- Email: [email protected]
Acute Renal Failure and Nephrotic Range Proteinuria due to Amyloidosis in an HIV-Infected Patient
Acute Renal Failure and Nephrotic Range Proteinuria due to Amyloidosis in an HIV-Infected Patient KIRK M. CHAN-TACK, MD; NAVNEET AHUJA, MBBS; EDWARD J. WEINMAN, MD; RAVINDER K. WALI, MD; ANAYOCHUKWU UCHE, MBBS; LISA A. GREISMAN, MD; CINTHIA DRACHENBERG, MD; PHILIP N. HAWKINS, PHD, FRCP; ROBERT R. REDFIELD, MD
ABSTRACT: Amyloidosis is an uncommon cause of renal disease in HIV-positive patients. Diagnosis is challenging, treatment options are limited, and prognosis remains poor. We discuss an HIV-positive patient with acute renal failure and nephrotic range proteinuria. The differential diagnosis included nephropathy due to trimethoprim/sulfamethoxazole, tenofovir, HIV, hepatitis C, heroin, or multifactorial causes. Serum and urine study findings were inconclusive. Rapid clinical deterioration ensued and a renal biopsy was performed. Pathologic examination revealed eosinophilic, amorphous material in the glomerular tufts that stained redorange with Congo red stain. Immunohistochemical
analysis confirmed amyloid A (AA) amyloidosis. AA amyloidosis occurs as a complication of chronic infection or chronic inflammatory disease. It has been reported in intravenous or subcutaneous drug abusers, some of whom were HIV-positive. This case underscores the importance of tissue diagnosis to determine the cause of renal disease in HIV-positive patients. Clinical diagnosis, based on CD4 count, viral load, and degree of proteinuria, may not predict the pathological diagnosis in HIV-positive patients. KEY INEXING TERMS: HIV; Renal failure; Nephrotic syndrome; Proteinuria; Amyloidosis. [Am J Med Sci 2006;332(6):364–367.]
U
teinuria who was diagnosed with biopsy-proven renal amyloidosis.
nderutilization of renal biopsies may affect the diagnosis and management of renal disease in HIV-positive patients. Clinical diagnosis, based on CD4 count, HIV viral load, and degree of proteinuria, may not predict the pathologic diagnosis in HIV-positive patients. Furthermore, treatment and prognosis may be influenced by the pathologic diagnosis.1–10 Amyloidosis, a protean disorder, is an uncommon cause of renal disease in HIV-positive patients.1– 4,11–14 Antiretroviral treatment is suggested, but there are no prospective data to corroborate its usefulness.1 We report an HIV-positive patient with acute renal failure (ARF) and nephrotic range proFrom the Institute of Human Virology, Baltimore, Maryland (KMC-T, AU, LAG, RRR), the University of Maryland School of Medicine, Baltimore, Maryland (KMC-T, NA, EJW, RKW, AU, LAG, CD, RRR), and the National Amyloidosis Centre, Department of Medicine, Royal Free and University College Medical School, London, United Kingdom (PNH). Submitted May 11, 2006; accepted in revised form July 11, 2006. Robert Redfield is a speaker/consultant for Abbott, Gilead, and GlaxoSmithKline. None of these companies had any contribution to this manuscript. Correspondence: Kirk M. Chan-Tack, MD, Institute of Human Virology, University of Maryland School of Medicine, 725 West Lombard Street, UMBI, N540, Baltimore, Maryland 21201 (Email: [email protected]).
