Antineutrophil cytoplasmic antibody-associated vasculitis predominantly manifesting tubulointerstitial nephritis: A case report

Abstract

The common histopathology of antineutrophil cytoplasmic antibody-associated vasculitis comprises pauci-immune crescentic glomerulonephritis with concomitant tubulointerstitial nephritis. Tubulointerstitial nephritis in the absence of glomerular involvement in patients with antineutrophil cytoplasmic antibody-associated vasculitis is uncommon. We report a case of antineutrophil cytoplasmic antibody-associated vasculitis-associated acute kidney injury manifesting as tubulointerstitial nephritis without glomerulonephritis. A 75-year-old woman with fever, cough, and myalgia developed kidney dysfunction with inflammatory reactions and tubular-type proteinuria, without glomerular hematuria. A kidney biopsy revealed tubulointerstitial nephritis with arteritis. We ruled out important underlying etiologies of tubulointerstitial nephritis, including infection, drug reactions, and autoimmune diseases. Since chest high-resolution computed tomography demonstrated mild interstitial pneumonia in bilateral lower lung fields, myeloperoxidase antineutrophil cytoplasmic antibody was measured and found to be positive. Therefore, we diagnosed the patient with antineutrophil cytoplasmic antibody-associated vasculitis-associated tubulointerstitial nephritis but not glomerulonephritis, and interstitial pneumonia. The patient’s kidney function and symptoms markedly improved with prednisolone treatment. Clinicians should maintain high-level vigilance for antineutrophil cytoplasmic antibody-associated vasculitis as a possible underlying component of tubulointerstitial nephritis, particularly when kidney function deteriorates with tubulointerstitial injuries without glomerular features.

Introduction

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of multisystem autoimmune diseases. It is characterized by ANCA production directed against either proteinase 3 or myeloperoxidase (MPO) and small- to medium-vessel inflammation. ¹ The typical histopathology of the kidney shows pauci-immune crescentic glomerulonephritis, with concomitant tubulointerstitial nephritis. Therefore, tubulointerstitial nephritis in the absence of glomerular involvement in patients with AAV is uncommon. ² Consistently, a study examining renal biopsy specimens from patients positive for ANCA reported that only approximately 1% of cases showed tubulointerstitial nephritis without glomerular lesions using light microscopy. ³ Although several rare cases of tubulointerstitial nephritis without glomerulonephritis have been reported,^4–9 determining the possibility of ANCA involvement in isolated tubulointerstitial nephritis could be difficult. Herein, we report a rare case of AAV predominantly manifesting as tubulointerstitial nephritis. We could make a diagnosis by taking into account extrarenal AAV-associated clinical features such as interstitial pneumonia.

Case presentation

A 75-year-old woman with hypertension and dyslipidemia developed anorexia, malaise, and dyspnea on exertion 4 months before admission. The patient had a fever within the physiological febrile range (38–40°C) at night and a cough starting 1 month before admission. The patient had no allergies to drugs or documented history of coronavirus disease 2019 (COVID-19). Two days before admission, she visited her family doctor due to muscle pain in both thighs. Blood test results showed elevated inflammatory markers: white blood cells (WBCs), 25,600 /µL, and C-reactive protein (CRP), 14.9 mg/dL. She was admitted to our hospital to evaluate the cause of her myalgia with high inflammatory reaction. The patient’s body temperature was 37.3°C, the blood pressure was 161/115 mmHg, the heart rate was 115 beats per min, and the percutaneous oxygen saturation was 99% on room air. Reverse transcription-polymerase chain reaction testing for severe acute respiratory syndrome coronavirus 2 RNA from nasopharyngeal swabs showed negative results. Physical examination revealed dry rales in both lung fields on auscultation and mild edema in both lower legs.

