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Abstract
Fibrillary glomerulonephritis (FGN) is a rare form of glomerulonephritis, and the incidence in native renal biopsies is less than 1%. The diagnosis of FGN is defined by the ultrastructural finding of organized, randomly oriented, nonbranching fibrils with a diameter of 10-30 nm. FGN is immune-mediated glomerulonephritis with predominant immunoglobulin (Ig) G deposits. Hypocomplementemia is very rare. We report the case of a 68-year-old Caucasian man with renal impairment, hematuria, subnephrotic proteinuria, hypocomplementemia (low C4, normal C3), and hypergammaglobulinemia. The kidney biopsy revealed a mesangial proliferative pattern with IgM deposits, and the electron microscopy demonstrated FGN. Upon further investigation, secondary causes, such as malignancy, monoclonal gammopathy, or autoimmune disease were excluded, and human immunodeficiency virus (HIV) infection was revealed. Only three cases with FGN associated with HIV infection without concurrent hepatitis C virus have been reported and all of them in already known medical records. Our patient received treatment with corticosteroids and highly active antiretroviral therapy, and the renal function improved.
Introduction 
Fibrillary glomerulonephritis (FGN) is a rare proliferative glomerular disease that is defined by the ultrastructural finding of organized, randomly oriented, nonbranching fibrils with a mean diameter of 20 nm (range 12-24 nm), which differs from amyloid deposits in their large size and lack of reactivity to Congo red.[1] The glomerular deposits are predominantly composed of polyclonal immunoglobulin (Ig) G and complement (C) 3, whereas predominant IgM deposits are very rare. Usually, the patients present renal insufficiency, nephrotic range proteinuria, and hematuria. Hypocomplementemia is very rare <10% and is often associated with systemic diseases. FGN was initially considered to be an idiopathic disorder. However, approximately 30%-50% of patients have secondary causes.[2],[3],[4] The diagnosis of FGN is established by kidney biopsy, with the pathognomonic changes seen on electron microscopy, which is not widely available. Recently, a novel biomarker DNAJ homolog subfamily B member 9 has been identified and will improve the diagnosis of this rare disease.[5]
Case Report A 68-year-old Caucasian man was referred for evaluation microscopic hematuria (dysmorphic RBCs 75%), proteinuria subnephrotic range (628 mg/24 h) and renal impairment (creatinine = 1.4 mg/dL, urea = 58 mg/dL). The patient had a 1-year history of microscopic hematuria. In addition, his medical history included: hypertension, thyroidectomy (benign goiter), nephrolithiasis, allergic rhinitis, and conjunctivitis.
Renal biopsy was done and the light microscopic study revealed mesangial expansion of immune deposits with mild mesangial hypercellularity and segmental moderate glomerular capillary wall thickening [Figure 1a and b]. By immunofluorescence examination glomerular positivity for IgM and C3 with a median intensity of (2+/3+) were observed mainly in mesangial areas. Staining with IgG, IgA, C4, C1q, λ light chain, klight chain was all negative [Figures 2 and 3]. Electron microscopy showed randomly arranged fibrillary electron-dense deposits (mean fibril thickness 14 nm) in the mesangium and paramesangium. On the extramembranous side, the podocytes displayed a marked fusion of epithelial foot processes. We did not observe tubuloreticular structures in endothelial cells. Finally, the patient was diagnosed as FGN with unusual IgM deposits [Figure 4].
Figure 1. (a and b) Mesangial expansion of immune deposits with mild mesangial hypercellularity and segmental moderate glomerular capillary wall thickening (PAS stain).
Figure 2. Immunofluorescence technique showing mesangial IgM deposits (×400).
Figure 3. Immunofluorescence technique showing mesangial C3 deposits (×400).
Figure 4. Electron microscopy reveals no branching, randomly oriented fibrils with a mean diameter of 14 mm in the mesangium (×22.000).First, we investigated the secondary causes, such as systemic autoimmune diseases, malignant neoplasm or infections, mainly hepatitis. Plasma cell dyscrasia and malignancy were eliminated with the results of bone marrow biopsy with immunohistochemistry, negative serum and urine immunofixation and thoraco-abdominal computed tomography scan. The other laboratory findings were as follows: hemoglobin = 13.6 g/dL, platelets = 171.000/uL, hematocrit = 42.2%, white blood cells = 6.350/uL (polymorphonuclears 47%, lymphocytes 36%, and monocytes 13%), albumin = 3.8 g/dL, aspartate aminotransferase = 27 U/L, alanine aminotransferase = 13 U/L, hypergammaglobulinemia IgG = 3584 mg/dL (700-1600), IgG4 serum normal range, IgM 245 mg/dL (40-230), low C4 8.1 mg/dL (10−40), normal C3 111 mg/dL (75-180), and antinuclear antibody 1/160. Serum cryoglobulin were negative, anti-double-stranded DNA (-), anti-citrulline antibody (-), anti-Ro/SSA (-), anti-La/SSB (-), anti-Smith (-), antiribonucleo-protein (-), and rheumatoid factor (-). There was no clinical evidence of systemic lupus erythematosus or rheumatoid arthritis. PSA, CEA and CA19-9 were at normal levels. Another investigation to exclude Hepatitis B (HBV) and C (HCV) were negative, whereas human immunodeficiency virus (HIV) antibodies I/II were positive. A western blot test confirmed HIV infection. CD4 cells before treatment were 280 cells/mm3.
