Acute Tubular Mitochondrial Injury, Consistent with HAART (Tenofovir) Arthur H. Cohen Cedars-Sinai Medical Center Los Angeles, California

History Fifty-eight year old Caucasian man with 22 year history of HIV infection developed heavy proteinuria (6.4 grams/24 hr) with renal insufficiency (creatinine clearance 78 ml/min with serum creatinine 1.6 mg/dl) one year prior to renal biopsy. Kidneys were of normal size by ultrasound (11.2 and 11.0 cm). He was started on an aggressive regimen of antiretroviral therapy; this led to a decrease in viral count to 50 and a dramatic reduction in protein excretion to 836 mg/24 hrs. The serum creatinine remained at 1.6 mg/dl. Two months prior to biopsy, renal function began to deteriorate and Scr was 2.0 mg/dl and clearance 59 ml/min. In addition, hypouricemia, hypophosphatemia and increased urinary acid excretion were noted. Protein excretion also increased. He was normotensive; urine analysis was "bland." Because of these developments he was referred to a nephrologist for renal biopsy. Past medical history was pertinent for HIV infection and hepatitis B infection. Liver biopsy in the past disclosed increased iron stores and no evidence of cirrhosis. Recent CD4 - 260/ cu mm, and HIV RNA by PCR was 73 copies/ml. He was hypertensive for two years. Medications included kaletra (lopinavir, ritonivir), epivir (lavimudine), viread (tenofovir), among many. Physical exam disclosed a chronically ill appearing man of stated age and in no distress and with BP 120/70. There were no abnormal findings. Laboratory data on admission: Hgb/Hct – 17.4 gm/50.5; WBC 5,900 with normal differential; platelets 173,000. Na 139; K 5.4; Cl 101; CO2 23. BUN/Cr – 223/2.3. Urine analysis protein 2+; 0 rbc; 26 granular casts. A biopsy was performed. Slide 1 - Jones Click to view with ImageScope Click to view with a Web-Based Viewer Slide 2 - PAS Click to view with ImageScope Click to view with a Web-Based Viewer Slide 3 - Trichrome Click to view with ImageScope Click to view with a Web-Based Viewer Slide 4 Click to view with ImageScope Click to view with a Web-Based Viewer Figure 1 - General overview to indicate mild tubular atrophy and interstitial fibrosis. (periodic acid-Schiff) Figure 2 - Glomeruli with no significant changes. (periodic acid-methenamine silver) Figure 3 - Glomeruli with no significant changes. (periodic acid-methenamine silver) Figure 4 - Some proximal tubular cells are enlarged with prominent nuclei while others are irregularly flattened. (periodic acid-Schiff) Figure 5 - Some proximal tubular cells are enlarged with prominent nuclei while others are irregularly flattened. (periodic acid-Schiff) Figure 6 - C3-weak granular staining in mesangial regions and possibly capillary walls. Figure 7 - Portion of glomerulus with segmental foot process effacement and no deposits. Figure 8 - Proximal tubular cells with abnormal mitochondria: enlarged, with increase in number and loss of cristae. Figure 9 - Proximal tubular cells with abnormal mitochondria: enlarged, with increase in number and loss of cristae. Differential Diagnosis (Clinical): Glomerulopathy – explanation for proteinuria membranous glomerulonephritis (primary or secondary, including HBV) IgA nephropathy focal and segmental glomerulosclerosis others Tubulo-interstitial process – explanation for progressive loss of renal function Acute interstitial nephritis/chronic interstitial nephritis Tubular cell damage Both manifestations Glomerulopathy progressing Final Diagnosis (Renal Biopsy) Acute tubular mitochondrial injury, consistent with HAART (Tenofovir) Resolving glomerulonephritis of undetermined nature Mild nephrosclerosis Discussion Although the initial reports associated various forms of renal damage to the newly described AIDS, more recent clinical experience and investigation have been directed at the effects of therapy of HIV infection on kidney function and structure. This discussion will focus on the highly active anti-retroviral agents and the renal injury they may cause. As is well known, the kidney is particularly susceptible to drug/toxin induced injury for several reasons: its excretory role results in exposure to high concentrates of the drugs and/or their metabolites; it is highly vascular, receiving 20-25% of cardiac output in contrast to combined kidney weights of 0.4% of body weight; proximal tubular cells represent a large area for binding and transporting toxins; reabsorption of glomerular filtrate progressively leads to increased intraluminal concentrations of toxin; specific transport pathways may promote site-specific toxicity. Thus, the resulting tubular cell injury caused by certain drugs/toxins represents a major limitation to their usage. The medications constituting HAART include several major categories: protease inhibitors, nucleoside reverse transcriptase inhibitors, and nucleotide transcriptase inhibitors. Drugs in each of these categories have been implicated in the development of abnormal structure and function of tubular cells. Among the protease inhibitors, indinivir was described to result in crystallization in tubules and bladder, with stone formation and its consequences such as renal colic, dysuria with flank pain, hematuria. In addition, acute renal failure, usually of a mild reversible nature, is estimated to occur in 15-20% of patients. Renal biopsy findings include the impressive accumulation of crystals in cells in collecting duct and other tubular lumina with associated acute and chronic tubulo-interstitial nephrits as initially described by Rosen and colleagues in 1997. Of only passing interest to pathologists because of lack of morphological studies, ritonavir has been implicated in generally transient acute renal failure in approximately 