Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities
2010; Elsevier BV; Volume: 78; Issue: 11 Linguagem: Inglês
10.1038/ki.2010.318
ISSN1523-1755
AutoresLeal Herlitz, Sumit Mohan, Michael B. Stokes, Jai Radhakrishnan, Vivette D. D’Agati, Glen S. Markowitz,
Tópico(s)Hepatitis B Virus Studies
ResumoTenofovir, a widely prescribed antiretroviral medication for treatment of HIV-1 infection, is infrequently associated with renal dysfunction and biopsy findings of acute tubular necrosis. We examined the clinical and pathological findings in 13 cases of tenofovir nephrotoxicity (7 men and 6 women, mean age of 51.1±9.6 years). Patients received tenofovir therapy for a mean of 19.6 months (range, 3 weeks to 8 years; median 8 months). Nine patients presented with acute kidney injury, and four had mild renal insufficiency with subnephrotic proteinuria. Mean baseline serum creatinine was 1.3±0.3 mg/dl, reaching 5.7±4.0 mg/dl at the time of biopsy, with mean proteinuria of 1.6±0.3 g/day. Glycosuria was documented in seven patients, five of whom were normoglycemic. Renal biopsy revealed toxic acute tubular necrosis, with distinctive proximal tubular eosinophilic inclusions representing giant mitochondria visible by light microscopy. Electron microscopy showed mitochondrial enlargement, depletion, and dysmorphic changes. Clinical follow-up after tenofovir discontinuation was available for 11 of 13 patients (mean duration 13.6 months). Significant recovery of renal function occurred in all patients, including four who required transient hemodialysis. Our study shows that tenofovir nephrotoxicity is a largely reversible form of toxic acute tubular necrosis targeting proximal tubules and manifesting distinctive light microscopic and ultrastructural features of mitochondrial injury. Tenofovir, a widely prescribed antiretroviral medication for treatment of HIV-1 infection, is infrequently associated with renal dysfunction and biopsy findings of acute tubular necrosis. We examined the clinical and pathological findings in 13 cases of tenofovir nephrotoxicity (7 men and 6 women, mean age of 51.1±9.6 years). Patients received tenofovir therapy for a mean of 19.6 months (range, 3 weeks to 8 years; median 8 months). Nine patients presented with acute kidney injury, and four had mild renal insufficiency with subnephrotic proteinuria. Mean baseline serum creatinine was 1.3±0.3 mg/dl, reaching 5.7±4.0 mg/dl at the time of biopsy, with mean proteinuria of 1.6±0.3 g/day. Glycosuria was documented in seven patients, five of whom were normoglycemic. Renal biopsy revealed toxic acute tubular necrosis, with distinctive proximal tubular eosinophilic inclusions representing giant mitochondria visible by light microscopy. Electron microscopy showed mitochondrial enlargement, depletion, and dysmorphic changes. Clinical follow-up after tenofovir discontinuation was available for 11 of 13 patients (mean duration 13.6 months). Significant recovery of renal function occurred in all patients, including four who required transient hemodialysis. Our study shows that tenofovir nephrotoxicity is a largely reversible form of toxic acute tubular necrosis targeting proximal tubules and manifesting distinctive light microscopic and ultrastructural features of mitochondrial injury. Tenofovir disoproxil fumarate (TDF) is an acyclic nucleotide analog reverse transcriptase inhibitor approved for the treatment of human immunodeficiency virus 1 (HIV-1) and hepatitis B infections. TDF is widely prescribed, and is an integral part of each of the four ‘preferred’ regimens for treatment of HIV-1 in antiretroviral-naïve adults and adolescents.1.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. US Department of Health and Human Services, Rockville, MD. 1 December 2009. Available athttp://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf, accessed in 5 April 2010Google Scholar TDF has gained popularity because of its convenient dosing schedule, antiviral efficacy, and relatively favorable side-effect profile, making it one of the most widely prescribed antiretroviral drugs for the treatment of HIV-1.2.Jimenez-Nacher I. Garcia B. Barreiro P. et al.Trends in the prescription of antiretroviral drugs and impact on plasma HIV-RNA measurements.J Antimicrob Chemother. 