IgA-dominant infection-related glomerulonephritis with NAPlr-positive tubulointerstitial nephritis

Abstract

Infection-related glomerulonephritis (IRGN) is one of the most common causes of acute kidney injury (AKI). Positive glomerular staining of the nephritis-associated plasmin receptor (NAPlr) has been reported as a useful biomarker of IRGN. Although the infection can provoke acute tubulointerstitial nephritis (AIN), there are few reports of positive staining for NAPlr with AIN. We report a case of methicillin-sensitive Staphylococcus aureus (MSSA) infection-related nephritis complicated with AIN, which showed positive staining for tubulointerstitial NAPlr. The patient developed AKI and nephrotic syndrome during an intraperitoneal MSSA infection. A diagnosis of IRGN complicated by infection-related acute tubulointerstitial nephritis (IRAIN) was made based on glomerular endocapillary proliferation with tubulointerstitial infiltrating cells and tubular atrophy. Tubulointerstitial infiltrating cells were positive for NAPlr staining and plasmin activity. Treatment of the infection by antibiotics and drainage did not improve the AKI, but steroid administration improved that. NAPlr evaluation is a helpful tool for identifying causes of AIN during infection.

Introduction

Cases of glomerulonephritis associated with Staphylococcus aureus and other bacteria have increased in adults; however, cases of acute post-streptococcal glomerulonephritis (APSGN) have decreased in children [1, 2]. The concept of infection-related glomerulonephritis (IRGN) has been proposed because the infection is still present at the onset of IRGN in adults [2]; however, in children, APSGN typically appears as acute nephritic syndrome after the resolution of streptococcal infection [1, 3, 4]. The nephritis-associated plasmin receptor (NAPlr) has been reported as a useful biomarker for IRGN [5]. NAPlr, isolated from group A streptococcus, is a nephritogenic protein associated with APSGN [6]. Most patients with APSGN will have positive staining for NAPlr in the glomeruli within 2 weeks of disease onset [3]. Glomerular plasmin activity co-localizes with NAPlr staining during APSGN [7]. Glomerular NAPlr deposition causes inflammation via three pathways: (1) NAPlr traps plasmin and preserves its activity, (2) NAPlr directly activates complements via the alternative pathway (AP), and (3) NAPlr causes antibody reaction and complement activation via the classical pathway [8]. This phenomenon has also been observed during infection with various other bacteria [9–11]. We report a case of acute kidney injury (AKI) with a nephrotic syndrome that developed during an intraperitoneal infection with methicillin-sensitive Staphylococcus aureus (MSSA). Renal biopsy revealed NAPlr staining in the tubulointerstitial compartment. MSSA infection can lead to acute tubulointerstitial nephritis (AIN) [12, 13], but few studies have reported positive NAPlr staining with AIN. Some studies support the use of steroids to treat IRGN and infection-related acute tubulointerstitial nephritis (IRAIN), but their efficacy remains controversial [2, 13]. In the case presented herein, the patient responded positively to steroid treatment.

Case report

A 78-year-old man with AKI and an intraperitoneal infection was referred to our institution. The patient had hypertrophy of the antral glands and hypertension, for which he was taking amlodipine besylate. There was no personal or family history of renal disease. He consumed 500 mL of beer and 270 mL of sake daily and had smoked 20 cigarettes/day for 50 years. He had no allergies. Two months prior to admission, he underwent a pancreatectomy to remove an intraductal papillary mucinous tumor; subsequently, he was readmitted due to the development of an abscess in the remaining pancreas. He was diagnosed with an intraperitoneal infection caused by MSSA and was treated by drainage via a tube placed postoperatively. AKI with nephrotic proteinuria and hematuria was observed 7 days post-intraperitoneal infection, and he was referred to us 7 days later. He had dyspnea with an oxygen demand of 2 L/min. Bilateral lower leg edema and a weight gain of 10 kg within 1 week were observed. There was no joint pain or purpura. Chest radiography showed bilateral pleural effusion. Respiratory failure caused by fluid overload was suspected. Laboratory tests on admission revealed the following: serum creatinine, 3.56 mg/dL; serum albumin, 1.9 g/dL; urine protein-to-creatinine ratio, 14 g/gCr; and urine β2-microglobulin, 7722 μg/L (Table 1). Anti-streptolysin O and anti-streptokinase levels were not elevated.