15%. The nucleoside reverse transcriptase inhibitors which include, among others, lamivudine and stavudine, result in two types of injury: acute renal failure with lactic acidosis and mitochondrial abnormalities, and proximal tubular dysfunction with likely Fanconi syndrome. The latter manifestations are similar to those associated with nucleotide reverse transcriptase inhibitors (see below) and also are characterized by abnormal mitochondria of proximal tubular cells. The nucleotide reverse transcriptase inhibitors include adefovir, cidofovir and tenofovir and are important injury-producing agents. Only tenofovir is approved fro use as an anti-HIV agent in the U. S. Adefovir is not because of significant side effects, but has similar nephrotoxicity as tenofivir. Cidofovir is used mainly for treatment of CMV infection; its renal effects are also similar to tenofovir and may contribute to renal impairment in HIV-infected patients. It is tenofovir which, at least in our renal biopsy practice, seems to be the major agent responsible for biopsies in HAART-treated patients who undergo biopsies for renal dysfunction, usually acute or less commonly chronic renal failure with Fanconi syndrome. As demonstrated in the biopsy presented, the major alteration is to mitochondria of proximal tubular cells. The light microscopic appearance of these cells is variable; some reports have indicated necrosis and vacuolization. In contrast, we have observed more subtle changes which include some degree of cellular enlargement, reduced or slight granularity of the cytoplasm, irregular amplitude, but generally preservation of brush borders. The mitochondria changes include enlargement, apparent increase in number or clustering, often massive dilatation and loss of cristae. Depending on length of renal involvement, there may be tubular atrophy with interstitial fibrosis. The cellular target of these agents appears to be an organic anion transporter (human renal organic anion transporter-1) on the basolateral plasma membranes; this mediates uptake of drugs from peritubular capillaries. Once in the cell, the drugs interfere with DNA synthesis and are secreted into the lumina via apical membrane carriers of channels. It should be emphasized that, despite the renal toxicities discussed here, these drugs have, of course, dramatically changed the management and prognosis of HIV infection. It has also proven beneficial in the treatment of HIV-associated nephropathy (HIVAN) in some patients. The use of HAART for other nephropathies in HIV-infected patients has not been evaluated. The specific proteinuria-producing glomerulopathy in the patient presented here could not be determined as no residual findings of a diagnostic nature were evident in the biopsy. It is almost tempting to suggest, but likely incorrect, that HAART played a role in its improvement. Despite the success in treating HIV infection, a recent report calculated that the prevalence of end stage renal disease in HIV infected patients will rise in the future because of increase in number of black patients who are living longer and who will be at risk for developing serious renal disease; this population has a particularly high risk for kidney disease. References: Atta MG, Gallant JE, Hafizur-Rahman M, Nagajothi N, Racusen LC, Scheel PJ, Fine, DM. Antiretroviral therapy in the treatment of HIV-associated nephropathy. Nephrol Dial Transplant. 2006;21:2809-13. Coca S, Perazella MA. Rapid communication: acute renal failure associated with tenofovir: evidence of drug-induced nephrotoxicity. Am J Med Sci. 2002;324:342-4. Cote HC, Magil AB, Harris M, Scarth BJ, Gadawski I, Wang N, Yu E, Yip B, Zalunardo N, Werb R, Hogg R, Harrigan PR, Montaner JS. Exploring mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction among HIV-infected patients on highly active antiretroviral therapy. Antivir Ther. 2006;11:79-86. Daugas E, Rougier JP, Hill G. HAART-related nephropathies in HIV-infected patients. Kid Int. 2005;67:393-403. Izzedine H, Launay-Vacher V, Deray G. Antiviral drug-induced nephrotoxicity. Am J Kid Dis. 2005;45:804-17. Khan S, Haragsim L, Laszik ZG. HIV-associated nephropathy. Adv Chronic Kidney Dis. 2006;13:307-13. Lam C, Stillman IE, Steinman TI. The many faces of HIV nephropathy: results of the disease and consequences of treatment. J Nephrol. 2005;18:106-10. Malik A, Abraham P, Malik N. Acute renal failure and Fanconi syndrome in an AIDS patient on tenofovir treatment-case report and review of literature. J Infect. 2005;51:E61-5. Markowitz GS, Perazella MA. Drug-induced renal failure: a focus on tubulointerstitial disease. Clinica Chimica Acta. 2005;351:31-47. Roling J, Schmid H, Fischereder M, Draenert R, Goebel FD. HIV-associated renal diseases and highly active antiretroviral therapy-induced nephropathy. Clin Infect Dis. 2006;42:1488-95. Schwartz EJ, Szczech LA, Ross MJ, Klotman ME, Winston JA, Klotman PE. Highly active antiretroviral therapy and the epidemic of HIV+ end-stage renal disease. J Am Soc Nephrol. 2005;16:2412-20. Tanji N, Tanji K, Kambham N, Markowitz GS, Bell A, D'agati VD. Adefovir nephrotoxicity: possible role of mitochondrial DNA depletion. Hum Pathol. 2001;32:734-40. Tashima KT, Horowitz JD, Rosen S. Indinavir nephropathy (letter). N Engl J Med. 1997;336:138-9. Valle R, Haragsim L. Nephrotoxicity as a complication of antiretroviral therapy. Adv Chronic Kidney Dis. 2006;13:314-9. Verheist D, Monge M, Meynard JL, Fouqueray B, Mougenot B, Girard PM, Ronco P, Rossert J. Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am J Kid Dis. 2002;40:1331-33. Wyatt CM, Klotman PE. Antiretroviral therapy and the kidney: balancing benefit and risk in patients with HIV infection. Expert Opin Drug Saf. 2006;5:275-87.