2008; 62: 186-822Crossref Scopus (35) Google Scholar Closely related drugs, including adefovir and cidofovir, are no longer used for HIV-1 infection because of their high incidence of renal toxicity.3.Tanji N. Tanji K. Kambham N. et al.Adefovir Nephrotoxicity: possible role of mitochondrial DNA depletion.Hum Pathol. 2001; 32: 734-740Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar,4.Meier P. Dautheville-Guibal S. Ronco P. et al.Cidofovir-induced end-stage renal failure.Nephrol Dial Transplant. 2002; 17: 148-149Crossref PubMed Scopus (58) Google Scholar In contrast, TDF appears to be generally well tolerated, with minimal nephrotoxicity reported in early studies.5.Gilead Sciences Viread (Tenofovir Disoproxill Fumarate): Highlights of Prescribing Information. Gilead Sciences, Foster City, CA2010www.viread.comGoogle Scholar Postmarketing safety data covering 455,392 person-years of TDF exposure showed a renal serious adverse event in only 0.5% of patients and graded elevations in serum creatinine in 2.2% of patients.6.Nelson M. Katlama C. Montaner J. et al.The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years.AIDS. 2007; 21: 1273-1281Crossref PubMed Scopus (281) Google Scholar Although relatively uncommon, TDF has been linked to the development of proximal tubular dysfunction,7.Labarga P. Barreiro P. Matin-Carbonero L. et al.Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir.AIDS. 2009; 23: 689-696Crossref PubMed Scopus (250) Google Scholar Fanconi syndrome, and acute kidney injury (AKI). Reports of Fanconi syndrome and acute renal failure attributed to TDF have been published in multiple individual case reports and small series.8.Verhelst D. Monge M. Meynard J.L. et al.Fanconi syndrome and renal failure induced by Tenofovir: a first case report.Am J Kid Dis. 2002; 40: 1331-1333Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, 9.Coca S. Perazella M. Acute renal failure associated with tenofovir: evidence of drug-induced nephrotoxicity.Am J Med Sci. 2002; 324: 342-344Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 10.Rifkin B. Perazella M. Tenofovir-associated nephrotoxicity: Fanconi syndrome and renal failure.Am J Med. 2004; 117: 282-283Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 11.Peyriere H. Reynes J. Rouanet I. et al.Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases.J Aquir Immune Defic Syndr. 2004; 35: 269-273Crossref PubMed Scopus (255) Google Scholar, 12.Zimmerman A. Pizzoferrato T. Bedford J. et al.Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions.Clin Infect Dis. 2006; 42: 283-290Crossref PubMed Scopus (270) Google Scholar, 13.Agarwala R. Mohan S. Herlitz L. et al.41-year-old HIV patient with proteinuria and progressive renal dysfunction.Kidney Int. 2010; 77: 475-476Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Although several patients underwent renal biopsy, only one previous series has examined the morphological features of TDF nephrotoxicity.14.Cote H. Magil A. Harris M. et al.Exploring mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction among HIV-infected patients on highly active antiretroviral therapy.Antivir Ther. 2006; 11: 79-86PubMed Google Scholar We present the first biopsy-based series of TDF-associated renal dysfunction, including presenting clinical features and outcome. A total of 13 cases of TDF nephrotoxicity, a toxic form of acute tubular necrosis related to treatment with TDF, were identified from the archives of the Columbia University Renal Pathology Laboratory between October 2001 and January 2010. Four additional potential cases were excluded, including two in which the tubular injury more likely related to prerenal azotemia and hypovolemia, one patient who had received a liver transplant for viral hepatitis and was on other nephrotoxic medications including cyclosporine, and one in which the patient was also taking cidofovir, a chemically related drug with established renal toxicity.4.Meier P. Dautheville-Guibal S. Ronco P. et al.Cidofovir-induced end-stage renal failure.Nephrol Dial Transplant. 