Table 1.

Physical examination and laboratory test results

	Normal value	On admission
Physical examination
Height, cm		161
Weight, kg		56
Body mass index, kg/m2		21.6
Body temperature, °C		36.6
Blood pressure, mmHg		93/52
Pulse, bpm		86
Laboratory investigations
WBC, /µL	3300–8600	14,500
Hb, g/dL	13.7–16.8	8.6
Plt, ^103/µL	158–348	469
Serum creatinine, mg/dL	0.65–1.07	3.56
Blood urea nitrogen, mg/dL	8–20	46
Amylase, U/L	44–132	40
Albumin, g/dL	4.1–5.1	1.9
CRP, mg/dL	0.00–0.14	7.22
IgG, mg/dL	861–1747	1038
IgA, mg/dL	93–393	435
IgM, mg/dL	33–183	30
Complement C3, mg/dL	80–160	104
Complement C4, mg/dL	10–40	26
Complement CH50, U/mL	30–45	45.2
Antinuclear antibody		Hemogeneous, 80 folds
PR3-ANCA, U/mL	< 3.5	< 1.0
MPO-ANCA, U/mL	< 3.5	< 1.0
Anti-GBM antibody, U/mL	< 3.0	< 2.0
M protein		negative
Urinary protein-to-creatinine ratio	< 0.30	14
Hematuria, RBC/HPF	< 10	30–49
Urinary NAG, U/L	5–6.8	176.7
Urinary β2MG, μg/L	40–150	7722
Urinary casts		Hyaline casts
		Waxy casts
Proteinuria selectivity index		0.50

WBC wight blood cells, Hb hemoglobin, Plt platelet, IgG Immunoglobulin G, IgM Immunoglobulin M, IgA Immunoglobulin A, PR3-ANCA PR3-antineutrophil cytoplasmic antibody, MPO-ANCA MPO-antineutrophil cytoplasmic antibody, GBM glomerular basement membrane, β2MG β2-microglobulin, CRP C-reactive protein, HPF high-power field, NAG N-acetylglucosaminidase, RBC red blood cell, proteinuria selective index = (serum transferrin × urine immunoglobulin G)/(serum immunoglobulin G × urine transferrin)

AKI with nephrotic syndrome was diagnosed. Drainage of the intraperitoneal MSSA infection was continued, and antibiotics were started. Hemodialysis was initiated the day after his referral to our center to treat the pulmonary edema-induced respiratory failure. The dyspnea, pulmonary edema, and pleural effusion resolved after six courses of hemodialysis, and the intraperitoneal infection improved after 2 weeks of treatment with antibiotics. Even though the infection was under control, his serum creatinine level increased to 8.36 mg/dL, and his urine β2-microglobulin level increased to 92649.7 μg/L with persistent proteinuria. 30 mg of prednisolone was administered orally once per day, starting 2 weeks after the withdrawal of hemodialysis. A renal biopsy was performed 1 week after starting steroid therapy (Fig. 1A).

Fig. 1.

