavir, lamivudine [69]. Renal biopsy revealed acute tubular toxicity likely secondary to tenofovir. Both tenofovir and enfuvirtide were held with resolution of renal function after 14 days. The patient was then rechallenged with enfuvirtide without tenofovir and had no recurrence of renal dysfunction for the subsequent eight months. Further studies are needed to determine the safety profile of enfuvirtide in patients with significantly impaired renal function.

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Fig. (3). Renal biopsy showing crystal nephropathy from indinavir. Indinavir crystals (arrows) are seen admixed with proteinacious material and cells obstructing the distal tubular lumen (H & E stain, x 350).

Crystal nephropathy and stone formation can be prevented by adequate hydration with least 2 liters of water intake per day to maintain high urinary flow rates, preventing urinary crystal deposition and stone formation. Indinavir can be restarted after adequate volume expansion. Urinary acidification should not be attempted to improve indinavir solubility since this is difficult to achieve and harmful to the patient. Dose reduction may be required in patients with underlying hepatic disease [33]. Both saquinavir and nelfinavir are protease inhibitors with relatively safe renal profiles. However, there is one case report that establishes nephrolithiasis as an adverse effect of these medications [63, 64]. INTERSTITIAL DISEASE Acute Interstitial Nephritis Acute interstitial nephritis (AIN) is often a result of drug therapy (allergic reaction) and generally uncommon from antiretroviral agents. Patients often present with nonspecific symptoms and evidence of acute and sometimes chronic kidney injury, although they may rarely manifest rash, fever or eosinophilia. The time to clinical manifestations range from three days to even weeks or months. The urine sediment typically has white cells, white cell casts or red cells, but

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CONCLUSION Combined use of antiretroviral drugs is currently considered the standard of care in the treatment of HIV disease. The advent of new antiretroviral agents has impacted the morbidity and mortality for patients with this disease. However, these therapeutic agents are not free from nephrotoxic effects and the clinician should be alerted to various renal manifestations, which can potentially be prevented or reduced if patient risk factors are identified and addressed (if possible) prior to therapy. Also, the long term effects of nephrotoxicity can be reduced with early identification of kidney injury in the course of therapy. As new antiretroviral agents become available to treat HIV patients, it is important to keep in mind potential drug-induced nephropathies and drug-drug interactions. Being cognizant of these potential nephrotoxicities is key to reversing acute kidney injury, and preventing development of chronic kidney disease.

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Revised: November 15, 2006

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[62]

Accepted: November 28, 2006