364
Case Report A 43-year-old, HIV-positive, African-American man presented with 2 weeks of progressive dyspnea, abdominal distention, and bilateral lower extremity edema. Comorbidities included hepatitis C and former heroin use (both intravenous and subcutaneous; quit 1 year ago). Medications were trimethoprim/sulfamethoxazole (160 mg/800 mg, one tablet/day), emtricitabine/tenofovir (200 mg/300 mg, one tablet/day), atazanavir (300 mg/day), and ritonavir (100 mg/day). Antiretroviral history included a tenofovir-based regimen for the past 11 months. Additionally, the patient had an unexplained elevated erythrocyte sedimentation rate for 3 years (Table 1). Review of systems was also notable for diarrhea of 1 year’s duration that had worsened over the past month. Results of stool studies were negative. Computed tomography of the abdomen showed hepatomegaly. Colonoscopy with biopsies, performed 6 months previously, was negative for malignancy, lymphoma, inflammatory bowel disease, and infectious (bacterial, mycobacterial, fungal, viral, parasitic, protozoal) agents. The patient was normotensive. Examination revealed sacral, scrotal, and 3⫹ bilateral lower extremity edema. Admission CD4 count was 45 cells/mL (CD4% ⫽ 6) and viral load was fewer than 75 copies/mL. Abnormal findings on laboratory tests included blood urea nitrogen (BUN) 25 mg/dL (normal range, 10 –20 mg/ dL), creatinine 1.9 mg/dL (normal range for males, 0.8 –1.4 mg/ dL), alkaline phosphatase 427 U/L (normal range, 30 –120 U/L), total protein 4.3 g/dL (normal range, 6.0 – 8.3 g/dL), albumin 0.7 g/dL (normal range, 3.5– 4.8 g/dL), and erythrocyte sedimentation rate 134 mm/hr (normal range, 0 –20 mm/hr). Urinalysis showed December 2006 Volume 332 Number 6
Chan-Tack et al
Table 1. Blood Urea Nitrogen (BUN), Creatinine (Cr), Proteinuria (by Urinalysis), and Erythrocyte Sedimentation Rate (ESR) Date (Month/Year)
BUN/Cr
Proteinuria
ESR, mm/hr
August 1997 April 2002 January 2005 November 2005 December 2005b
11/1.0 8/0.8 7/1.0 6/1.2 25/1.9
Negative Trace 1⫹ 2⫹ 4⫹
18 80a 129 ND 134
ND, not done. C-reactive protein was 2.6 mg/L (normal range, 0–0.5 mg/L). This was obtained at the same time as the ESR of 80 (April 2002). b BUN, Cr, urinalysis, and ESR were obtained at admission. a
4⫹ proteinuria and was otherwise negative. One month before, the patient’s BUN and creatinine levels were 6 mg/dL and 1.2 mg/dL, respectively (Table 1). All antiretrovirals and trimethoprim/sulfamethoxazole were discontinued upon admission. Findings on serum antinuclear antibodies test (ANA), rapid plasma reagin test (RPR), hepatitis B serologies, cryoglobulin test, antimyeloperoxidase antibodies test, and anti-glomerular basement membrane antibodies test were negative. Complement levels were normal. Serum and urine protein electrophoreses were negative. Twenty-four-hour urine collection documented 9 grams of protein. Over the first 6 hospital days, the patient’s BUN and creatinine levels increased to 63 mg/dL and 3 mg/dL, respectively. Renal biopsy revealed eosinophilic, amorphous material in the glomerular tufts (Figure 1). There were no collapsing glomeruli, tubular dilatation, or crystal deposition. Congo red stain demonstrated that this material stained red-orange, consistent with amyloid (Figure 2). Immunohistochemical staining was positive only for amyloid A protein. The final diagnosis was amyloid A amyloidosis. An antiretroviral regimen of abacavir (600 mg/day), lamivudine (150 mg/day), atazanavir (300 mg/day), and ritonavir (100 mg/day) were started upon receipt of the biopsy results. The patient required hemodialysis due to intractable volume overload and worsening electrolyte derangements. He subsequently developed Staphylococcus aureus catheter-related bloodstream infection and eventually died from septicemia and multiorgan-failure. His family declined the medical team’s request for an autopsy.
Figure 1. Alteration of the glomerular architecture due to the accumulation of eosinophilic amorphous material in the glomerular tufts. (Hematoxylin and eosin stain.)
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Figure 2. The glomerular amorphous material stained red-orange in a manner typical of amyloid. (Congo red stain.)
