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Focal Glomerulosclerosis With Tubuloreticular Inclusions: Possible Predictive Value for Acquired Immunodeficiency Syndrome (AIDS)
RENAL BIOPSY CASE
Focal Glomerulosclerosis With Tubuloreticular Inclusions: Possible Predictive Value for Acquired Immunodeficiency Syndrome (AIDS) Charles E. Alpers, MD, Sami Harawi, MD, and Helmut G. Rennke, MD INDEX WORDS: Focal and segmental glomerulosclerosis; tubuloreticular inclusions; acquired immunodeficiency syndrome.
A N ASSOCIATION between the glomerular leasion of focal and segmental glomerulosclerosis and the acquired immunodeficiency syndrome (AIDS) has been reported, and in some populations may be seen in up to 8 % of patients with AIDS. I 5 We have studied renal biopsies from three patients with focal and segmental glomerulosclerosis associated with the presence of prominent tubuloreticular structures in glomerular endothelial cells in whom no clinical features diagnostic of AIDS were present at the time of renal biopsy. Each of these patients belonged to a population group known to be at high risk for the development of AIDS, and each patient subsequently developed overt AIDS 3 to 15 months after the onset of their renal disease. These cases provide further evidence for the existence of an AIDS-related glomerulopathy and suggest that this lesion can be a prodromal manifestation of overt AIDS. CASE REPORT
Patient No. 3 A 40-year-old black male homosexual developed the nephrotic syndrome in 1983 with a proteinuria of 5 g/d but without clinical or laboratory features of glomerulosclerosis or renal insufficiency. Previous medical history included episodes of syphilis, viral hepatitis, giardiasis, and persistent diarrhea. A renal biopsy was performed 8 months later, which revealed focal and segmental glomerulosclerosis. Serum creatinine at that time was 1.4 mg/dL (123.8 j.tmoIlL). He then developed unexplained lymphadenopathy. Six months after renal biopsy, during which time there was no progression of his renal disease, the patient developed a cough and dyspnea and was found to have pneumocystis pneumonia, which eventually led to his death. Serologic tests for antibodies to human immunodeficiency virus were positive in patient nos. 2 and 3; they were not performed in patient no. 1.
PATHOLOGIC FINDINGS
Patient No. 1 A 30-year-old black male homosexual with a lO-year history of intravenous (IV) heroin abuse developed rapidly progressive renal failure in October 1983. A renal biopsy was performed. Beginning early in 1984, his course was characterized by a series of opportunistic infections and he died in December 1984 of disseminated Mycobacterium avium intracellulare infection.
Patient No. 2 This patient was a 28-year-old Hispanic woman with an acknowledged history of cocaine abuse who was suspected to have engaged in IV drug abuse. She developed acute renal failure (serum creatinine, 10.3 mg/dL [91 j.tmoIlL]) and nephrotic syndrome (9.4 g protein excretion/d), prompting reFrom the Department of Pathology, Brigham and Women's Hospital, and the Mallory Institute of Pathology, Boston. Address reprint requests to Charles E. Alpers, MD, Department of Pathology, RC-72, University of Washington Hospital, Seattle, U{4 98195. © 1988 by the National Kidney Foundation, Inc. 0272-6386/8811203-0011$3.00/0 240
nal biopsy in 1983. Her renal failure progressed to end-stage renal disease requiring dialysis. She subsequently developed a series of vaginal and oral infections as well as diffuse lymphadenopathy. Fifteen months after renal biopsy, she developed a pneumonia unresponsive to antibiotic therapy and died. An autopsy revealed disseminated cryptococcosis involving heart, lungs, spleen, liver, lymph nodes, kidney, and brain.
In each case, the renal biopsy findings were those of focal and segmental glomerulosclerosis, with glomerular morphology ranging from normal to mesangial thickening only to distinct segmental scarring with hyalinosis and capsular adhesions (Fig 1). These were variable degrees of nonspecific chronic interstitial injury and tubular obstruction by proteinaceous casts. Immunofluorescence and electron microscopy revealed no significant deposition of immune reactants in glomeruli or interstitium. Electron microscopy of better preserved glomeruli showed collapsed capillaries, variable mesangial expansion, and numerous tubuloreticular structures in endothelial cells (Fig 2). In the single case where autopsy tissue was available for ultrastructural study (patient no. 1), the kidneys showed advanced glomerulosclerosis and the tubuloreticular structures were no longer seen.
