Transition from endocapillary proliferative glomerulonephritis to membranoproliferative glomerulonephritis in a patient with a prolonged human parvovirus B19 infection
Takahiro Uchida, M.D.,1 Takashi Oda, M.D.,1 Atsushi Watanabe, M.D.,1 Kojiro Yamamoto, M.D.,1 Yuka Katsurada, M.D.,2 Hideyuki Shimazaki, M.D.,2 Seiichi Tamai M.D.,2 and Hiroo Kumagai M.D.1
1Department of Nephrology, 2Department of Laboratory Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan
Correspondence: Takahiro Uchida, M.D.
Department of Nephrology, National Defense Medical College,
3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
Tel: +81-4-2995-1609
Fax: +81-4-2996-5201
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Financial disclosure: None declared.
Conflict of interest statement: None declared.
Abstract
We report a case in which renal biopsies were performed 4 years apart in a woman with a prolonged human parvovirus B19 (HPV) infection. When she was 29 years old the first biopsy, performed because of microscopic hematuria and mild proteinuria, showed endocapillary and mesangial proliferative glomerulonephritis in light microscopy and showed deposits of complement C3 on capillary walls. Mesangial, intramembranous, and subepithelial hump-like electron dense deposits were seen in electron microscopy. The principal differential diagnoses, acute poststreptococcal glomerulonephritis and lupus nephritis, were unlikely, and her serological positivity for immunoglobulin (Ig)M antibody for HPV made us diagnose acute glomerulonephritis associated with HPV infection. The second biopsy, performed 4 years later because of persistent proteinuria and prolonged positivity for IgM antibody for HPV, showed membranoproliferative glomerulonephritis (MPGN) with mesangial interposition and with thickening and double contours of glomerular basement membrane. In tissues obtained in both biopsies, HPV DNA was detected by polymerase chain reaction. HPV infection has been widely known to cause various glomerular diseases. This case reveals that acute endocapillary proliferative glomerulonephritis can change into MPGN during prolonged HPV infection.
Key words
human parvovirus B19 - membranoproliferative glomerulonephritis - acute glomerulonephritis - hypocomplementemia - prolonged infection
Running title
MPGN caused by a prolonged HPV infection
Introduction
Endocapillary proliferative glomerulonephritis associated with human parvovirus B19 (HPV) infection has recently been attracting considerable attention as an important cause of acute glomerulonephritis (AGN). Its most common clinical presentation is an acute nephritic syndrome with hypocomplementemia, often following a prodrome of fever, rash, and arthritis, and its typical pathologic features are endocapillary and/or mesangial proliferative glomerulonephritis with granular deposition of complement C3 and immunoglobulin (Ig)G on glomerular capillary walls and mesangium [1, 2, 3]. It usually recovers spontaneously in immunocompetent patients.
However, a causal relation between HPV infection and other glomerular diseases, such as idiopathic focal segmental glomerulosclerosis (FSGS) and collapsing glomerulopathy, has also been suggested [4, 5]. In these reports, HPV DNA was detected in high prevalence within kidney tissue. Chronic diseases such as bone marrow failure, arthropathy, and rheumatoid arthritis have also been suggested to be associated with persistent HPV infection [6].
Here we report a case in which the first renal biopsy showed endocapillary proliferative glomerulonephritis typical of AGN associated with HPV infection and the second showed that membranoproliferative glomerulonephritis (MPGN) had developed during the patient’s prolonged HPV infection.
Case Report
A previously healthy 29-year-old woman in whom proteinuria was found at a medical checkup was referred to our Renal Department. She complained of mild arthralgia, mainly in her wrists, but was afebrile and normotensive. Other physical examination findings were unremarkable.