Discussion Amyloid A (AA) amyloidosis, also classified as secondary, reactive, or acquired amyloidosis, occurs most frequently as a complication of chronic infection or chronic inflammatory disease.11–25 AA amyloidosis has been reported in intravenous or subcutaneous (“skin-popping”) drug abusers,12–17 some of whom have been HIV-positive.12–14 Among drug abusers, it is postulated that prolonged inflammation of the skin is important in the pathogenesis of amyloidosis.12–17 AA amyloidosis has been rarely identified in HIV-positive patients without any history drug abuse.11 The chronic phase of HIV infection is characterized by partial control of viral replication, chronic immune activation, progressive decline of the naive and memory T-cell pool, and systemic CD4 T-cell depletion.18 Serum amyloid A (SAA) is an acute phase reactant that is produced by hepatocytes due to chronic immune activation. Elevated SAA levels have been found in HIV-positive patients with low CD4 cell counts (⬍200 cells/mL).19 Chronic immune activation from advanced HIV disease may independently contribute to the pathogenesis of AA amyloidosis. The kidneys, liver, and gastrointestinal tract are the main sites of SAA deposition. The characteristic clinical presentation is a patient with a chronic infection or chronic inflammatory disease who develops renal disease, hepatomegaly, or unexplained gastrointestinal disease. Patients are usually normotensive. The degree of proteinuria ranges from mild to nephrotic and does not consistently correlate with the extent of renal disease or with prognosis. Renal amyloidosis typically manifests as gradually deteriorating renal function; acute renal failure is an uncommon presentation of AA amyloidosis. Azotemia and hypoalbuminemia are poor prognostic markers for patients with AA amyloidosis.20,21 365
Renal Failure and Amyloidosis
Positive immunohistochemical staining of tissue for AA protein using commercially available monoclonal antibodies is highly sensitive and highly specific for AA amyloidosis. Treatment of the underlying condition has induced clinical remission in some cases, including patients with rheumatologic disorders, familial Mediterranean fever, inflammatory bowel disease, bronchiectasis, and osteomyelitis.21–24 The outcome of AA amyloidosis is favorable when therapy can maintain SAA levels less than 10 mg/L. Under these circumstances, there is potential for amyloid deposits to regress and for the affected organs to recover function.24 Supportive therapy is essential to maintain organ function.20 Renal transplantation is another option for patients with AA amyloidosis.25 Amyloidosis is a rare cause of ARF and nephrotic range proteinuria in HIV-positive patients. Since most cases of AA amyloidosis in HIV-positive patients have been diagnosed at autopsy, there are no evidence-based recommendations for therapy.11,12 Review of the literature identified one HIV-positive patient with renal AA amyloidosis who had clinical remission induced by colchicine.13 Due to the hypothesis that chronic immune activation from advanced HIV may contribute to the development of AA amyloidosis, antiretroviral treatment is suggested. However, there are no prospective data to corroborate its usefulness.1 Amyloidosis was not suspected as the cause of ARF for this patient. Initial concern that concurrent tenofovir and trimethoprim/sulfamethoxazole may have contributed to his ARF prompted their immediate discontinuation. The differential diagnosis also included nephropathy due to HIV, hepatitis C, heroin, or any combination of the above causes. Tenofovir has been associated with Fanconi syndrome, acute tubular necrosis, and intratubular precipitation of crystals.8,9 Trimethoprim/sulfamethoxazole typically causes interstitial nephritis with intratubular precipitation of crystals.8 However, the patient’s clinical course, laboratory data, and pathology results were not consistent with either tenofovir- or trimethoprim/sulfamethoxazole-related nephrotoxicities. HIV-associated nephropathy (HIVAN) is the primary cause of chronic kidney disease in HIV-positive patients. Similar to this case, patients with HIVAN generally have low CD4 counts, are normotensive, and present with nephrotic range proteinuria, azotemia, and hypoalbuminemia. However, the characteristic HIVAN pathology is collapsing, focal segmental glomerulosclerosis with tubulointerstitial injury.2– 8 Such findings were not observed in this patient’s biopsy. The clinical presentation, laboratory results, and pathologic findings were also incompatible with hepatitis C nephropathy and heroin nephropathy, respectively. Indications for renal biopsy, regardless of HIV status, include significant proteinuria, evidence of 366