Blood test results on admission demonstrated a serum creatinine level of 1.6 mg/dL, suggestive of acute kidney injury, high inflammatory reaction (CRP, 10.43 mg/dL), and anemia (hemoglobin, 10.2 g/dL). Urinalysis showed tubular-type proteinuria with an elevated level of β2-microglobulin (28,525 µg/dL) without glomerular hematuria (Table 1).

Table 1.

Laboratory data on admission.

Blood cell count		Serology
WBC	22,000 /μL	CRP	10.43 mg/dL
Stab + Seg	87.9%	IgG	2014 mg/dL
Lymph	7.3%	IgA	165 mg/dL
Mono	4.2%	IgM	116 mg/dL
Eosino	0.4%	RF	288 U/mL
Baso	0.2%	ANA	<40×
RBC	3.86 × 106/μL	Anti-dsDNA Ab	<12 U/mL
Hb	10.2 g/dL	Anti-SS-A Ab	<1.0 U/mL
Ht	31.0%	Anti-SS-B Ab	<10.0 U/mL
Plt	156 × 103/μL	MPO-ANCA	131.0 U/mL
Biochemistry		PR3-ANCA	<1.0 U/mL
TP	6.3 g/dL	Anti-GBM Ab	<2.0 U/mL
Alb	2.1 g/dL	CH50	39.7 U/mL
T-Bil	0.8 mg/dL	C3	88 mg/dL
AST	24 U/L	C4	25 mg/dL
ALT	13 U/L	KL-6	308 U/mL
ALP	112 U/L	Urinalysis
LDH	407 U/L	Protein	(±)
γ-GTP	32 U/L	Blood	(1+)
Amylase	127 U/L	Glomerular hematuria	(−)
Na	128.6 mmol/L	β2 microglobulin	28,525 μg/dL
K	3.0 mmol/L	Protein	0.34 g/day
Cl	91 mmol/L	Granular cast	2+
Ca	8.0 mg/dL	Epithelial cast	1+
P	3.2 mg/dL
BUN	40.6 mg/dL
Cre	1.6 mg/dL
eGFR	25 mL/min/1.73m2
UA	4.3 mg/dL
HbA1c	5.9%

WBC: white blood cell; RBC: red blood cell; Hb: hemoglobin; Ht: hematocrit; Plt: platelet; TP: total protein; Alb: albumin; T-Bil: total bilirubin; AST: aspartate aminotransferase; ALT: alanine aminotransferase; ALP: alkaline phosphatase; LDH: lactate dehydrogenase; γ-GTP: γ-glutamyl transpeptidase; Na: sodium; K: potassium; Cl: chloride; Ca: calcium; P: phosphorus; BUN: blood urea nitrogen; Cre: creatinine; eGFR: estimated glomerular filtration rate; UA: uric acid; HbA1c: Hemoglobin A1c; CRP: C-reactive protein; RF: rheumatoid factor; ANA: antinuclear antibody; Anti-ds-DNA Ab: anti-double-stranded DNA antibody; Anti-SS-A Ab: anti-SSA/Ro antibody; Anti-SS-B Ab: anti-SS-B/La antibody; MPO-ANCA: myeloperoxidase-antineutrophil cytoplasmic antibody; PR3-ANCA: proteinase3 antineutrophil antibody; Anti-GBM Ab: antiglomerular basement membrane antibody; KL-6: sialylated carbohydrate antigen KL-6.