Her white blood cell count was 7.6 x 103/ml; hemoglobin concentration, 11.7 g/dl; platelet count, 303 x 103/ml. Serum creatinine was 0.64 mg/dL; urea nitrogen, 15 mg/dL; TP/Alb, 6.3/3.4 g/dL. C-reactive protein was negative. IgG was 1270 mg/dL; IgA/M, 161/95 mg/dL. Complement C3 was low, 0.33 mg/mL (reference range, 0.65-1.35 g/L), but C4 and CH50 were normal. The level of circulating immune complexes detected by C1q-binding assay was high, 5.0 mg/mL (reference range, <3.0 mg/mL). Antistreptolysin O (ASO) titer was 733 IU/mL (reference range, <166 IU/mL) and antistreptokinase (ASK) titer was 1280 (reference range, <640). Antinuclear antibody titer was 1:80, which was slightly positive, but anti-double-stranded DNA antibody was negative. Cryoglobulin and antineutrophil cytoplasmic antibody were negative. Viral antibodies for hepatitis B and C were negative, but IgM antibody for HPV (IgM-HPV-Ab) was positive; the titer was 8.54 (reference range, <0.8). Urinalysis showed a 3+ proteinuria and a 1+ occult blood. Microscopic examination showed dysmorphic erythrocytes. Protein excretion was 0.7 g/day.
The first renal biopsy yielded light microscopy (LM) sections of 60 glomeruli showing no sclerosis or crescents but showing endocapillary and mesangial proliferative glomerulonephritis (Fig 1-A(1)). There was prominent glomerular leukocytic infiltration; most of the infiltrating leukocytes were macrophages but some were neutrophils (Fig 1-A(2)). Tubulo-interstitial change was minimal. Immunoperoxidase staining for complement C3 was positive on capillary walls (data not shown). Immunofluorescence (IF) staining showed granular + deposition of complement C3 and IgM and showed ± deposition of IgG on capillary walls (data not shown). Electron microscopy (EM) revealed an electron dense subepithelial hump-like deposit as well as mesangial and intramembranous deposits but no subendothelial deposits (Fig 1-A(3)).
Acute poststreptococcal glomerulonephritis (APSGN) and lupus nephritis, which are the principal differential diagnoses, were clinically and serologically unlikely, and her serological positivity for IgM-HPV-Ab made us diagnose AGN associated with HPV infection.
On the basis of this diagnosis, she was conservatively treated with angiotensin Ⅱ type 1 receptor blocker and dipyridamole. The microscopic hematuria disappeared and kidney functions were within a normal range. Mild proteinuria (about 0.5 g/day), however, persisted. Her serum C3 remained low, and serological tests for IgM-HPV-Ab remained positive. Because we suspected a relationship between the persistent proteinuria and the prolonged positivity for IgM-HPV-Ab, we decided to re-evaluate her renal histology.
A second renal biopsy was performed about four years after the first, and LM sections with 7 glomeruli revealed MPGN. The thickening and double contours of the glomerular basement membrane were more diffuse than in the first renal biopsy tissue, and the endocapillary proliferation was much milder (Fig 1-B(1)). Mesangial interposition was also seen. Immunoperoxidase staining for complement C3 was positive on capillary walls (data not shown). IF sections showed granular deposition of complement C3 and IgM on capillary walls (data not shown) and EM sections showed small intramembranous electron dense deposits, some of which were washed out (Fig 1-B(2)).
As summarized in Table 1, serum IgM-HPV-Ab titer was lower at the time of the second renal biopsy but was still above the reference range. IgG-HPV-Ab was also positive, and HPV DNA in serum could not be detected by polymerase chain reaction (PCR) at the time of the second renal biopsy. In tissues obtained in both renal biopsies, however, HPV antigen was detected in glomeruli stained with monoclonal antibody against HPV antigen (Fig 2-A(1) and Fig 2-A(2)) and HPV DNA was detected by PCR (Fig 2-B).
Discussion
Either APSGN or lupus nephritis is generally considered the principal differential diagnosis of AGN associated with HPV infection. In this case, however, APSGN was unlikely for the following reasons: 1. Symptoms of prior streptococcal infection such as upper airway or skin infection were absent. 2. The minor glomerular neutrophil infiltration compared with much macrophage infiltration is atypical of APSGN but not uncommon in AGN associated with HPV infection [2]. 3. ASO and ASK titers were high but did not change over a period of six months, so there was no evidence of active or recent streptococcal infection. 4. Glomerular deposition of nephritis-associated plasmin receptor, which we identified as a nephritogenic antigen for APSGN [7], was not detected (data not shown). Lupus nephritis was also unlikely because diagnostic criteria of systemic lupus erythematosus were not satisfied. And the clinical course of this case, i.e., spontaneous remission of arthralgia and the disappearance of hematuria with just conservative therapy, was different from usual clinical course of lupus nephritis.