2002; 17: 148-149Crossref PubMed Scopus (58) Google Scholar Patient demographics and clinical characteristics are presented in Table 1. The cohort of 13 patients had a male:female ratio of 7:6 and included seven African-American, five Caucasian, and one Hispanic patient. The mean age at biopsy was 51.1±9.6 years (range, 38–68 years). All patients had HIV-1 infection, including two patients who were coinfected with hepatitis C virus and two who had a history of coinfection with hepatitis B virus but no detectable hepatitis B viremia at the time of biopsy. A complete list of antiviral medications for each patient is presented in Table 1. Information on viral load and/or CD4 count was available for 10 of 13 patients. All 10 patients had undetectable viral load, with mean CD4 count of 339±270 cells/ml (range, from 11 to 728 cells/ml). The duration of TDF therapy at the time of biopsy ranged from 3 weeks to 8 years, with a mean of 19.6±26.1 months and a median of 8 months.Table 1Demographics, clinical characteristics, and follow-up12345678910111213Age/gender40/M51/F63/M53/M68/F52/F56/M38/M41/F55/M60/M57/F58/FRaceAAAAAAAAAACHispCCCCAAAAViral infectionsHIV, HBV (tx’d)HIVHIVHIVHIVHIVHIVHIV, Anti-HBc+HIVHIVHIVHIV, HCVHIV, HCVHIV controlVL<50; CD4 417aCD4 is measured as cells/ml.VL<50; CD4 75aCD4 is measured as cells/ml.NAVL<50; CD4 82aCD4 is measured as cells/ml.VL<50; CD4 11aCD4 is measured as cells/ml.‘Good control’VL<50; CD4 728aCD4 is measured as cells/ml.VL<50‘Good control’VL 500aCD4 is measured as cells/ml.VL<50VL<50; CD4 275aCD4 is measured as cells/ml.VL<50; CD4 624aCD4 is measured as cells/ml.Antiviral medicationsTDF, FTC, ATV, RTVTDF, FTCTDF, FTC, EFVTDF, DDI, ATV, RTVTDF, DDI, LPVTDF, FTC, EFVTDF, LPV, RTVTDF, AZT, RTVTDF, FTC, EFVTDF, DRV, RTVTDF, FTC, LPV, RTVTDF, NVP, LPV, RTVTDF, FTC, ATV, RTVDuration of TDF Rx (months)482486680.752412796124DiabetesNoYesYesNoNoYesNoNoNoNoNoNoNoHypertensionNoNoYesNoNoYesNoNoNoYesNoNoNoBaseline SCr (mg/dl)/(months before bx)1.4 (1)1.8 (5)1.5 (1)1.2 (6)1.6 (2)1.2 (8)1.0 (0.75)1.0 (5)0.8 (12)1.3 (12)1.6 (12)1.3 (4)1.0 (4)Findings at the time of biopsy Indication for biopsyProtAKIAKIProtAKIAKIAKIProtProtAKIAKIAKIAKI SCr (mg/dl)1.76.35.52.16.84.6131.61.11394.84.9 Proteinuria1.86 g/day2.07 g/day1+1.5 g/day3+1+Anuria1.3 g/day1.2 g/day2 g/dayAnuria1.47 g/day2+ HematuriaNoMicroscopicNoNoMicroscopicNoAnuriaNoNoNoAnuriaNoNo Glycosuria1+3+Neg1+1+3+Anuria1+Neg250 mg/dlAnuriaNegNeg Serum glucose106138NormalNormal76170Normal94NormalNormalNormal12589Follow-upbAll patients were taken off tenofovir therapy, and follow-up duration is calculated from the date of tenofovir discontinuation. Required HD?NoYes, for 4 monthsYes, for 1 monthNANoNoYes, for 1 monthNoNoYesYes, for 1 monthNoNo Duration (days)15814434NA16117291701183146NA131309338 SCr (mg/dl)1.31.2Off HDNA1.61.61.40.80.8NA1.941.21.2 Proteinuria66 mg/dlNANegNANANegNegNeg25 mg/dlNANANegTraceAbbreviations: AA, African American; AKI, acute kidney injury; Anti-HBc+, hepatitis B core antibody positive; ATV, atazanavir; AZT, zidovudine; bx, biopsy; C, Caucasian; DRV, darunavir; EFV, efavirenz; F, female; FTC, emtricitabine; HBV, hepatitis B virus; HCV, hepatitis C virus; HD, hemodialysis; Hisp, Hispanic; HIV, human immunodeficiency virus; LPV, lopinavir; M, male; NA, not available; Neg, negative; NVP, nevirapine; prot, proteinuria (≥1 g/day); RTV, ritonavir; Rx, treatment; SCr, serum creatinine; TDF, tenofovir disoproxil fumarate; tx’d, treated; VL, viral load (copies/ml).a CD4 is measured as cells/ml.b All patients were taken off tenofovir therapy, and follow-up duration is calculated from the date of tenofovir discontinuation. Open table in a new tab Abbreviations: AA, African American; AKI, acute kidney injury; Anti-HBc+, hepatitis B core antibody positive; ATV, atazanavir; AZT, zidovudine; bx, biopsy; C, Caucasian; DRV, darunavir; EFV, efavirenz; F, female; FTC, emtricitabine; HBV, hepatitis B virus; HCV, hepatitis C virus; HD, hemodialysis; Hisp, Hispanic; HIV, human immunodeficiency virus; LPV, lopinavir; M, male; NA, not available; Neg, negative; NVP, nevirapine; prot, proteinuria (≥1 g/day); RTV, ritonavir; Rx, treatment; SCr, serum