progressive disease (such as increasing proteinuria or decreasing glomerular filtration rate), unexplained ARF or subacute renal failure, or an acute nephritic syndrome (example, hematuria, proteinuria, or hypertension with renal insufficiency).8,10 However, HIV-positive patients are often given the clinical diagnosis of HIVAN without pathological confirmation. As this case demonstrates, clinical diagnosis on the basis of markers such as CD4, viral load, and degree of proteinuria may not accurately predict the pathologic diagnosis in HIV-positive patients. Additionally, treatment options and prognosis may be influenced by the actual histologic diagnosis. Consequently, renal biopsy is recommended whenever feasible to conclusively determine the cause of renal disease in HIV-positive patients.1–9 In retrospect, this patient’s elevated erythrocyte sedimentation rate, elevated alkaline phosphatase, hepatomegaly, and prolonged gastrointestinal illness and may have been manifestations of AA amyloidosis. Unfortunately, the diagnosis was only made by renal biopsy after ARF had developed. AA amyloidosis remains a difficult disease due to its low incidence, protean manifestations, diagnostic challenges, limited treatment options, and poor prognosis. This entity should be considered in the differential diagnosis of renal failure and nephrotic range proteinuria in HIV-positive patients as well as among intravenous or subcutaneous drug abusers. Acknowledgments The authors thank Richard Milanich for technical assistance with the pathology images. References 1. Joseph A, Wali RK, Weinman EJ. Renal amyloidosis in AIDS. Ann Intern Med 2000;133:75. 2. Berggren R, Batuman V. HIV-associated renal disorders: recent insights into pathogenesis and treatment. Curr HIV/ AIDS Rep 2005;2:109–15. 3. Atta MG, Choi MJ, Longenecker JC, et al. Nephrotic range proteinuria and CD4 count as noninvasive indicators of HIV-associated nephropathy. Am J Med 2005;118: 1288.e21–1288.e26. 4. Lanjewar DN, Ansari MA, Shetty CR, et al. Renal lesions associated with AIDS-an autopsy study. Ind J Pathol Microbiol 1999;42:63–8. 5. Szczech LA, Gupta SK, Habash R, et al. The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection. Kidney Int 2004;66:1145–52. 6. Szczech LA, Kalayjian R, Rodriguez R, et al. The clinical characteristics and antiretroviral dosing patterns of HIVinfected patients receiving dialysis. The Adult Aids Clinical Trial Group Renal Complications Committee. Kidney Int 2003;63:2295–301. 7. Winston JA, Klotman ME, Klotman PE. HIV-associated nephropathy is a late, not early, manifestation of HIV-1 infection. Kidney Int 1999;55:1036–40.
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8. Gupta SK, Eustace JA, Winston JA, 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;40:1559–85. 9. Zimmermann AE, Pizzoferrato T, Bedford J, et al. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis 2006;42:283–90. 10. Richards NT, Darby S, Howie AJ, et al. Knowledge of renal histology alters patient management in over 40% of cases. Nephrol Dial Transplant 1994;9:1255–9. 11. Cozzi PJ, Abu-Jawdeh GM, Green RM, et al. Amyloidosis in association with human immunodeficiency virus infection. Clin Infect Dis 1992;14:189–91. 12. Osick LA, Lee TP, Pedemonte MB, et al. Hepatic amyloidosis in intravenous drug abusers and AIDS patients. J Hepatol 1993;19:79–84. 13. Tan AU Jr, Cohen AH, Levine BS. Renal amyloidosis in a drug abuser. J Am Soc Nephrol 1995;5:1653–8. 14. Martin Navarro J, Caramelo Diaz C, Marron B, et al. AA amyloidosis in an HIV-seropositive patient: case report and review of the literature. Rev Clin Esp 2003;203:51–3. 15. Menchel S, Cohen D, Gross E, et al. AA protein-related renal amyloidosis in drug addicts. Am J Pathol 1983;112:195–9. 16. Neugarten J, Gallo GR, Buxbaum J, et al. Amyloidosis in subcutaneous heroin abusers (‘skin poppers’ amyloidosis). Am J Med 1986;81:635–40.