To our knowledge, there has been no reported case in which the AGN in a patient with an HPV infection made a transition to MPGN. There is one case in which the first renal biopsy of a patient with sickle cell disease showed focal proliferative glomerulonephritis but the second renal biopsy was compatible with FSGS [8]. Furthermore, in that case a PCR-based test detected HPV DNA in kidney tissue but not in blood, in analogy with our case [8]. The cellular receptor of HPV was originally identified as the glycolipid globoside or P antigen on erythrocytes [9], but other cells and tissues, including kidney tissue, have since been found to also have HPV receptors [10]. So it is probable that HPV resided in kidney tissue and caused MPGN. Indeed, there are many examples of secondary MPGN that appear to be caused by immune complexes produced during chronic infections [11].
The reason for persistent infection despite the immunocompetent condition of this case (normal concentrations of serum immunoglobulins, normal lymphocyte response to concanavalin A and pokeweed mitogen (date not shown)) is difficult to infer.
However, we offer two possible reasons for the persistent HPV infection in this case. The first is that the ability of IgG antibody to neutralize HPV was low. Evidence for this is that treatment with intravenous immunoglobulin therapy has been reported to be effective in patients with persistent HPV infection [12, 13]. This could explain why the HPV infection in this case persisted despite the presence of IgG-HPV-Ab in blood.
The second possibility is that the virus stayed alive at focal infectious sites difficult for circulating antibodies to get to. It was reported that tests for HPV DNA were positive in bone marrow but negative in blood in a patient who again manifested symptoms of autoimmune disease 6 years after the onset of HPV infection [14]. Not only bone marrow but also other tissues probably provide good places for HPV to hide from the host’s immune defense, since a causal relation between HPV infection and many chronic diseases has been indicated [6]. This might explain the cause of prolonged presence of IgM-HPV-Ab in this case, i.e., concentration of HPV had remained high in kidney tissue and the virus sometimes got into blood and produced IgM-HPV-Ab. DNA sequence variability of HPV is thought to be fairly low. However, recently detected two variants diverge from other HPV DNA by over 10% [6]. Such variability might be associated with viral resistance.
In summary, we report a case in which the histology of renal biopsy samples from a patient with a prolonged HPV infection indicates a transition from endocapillary proliferative glomerulonephritis to MPGN, thus, suggesting a profound relation between infection (acute/chronic), AGN and MPGN.
Acknowledgements
We thank Professor Yoshihiko Ueda, at Department of Pathology in Dokkyo Medical University Koshigaya Hospital, for valuable advice and staining for complement C3; our colleague Ms. Miho Nakayama for expert secretarial assistance.
References
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Figure legends
Fig. 1-A. Histological features of the first renal biopsy. (1) Diffuse endocapillary and mesangial proliferation seen in light microscopy (LM) sections stained with hematoxylin and eosin. (2) Double immunofluorescence staining for neutrophils (neutrophil elastase [Calbiochem, CA, USA] labeled with Alexa Fluor 594 [Invitrogen, CA, USA], red) and macrophages (CD68 [DAKO, CA, USA] labeled with Alexa Fluor 488 [Invitrogen], green) showing that the glomerulus contained far more macrophages than neutrophils. (3) Electron microscopy (EM) showed an electron dense subepithelial hump-like deposit (arrow) as well as mesangial and intramembranous deposits but did not show subendothlial deposits.
Fig. 1-B. Histological features of the second renal biopsy, performed about 4 years after the first. (1) Membranoproliferative glomerulonephritis, that is, thickening and double contours of the glomerular basement membrane, was seen in LM sections (periodic acid silver-methenamin stain). Mesangial interposition was also seen. (2) Small intramembranous electron dense deposits (arrowheads), some of which were washed out (arrows), were found in EM. (Original magnification, A(1), A(2), × 260, B(1), × 520)