Four cases of PVB19-associated kidney diseases
Case report n°1 (2018): lupus-like glomerulonephritis (Figure 1A).
A 42-year-old women was admitted to the Nephrology department in 2018 for a weight gain of 12 kg over a week, with exertional dyspnea. She had no past medical history. Physical examination revealed normal blood pressure (120/60mmHg), lower limb edema, and bilateral pleural effusion. A nephrotic syndrome was diagnosed (serum albumin 2.5 g/dL, proteinuria 9.6 g/24h), with a rise in serum creatinine (1.17 mg/dL), active urinary sediment (red blood cells (RBC) 27/mm3, white blood cells (WBC) 60/mm3), and non-regenerative anemia (hemoglobin 10.7 g/dL, reticulocytes 35 G/L). The complement C3 was low (0.69g/l), with normal C4 (0.12 g/L), and low CH50 (36%). The exploration of the complement alternative pathway revealed no deficiency in complement factors B, I and H, no antibodies against factor H, and no C3 nephritic factor. No antinuclear or anti-dsDNA antibodies were detected.
A kidney biopsy revealed a membrano-proliferative glomerulonephritis (MPGN), with a “full-house” pattern of endo-membranous deposits comprising IgA (+or-), IgM (++), IgG (+), C3 (++), C1q (+or-).
Anti-PVB19 IgG and IgM antibodies were detected, with a positive viremia, consistent with PVB19 primo-infection. No immunosuppressive therapy was introduced, and because the patient was previously immuno-competent, no intravenous immunoglobulin was administered. A remission of the nephrotic syndrome was observed after 4 weeks, with a decrease in serum creatinine. After six months, no relapse has occurred, renal function has normalized (estimated glomerular filtration rate (eGFR) 86 ml/min/1,73m2) without residual proteinuria (0.09g/24h).
Case report n°2 (2015): minimal change disease (MCD) and acute tubular necrosis (Figure 1B).
A 42-year-old women was admitted to the Nephrology department in 2015 for an acute nephritic syndrome. She reported a fever and 3-day rash of the arms and legs one month earlier, with a transient consumption of non-steroidal anti-inflammatory drugs. She had no remarkable medical history. Upon admission, she displayed a high blood pressure (190/90 mmHg), with a weight gain of 7 kg over a few days, and gross hematuria. Serum creatinine was elevated (1.33 mg/dL increasing to 2.24 mg/dl), with proteinuria (1 g/24h rising to 4 g/24h) and hematuria (>106/mm3). She displayed non-regenerative anemia (hemoglobin 11 g/dL, which lowered to 7 g/dL before the kidney biopsy, without schizocytes, and a normal haptoglobin level), leukopenia (3.5 G/L), thrombocytopenia (121 G/L), and polyclonal hypergammaglobulinemia. C3 and CH50 levels were low, with a normal C4, without anti-nuclear or anti-dsDNA antibodies. Bone marrow aspiration was normal, and abdominal CT scanner revealed no abnormality.
The kidney biopsy showed minimal change disease and acute tubular necrosis, without immune deposits or glomerular proliferation.
Viral and bacterial serologies were negative (HIV, HBV, HCV, Treponema pallidum), except for PVB19 which showed elevated titers of both IgG and IgM, with a positive viremia. PVB19 was also detected by PCR in the renal tissue.
The patient received oral corticosteroids (initiated at 1mg/kg/day for 1 month, then decreased over 5 months), and quickly recovered a normal renal function (eGFR 86 mL/min/1.73m²), without residual proteinuria (<0.2 g/24h). No relapse occurred after steroids withdrawal.
Case report n°3 (2012): Hemolytic and Uremic Syndrome (HUS)
A 28-year-old man was admitted to the Nephrology Intensive Care Unit in 2012 for HUS. He reported fever, abdominal pain and non-hemorrhagic diarrhea, 10 days earlier. He came to the emergency room for a worsening asthenia. Physical examination showed only pallor, a blood pressure of 128/97 mmHg, without fever. The blood tests revealed acute renal failure (serum creatinine 6.14 mg/dl), microangiopathic hemolytic anemia (Hemoglobin 11.9 g/dL, undetectable serum haptoglobin, positive schizocytes 1.5%, elevated lactate deshydrogenase 2000 UI/L), without regeneration (reticulocytes 4.2 G/L) associated with a thrombocytopenia (platelets 16 G/L). Urinary tests showed proteinuria (0.8 g/L) and leukocyturia (350/mm3) without hematuria.