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17. Thompson B, Burns A, Davenport A. Recreational drug abuse in a dialysis patient. Nephrol Dial Transplant 2002;17: 675–6. 18. Paiardini M, Cervasi B, Dunham R, et al. Cell-cycle dysregulation in the immunopathogenesis of AIDS. Immunol Res 2004;29:253–68. 19. Husebekk A, Permin H, Husby G. Serum amyloid protein A (SAA): an indicator of inflammation in AIDS and AIDSrelated complex (ARC). Scand J Inf Dis 1986;18:389–94. 20. Buxbaum J. Amyloidosis, AA (Inflammatory). Available at: www.emedicine.com. Accessed January 10, 2006. 21. Gertz MA, Kyle RA. Secondary systemic amyloidosis: response and survival in 64 patients. Medicine 1991;70:246–56. 22. Korkmaz C. Immunosuppressive treatment of AA amyloidosis of familial Mediterranean fever. Clin Exp Rheumatol 2005;23:S107–8. 23. Perez Equiza E, Arguinano JM, Gastearena J. Successful treatment of AA amyloidosis secondary to Hodgkin’s disease with 4=-iodo-4=-deoxydoxorubicin. Haematologica 1999; 84:93–4. 24. Gillmore JD, Lovat LB, Persey MR, et al. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 2001;358:24–9. 25. Nishikido M, Koga S, Kanetake H, et al. Renal transplantation in systemic amyloidosis. Clin Transplant 1999;13 Suppl 1:S63–6.
367
ABSTRACT: Amyloidosis is an uncommon cause of renal disease in HIV-positive patients. Diagnosis is challenging, treatment options are limited, and prognosis remains poor. We discuss an HIV-positive patient with acute renal failure and nephrotic range proteinuria. The differential diagnosis included nephropathy due to trimethoprim/sulfamethoxazole, tenofovir, HIV, hepatitis C, heroin, or multifactorial causes. Serum and urine study findings were inconclusive. Rapid clinical deterioration ensued and a renal biopsy was performed. Pathologic examination revealed eosinophilic, amorphous material in the glomerular tufts that stained redorange with Congo red stain. Immunohistochemical
analysis confirmed amyloid A (AA) amyloidosis. AA amyloidosis occurs as a complication of chronic infection or chronic inflammatory disease. It has been reported in intravenous or subcutaneous drug abusers, some of whom were HIV-positive. This case underscores the importance of tissue diagnosis to determine the cause of renal disease in HIV-positive patients. Clinical diagnosis, based on CD4 count, viral load, and degree of proteinuria, may not predict the pathological diagnosis in HIV-positive patients. KEY INEXING TERMS: HIV; Renal failure; Nephrotic syndrome; Proteinuria; Amyloidosis. [Am J Med Sci 2006;332(6):364–367.]
U
teinuria who was diagnosed with biopsy-proven renal amyloidosis.
nderutilization of renal biopsies may affect the diagnosis and management of renal disease in HIV-positive patients. Clinical diagnosis, based on CD4 count, HIV viral load, and degree of proteinuria, may not predict the pathologic diagnosis in HIV-positive patients. Furthermore, treatment and prognosis may be influenced by the pathologic diagnosis.1–10 Amyloidosis, a protean disorder, is an uncommon cause of renal disease in HIV-positive patients.1– 4,11–14 Antiretroviral treatment is suggested, but there are no prospective data to corroborate its usefulness.1 We report an HIV-positive patient with acute renal failure (ARF) and nephrotic range proFrom the Institute of Human Virology, Baltimore, Maryland (KMC-T, AU, LAG, RRR), the University of Maryland School of Medicine, Baltimore, Maryland (KMC-T, NA, EJW, RKW, AU, LAG, CD, RRR), and the National Amyloidosis Centre, Department of Medicine, Royal Free and University College Medical School, London, United Kingdom (PNH). Submitted May 11, 2006; accepted in revised form July 11, 2006. Robert Redfield is a speaker/consultant for Abbott, Gilead, and GlaxoSmithKline. None of these companies had any contribution to this manuscript. Correspondence: Kirk M. Chan-Tack, MD, Institute of Human Virology, University of Maryland School of Medicine, 725 West Lombard Street, UMBI, N540, Baltimore, Maryland 21201 (Email: [email protected]).