Despite appropriate hydration, renal function further deteriorated with the emergence of granular and epithelial casts and an increase in β2-microglobulin (35,704 µg/dL). These findings suggested a possibility of tubulointerstitial nephritis that could contribute to high levels of CRP. A kidney biopsy was performed 10 days after admission. Light microscopy revealed 27 glomeruli, of which two were globally sclerosed and five had collapsed. The remaining glomeruli showed minor abnormalities (Figure 1(a)). Diffuse interstitial inflammation and fibrosis were observed (Figure 1(b) and (c)). Large fibrotic foci were also observed, and some of the arterioles showed inflammation and fibrosis of the wall with focal destruction of the internal elastic lamina (Figure 1(d) and (e)). However, peritubular capillaritis (PTC) were not observed. Immunofluorescence analysis revealed no deposits of immunoglobulin or complement. No tissue was available for electron microscopic evaluation. Based on these pathological findings, a diagnosis of tubulointerstitial nephritis was confirmed. Therefore, we investigated the underlying etiologies of tubulointerstitial nephritis, such as infection, drug reactions, and autoimmune diseases. Blood and sputum culture results were negative. Since the patient had not received any medication prior to admission, drug-induced tubulointerstitial injury was unlikely. Furthermore, levels of anti-double-stranded deoxyribonucleic acid and anti-Sjogren’s-syndrome-related antigen A and B antibodies were within the normal range.

Figure 1.

Histopathological findings of renal biopsy. (a) Glomeruli showed no mesangial expansion and hypercellularity (PAS). Formation of a crescent or discontinuation and rupture of the capillary basement membrane are not observed (PAM). (b) Biopsy specimens reveal diffuse interstitial fibrosis and inflammation (Masson trichrome staining). (c) Foci of tubulitis (PAS). (d) Relatively large fibrotic foci are observed (HE and EVG). (e) Fibrosis of the arterial wall with focal destruction of the internal elastic lamina (EVG).

Given that high-resolution computed tomography (CT) of the chest revealed interstitial changes in bilateral lung bases (Figure 2), we performed MPO-ANCA measurements and found that the titer of MPO-ANCA was elevated to 131 U/mL.

Figure 2.

High-resolution computed tomography of the chest. A chest CT scan on admission shows interstitial changes in bilateral lung bases accompanied by emphysema from the neck to the mediastinum and mild pneumothorax in both lungs.

Based on the positive ANCA serology and findings in the kidney biopsy and lung, we diagnosed the patient with tubulointerstitial nephritis with ANCA-associated arteritis.

The patient received prednisolone 1 mg/kg (40 mg) daily from day 10 after admission, tapered to 30 mg on day 21 and 25 mg on day 28. Her renal function worsened, showing a maximum serum creatinine of 2.80 mg/dL on day 18 but decreased to 1.54 mg/dL on day 36 along with a prompt improvement in inflammatory reaction (CRP 0.04 mg/dL). The patient was discharged on day 38. Serum creatinine improved to 0.99 mg/dL, urine protein-to-creatinine ratio turned negative 4 months after admission, and MPO-ANCA became undetectable after 1 year, with prednisolone 10 mg/day (Figure 3).

Figure 3.

Clinical course of the patient.

Discussion

Herein, we describe a rare case of AAV that predominantly presented with tubulointerstitial nephritis. Our case was unique in that we suspected ANCA involvement even though urinalysis and renal biopsy revealed negative results suggestive of glomerular lesions. Regarding identifying the cause of tubulointerstitial nephritis, drug-related, infectious, and autoimmune diseases should be excluded.^10–12 The patient was not administered any medications before admission. The blood and sputum cultures revealed negative results. Systemic lupus nephritis and Sjögren’s disease were ruled out based on immunological tests and clinical manifestations. Importantly, she did not experience eye pain or redness. Therefore, we excluded the possibility of tubulointerstitial nephritis and uveitis syndrome. We sampled arterioles with inflammation and destructed internal elastic lamina and found large fibrotic foci, which could represent scarring originating from arteritis in the kidney biopsy. Ohashi et al. ¹³ suggested that not only PTC, but also arteriolitis could play an important role in the pathogenesis of tubulointerstitial nephritis due to AAV. In our case, arteriolitis but not PTC was observed. Therefore, we determined that the underlying mechanism of tubulointerstitial nephritis in our case was likely due to arteriolitis and/or arteritis.

