1 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 2 Department of Pathology, Section of Renal Immunopathology, University of Texas Medical Branch, Galveston, TX, 3 Division of Nephrology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, 4 Department of Medicine, Elmhurst Memorial Hospital, Elmhurst, IL and 5 Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
Keywords: acquired immune deficiency syndrome; fibrillary glomerulonephritis; hepatitis C; HIV; immunotactoid glomerulopathy; nephrotic syndrome
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Introduction |
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Cases |
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The biopsy specimen contained a total of nine glomeruli, four being globally sclerotic. The remaining glomeruli appeared mildly enlarged, with a mild to moderate increase in mesangial matrix and a mild segmental increase in mesangial cellularity (Fig. 1A). No crescents were seen. There was moderate tubular atrophy and interstitial fibrosis, with mild to moderate hypertensive vascular changes. A Congo red stain was negative with an appropriately positive control.
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Electron microscopy showed deposits of randomly oriented fibrils within the mesangial areas (Fig. 1C) and glomerular basement membranes (GBMs; Fig. 1D
). The fibrils measured 1013 nm in thickness, and did not have a microtubular structure. Multiple tubulo-reticular inclusions were present in endothelial cell cytoplasm (Fig. 1D
). There was extensive but not complete epithelial foot process effacement. The renal biopsy diagnosis was fibrillary GN, with mild-moderate hypertensive nephrosclerosis.
Patient 2
Patient 2 is a 42-year-old Hispanic male who presented for evaluation of proteinuria and lower extemity oedema of 6 months duration. He is heterosexual, and reported no history of intravenous drug abuse or other risk factors commonly associated with HIV infection. HIV infection was diagnosed 4 years earlier after the excision of a benign lymphoid hyperplastic lesion from the nasal cavity. There was no history of opportunistic infections or malignancies associated with acquired immune deficiency syndrome. The patient was receiving zidovudine 300 mg/day, sulfamethoxazoletrimethoprim 800 mg/160 mg every other day, and furosemide 40 mg as needed. Physical examination was remarkable only for severe pitting oedema of both legs up to the knees. Serum creatinine was 0.8 mg/dl. Urine sediment was benign, but 24-h urinary protein excretion was 10.2 g. Serologic tests for anti-nuclear antibodies, hepatitis B antigens, and for antibodies to Sm antigen, double-stranded DNA, hepatitis C virus, and cytomegalovirus were all negative. Cryoglobulins were also negative and serum complement levels were normal. Serum and urine protein electrophoresis was negative for monoclonal bands. A percutaneous renal biopsy was performed.
The biopsy specimen contained 10 glomeruli, all of which showed moderate mesangial matrix expansion without significant hypercellularity, and irregular thickening of the capillary loops. No crescents were seen. There was minimal tubular atrophy, interstitial fibrosis, or interstitial inflammation. Congo red and thioflavin T stains were negative with appropriately positive controls. Immunofluorescence studies showed granular mesangial and confluent granular capillary loop deposits of IgM (1+), C3 (23+), and kappa (3+), with no specific staining for IgG, IgA, lambda, or fibrinogen. No extraglomerular deposits were seen.
Electron microscopy showed massive arrays of microtubular structures in the mesangial areas, along the epithelial aspect of the GBM, and much more focally in a subendothelial location. The diameter of these hollow-appearing microtubules was 40 nm. The tubular structures were segmentally co-deposited with granular electron-dense material typical of immune complex. No tubulo-reticular inclusions were identified in endothelial cells. There was extensive epithelial foot process effacement, particularly in capillary loops with deposits. The renal biopsy diagnosis was immunotactoid glomerulopathy.
Patient 3
Patient 3 is a 42-year-old white female with a history of intravenous drug abuse, who was found to be HIV-positive 7 years previously when she developed oesophageal candidiasis. One year prior to her renal biopsy she was found to have proteinuria (later quantitated at 7.5 g/day), moderate lower extremity oedema, hypertension (blood pressure 170/98), and renal insufficiency. Serum creatinine at the time of renal biopsy was 3.7 mg/dl. In addition to proteinuria, urinalysis showed two white blood cells and 25 red blood cells per high power field, and no casts. Hepatitis C antibody was positive, though cryoglobulins were negative and serum complement levels were normal. Hepatitis B surface antigen was negative. Serum and urine protein electrophoresis was unremarkable. A percutaneous renal biopsy was performed.