364
Case Report A 43-year-old, HIV-positive, African-American man presented with 2 weeks of progressive dyspnea, abdominal distention, and bilateral lower extremity edema. Comorbidities included hepatitis C and former heroin use (both intravenous and subcutaneous; quit 1 year ago). Medications were trimethoprim/sulfamethoxazole (160 mg/800 mg, one tablet/day), emtricitabine/tenofovir (200 mg/300 mg, one tablet/day), atazanavir (300 mg/day), and ritonavir (100 mg/day). Antiretroviral history included a tenofovir-based regimen for the past 11 months. Additionally, the patient had an unexplained elevated erythrocyte sedimentation rate for 3 years (Table 1). Review of systems was also notable for diarrhea of 1 year’s duration that had worsened over the past month. Results of stool studies were negative. Computed tomography of the abdomen showed hepatomegaly. Colonoscopy with biopsies, performed 6 months previously, was negative for malignancy, lymphoma, inflammatory bowel disease, and infectious (bacterial, mycobacterial, fungal, viral, parasitic, protozoal) agents. The patient was normotensive. Examination revealed sacral, scrotal, and 3⫹ bilateral lower extremity edema. Admission CD4 count was 45 cells/mL (CD4% ⫽ 6) and viral load was fewer than 75 copies/mL. Abnormal findings on laboratory tests included blood urea nitrogen (BUN) 25 mg/dL (normal range, 10 –20 mg/ dL), creatinine 1.9 mg/dL (normal range for males, 0.8 –1.4 mg/ dL), alkaline phosphatase 427 U/L (normal range, 30 –120 U/L), total protein 4.3 g/dL (normal range, 6.0 – 8.3 g/dL), albumin 0.7 g/dL (normal range, 3.5– 4.8 g/dL), and erythrocyte sedimentation rate 134 mm/hr (normal range, 0 –20 mm/hr). Urinalysis showed December 2006 Volume 332 Number 6
Chan-Tack et al
Table 1. Blood Urea Nitrogen (BUN), Creatinine (Cr), Proteinuria (by Urinalysis), and Erythrocyte Sedimentation Rate (ESR) Date (Month/Year)
BUN/Cr
Proteinuria
ESR, mm/hr
August 1997 April 2002 January 2005 November 2005 December 2005b
11/1.0 8/0.8 7/1.0 6/1.2 25/1.9
Negative Trace 1⫹ 2⫹ 4⫹
18 80a 129 ND 134
ND, not done. C-reactive protein was 2.6 mg/L (normal range, 0–0.5 mg/L). This was obtained at the same time as the ESR of 80 (April 2002). b BUN, Cr, urinalysis, and ESR were obtained at admission. a
4⫹ proteinuria and was otherwise negative. One month before, the patient’s BUN and creatinine levels were 6 mg/dL and 1.2 mg/dL, respectively (Table 1). All antiretrovirals and trimethoprim/sulfamethoxazole were discontinued upon admission. Findings on serum antinuclear antibodies test (ANA), rapid plasma reagin test (RPR), hepatitis B serologies, cryoglobulin test, antimyeloperoxidase antibodies test, and anti-glomerular basement membrane antibodies test were negative. Complement levels were normal. Serum and urine protein electrophoreses were negative. Twenty-four-hour urine collection documented 9 grams of protein. Over the first 6 hospital days, the patient’s BUN and creatinine levels increased to 63 mg/dL and 3 mg/dL, respectively. Renal biopsy revealed eosinophilic, amorphous material in the glomerular tufts (Figure 1). There were no collapsing glomeruli, tubular dilatation, or crystal deposition. Congo red stain demonstrated that this material stained red-orange, consistent with amyloid (Figure 2). Immunohistochemical staining was positive only for amyloid A protein. The final diagnosis was amyloid A amyloidosis. An antiretroviral regimen of abacavir (600 mg/day), lamivudine (150 mg/day), atazanavir (300 mg/day), and ritonavir (100 mg/day) were started upon receipt of the biopsy results. The patient required hemodialysis due to intractable volume overload and worsening electrolyte derangements. He subsequently developed Staphylococcus aureus catheter-related bloodstream infection and eventually died from septicemia and multiorgan-failure. His family declined the medical team’s request for an autopsy.
Figure 1. Alteration of the glomerular architecture due to the accumulation of eosinophilic amorphous material in the glomerular tufts. (Hematoxylin and eosin stain.)
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Figure 2. The glomerular amorphous material stained red-orange in a manner typical of amyloid. (Congo red stain.)