American Journal of Kidney Diseases, Vol XII, No 3 (September), 1988: pp 240-242
241
AIDS NEPHROPATHY
One case (patient no. 1) also contained intraendothelial vesicular rosettes. DISCUSSION
We believe that the clinical manifestation of focal and segmental glomerulosclerosis in our three patients at a time preceding the manifestation of typical features of AIDS provides additional evidence for an uncommon but distinct glomerulopathy associated with AIDS. Two additional reports, in abstract form, also support our experience that this lesion, in conjunction with numerous tubuloreticular inclusions in glomerular endothelium, may be a prodromal manifestation of AIDS.5,6
Fig 1. (Patient no. 2) Glomerulus showing segmental lesion of capillary collapse, hyalinosis, and sclerosis. Remaining capillary loops are widely patent. The surrounding interstitium shows tubular atrophy and fibrosis. Periodic acid-Schiff, original magnification x 410.
Fig 2. Ultrastructural appearance of tubuloretlcular inclusions seen in glomerular endothelium In each on the renal biopsies; orlgll\8l magnification x 20,800.
The tubuloreticular structures present in these biopsies are distinct cytoplasmic inclusions with an appearance of branching microtubules, 20 to 30 nm in diameter, that have been seen by electron microscopy in a variety of disease states. Previously, they have been associated most commonly with lupus nephritis, where they are found in glomerular endothelial cells. 7 They are also the most common ultrastructural finding in AIDS, where they may be seen in lymphoid cells, endothelium, and other cell typeS.4.8.9 They have not been previously associated with focal and segmental glomerulosclerosis. While these structures are not specific for any single disease entity, when present in large numbers, they have served as a useful
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marker for certain diseases such as systemic lupus erythematosus. 7 Accordingly, it is the presence of numerous tubuloreticular inclusions in conjunction with focal and segmental glomerulosclerosis that suggests that the lesions seen in our patients are associated with AIDS and are not an epiphenomenon. Many patients with systemic lupus erythematosus and patients with AIDS have the presence in their serum of an acid-labile a-interferon in common. 9 a-interferon has been shown to be capable of inducing production of tubuloreticular structures in experimental systems. 9 Accordingly, it has
been proposed that tubuloreticular structures may be a morphologic manifestation of a-interferon activity, and thus account for their presence in viral diseases and in diseases of altered immune function. 9 In conclusion, our cases suggest that the presence of tubuloreticular structures and focal segmental glomerulosclerosis in selected renal biopsies may be a predictive marker for subsequent development of AIDS. In order to assess the strength of this association, it will be important to continue to search for this lesion as the AIDS patient population expands.
REFERENCES I. Rao TKS, Filippone EJ, Nicastri AD, et al: Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N Engl1 Med 310:669-673, 1984 2. Rao TKS, Friedman EA, Nicastri AD: The types of renal disease in the acquired immunodeficiency syndrome. N Engl1 Med 316:1062-1068,1987 3. Pardo V, Meneses R, Ossa L, et al: AIDS-related glomerulopathy: Occurrence in specific risk groups. Kidney Int 31: 1167-1173, 1987 4. Chander P, Soni A, Suri A, et al: Renal ultrastructural markers in AIDS-associated nephropathy. Am 1 Pathol 126: 153-526, 1987 5. D' Agati V, Suh 1-1, Carbone L, et al: HTLV III associated nephropathy: A comparative pathologic study. Kidney Int 31:336, 1987 (abstr)
6. Pardo V, 1affe D, Roth D, et at: Nephrotic syndrome associated with focal and segmental glomerular sclerosis (FSS) as a prodrome of AIDS: Report of 7 patients. Kidney Int 29:288, 1986 (abstr) 7. Grimley PM, Schaff Z: Significance of tubuloreticular inclusions in the pathobiology of human diseases. Pathobiol Ann 6:221-257, 1976 8. Sidhu GS, Stahl RD, EI-Sadr W, et al: The acquired immunodeficiency syndrome: An ultrastructural study. Hum Pathol 16:377-387, 1985 9. Grimley PM, Kang Y-H, Frederick W, et al: Interferonrelated leukocyte inclusions in acquired immune deficiency syndrome: Localization in T cells. Am 1 Clin Pathol 81:147155, 1984
Focal Glomerulosclerosis With Tubuloreticular Inclusions: Possible Predictive Value for Acquired Immunodeficiency Syndrome (AIDS) Charles E. Alpers, MD, Sami Harawi, MD, and Helmut G. Rennke, MD INDEX WORDS: Focal and segmental glomerulosclerosis; tubuloreticular inclusions; acquired immunodeficiency syndrome.