The biopsy specimen contained 30 glomeruli, three of which were globally sclerotic. The remaining glomeruli appeared moderately enlarged with marked, diffuse expansion of the mesangial matrix and a moderate increase in mesangial cellularity. The GBM were uniformly and markedly thickened, with some containing amorphous eosinophilic deposits. Segmental sclerosis was noted in several glomeruli, although no crescents or segmental necrotizing lesions were seen in any glomeruli. There was marked tubular atrophy and interstitial fibrosis. Small arteries showed moderate intimal thickening. Amyloid stains were negative with appropriately positive controls.
Immunofluorescence showed diffuse, confluent granular to globular staining along the glomerular capillary loops and in mesangial areas for IgG (4+) and C3 (4+), with more segmental staining for IgM (3+) and C4 (trace). Granular-globular staining for IgM and C3 was also noted in arteriolar walls. IgA staining was limited to tubular casts.
Electron microscopy showed marked, irregular GBM thickening with extensive deposits comprised of randomly oriented fibrils, 2025 nm in diameter. Many of these fibrillary deposits appeared as spikes extending from the epithelial aspect of the GBM through most or all of the GBM; subendothelial fibrillary deposits were noted as well. There were also extensive deposits of this fibrillary material in the expanded mesangial areas. No tubulo-reticular inclusions were seen. There was diffuse effacement of epithelial foot processes. The renal biopsy diagnosis was fibrillary GN, with moderate underlying hypertensive nephrosclerosis.
Clinical data and renal biopsy findings for these three patients are summarized in Table 1.
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Discussion |
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Fibrillary GN and immunotactoid glomerulopathy are felt to represent immune complex-related glomerular diseases, in which the immune complex deposits have a distinct, organized substructure but do not represent deposits of amyloid or cryoglobulins [10]. Notably, both fibrillary GN and immunotactoid glomerulopathy have been reported in association with hepatitis C [7], and both patients with fibrillary GN (but not that with immunotactoid glomerulopathy) in this report had positive hepatitis C serologies. However, of these glomerular lesions only immunotactoid glomerulopathy has been previously reported in HIV-positive patients [7,8]. It is of interest that our patient with immunotactoid glomerulopathy (patient 2) appears to have had monoclonal (IgM-kappa) glomerular deposits, though a monoclonal protein was not detected in the serum or urine. Three of six patients with immunotactoid glomerulopathy reported by Fogo et al. [10] had monoclonal proteins and/or abnormal plasma cell proliferation. Monoclonal glomerular deposits and/or circulating monoclonal paraproteins may also be seen in patients with fibrillary GN, though this appears to be considerably less frequent than with immunotactoid glomerulopathy [10].
Fibrillary GN and immunotactoid glomerulopathy are rather uncommon glomerular diseases, being present on only 1 and 0.2%, respectively, of 2649 native renal biopsies examined by Fogo and coworkers [10] between 1982 and 1993. Still, noting the recently described association between these lesions and hepatitis C [7] and the high frequency of hepatitis C coinfection in HIV-positive patients [6], it is somewhat surprising that more cases of these glomerular lesions, and in particular fibrillary GN, have not been reported in HIV-positive patients. One possible explanation for this is that these lesions tend to occur most often in middle-aged and older adults [10], and until recently it was unlikely for HIV-infected patients to survive into this age range. In addition, because the clinical presentation of these lesions is in many instances also consistent with that of HIVAN, some HIV-positive patients with fibrillary GN and/or immunotactoid glomerulopathy may have been diagnosed on clinical grounds as having HIVAN and did not undergo a renal biopsy. Although still uncommon, fibrillary GN and immunotactoid glomerulopathy should be considered in the differential diagnosis of nephrotic range proteinuria in the setting of HIV infection, particularly in non-black patients.
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Notes |
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References |
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