Discussion Amyloid A (AA) amyloidosis, also classified as secondary, reactive, or acquired amyloidosis, occurs most frequently as a complication of chronic infection or chronic inflammatory disease.11–25 AA amyloidosis has been reported in intravenous or subcutaneous (“skin-popping”) drug abusers,12–17 some of whom have been HIV-positive.12–14 Among drug abusers, it is postulated that prolonged inflammation of the skin is important in the pathogenesis of amyloidosis.12–17 AA amyloidosis has been rarely identified in HIV-positive patients without any history drug abuse.11 The chronic phase of HIV infection is characterized by partial control of viral replication, chronic immune activation, progressive decline of the naive and memory T-cell pool, and systemic CD4 T-cell depletion.18 Serum amyloid A (SAA) is an acute phase reactant that is produced by hepatocytes due to chronic immune activation. Elevated SAA levels have been found in HIV-positive patients with low CD4 cell counts (⬍200 cells/mL).19 Chronic immune activation from advanced HIV disease may independently contribute to the pathogenesis of AA amyloidosis. The kidneys, liver, and gastrointestinal tract are the main sites of SAA deposition. The characteristic clinical presentation is a patient with a chronic infection or chronic inflammatory disease who develops renal disease, hepatomegaly, or unexplained gastrointestinal disease. Patients are usually normotensive. The degree of proteinuria ranges from mild to nephrotic and does not consistently correlate with the extent of renal disease or with prognosis. Renal amyloidosis typically manifests as gradually deteriorating renal function; acute renal failure is an uncommon presentation of AA amyloidosis. Azotemia and hypoalbuminemia are poor prognostic markers for patients with AA amyloidosis.20,21 365
Renal Failure and Amyloidosis
Positive immunohistochemical staining of tissue for AA protein using commercially available monoclonal antibodies is highly sensitive and highly specific for AA amyloidosis. Treatment of the underlying condition has induced clinical remission in some cases, including patients with rheumatologic disorders, familial Mediterranean fever, inflammatory bowel disease, bronchiectasis, and osteomyelitis.21–24 The outcome of AA amyloidosis is favorable when therapy can maintain SAA levels less than 10 mg/L. Under these circumstances, there is potential for amyloid deposits to regress and for the affected organs to recover function.24 Supportive therapy is essential to maintain organ function.20 Renal transplantation is another option for patients with AA amyloidosis.25 Amyloidosis is a rare cause of ARF and nephrotic range proteinuria in HIV-positive patients. Since most cases of AA amyloidosis in HIV-positive patients have been diagnosed at autopsy, there are no evidence-based recommendations for therapy.11,12 Review of the literature identified one HIV-positive patient with renal AA amyloidosis who had clinical remission induced by colchicine.13 Due to the hypothesis that chronic immune activation from advanced HIV may contribute to the development of AA amyloidosis, antiretroviral treatment is suggested. However, there are no prospective data to corroborate its usefulness.1 Amyloidosis was not suspected as the cause of ARF for this patient. Initial concern that concurrent tenofovir and trimethoprim/sulfamethoxazole may have contributed to his ARF prompted their immediate discontinuation. The differential diagnosis also included nephropathy due to HIV, hepatitis C, heroin, or any combination of the above causes. Tenofovir has been associated with Fanconi syndrome, acute tubular necrosis, and intratubular precipitation of crystals.8,9 Trimethoprim/sulfamethoxazole typically causes interstitial nephritis with intratubular precipitation of crystals.8 However, the patient’s clinical course, laboratory data, and pathology results were not consistent with either tenofovir- or trimethoprim/sulfamethoxazole-related nephrotoxicities. HIV-associated nephropathy (HIVAN) is the primary cause of chronic kidney disease in HIV-positive patients. Similar to this case, patients with HIVAN generally have low CD4 counts, are normotensive, and present with nephrotic range proteinuria, azotemia, and hypoalbuminemia. However, the characteristic HIVAN pathology is collapsing, focal segmental glomerulosclerosis with tubulointerstitial injury.2– 8 Such findings were not observed in this patient’s biopsy. The clinical presentation, laboratory results, and pathologic findings were also incompatible with hepatitis C nephropathy and heroin nephropathy, respectively. Indications for renal biopsy, regardless of HIV status, include significant proteinuria, evidence of 366