creatinine; TDF, tenofovir disoproxil fumarate; tx’d, treated; VL, viral load (copies/ml). Indications for renal biopsy included AKI in nine patients and milder reductions in renal function accompanied by proteinuria (≥1 g/day) in four patients. Serum creatinine measurements are provided in Table 1. Among the 13 patients, 7 had already been taking TDF for some period of time when the ‘baseline’ creatinine was recorded. The remaining six patients had not yet commenced treatment with TDF. Mean baseline serum creatinine was 1.3±0.3 mg/dl, ranging from 0.8 to 1.8 mg/dl. TDF requires renal dosing when glomerular filtration rate is below 50 ml/min, a condition met by three patients in this series. Data regarding TDF dosage was available for only one of these patients who was receiving an appropriately adjusted dose based on the level of renal insufficiency. The mean serum creatinine at the time of biopsy was 5.7±4.0 mg/dl (range, 1.1–13 mg/dl). Proteinuria was quantitated by 24-h collection or by dipstick in all of the 11 patients who were not anuric at the time of biopsy. Among the seven patients with a 24-h urine collection, the mean proteinuria was 1.6±0.3 g/day (range, 1.2–2.07 g/day). The remaining four patients had evidence of 1–3+ proteinuria on urinalysis. Glycosuria was detected in seven patients, five of whom were normoglycemic and two of whom were hyperglycemic with a history of diabetes. Microscopic hematuria was present in 2 of 11 patients. Renal biopsy findings are presented in Table 2. The major finding in all cases was proximal tubular injury, which ranged from diffuse and severe (n=11) (Figure 1a) to mild and localized (‘patchy’; n=2), and was associated with varying degrees of chronic tubulointerstitial scarring (that is, tubular atrophy and interstitial fibrosis) (Figure 1b). In 10 of the 13 cases, findings of acute tubular injury predominated, meriting a diagnosis of toxic acute tubular necrosis. In the remaining three cases, the findings of chronic injury predominated, leading to a diagnosis of acute and chronic tubulointerstitial nephropathy. Additional unrelated processes were identified in five cases, including two with diabetic glomerulosclerosis, two with significant arterionephrosclerosis (including subcapsular scarring, ischemic glomeruli, and at least moderate vascular disease), and one with resolving postinfectious glomerulonephritis.Table 2Biopsy findings12345678910111213Light microsocpy Acute tubular injuryDiffuseDiffuseDiffusePatchy, mildDiffuseDiffuseDiffusePatchy, mildDiffuseDiffuseDiffuseDiffuseDiffuse Global GS3/271/53/62/4215/215/321/92/70/200/72/221/2329/44 T/IF %10%20%10%15%30%50%0%10%5%10%15%5%40% Mitochondria on LM?YesNoYesYesYesYesYesNoYesYesYesYesYes ArteriosclerosisMildModerateMildMildModerateMildMildMildMildModerateModerateMildModerate to severe Primary diagnosisToxic ATNToxic ATNToxic ATNA/C TINToxic ATNA/C TINToxic ATNA/C TINToxic ATNToxic ATNToxic ATNToxic ATNToxic ATN Secondary diagnosisNoneDiffuse DGS, modRes. PIGNNoneArtNSDiffuse DGS, mildNoneNoneNoneNoneNoneNoneArtNSElectron microscopy Dysmorphic mitochondriaYesYesYesYesYesYesNoYesYesYesYesYesYes TRIs?NoNoNoNoNoNoNoNoNoNoNoYesYes FPE15%30%30%20%20%50%5%5%30%10%10%20%10%Abbreviations: A/C TIN, acute and chronic tubulointerstitial nephropathy; ArtNS, arterionephrosclerosis; ATN, acute tubular necrosis; DGS, diabetic glomerulosclerosis; FPE, foot process effacement; GS, glomerulosclerosis; LM, light microscopy; Res. PIGN, resolving post-infectious glomerulonephritis; T/IF, tubular atrophy and interstitial fibrosis; TRIs, endothelial tubuloreticular inclusions. Open table in a new tab Abbreviations: A/C TIN, acute and chronic tubulointerstitial nephropathy; ArtNS, arterionephrosclerosis; ATN, acute tubular necrosis; DGS, diabetic glomerulosclerosis; FPE, foot process effacement; GS, glomerulosclerosis; LM, light microscopy; Res. PIGN, resolving post-infectious glomerulonephritis; T/IF, tubular atrophy and interstitial fibrosis; TRIs, endothelial tubuloreticular inclusions. The mean number of glomeruli sampled for light microscopy was 20.6, of which on average 22.4±24.6% (range, 0–71%) were globally sclerotic. Tubular