Complement fractions were normal, and no abnormality was detected in the complement alternative pathway proteins (normal complement factors B, I, H, absence of antibodies against factor H, absence of C3 nephritic factor). There was no marker of auto-immunity, and the search for E.Coli O157:H7 and Shigatoxin in the stool was negative. Because of the low reticulocyte count, despite hemolytic anemia, a PVB19 infection was suspected and confirmed, with elevated IgG and IgM titers and positive viremia.
One session of plasma exchange was performed, and the patient subsequently reached hematological remission, followed by renal remission. Nine days after his admission, platelet count had normalized (382 G/L), LDH decreased (400 UI/L), and renal function improved (serum creatinine 3.64 mg/dL). No kidney biopsy was performed. The patient recovered a normal renal function (eGFR 95 ml/min/1,73m2) at 1 month. No relapse occurred subsequently.
Case report n°4 (2002): membrano-proliferative glomerulonephritis (MPGN) (Figure 1C and 1D).
A 19-year-old woman with a history of sickle cell disease was admitted, in 2002, to the Nephrology department to investigate a nephrotic syndrome. One year earlier, she had presented a PVB19 primary infection which had resulted in an aplastic crisis. Shortly after, she had developed a moderate proteinuria (1g/day) which had not been explored.
Upon admission, physical examination revealed a normal temperature, blood pressure 130/80 mmHg, pulse 64/min. She was pale, with worsened exertional dyspnea, lower limb edema, and a grade 2/6 systolic murmur. Laboratory tests revealed a nephrotic syndrome (serum albumin 2.4 g/dL, proteinuria 3.5 g/24) with preserved renal function (serum creatinine 1 mg/dL), without hematuria or leukocyturia, and poorly regenerative anemia (hemoglobin 6.3 g/dL, reticulocytes 136 G/L, platelets 882 G/L) without vitamin deficiency. Complement C3 and C4 were normal, and anti-nuclear antibodies were negative. PVB19 viremia was negative, but both IgG and IgM titers remained elevated, rising the hypothesis of a chronic PVB19 infection.
A kidney biopsy was performed and showed a mild endocapillary hypercellularity associated with subendothelial and subepithelial deposits leading to segmental duplicated basement membrane or intervening spikes. Red blood cells within the glomerular capillaries sometimes had a sickled pattern. Immunofluorescence with anti-C3 antibody showed a diffuse, almost continuous, strong staining. Electron micrograph confirmed this thickening of capillary basal membrane with granular dense deposits and effacement of foot processes. Search for PB19 by immunohistochemistry was negative.
The patient received ACE inhibitors, with a remission of the nephrotic syndrome, but with a progressive deterioration of renal function leading to end-stage renal disease 10 years later.
Prevalence or PVB19 immunization, and incidence of PVB19 primary infection
One hundred consecutive patients who underwent a native kidney biopsy were tested for PVB19 immunization and viremia. Their clinical characteristics and kidney biopsy results are provided in Table 1. There were 41 females and 59 males, with a mean age of 51.5 years; 40 were taking an immunosuppressive therapy (including corticosteroids) at the time of the biopsy.
Elevated titers of anti-PVB19 IgG antibodies were found in 67 (67%) patients, among whom 8 (2 females and 6 males, aged 31 to 83 years) also had elevated IgM titers, without PVB19 viremia (Table 2). The renal pathological results of these 8 patients with both IgG and IgM antibodies were: acute kidney tubular necrosis in 2, minimal change disease in 1, class III lupus nephritis in 1, MPGN with a “full-house” pattern of endo-membranous deposits in 1 (lupus-like GN without lupus auto-antibodies), pauci-immune crescentic GN in 1, hypertensive nephropathy in 1, acute interstitial nephritis with lymphocytic infiltration in 1.
One additional patient, a 63-year-old women, initially had elevated anti-PVB19 IgM without IgG antibodies, and subsequently developed anti-PVB19 IgG when she was tested again 4 months later. This was consistent with a PVB19 primary infection at the time of kidney biopsy, although viremia was negative. She had been admitted for arthralgia, and nephrotic syndrome with acute kidney injury (serum creatinine 1.23 mg/dl). Laboratory tests had revealed a non-regenerative anemia (hemoglobin 9,6 g/dl, reticulocytes 26 G/L). Renal pathological examination showed a membranous nephropathy (Figure 1D). Serum anti-PLA2R antibodies were negative, but there were positive anti-nuclear (> 1/1280) and anti-dsDNA (41 UI/mL) antibodies. The diagnosis retained was a class V lupus nephritis.
Overall, only 1 patient (1%) had a documented primary PVB19 infection in this cohort, and no patient had a PVB19 viremia. Among the 9 patients with elevated IgM titers, 4 had auto-reactive antibodies (antinuclear, ANCA, anti-MBG or PLA2R antibodies), and 6 had a mixed cryoglobulinemia (all with a negative hepatitis C virus serology).