Clinical course and renal biopsy findings of a patient who developed acute kidney injury with nephrotic syndrome during treatment for methicillin-sensitive Staphylococcus aureus infection. (A) The clinical course involved increased creatinine at 3 weeks after the CRP level increased. Antibiotics and hemodialysis were started. Although the infection was controlled, the serum creatinine level increased. After prednisolone 30 mg was started, the serum creatinine level decreased. (B) High-power views of the glomerulus show endocapillary proliferative glomerulonephritis with fibrocellular crescents (periodic acid-methenamine-silver stain; original magnification × 400). (C) Staining for plasmin activity using in situ zymography. Plasmin activity was negative in the glomerulus. Yellow dotted line shows the glomerulus (original magnification × 400). (D) Immunofluorescence staining in the glomerulus for NAPlr (fluorescein isothiocyanate; green) and complement C3 (Alexa Fluor 594; red). NAPlr was negative in the glomerulus. Yellow dotted line shows the same glomerulus in C (original magnification × 400). (E) Low-power views of the tubulointerstitial compartment show inflammatory cell infiltration and atrophy of tubular epithelium. High-power views show peritubular capillaritis in the white square (periodic acid-Schiff stain; original magnifications × 100 low-power and × 400 high-power). (F) Staining for plasmin activity using in situ zymography shows plasmin activity in the tubulointerstitial compartment. Blue dotted line shows the tubular lumen (original magnification × 400). (G) Immunofluorescence staining in the tubulointerstitial compartment for NAPlr (fluorescein isothiocyanate; green) and complement C3 (Alexa Fluor 594; red) (original magnification × 400). Positive NAPlr staining was observed in a portion similar to the plasmin activity positive portion in the tubulointerstitial region shown in (F). Blue dotted line shows the same tubular lumen in (F) (original magnification × 400). (H) Immunofluorescence staining in the glomerulus for IgA (Alexa Fluor 488; green). (I,J) Electron microscopy shows endocapillary proliferation, with enlarged endothelial cells and infiltration of migratory cells. Electron-dense deposits were observed in the mesangial region and the subendothelium

Light microscopy showed ten glomeruli. One was completely sclerosed, and the other glomeruli showed mild endocapillary proliferative glomerulonephritis. Three of these had fibrocellular crescents (Fig. 1B). There was no adhesion or segmental glomerulosclerosis. Plasmin activity assessed by in situ zymography was negative in the glomerulus (Fig. 1C). NAPlr staining was also negative in the glomerulus (Fig. 1D). The interstitium showed inflammatory cell infiltration, mild focal tubular atrophy, interstitial fibrosis on approximately 10% of the cortical parenchyma, and peritubular capillaritis (Fig. 1E). Plasmin activity assessed by in situ zymography was positive in the tubulointerstitial compartment on the tubulointerstitial infiltrating cells (Fig. 1F). Staining for NAPlr co-localized to the positive plasmin activity area (Fig. 1G). Light microscopy revealed endocapillary proliferative glomerulonephritis and AIN. Immunofluorescence microscopy for IgG, IgA, and C3 revealed granular deposits on the glomerular capillary walls (Fig. 1D, H). Electron microscopy showed endocapillary proliferation, with enlarged endothelial cells and infiltration of migratory cells (Fig. 1I, J). Electron-dense deposits were observed in the mesangial region and the subendothelium. No hump-shaped subepithelial deposits were observed. There was inflammatory cell infiltration in the interstitium, and the tubular epithelium was atrophic. The pathological findings, including endocapillary proliferative glomerulonephritis and peripheral granular deposits of IgA and C3, were consistent with IRGN. Although the possibility of drug-induced AIN due to antibiotics was considered, NAPlr-positive infiltrating cells were found in the tubulointerstitial compartment, suggesting IRAIN. Therefore, the diagnosis was IgA-dominant IRGN complicated by IRAIN.

Due to the possibility of a persistent infection, drainage for the intra-abdominal infection was continued. Within 4 weeks of starting the steroid treatment, his renal function improved. His serum creatinine decreased to approximately 2.0 mg/dL, urine protein-to-creatinine ratio decreased to 5 g/gCre, and urine β2-microglobulin level decreased to 269 μg/L. The prednisolone dose was tapered by 5 mg at 4-week intervals to 15 mg over the course of 3 months. His renal function recovered despite persistent proteinuria, and he was discharged from the hospital. He is currently an outpatient with stable renal function.

Discussion

Typical IRGN findings include endocapillary proliferative glomerulonephritis with C3 deposits during or after treatment for infections. This is often complicated by hypocomplementemia, with hump-shaped subepithelial deposits visible on electron microscopy. Although there are no definitive diagnostic criteria for IRGN, the diagnostic criteria for postinfectious glomerulonephritis (PIGN) by Nasr et al. are often referenced. It has been reported that at least three of the following five criteria are required for the diagnosis: (1) complicated with infection; (2) reduced serum complement; (3) endocapillary proliferative and exudative glomerulonephritis; (4) C3-dominant or codominant glomerular staining; and (5) hump-shaped subepithelial deposits [14, 15]. IRGN was diagnosed based on his concurrent staphylococcal infection, endocapillary proliferative glomerulonephritis, and C3-dominant glomerular immunofluorescence staining. IgA-dominant IRGN has recently been identified as a morphologic variant of IRGN that involves IgA-dominant or co-dominant immune complex deposits; it typically affects elderly individuals with a history of diseases, such as diabetes mellitus and is often associated with staphylococcal infection [16]. Our patient was found to have both IgA and C3 deposits in the glomeruli and was diagnosed with IgA-dominant IRGN.