atrophy and interstitial fibrosis involved a mean of 16.9±14.7% of the cortex sampled (range, 0–50%; ≤20% in 10 of 13 cases), and vessels showed mild-to-moderate arteriosclerosis. None of the biopsies had collapsing focal segmental glomerulosclerosis or tubular microcysts typical of HIV-associated nephropathy. The light microscopic findings in TDF nephrotoxicity broadly resemble changes seen in other forms of toxic ATN and include luminal ectasia, cytoplasmic simplification and hypereosinophilia, irregular luminal contours, prominent nucleoli, and loss of brush border (Figure 1a). A distinctive, additional finding seen in TDF nephrotoxicity, but not in other forms of toxic ATN, is prominent eosinophilic intracytoplasmic inclusions within proximal tubular epithelial cells. These structures, which stain brightly with hematoxylin and eosin and can appear as large as tubular nuclei, represent giant mitochondria that are visible at the light microscopic level (Figure 1c). The tubular inclusions can also be identified by their fuchsinophilic appearance with trichrome stain (Figure 1d), but do not stain with periodic acid-Schiff or silver stains. The major ultrastructural findings were acute proximal tubular degenerative changes and dysmorphic mitochondria, which were identified in 12 of 13 cases (Figure 2). Mitochondria varied widely in size and shape, ranging from small and rounded to markedly enlarged and swollen with irregular contours (Figure 2a). In some cells, mitochondria approached the size of the nucleus (Figure 2b and c). Many of the enlarged mitochondria displayed prominent clumping, loss, and disorientation of cristae, which frequently were only identified along the inner mitochondrial membrane (Figure 2d). In some proximal tubular epithelia, the number of mitochondria was markedly reduced, consistent with mitochrondrial depletion. Ultrastructural evaluation of glomeruli revealed a rare endothelial tubuloreticular inclusion in 2 of 13 cases, and only mild podocyte foot process effacement (mean, 20%, range, 5–50%). Immune-type electron-dense deposits were identified in a single case (case no. 3) and were attributed to resolving postinfectious glomerulonephritis with corresponding mesangial positivity for immunoglobulin M (IgM), C3, C1, kappa, and lambda by immunofluorescence. Clinical follow-up was available for 11 of 13 patients (Table 1; Figure 3). The mean duration of follow-up was 19.6±26.1 months (range, 1.1–56.8 months), and TDF therapy was discontinued at the time of renal biopsy in all patients. Complete recovery of renal function to ‘baseline’ levels was seen in six patients (patients 1, 2, 5, 8, 9, and 12) who had a mean follow-up time of 11.5±13.6 months (range, 4.7–38.9 months), including patient no. 2 who was dialysis dependent for 4 months. Among these six patients, the mean biopsy and follow-up serum creatinine were 3.72±2.56 and 1.15±0.31 mg/dl. Five additional patients exhibited partial recovery of renal function but did not return to baseline within the mean follow-up period of 13.6±21.5 months (range, 1.1–56.8 months; patients 3, 6, 7, 11, and 13). Serum creatinine values were available for four of the five patients with partial recovery, and among these four patients, the mean peak and follow-up serum creatinine levels were 5.6±3.8 and 1.5±0.3 mg/dl, respectively. Of note, three of the five patients required dialysis, each for ∼1 month. Patient 3 is known to have recovered sufficient renal function to discontinue dialysis after 1 month, but no further follow-up is available. Follow-up data on proteinuria is available for eight patients. As evaluated by urine dipstick, five patients were negative for proteinuria and one patient showed trace protein. Protein excretion was quantified in two patients, who had urine protein concentrations of 66 and 25 mg/dl, respectively. Outcomes can also be viewed in terms of clinical presentation and indication for biopsy. Of the four patients who presented with AKI and required dialysis, there was one complete recovery and two substantial partial recoveries (decline in creatinine from 13 and 9 to 1.4 and 1.94 mg/dl, respectively). A fourth patient