Acute tubulointerstitial nephritis with germinal centers in antineutrophil cytoplasmic antibody-associated vasculitis

Abstract Rationale: Occasionally, tubulointerstitial lesions can be found in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, significantly isolated tubulointerstitial nephritis (TIN) with germinal centers is rare. Patient concerns: A 17-year-old Chinese Han patient showed rapidly progressive glomerulonephritis, anuria, and serum creatinine of 19.4 mg/dL. Diagnosis: He had positive ANCA targeting myeloperoxidase (55.0 RU/mL). The renal biopsy showed crescent formation in 100% of glomeruli. Of special note, the glomerular crescents were surrounded by granulomatous inflammation, extensive tubular destruction or disappearance, and massive interstitial infiltration. A diagnosis of AAV was thus made with the involved organ restricted to the kidney. Interventions: The patient underwent 7 rounds of plasmapheresis, 3 pulses of methylprednisolone therapy (500 mg per pulse), and oral prednisolone (50 mg/d). Rituximab (500 mg) was used after the plasma exchange treatment. Outcomes: ANCA was negative, while anti-modified C-reactive protein (anti-mCRP) antibodies remained positive. The patient was dependent on hemodialysis. We found anti-mCRP antibody in the serum of the patient, with the major epitope on amino acids 35 to 47 of mCRP. Lessons: We proposed that the anti-mCRP antibody might play an important role in this case of acute TIN in AAV.


Introduction
Renal involvement is common in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and patients often present with pauci-immune necrotizing crescentic glomerulonephritis. [1] Tubulointerstitial (TI) lesions can also be found in the kidneys in AAV, although their pathogenesis remains to be elucidated. [1][2][3] Modified C-reactive protein (mCRP) is a tissue and/or cell-based form of the acute phase protein and has been suggested to be a possible antigen in acute tubulointerstitial nephritis (ATIN). However, there is no report of an anti-mCRP antibody in patients with AAV. Here, we present a case of ATIN in AAV with positive serum anti-mCRP antibody, which might provide some insights into the pathogenesis of the disease.

Case presentation
A 17-year-old Chinese Han man was admitted with a 23-day history of edema, fatigue, and subsequent anuria. He had no fever. Ten days before admission, his serum creatinine was 19.4 mg/dL, and urinalysis revealed proteinuria 1+ and hematuria with 228 red blood cells/high-power field (HPF). He was positive for perinuclear ANCA (pANCA) by immunofluorescence. He received hemodialysis and renal biopsy and was referred to our Editor: N/A. The authors have no conflicts of interest to disclose.
hospital. He had suffered from hyperthyroidism for 7 years and had been prescribed thiamazole and propylthiouracil (PTU) for 3 years. Moreover, he had a 5-year history of allergic rhinitis and allergic asthma. He had no family history of hypertension, glomerulonephritis or end-stage renal disease, and he had no drug addiction.
On admission, the physical examination revealed a blood pressure of 128/73 mm Hg, temperature of 36.5°C, heart rate of 78/min, and respiratory rate of 20/min. The patient was anemic, although further systemic clinical examination was unremarkable.
The laboratory data revealed serum creatinine of 12.3 mg/dL and interleukin-6 of 66.0 pg/mL (normal range: 0-0.64 pg/mL). The patient's urinalysis revealed proteinuria 1+ and dysmorphic red blood cells >100/HPF; he was positive for pANCA by immunofluorescence, and anti-MPO antibody was shown to be positive at 55.0 RU/mL by enzyme-linked immunosorbent assay. Anti-glomerular basement membrane antibody and antinuclear antibody were negative. The ophthalmological examination excluded tubulointerstitial nephritis with uveitis (TINU), and positron emission tomography-computed tomography scan indicated no tumor or infection.
Because of the severe TI injury observed in his kidney specimens, we detected anti-mCRP antibodies. The patient was strongly positive (112%) for serum anti-mCRP antibodies. As illustrated in Figure 2, the anti-mCRP antibody titer was 1:800, the subclasses of immunoglobulin G (IgG) were IgG2 and IgG3, and the major epitope was amino acids (a.a.) 35 to 47. Eight months later, the titer was still 1:800, while the main IgG subclass was IgG1.
The patient received 7 rounds of plasmapheresis, 3 pulses of methylprednisolone therapy (500 mg per pulse), and oral prednisolone (50 mg/d). Rituximab (500 mg) was used after the plasma exchange treatment. ANCA was negative, while anti-mCRP antibodies remained positive. The patient was dependent on hemodialysis.

Discussion
This patient presented with rapidly progressive glomerulonephritis, positive serum ANCA and pauci-immune crescentic glomerulonephritis with severe interstitial nephritis. Thus, a diagnosis of AAV was highly suspected. However, several other diseases should be excluded.
First, PTU-induced ANCA-positive vasculitis must be highly suspected. Increasing evidence has demonstrated that PTU could induce ANCA-positive vasculitis, and the withdrawal of the drug was closely related to the improvement of active vasculitis and renal function. [4] However, this patient stopped taking PTU 4 years ago. Second, TINU syndrome also need to be considered. However, his ophthalmological examination was normal, and severe glomerular crescent formation was not consistent with the characteristics of TINU. By excluding other possible diagnoses, a diagnosis of AAV was made with its target organ restricted to the kidney.
Renal involvement of AAV is predominant in glomerular lesions, especially pauci-immune necrotizing crescentic glomerulonephritis. The TI lesions are thought to be secondary damage to the glomeruli. [1][2][3] However, the current patient showed severe TI lesions with germinal centers and Bowman capsule rupture, which could not be explained simply by AAV.
More interestingly, there were many ectopic germinal centers and nonlymphoid collections of mature B lymphocytes in the renal interstitium of this patient, suggesting that severe renal interstitial inflammation may be associated with his autoimmune disease. The patient also presented with elevated interleukin (IL)-6. Recently, Espeli et al [20] showed that in LN, the kidneys are a major source of autoantibody-producing plasma cells. The inflammatory cytokine IL-6 supports long-lived plasma cell survival in vitro and is increased in the serum of patients with lupus. Arkatkar et al [21] demonstrated that B cell-derived IL-6 is critical for spontaneous germinal center formation. Ectopic germinal center formation may contribute to the progression of lupus interstitial nephritis by selecting for cells that locally secrete pathogenic antibodies in the tubulointerstitium. [22] It is unclear whether a similar process occurred in the current case, but further study is needed.
In conclusion, we reported a case of severe TI lesions with many germinal centers and rupture of all Bowman capsules in AAV, which may result from anti-mCRP antibodies.