Glomerular-positive staining for NAPlr is often associated with endocapillary proliferation in IRGN [9–11] and has also been observed in IgA-dominant IRGN [17]. It has been reported that NAPlr deposition decreases over time [3]. The delay in obtaining the renal biopsy may have caused the NAPlr staining to change to a focal glomerular pattern, resulting in negative NAPlr staining in this case. Therefore, a limitation of this paper is that only one glomerulus was stained from frozen sections.

During the acute phase of IRGN, tubulointerstitial compartments show infiltration of inflammatory cells in most cases [14]. AIN can be caused by various factors, including infection, drugs such as antibiotics and NSAIDs, autoimmune diseases, and metabolic abnormalities. In this case, renal function continued to worsen after antibiotics were discontinued, and NAPlr-positive cells were found in the tubulointerstitial compartment, suggesting that infection caused AIN.

Interestingly, in IgA vasculitis, NAPlr staining, and plasmin activity were observed in perivascular tissue, but not in intravascular lesions [18, 19]. It is possible that NAPlr causes AIN through a mechanism similar to that of small vessel vasculitis.

Abnormal complement activation may also be involved in IRAIN because complements reported to mediate tubulointerstitial injury [20]. AP is also activated during infections that triggers APSGN development [21]. PIGN is severe in those with defective AP regulation, resulting in persistent hematuria and proteinuria or progression to end-stage kidney disease [22]. Anti-factor B auto-antibodies that drive AP activation were identified during acute-phase PIGN in 31 of 34 (91%) children [23]. The pathological absence of C1q deposition in the glomerulus and normal serum C4 levels suggest that the AP, rather than the classical pathway, was activated in this case, as previously reported in PIGN. Further studies on complement activation in IgA-dominant IRGN and IRAIN are needed.

A few case reports have described NAPlr with IRAIN complicated by IRGN [24, 25]. In that case, blood eosinophilia and renal tubulointerstitial infiltration of eosinophils were observed, neither of which are common in IRGN [24]. Neither blood eosinophilia nor tubulointerstitial infiltration of eosinophils was observed in our patient. Therefore, this is the first reported case of NAPlr-positive tubulointerstitial infiltration with typical glomerular histological findings of IRGN. Another report described a case of IRGN complicated with AIN with positive NAPlr staining in the glomeruli but negative NAPlr staining in the tubulointerstitial compartments [24]. Therefore, the pathophysiology of IRGN and IRAIN may be different. Further research is needed to elucidate the pathogenesis.

The most important treatment for IRGN and IRAIN is controlling the underlying infection. Proteinuria and renal dysfunction often improve after infection resolution. If renal dysfunction and proteinuria persist after antibacterial treatment, immunosuppressive therapy, such as steroid therapy, should be considered. Caution is required because this may potentially exacerbate infections. In the present case, careful monitoring for the exacerbation of intra-abdominal infections was performed by contrast examination via the drainage tube for the pancreatic fistula. This was necessary during steroid treatment.

We described a case of IRAIN associated with an intra-abdominal infection caused by MSSA. NAPlr was useful in diagnosing IRAIN. When AKI develops during the treatment of an infection and is accompanied by elevated tubulointerstitial markers, it is important to determine the presence of IRAIN by staining for NAPlr and zymography for plasmin activity.

Declarations

Conflicts of interest

The authors have declared that no conflict of interest exists.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted (IRB approval number1178(899)) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This case report is conducted in compliance with the bioethical rules of Chiba University Hospital. This study has been approved by the Bioethics Review Committee of Chiba University.

Informed consent

Written informed consent for treatment and for publication of this report was obtained from the patient.