Fibrillary/immunotactoid glomerulonephritis in HIV-positive patients: a report of three cases

Mark Haas1,, Srinivasan Rajaraman2, Tejinder Ahuja3, Martin Kittaka4 and Tito Cavallo5

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



   Introduction
 Top
 Introduction
 Cases
 Discussion
 References
 
Renal disease is a common complication in patients infected with human immunodeficiency virus (HIV) [1]. Among HIV-positive patients undergoing a renal biopsy, the most common lesion observed is HIV-associated nephropathy (HIVAN). This histologically resembles the collapsing glomerulopathy variant of focal-segmental glomerulosclerosis, and typically presents with nephrotic range proteinuria and renal insufficiency with rapid progression to end-stage renal disease in the majority of cases [1]. Like idiopathic collapsing glomerulopathy [2], HIVAN shows a strong predilection for affecting black patients, both among intravenous drug abusers (IVDA) and non-IVDA [1]. In a review of over 200 patients from multiple centres with HIVAN, 89% were black [3]. By contrast, HIVAN accounted for fewer than 10% of renal biopsy diagnoses in HIV-infected white patients in two European studies [4,5]. In these latter patient populations, immune complex-related glomerulopathies comprised the majority of lesions seen on renal biopsies [4,5]. A considerable number of different types of immune complex glomerulopathies have been reported in association with HIV infection, including IgA nephropathy, lupus and lupus-like nephritis, post-infectious glomerulonephritis (GN), membranous nephropathy, mesangial proliferative GN, and membranoproliferative GN [1,46]. The latter three lesions, and in particular membranoproliferative GN (types 1 and 3), have been reported in patients with concurrent hepatitis C and HIV infection [1,6]. Fibrillary GN and immunotactoid glomerulopathy have also been reported in association with hepatitis C infection [7]. To date, however, only two cases of immunotactoid glomerulopathy (both in hepatitis C-positive patients [7,8]) and none of fibrillary GN have been reported in association with HIV, a somewhat surprising finding noting that hepatitis C infection is found in the great majority of HIV-positive IVDA [6]. In this report, we describe two HIV-positive patients with fibrillary GN and one with immunotactoid GN; two of these patients (each with fibrillary GN) had concurrent hepatitis C infection.



   Cases
 Top
 Introduction
 Cases
 Discussion
 References
 
Patient 1
Patient 1 is a 59-year-old white male who presented with the nephrotic syndrome and renal insufficiency. The patient was in his usual state of good health until approximately 3 years previously, when he became acutely ill, and was found to have Pneumocystis carinii pneumonia and to be HIV-positive. The patient had no known risk factors for HIV infection except for blood transfusions given during gastric stapling and jejunal bypass surgery done for obesity in 1980. He recovered from this pneumonia and was subsequently treated with a number of different drug regimens for his HIV, with the current regimen consisting of lamivudine, indinavir, dapsone, and rifabutin. At the time of his presentation with the nephrotic syndrome, he was found to have a serum creatinine of 1.6 mg/dl, creatinine clearance of 50 ml/min, and 24-h urine protein of 5047 mg. Urinary sediment was benign. No paraprotein was found. Hepatitis C serology was positive, serum C3 was slightly low, C4 was normal, and cryoglobulins were negative. He underwent a percutaneous renal biopsy.

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. 1AGo). 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.



View larger version (194K):
[in this window]
[in a new window]
 
Fig. 1. Renal biopsy findings in patient 1. (A) Light microscopy shows mild to moderate mesangial matrix expansion with mild segmental mesangial hypercellularity (haematoxylin–eosin stain; original magnification x200). (B) Immunofluorescence shows linear to smooth deposition of IgG (2+ on a 0–4+ scale) along the glomerular capillary loops and in the mesangium (original magnification x400). (C) Electron microscopy shows mesangial deposits of randomly oriented fibrils, 10–13 nm in thickness (uranyl acetate and lead citrate stain, original magnification x15 500). (D) In the same glomerulus as shown in (C), one of multiple tubulo-reticular inclusions present within endothelial cell cytoplasm. The underlying glomerular basement membrane contains numerous fibrils (original magnification x28 500).

 
Immunofluorescence studies (three glomeruli) showed diffuse, predominantly linear to smooth staining for IgG (2+ on a scale of 0–4+; Fig. 1BGo), kappa light chains, lambda light chains, fibrinogen (all 1+) and C3 (trace) in the glomerular capillary loops and in the mesangium. There was no glomerular staining for IgA, IgM, or C1q, and no extraglomerular staining was noted except for IgA and approximately equivalent kappa and lambda in tubular casts.