Our patient was treated with highly active antiretroviral therapy (HAART) (dolutegravir and lamivudine) and steroids 1 mg/kg body weight with gradual tapering for 6 months with renal improvement [Table 1].
Table 1. Posttreatment laboratory findings.The authors obtained all appropriate consent forms from the patient for the publication of this case report.
Discussion FGN was initially thought to be idiopathic, but recent series revealed frequent (30%-58%) association with autoimmune disease (systemic lupus erythematosus, Crohn’s disease, Graves’ disease, Sjogren syndrome, rheumatoid arthritis), malignant neoplasm, or hepatitis.[2],[3],[4] Autoimmune disease appears to be the most commonly associated condition, reported in 13-30% of patients in different series.[2],[3] As far as infections, the association between FGN and HCV infection is well recorded,[3],[4] whereas HIV infection is rare. The classic kidney disease of HIV infection is HIV-associated nephropathy (HIVAN), whichis a collapsing form of focal segmental glomerulosclerosis.[6] A number of immune complex kidney diseases have been reported in patients with HIV infection, including membranous nephropathy, membranoprolife-rative and mesangial proliferative glomerulonephritis, and “lupus-like” proliferative glomerulonephritis.[7]
Six cases of FGN associated with HIV infection have been reported to date, the three of them coinfected with HCV.[3],[4],[8],[9],[10] Recently, two cases have been reported, one in African-American male and the other in Indian male with FGN related to HIV infection without concurrent HCV infection, both of them had a history of HIV infection.[9],[10] In addition, Payan Schober et al in a cohort of 42 patients with FGN, recorded one patient with HIV infection (5% 1/19).[3]
Our patient exhibited more various atypical characteristics, including a strong positive immunofluorescence intensity of IgM without IgG and hypocomplementemia.
FGN is associated with five patterns of glomerular involvement by light microscopy and the most common pattern in the majority of cases series is the mesangial proliferative. The IF findings include deposits intensely composed of IgG and C3, and both kappa and lambda (i.e., polyclonal) light chains and less intensely composed of IgM, IgA, C1q.[1]
There are just two cases of FGN with intense predominant IgM deposition in the literature.
A 69-year-old woman who presented with a nephrotic syndrome and renal failure (serum creatinine level 112 μmol/L) and the kidney biopsy revealed FGN with IgM deposits with a very particular “barbed wire” morphological aspect.[11] The other case was a 12-year-old girl who presented with acute nephrotic-nephritic syndrome with low complement (both C3 and C4) (mimicking atypical clinical features of acute poststreptococcal GN) and six months later the kidney biopsy revealed FGN with unusual IgM deposits.[12] This case is the only case of FGN with unusual IgM deposits and hypocomplementemia that has been reported.
Hypocomplementemia is rare, present in <10% of patients (range 0−9%)[2],[4],[13] even in patients with the underlying autoimmune disease or HCV infection.[2],[4] Other reviews/ case reports showed that patients with hypocomplementemia were associated with systemic diseases, such as systemic lupus erythematosus, rheumatoid arthritis, IgM-kappa monoclonal gammopathy, leukocyto-clastic vasculitis, hepatitis B.[14],[15],[16] Three were not associated with systemic diseases.[17],[18],[19] It is worth mentioning that there are few cases with isolated low C4 in patients with HIV infection, although without concurrent FGN.[20]
Prognosis is poor with nearly half of patients progressing to end-stage renal disease within four years. Predictors of progression are older age, serum creatinine level and proteinuria at diagnosis, glomerular pattern (membranoproli-ferative vs. mesangial proliferative pattern), and more extensive glomerulosclerosis and interstitial fibrosis.[5] There are limited data to suggest the optimal therapy for FGN. For patients who have chronic HCV infection and have not yet received therapy, HCV treatment is recommended. However, there is no evidence that treating HCV infection results in improvement of FGN, as does HIV infection.
Conclusively, we report herein a rare case with FGN with dominant IgM deposits and hypocomplementemia in a Caucasian man, which revealed HIV infection. It is quite rare for FGN to be associated with HIV infection without concurrent HCV. In that case, treatment with HAART and corticosteroids was appropriate and renal function improved, although FGN has poor renal prognosis, as we mentioned above. This case illustrates the need for screening HIV infection in any patient with FGN and evaluating the optimal treatment of FGN in HIV patients.
Conflict of interest: None declared.
References 
Correspondence Address:
Aglaia Chalkia
Department of Nephrology, Hippokration General Hospital, Athens, Greece.
Greece
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/1319-2442.352448
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