discontinued dialysis at 1 month, but additional follow-up is not known. Of the four patients who presented with AKI but did not require dialysis, there were two complete and two substantial partial recoveries (decline in creatinine from 4.6 and 4.9 to 1.6 and 1.2 mg/dl, respectively). All three patients biopsied for proteinuria and mild renal dysfunction made a full recovery to ‘baseline’ serum creatinine with resolution of proteinuria. Multiple case reports and small series have demonstrated the potential for TDF to cause renal injury. Compared with existing series in the literature in which the mean peak creatinine was 1.96, 1.98, and 3.9 mg/dl,10.Rifkin B. Perazella M. Tenofovir-associated nephrotoxicity: Fanconi syndrome and renal failure.Am J Med. 2004; 117: 282-283Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 11.Peyriere H. Reynes J. Rouanet I. et al.Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases.J Aquir Immune Defic Syndr. 2004; 35: 269-273Crossref PubMed Scopus (255) Google Scholar, 12.Zimmerman A. Pizzoferrato T. Bedford J. et al.Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions.Clin Infect Dis. 2006; 42: 283-290Crossref PubMed Scopus (270) Google Scholar patients in our cohort had higher serum creatinine at the time of renal biopsy (mean 5.7±4.0 mg/dl), likely reflecting the relatively high clinical threshold to perform this procedure. Consistent with previous reports, patients in our cohort displayed subnephrotic proteinuria and proximal tubular dysfunction including normoglycemic glycosuria. Information regarding additional parameters of Fanconi syndrome was not available in most patients at the time of biopsy. Patients had been taking TDF for a mean of 19.6±26.1 months and a median of 8 months (range, 3 weeks to 8 years). HIV viral control was good in all patients with available data. In the previously published analysis of postmarketing safety data for TDF,6.Nelson M. Katlama C. Montaner J. et al.The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years.AIDS. 2007; 21: 1273-1281Crossref PubMed Scopus (281) Google Scholar a multivariate analysis identified advanced age, low body weight, elevated creatinine before starting TDF therapy, and lower CD4 count as risk factors for the development of increased creatinine during TDF use. Our patient population showed a mean age of 51.1 years and a mean CD4 count of 339±270 cells/μl, as compared with a mean age of 42 years and a mean CD4 count of 215 cells/μl in the postmarketing safety data. All but three of our patients were over the age of 50 years, underscoring the risk of greater age. Thus, as patients with HIV-1 infection are living longer, the risk of this toxicity is likely to increase. Interestingly, the concurrent use of ‘boosted’ protease inhibitors lopinavir and ritonavir, which had been suggested to be a risk factor in previous reports,12.Zimmerman A. Pizzoferrato T. Bedford J. et al.Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions.Clin Infect Dis. 2006; 42: 283-290Crossref PubMed Scopus (270) Google Scholar was not shown to increase risk in the postmarketing safety data. At least one of these agents was used in 9 of our 14 patients. Clinical outcomes in our series are consistent with previous series showing significant improvement in renal dysfunction after TDF cessation, and demonstrate the potential for renal recovery from TDF nephrotoxicity, despite the presence of profound renal dysfunction requiring as long as 4 months of renal replacement therapy. In a small case series and literature review, Zimmerman et al.12.Zimmerman A. Pizzoferrato T. Bedford J. et al.Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions.Clin Infect Dis. 2006; 42: 283-290Crossref PubMed Scopus (270) Google Scholar identified 5 of 27 patients with incomplete recovery from TDF toxicity. In our series, six patients achieved complete recovery of renal function, and the remaining five patients with available data showed partial but significant recovery. Although these outcomes are encouraging, almost half of our patients with TDF nephrotoxicity were left with mild chronic kidney disease, underscoring the importance of close monitoring of at-risk patients receiving TDF therapy. The current report provides a detailed histological description of the light microscopic and ultrastructural abnormalities in TDF toxicity. Light microscopy revealed acute proximal tubular injury in all cases, with varying degrees of chronic tubulointerstitial scarring. We are the first to report the light microscopic finding of eosinophilic inclusions within the cytoplasm of proximal tubular epithelial cells; these ‘inclusions’ represent giant mitochondria that were identifiable by light microscopy in 12 of 13 cases. Electron microscopy revealed a spectrum of distinctive mitochondrial abnormalities involving mitochondrial number, size, shape, and cristal patterns, resembling the changes in other mitochondrial DNA (mtDNA) depletion syndromes. Mild variation in mitochondrial size and shape can be seen in normal kidney; however, the mitochondrial depletion, marked variation in size, and the highly irregular shapes seen in TDF toxicity fall well outside the normal spectrum. Importantly, in many types of acute tubular injury, mitochondria can display prominent swelling and expansion of the mitochondrial matrix by electron lucent aqueous fluid, which in turn disrupts the cristal architecture. In TDF toxicity, the expanded mitochondrial matrix retains its normal electron density, and the cristae display abnormal numbers and orientations that cannot be attributed to mechanical distortion by ballooning degeneration. The light microscopic and ultrastructural findings support the hypothesis that TDF toxicity primarily targets mitochondria, and that as a result, the pathological changes are most prominent in the proximal tubules, leading to histological findings of toxic ATN and clinical findings of proximal tubular dysfunction with Fanconi syndrome. Nucleotide reverse transcriptase inhibitors are known to impair mitochondrial replication by inhibition of DNA polymerase-γ.15.Brinkman K. ter Hofstede H. Burger D. et al.Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as a common pathway.AIDS. 1998; 12: 1735-1744Crossref PubMed Scopus (757) Google Scholar The potential role of mitochondrial toxicity in the mediation of TDF nephrotoxicity was studied by Cote et al.,14.Cote H. Magil A. Harris M. et al.Exploring mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction among HIV-infected patients on highly active antiretroviral therapy.Antivir Ther. 2006; 11: 79-86PubMed Google Scholar who reported dysmorphic mitochondria at the ultrastructural level, similar to reported changes following adefovir administration,3.Tanji N. Tanji K. Kambham N. et al.Adefovir Nephrotoxicity: possible role of mitochondrial DNA depletion.Hum Pathol. 2001; 32: 734-740Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar but were unable to demonstrate mtDNA depletion that could be directly attributed to the use of TDF. mtDNA depletion has been demonstrated in animal models of TDF toxicity. TDF-exposed rats show low mtDNA copy number and impaired expression of mitochondrial-encoded proteins (such as cytochrome c oxidase 1; COX 1), but not nuclear-encoded COX IV.16.Lebrecht D. Venhoff A. Kirschner J. et al.Mitochondrial tubulopathy in tenofovir disoproxil fumarate-treated rats.J Acquir Immune Defic Syndr. 2009; 51: 258-263Crossref PubMed Scopus (81) Google Scholar Additional support for TDF mitochondrial toxicity comes from Kohler et al., who studied TDF exposure in a murine HIV transgenic model. Using laser capture microdissection to specifically isolate renal proximal tubules, they found that TDF exposure resulted in decreased proximal tubular mtDNA content and corresponding mitochondrial ultrastructural abnormalities.17.Kohler J. Hosseini S. Hoying-Brandt A. et al.Tenofovir renal toxicity targets mitochondria of renal proximal tubules.Lab Invest. 