Electron microscopy showed deposits of randomly oriented fibrils within the mesangial areas (Fig. 1CGo) and glomerular basement membranes (GBMs; Fig. 1DGo). The fibrils measured 10–13 nm in thickness, and did not have a microtubular structure. Multiple tubulo-reticular inclusions were present in endothelial cell cytoplasm (Fig. 1DGo). 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, sulfamethoxazole–trimethoprim 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 (2–3+), 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 2–5 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, 20–25 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 1Go.


View this table:
[in this window]
[in a new window]
 
Table 1. Summary of clinical and renal biopsy findings

 



   Discussion
 Top
 Introduction
 Cases
 Discussion
 References
 
The clinical presentations of these three patients, with nephrotic range proteinuria without a floridly active urinary sediment, and marked renal insufficiency in two (Table 1Go), are consistent with that of HIVAN [1], although these findings are often seen with other glomerulopathies as well. However, unlike the situation in black patients where HIVAN is by far the most common glomerular disease associated with HIV [1,3,4], in non-black HIV-positive patients immune complex-related glomerulopathies predominate [4,5], and none of our three patients were black (two white, one Hispanic). Immune complex GN in the setting of HIV infection may be related to infectious agents other than HIV, most notably hepatitis C which has been associated with membranoproliferative GN, and possibly mesangial proliferative GN, membranous nephropathy, and immunotactoid glomerulopathy as well [1,6]. In addition, HIV itself may be involved in the development of immune complex-related glomerular lesions. Kimmel et al. [9] reported four cases of immune complex GN in HIV-positive patients who had circulating immune complexes containing HIV antigen. Furthermore, immune complexes containing HIV antigens and HIV-reactive antibodies were eluted from renal biopsy tissue from all four patients, and HIV antigens were detected in glomeruli from each patient [9].

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.



   Notes
 
Correspondence and offprint requests to: Mark Haas, Department of Pathology, Johns Hopkins University School of Medicine, 519 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205–2196, USA. Back



   References
 Top
 Introduction
 Cases
 Discussion
 References
 

  1. D'Agati V, Appel GB. Renal pathology of human immunodeficiency virus infection. Semin Nephrol1998; 18: 406–421[ISI][Medline]
  2. Detwiler RK, Falk RJ, Hogan SL, Jennette JC. Collapsing glomerulopathy: a clinically and pathologically distinct variant of focal segmental glomerulosclerosis. Kidney Int1994; 45: 1416–1424[ISI][Medline]
  3. Bourgoignie JJ, Ortiz-Interian C, Green DF, Roth D. Race, a cofactor in HIV-1-associated nephropathy. Transplant Proc1989; 21: 3899–3901[ISI][Medline]
  4. Nochy D, Glotz D, Dosquet P et al. Renal disease associated with HIV infection: a multicentric study of 60 patients from Paris hospitals. Nephrol Dial Transplant1993; 8: 11–19[Abstract]
  5. Casanova S, Mazzucco G, Barbiano di Belgiojoso G et al. Pattern of glomerular involvement in human immunodeficiency virus-infected patients: an Italian study. Am J Kidney Dis1995; 26: 446–453[ISI][Medline]
  6. Stokes MB, Chawla H, Brody RI et al. Immune complex glomerulonephritis in patients coinfected with human immunodeficiency virus and hepatitis C virus. Am J Kidney Dis1997; 29: 514–525[ISI][Medline]
  7. Markowitz GS, Cheng J-T, Colvin RB, Trebbin WM, D'Agati VD. Hepatitis C viral infection is associated with fibrillary glomerulonephritis and immunotactoid glomerulopathy. J Am Soc Nephrol1998; 9: 2244–2252[Abstract]
  8. Barbiano di Belgiojoso G, Genderini A, Bertoli S, Boldorini R, Tosoni A, Vago L. Immunotactoid glomerulopathy in a HIV-infected patient: a novel association. Nephrol Dial Transplant1996; 11: 857–859[ISI][Medline]
  9. Kimmel PL, Phillips TM, Ferreira-Centeno A, Farkas-Szallasi T, Abraham AA, Garrett CT. HIV-associated immune-mediated renal disease. Kidney Int1993; 44: 1327–1340[ISI][Medline]
  10. Fogo A, Qureshi N, Horn RG. Morphologic and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy. Am J Kidney Dis1993; 22: 367–377[ISI][Medline]
Received for publication: 29. 2.00
Revision received 24. 4.00.