progressive disease (such as increasing proteinuria or decreasing glomerular filtration rate), unexplained ARF or subacute renal failure, or an acute nephritic syndrome (example, hematuria, proteinuria, or hypertension with renal insufficiency).8,10 However, HIV-positive patients are often given the clinical diagnosis of HIVAN without pathological confirmation. As this case demonstrates, clinical diagnosis on the basis of markers such as CD4, viral load, and degree of proteinuria may not accurately predict the pathologic diagnosis in HIV-positive patients. Additionally, treatment options and prognosis may be influenced by the actual histologic diagnosis. Consequently, renal biopsy is recommended whenever feasible to conclusively determine the cause of renal disease in HIV-positive patients.1–9 In retrospect, this patient’s elevated erythrocyte sedimentation rate, elevated alkaline phosphatase, hepatomegaly, and prolonged gastrointestinal illness and may have been manifestations of AA amyloidosis. Unfortunately, the diagnosis was only made by renal biopsy after ARF had developed. AA amyloidosis remains a difficult disease due to its low incidence, protean manifestations, diagnostic challenges, limited treatment options, and poor prognosis. This entity should be considered in the differential diagnosis of renal failure and nephrotic range proteinuria in HIV-positive patients as well as among intravenous or subcutaneous drug abusers. Acknowledgments The authors thank Richard Milanich for technical assistance with the pathology images. References 1. Joseph A, Wali RK, Weinman EJ. Renal amyloidosis in AIDS. Ann Intern Med 2000;133:75. 2. Berggren R, Batuman V. HIV-associated renal disorders: recent insights into pathogenesis and treatment. Curr HIV/ AIDS Rep 2005;2:109–15. 3. Atta MG, Choi MJ, Longenecker JC, et al. Nephrotic range proteinuria and CD4 count as noninvasive indicators of HIV-associated nephropathy. Am J Med 2005;118: 1288.e21–1288.e26. 4. Lanjewar DN, Ansari MA, Shetty CR, et al. Renal lesions associated with AIDS-an autopsy study. Ind J Pathol Microbiol 1999;42:63–8. 5. Szczech LA, Gupta SK, Habash R, et al. The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection. Kidney Int 2004;66:1145–52. 6. Szczech LA, Kalayjian R, Rodriguez R, et al. The clinical characteristics and antiretroviral dosing patterns of HIVinfected patients receiving dialysis. The Adult Aids Clinical Trial Group Renal Complications Committee. Kidney Int 2003;63:2295–301. 7. Winston JA, Klotman ME, Klotman PE. HIV-associated nephropathy is a late, not early, manifestation of HIV-1 infection. Kidney Int 1999;55:1036–40.
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8. Gupta SK, Eustace JA, Winston JA, 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;40:1559–85. 9. Zimmermann AE, Pizzoferrato T, Bedford J, et al. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis 2006;42:283–90. 10. Richards NT, Darby S, Howie AJ, et al. Knowledge of renal histology alters patient management in over 40% of cases. Nephrol Dial Transplant 1994;9:1255–9. 11. Cozzi PJ, Abu-Jawdeh GM, Green RM, et al. Amyloidosis in association with human immunodeficiency virus infection. Clin Infect Dis 1992;14:189–91. 12. Osick LA, Lee TP, Pedemonte MB, et al. Hepatic amyloidosis in intravenous drug abusers and AIDS patients. J Hepatol 1993;19:79–84. 13. Tan AU Jr, Cohen AH, Levine BS. Renal amyloidosis in a drug abuser. J Am Soc Nephrol 1995;5:1653–8. 14. Martin Navarro J, Caramelo Diaz C, Marron B, et al. AA amyloidosis in an HIV-seropositive patient: case report and review of the literature. Rev Clin Esp 2003;203:51–3. 15. Menchel S, Cohen D, Gross E, et al. AA protein-related renal amyloidosis in drug addicts. Am J Pathol 1983;112:195–9. 16. Neugarten J, Gallo GR, Buxbaum J, et al. Amyloidosis in subcutaneous heroin abusers (‘skin poppers’ amyloidosis). Am J Med 1986;81:635–40.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
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