A N ASSOCIATION between the glomerular leasion of focal and segmental glomerulosclerosis and the acquired immunodeficiency syndrome (AIDS) has been reported, and in some populations may be seen in up to 8 % of patients with AIDS. I 5 We have studied renal biopsies from three patients with focal and segmental glomerulosclerosis associated with the presence of prominent tubuloreticular structures in glomerular endothelial cells in whom no clinical features diagnostic of AIDS were present at the time of renal biopsy. Each of these patients belonged to a population group known to be at high risk for the development of AIDS, and each patient subsequently developed overt AIDS 3 to 15 months after the onset of their renal disease. These cases provide further evidence for the existence of an AIDS-related glomerulopathy and suggest that this lesion can be a prodromal manifestation of overt AIDS. CASE REPORT
Patient No. 3 A 40-year-old black male homosexual developed the nephrotic syndrome in 1983 with a proteinuria of 5 g/d but without clinical or laboratory features of glomerulosclerosis or renal insufficiency. Previous medical history included episodes of syphilis, viral hepatitis, giardiasis, and persistent diarrhea. A renal biopsy was performed 8 months later, which revealed focal and segmental glomerulosclerosis. Serum creatinine at that time was 1.4 mg/dL (123.8 j.tmoIlL). He then developed unexplained lymphadenopathy. Six months after renal biopsy, during which time there was no progression of his renal disease, the patient developed a cough and dyspnea and was found to have pneumocystis pneumonia, which eventually led to his death. Serologic tests for antibodies to human immunodeficiency virus were positive in patient nos. 2 and 3; they were not performed in patient no. 1.
PATHOLOGIC FINDINGS
Patient No. 1 A 30-year-old black male homosexual with a lO-year history of intravenous (IV) heroin abuse developed rapidly progressive renal failure in October 1983. A renal biopsy was performed. Beginning early in 1984, his course was characterized by a series of opportunistic infections and he died in December 1984 of disseminated Mycobacterium avium intracellulare infection.
Patient No. 2 This patient was a 28-year-old Hispanic woman with an acknowledged history of cocaine abuse who was suspected to have engaged in IV drug abuse. She developed acute renal failure (serum creatinine, 10.3 mg/dL [91 j.tmoIlL]) and nephrotic syndrome (9.4 g protein excretion/d), prompting reFrom the Department of Pathology, Brigham and Women's Hospital, and the Mallory Institute of Pathology, Boston. Address reprint requests to Charles E. Alpers, MD, Department of Pathology, RC-72, University of Washington Hospital, Seattle, U{4 98195. © 1988 by the National Kidney Foundation, Inc. 0272-6386/8811203-0011$3.00/0 240
nal biopsy in 1983. Her renal failure progressed to end-stage renal disease requiring dialysis. She subsequently developed a series of vaginal and oral infections as well as diffuse lymphadenopathy. Fifteen months after renal biopsy, she developed a pneumonia unresponsive to antibiotic therapy and died. An autopsy revealed disseminated cryptococcosis involving heart, lungs, spleen, liver, lymph nodes, kidney, and brain.
In each case, the renal biopsy findings were those of focal and segmental glomerulosclerosis, with glomerular morphology ranging from normal to mesangial thickening only to distinct segmental scarring with hyalinosis and capsular adhesions (Fig 1). These were variable degrees of nonspecific chronic interstitial injury and tubular obstruction by proteinaceous casts. Immunofluorescence and electron microscopy revealed no significant deposition of immune reactants in glomeruli or interstitium. Electron microscopy of better preserved glomeruli showed collapsed capillaries, variable mesangial expansion, and numerous tubuloreticular structures in endothelial cells (Fig 2). In the single case where autopsy tissue was available for ultrastructural study (patient no. 1), the kidneys showed advanced glomerulosclerosis and the tubuloreticular structures were no longer seen.