2009; 89: 513-519Crossref PubMed Scopus (160) Google Scholar The current series expands the literature on TDF toxicity, further defines the histological and ultrastructural findings, and emphasizes the need for early recognition of this entity, which in many cases is only partially reversible. Current guidelines from the HIV Medicine Association of the Infectious Disease Society of America recommend that patients receiving TDF, who have a glomerular filteration rate <90 ml/min per 1.73 m2, other comorbid diseases (such as diabetes or hypertension), or who are receiving ritonavir-boosted protease inhibitors, be screened at least biannually for measurements of renal function, serum phosphorus, proteinuria, and glycosuria.18.Gupta S. Eustace J. Winston J. et al.Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America.Clin Infect Dis. 2005; 40: 1559-1585Crossref PubMed Scopus (511) Google Scholar Efforts have been made to identify subsets of patients at risk for developing TDF renal toxicity. One study found a strong association between TDF-induced tubular dysfunction and a polymorphism in ABCC2, the gene encoding multidrug resistance protein 2, which is in part responsible for the efflux of tenofovir from proximal tubular cells.19.Rodriguez-Novoa S. Labarga P. Soriano V. et al.Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir: a pharmacogenetic study.Clin Infect Dis. 2009; 48: e108-e116Crossref PubMed Scopus (214) Google Scholar The possibility of reducing the renal toxicity of TDF by administering other drugs that regulate intracellular transport and bioavailability of tenofovir is an intriguing strategy. In their review of the nephrotoxic effects of HAART,20.Izzedine H. Harris M. Perazella M. The nephrotoxic effects of HAART.Nat Rev Nephrol. 2009; 5: 563-573Crossref PubMed Scopus (104) Google Scholar Izzedine et al. noted that probenecid is an effective inhibitor of hOAT1, the transporter primarily responsible for tenofovir entry into tubular cells. The potential use of such medications to mitigate or prevent TDF nephrotoxicity deserves further study. In summary, we present a renal biopsy series of 13 patients with TDF nephrotoxicity. The histological and ultrastructural findings demonstrate a distinctive pattern of proximal tubular injury characterized by severe mitochondrial damage, supporting a mechanism of drug-induced mitochondrial toxicity. Despite the presence of severe renal failure, in some cases requiring renal replacement therapy, outcomes were quite good after discontinuation of TDF. Careful monitoring of renal function for prompt detection of TDF nephrotoxicity is critically important to ensure timely drug withdrawal before the development of irreversible tubulointerstitial injury. Although TDF nephrotoxicity appears to be a relatively rare complication, it is a potentially serious one, warranting careful screening of patients at risk. A total of 17 cases of tubular injury in the setting of TDF use were identified retrospectively from the archives of the Columbia University Renal Pathology Laboratory between October 2001 (when TDF was granted Food and Drug Administration approval) and January 2010. Diagnostic criteria for TDF nephrotoxicity included (1) documented use of TDF at the time of renal presentation, (2) pathological findings of acute and/or chronic tubular injury, (3) an acute decline in renal function, and (4) the absence of alternative causes of acute renal dysfunction. AKI was defined as a doubling of serum creatinine. Renal biopsies were processed according to standard techniques. All biopsies were stained with hematoxylin and eosin, periodic acid-Schiff, Masson's trichrome, and Jones methenamine silver for light microscopy. Immunofluorescence was performed on 3 μm cryostat sections with fluorescein isothiocyanate-conjugated polyclonal antibodies to IgG, IgM, IgA, C3, C1q, kappa, lambda, fibrinogen, and albumin (Dako, Carpinteria, CA, USA). Electron microscopy was performed using a JEOL 1011 electron microscope (JEOL, Tokyo, Japan). Statistical analysis was performed with Stata (version 10.1; StataCorp, College Station, TX, USA). Continuous variables were compared with student t-test and the paired t-test as appropriate, whereas the categorical variables were compared using the Fisher's exact test. We thank Drs Haider, Curley, Dalal, Haratz, Liss, Sterman, Wang-Joy, Bloom, and Miyawaki for providing clinical history and follow-up on their patients in this series.
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