Granulomatous interstitial nephritis with CTLA-4 haploinsufficiency: a case report

A 44-year-old Japanese man presented with fever and malaise to the Department of Hematology at our hospital. He was prescribed medication for the common cold and levofloxacin (LVFX), 500 mg once daily, for a week; however, his fever did not subside. He presented to our hospital again and was prescribed the same medications for an additional week. However, the fever persisted, and the patient experienced loss of appetite. He was then admitted to our hospital for further examination and treatment. The patient had a prior history of immune thrombocytopenia at 19 years of age and of autoimmune hemolytic anemia at 32 years of age. During his late thirties, three of his children showed similar symptoms (Fig. 1a) and genetic testing revealed the same genetic mutation, a heterozygous nonsense p. Q12X mutation in CTLA4, in them. The expression level of reactive CTLA4 mRNA in his two daughters, measured by real-time PCR, was decreased compared to that in the control group (Fig. 1b). Although a PCR test was not performed for the patient, he and his two daughters were diagnosed with CTLA-4 haploinsufficiency due to the presence of the same mutation.

Fig. 1figure 1

CTLA4 mutation in our patient’s family and decreased CTLA4 mRNA expression in his two daughters. a The family tree shows the same genetic mutation, heterozygous nonsense p. Q12X mutation in CTLA4, found in our patient (blue arrow) and his three children. His wife has wild type with no mutation. Their main clinical symptoms are described. b Real-time PCR using peripheral blood mononuclear cells (PBMCs), after stimulation with anti-CD3 and anti-CD28 obtained from his two daughters, showed decreased expression of the reactive CTLA4 mRNA compared to that in the control group

On physical examination at admission, his temperature was 37.8 °C. The patient’s cardiovascular, pulmonary, abdominal, and neurological examinations were normal, and no edema, arthralgia, swelling, or pain in the cervical lymph nodes were reported.

His laboratory data on admission are described in Table 1. His serum creatinine level was significantly elevated from the baseline level of 0.8 mg/ dL. No occult blood, proteinuria, pyuria, or urinary casts were detected on urinalysis. However, tubular injury markers were elevated. After admission, oral LVFX was discontinued, and piperacillin-tazobactam was initiated to treat the persistent fever. However, the fever did not subside, and serum creatinine levels increased to 4.23 mg/dL on the fourth day of admission. He was then referred to our department.

Table 1 Laboratory findings on admission

The laboratory data on admission are shown. Inflammatory markers were elevated. IgG did not change remarkably compared to baseline levels. Upon urinalysis, occult blood, pyuria, or any casts were not detected; however, mild proteinuria and elevated tubular injury markers were found.

A kidney biopsy was performed on the seventh day. The specimen contained 12 glomeruli, of which one was globally sclerosed Light microscopy showed diffuse interstitial inflammation composed of numerous lymphocytes with foreign body giant cells associated with non-caseating granulomas, few eosinophils, and plasma cells. Tubulitis, with no evidence of vasculitis, was also observed. All other glomeruli, excluding the sclerosed, showed no significant changes (Fig. 2a). Immunofluorescence revealed non-specific findings, and electron microscopy revealed no electron-dense deposits. Ziehl–Neelsen acid-fast staining was negative. Immunohistological staining showed CD3+ and CD4+ T cells dominantly infiltrating the interstitial area (Fig. 2b). Moreover, immunostaining for FOXP3, the master transcription factor of Tregs, showed a decrease in the percentage of FOXP3+ cells within CD4+ T cells was decreased (Fig. 2c).

Fig. 2figure 2

Pathological findings of renal and colon biopsy. (a-i) Light microscopy of the first renal biopsy at low power showing diffuse interstitial infiltrating of lymphocytes. (a-ii) Numerous lymphocytes with foreign body giant cells associated with non-caseating granulomas and a few eosinophils and plasma cells (yellow arrowheads). (a-iii) Granuloma formation at high power field. b Immunohistochemistry showing a more dominant infiltration of CD3+ and CD4+ T cells in the interstitial area compared to CD8+ and CD20+ T-cells. c FOXP3 staining of the first renal biopsy, wherein the proportion of FOXP3+ cells within CD4+ T cells was not as high. d Improved interstitial inflammation and diminished granuloma in the second renal biopsy compared to that in the first biopsy using light microscopy at low power (d-i), and high power (d-ii). e Dominant CD3+ and CD4+ T cell infiltration in the interstitial area in both the first and second renal biopsy, even though the stained area was decreased in the second biopsy compared with that in the first biopsy. f Colon biopsy showing CD4+ cells as the dominant lymphocytes infiltrating the intestinal mucosa in immunohistological staining, similar to the findings in the kidney

Based on the histopathological findings, the patient was diagnosed with granulomatous TIN. We thus speculated that granulomatous TIN was either associated with the use of LVFX or with the presence of CTLA-4 haploinsufficiency.

Clinical course during hospitalization is shown in Fig. 3. We initiated oral prednisolone (PSL) therapy, 30 mg/day (0.5 mg/kg of body weight). After treatment, the fever subsided, and renal function improved gradually. The serum creatinine level decreased to 1.99 mg/dL within 2 weeks. The patient was discharged on the 17th day, and the dose of PSL was tapered to 25 mg/day. During outpatient follow-up, serum creatinine levels gradually improved, but did not decrease beyond 1.0–1.4 mg/dL even after PSL was tapered to 10 mg/day; moreover, malaise and arthralgia reoccurred. To re-evaluate the pathophysiology, we performed a second biopsy 5 months after the first. The results indicated that interstitial inflammation had improved and granuloma had diminished compared to that in the first biopsy (Fig. 2d). Similar to the first biopsy, CD3+ and CD4+ T cells predominantly infiltrated the interstitial area. However, in all immunohistological staining, the stained area was decreased (Fig. 2e) compared to that in the first biopsy. We evaluated five nonoverlapping interstitial fields in each tissue stained with CD3. CD3 positive areas were measured with the WinRoof Image Analyzer, version 4.3.0 (Mitani, Tokyo, Japan) and we compared the ratio of CD3 positive area relative to the entire area between the first and the second biopsy. As a result, there is significant decrease in the ratio of CD3 positive area in the second biopsy(9.6% ± 2.1) compared with the first(46.8% ± 5.3)(p = 0.043).

Fig. 3figure 3

Clinical course during hospitalization. Although piperacillin-tazobactam was initiated after admission, the fever did not subside, and serum creatinine levels increased, then he was referred to our department. A kidney biopsy was performed on the 7th hospital day, and oral prednisolone (PSL) therapy, 30 mg (0.5 mg/kg) daily was initiated. After treatment, the fever subsided, and renal function improved gradually. The serum creatinine level decreased to 1.99 mg/dL within 2 weeks. Patient was discharged on the 17th day

A colon biopsy was also performed as the patient reported diarrhea. The results showed lymphocytes infiltrating the intestinal mucosa; furthermore, CD4+ cells were the dominant lymphocytes (Fig. 2f). This was similar to the findings of the first renal biopsy.

The patient was then transferred to the same hospital as his children to receive further therapeutic intervention for CTLA-4 haploinsufficiency. In the other hospital, the patient was treated with abatacept, a recombinant fusion protein comprising the extracellular domain of human CTLA4, which inhibits the activation of T cells. PSL was maintained at 5 mg/day. After stating abatacept, his general symptoms (malaise, arthralgia) significantly improved and his creatinine level stayed around 1.0–1.2 mg/dl without more elevation.

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