American Journal of Kidney Diseases, Vol XII, No 3 (September), 1988: pp 240-242
241
AIDS NEPHROPATHY
One case (patient no. 1) also contained intraendothelial vesicular rosettes. DISCUSSION
We believe that the clinical manifestation of focal and segmental glomerulosclerosis in our three patients at a time preceding the manifestation of typical features of AIDS provides additional evidence for an uncommon but distinct glomerulopathy associated with AIDS. Two additional reports, in abstract form, also support our experience that this lesion, in conjunction with numerous tubuloreticular inclusions in glomerular endothelium, may be a prodromal manifestation of AIDS.5,6
Fig 1. (Patient no. 2) Glomerulus showing segmental lesion of capillary collapse, hyalinosis, and sclerosis. Remaining capillary loops are widely patent. The surrounding interstitium shows tubular atrophy and fibrosis. Periodic acid-Schiff, original magnification x 410.
Fig 2. Ultrastructural appearance of tubuloretlcular inclusions seen in glomerular endothelium In each on the renal biopsies; orlgll\8l magnification x 20,800.
The tubuloreticular structures present in these biopsies are distinct cytoplasmic inclusions with an appearance of branching microtubules, 20 to 30 nm in diameter, that have been seen by electron microscopy in a variety of disease states. Previously, they have been associated most commonly with lupus nephritis, where they are found in glomerular endothelial cells. 7 They are also the most common ultrastructural finding in AIDS, where they may be seen in lymphoid cells, endothelium, and other cell typeS.4.8.9 They have not been previously associated with focal and segmental glomerulosclerosis. While these structures are not specific for any single disease entity, when present in large numbers, they have served as a useful
242
ALPERS, HARAWI, AND RENNKE
marker for certain diseases such as systemic lupus erythematosus. 7 Accordingly, it is the presence of numerous tubuloreticular inclusions in conjunction with focal and segmental glomerulosclerosis that suggests that the lesions seen in our patients are associated with AIDS and are not an epiphenomenon. Many patients with systemic lupus erythematosus and patients with AIDS have the presence in their serum of an acid-labile a-interferon in common. 9 a-interferon has been shown to be capable of inducing production of tubuloreticular structures in experimental systems. 9 Accordingly, it has
been proposed that tubuloreticular structures may be a morphologic manifestation of a-interferon activity, and thus account for their presence in viral diseases and in diseases of altered immune function. 9 In conclusion, our cases suggest that the presence of tubuloreticular structures and focal segmental glomerulosclerosis in selected renal biopsies may be a predictive marker for subsequent development of AIDS. In order to assess the strength of this association, it will be important to continue to search for this lesion as the AIDS patient population expands.
REFERENCES I. Rao TKS, Filippone EJ, Nicastri AD, et al: Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N Engl1 Med 310:669-673, 1984 2. Rao TKS, Friedman EA, Nicastri AD: The types of renal disease in the acquired immunodeficiency syndrome. N Engl1 Med 316:1062-1068,1987 3. Pardo V, Meneses R, Ossa L, et al: AIDS-related glomerulopathy: Occurrence in specific risk groups. Kidney Int 31: 1167-1173, 1987 4. Chander P, Soni A, Suri A, et al: Renal ultrastructural markers in AIDS-associated nephropathy. Am 1 Pathol 126: 153-526, 1987 5. D' Agati V, Suh 1-1, Carbone L, et al: HTLV III associated nephropathy: A comparative pathologic study. Kidney Int 31:336, 1987 (abstr)
6. Pardo V, 1affe D, Roth D, et at: Nephrotic syndrome associated with focal and segmental glomerular sclerosis (FSS) as a prodrome of AIDS: Report of 7 patients. Kidney Int 29:288, 1986 (abstr) 7. Grimley PM, Schaff Z: Significance of tubuloreticular inclusions in the pathobiology of human diseases. Pathobiol Ann 6:221-257, 1976 8. Sidhu GS, Stahl RD, EI-Sadr W, et al: The acquired immunodeficiency syndrome: An ultrastructural study. Hum Pathol 16:377-387, 1985 9. Grimley PM, Kang Y-H, Frederick W, et al: Interferonrelated leukocyte inclusions in acquired immune deficiency syndrome: Localization in T cells. Am 1 Clin Pathol 81:147155, 1984