AAV is a group of disorders characterized by inflammation, destruction of small- and medium-sized blood vessels, and presence of circulating ANCA. ² The typical kidney histopathology of AAV indicates necrotizing or crescentic glomerulonephritis, without significant immune complex deposition. Glomerular involvement is often accompanied by tubulointerstitial nephritis, ¹⁴ which suggests that tubulointerstitial nephritis without glomerular lesions is rare. A study including 232 ANCA-positive cases demonstrated that necrotizing or crescentic glomerulonephritis accounted for 75% of cases, while tubulointerstitial nephritis without glomerular lesions accounted for just 1%. ³ To date, a few rare cases of AAV with tubulointerstitial nephritis without glomerulonephritis have been reported.^4–9 Consistently, the findings of a study on 66 kidney biopsy specimens with MPO-ANCA-associated nephritis in Japan revealed three specimens (4.5%) showing tubulointerstitial nephritis without glomerulonephritis. ⁵ Importantly, these cases of tubulointerstitial nephritis without glomerulonephritis demonstrate the difficulties in determining the possibility of ANCA involvement. Therefore, clinicians should maintain clinical vigilance that systemic symptoms such as fatigue, cough, myalgia, arthralgia, and weight loss, as well as pulmonary involvement could be key factors for suspecting ANCA-associated tubulointerstitial nephritis, as in our case.

He et al. ⁴ reported, in a case series and literature review, that AAV-associated interstitial nephritis tended to occur in older patients without specific symptoms related to MPO-ANCA. Importantly, these patients typically responded well to immunosuppressive therapy, which often includes a combination of corticosteroids and cyclophosphamide. Previous reports have described remission of AAV-associated tubulointerstitial nephritis with a combination of corticosteroids and rituximab.^4,7 In our case, we only administered corticosteroids, without cyclophosphamide or rituximab because of the infectious risk due to immunosuppression amid the COVID-19 pandemic. The patient’s kidney function and symptoms including inflammatory reactions improved with prednisolone treatment alone. The ideal tapering regimen of glucocorticoids for ANCA-associated isolated tubulointerstitial nephritis has not been established. In our case, the prednisolone dose was 10 mg per day after a year of treatment (Figure 3). The dose and duration of corticosteroid administration should be adjusted according to the patient’s condition.

The mechanism responsible for AAV-associated isolated tubulointerstitial nephritis remains unclear but may involve the affinity of MPO-ANCA. Kasahara et al. ⁶ reported that neutrophils were less activated in the low-affinity type of MPO-ANCA, suggesting that neutrophils adhered to endothelial cells in the peritubular capillary than in the glomeruli, ultimately resulting in tubulointerstitial nephritis rather than glomerulonephritis. Although proteinase 3 (PR3)-ANCA-associated tubulointerstitial nephritis is rare, there are a few case reports demonstrating that isolated tubulointerstitial nephritis was due to PR3-ANCA.^15,16 Endothelial tubular cell injury was likely induced by the adhesion of leukocytes that express PR3 on the cell surface, which is similar to MPO-ANCA.

We should point out the importance of tubulointerstitial lesions in assessing the prognosis of kidney function in patients with ANCA-associated nephritis. In a clinicopathological analysis of 157 renal biopsies from patients with AAV, diffuse interstitial infiltrates, tubular necrosis, and tubular atrophy were reliable predictors of kidney function, either at entry or 1-year follow-up. ¹⁷ A prospective analysis of 96 patients with AAV revealed interstitial fibrosis, and tubular atrophy was correlated with kidney function at entry and 18 months. ¹⁸ These previous studies emphasized the importance of tubulointerstitial lesions as a prognostic factor.

Conclusions

We report a case of AAV that predominantly presented as tubulointerstitial nephritis. Clinicians should be aware of AAV as a possible underlying component of tubulointerstitial nephritis, even if signs of glomerular involvement are absent. An accumulation of reports and evidence is required to clarify the pathogenesis, treatment regimen, and prognosis of ANCA-associated tubulointerstitial nephritis.