Received: 22 December 2023 Revised: 9 March 2024 Accepted: 15 March 2024

DOI: 10.1111/nep.14298

CASE REPORT

Atypical post-infectious glomerulonephritis with c-ANCA

positivity followed by endocarditis

Seyoung Ryou 1 | Hyeran Park 1 | Seung Yun Chae 1 | Yaeni Kim 1 |

2 1,3
Yeong-Jin Choi | Cheol Whee Park

1
Division of Nephrology, Department of
Internal Medicine, Seoul St. Mary's Hospital, Abstract
College of Medicine, The Catholic University
Post-infectious glomerulonephritis (PIGN), an uncommon variety of glomerulonephri-
of Korea, Seoul, Republic of Korea
2
Department of Hospital Pathology, Seoul
tis (GN), is characterized by emergence of nephritic syndrome within a few weeks fol-
St. Mary's Hospital, College of Medicine, The lowing an infectious event. PIGN typically presents as a mild condition and tends to
Catholic University of Korea, Seoul, Republic
of Korea
resolve by the time of diagnosis for GN. Aggregatibacter actinomycetemcomitans
3
Institute for Aging and Metabolic Diseases, belongs to the HACEK group of bacteria, which constitutes less than 3% of bacteria
Seoul St. Mary's Hospital, College of Medicine,
responsible for community-acquired infective endocarditis. We present a case of
The Catholic University of Korea, Seoul,
Republic of Korea 29-year-old man suspected of lymphoma with B-symptoms along with severe
splenomegaly and nephromegaly. Shortly after, he developed an episode of nephritic
Correspondence
Cheol Whee Park, Division of Nephrology, syndrome accompanied by acute kidney injury (AKI) and high titers of cytoplasmic
Department of Internal Medicine, College of
ANCA (c-ANCA)-positivity. Kidney biopsy revealed PIGN with tubulointerstitial
Medicine, Seoul St. Mary's Hospital, The
Catholic University of Korea, 222 Banpo- nephritis. Despite treatment with antibiotics and corticosteroid, he visited the emer-
daero, Seocho-gu, Seoul 06591, Republic of
gency room due to worsening dyspnea and multi-organ failure. An echocardiogram
Korea.
Email: [email protected] showed a bicuspid aortic valve with vegetation unseen on previous echocardiogram.
He underwent aortic valve replacement immediately without adverse events. Four
Funding information
National Research Foundation of Korea, months after valve replacement, his renal function and cardiac performance have
Grant/Award Number: RS-2023-00251436 remained stable. We report a case of PIGN with AKI and high titers of c-ANCA
appearing later as an infective endocarditis due to Aggregatibacter actinomycetemco-
mitans. With careful clinical observation and appropriate and timely management,
satisfactory outcomes for patient health are possible.

KEYWORDS
acute kidney injury, c-ANCA-positive vasculitis, infective endocarditis, post-infectious
glomerulonephritis

1 | I N T RO DU CT I O N syndrome within a few weeks of an infectious episode, which is often

mild and typically resolves by the time of GN is diagnosed.2 The
Post-infectious glomerulonephritis (PIGN) is a rare glomerulonephritis majority of patients achieve complete remission of the nephritic syn-
(GN) seen in both children and adults following an infection.1 It is drome following PIGN. However, in a few patients, it takes longer to
characteristically expressed by the development of nephritic resolve or renal dysfunction is sustained with continuing hematuria

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© 2024 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.

Nephrology. 2024;1–5. wileyonlinelibrary.com/journal/nep 1

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2 RYOU ET AL.

and proteinuria. Some patients may even progress to end-stage renal interest, the patient was tested positive for Anti-PR3 antibody (c-
disease.3 ANCA) with a titre of 73 CU (reference range: <20 CU). He exhibited
Aggregatiacter actinomycetemcomitans is an important microor- a low level of C3 (50 mg/dL) but not C4 (12.5 mg/dL). Notably, the
ganism in the aetiology of localized juvenile periodontitis.4 Less fre- serum level of anti-streptolysin O level was 60 IU/mL. We performed
quently, it is associated with non-oral infections such as endocarditis, a renal biopsy for suspected renal enlargement of AKI due to lym-
brain abscess, pneumonia, and osteomyelitis. However, PIGN due to phoma infiltration. Kidney biopsy findings showed diffuse proliferative
Aggregatibacter actinomycetemcomitans mimicking cytoplasmic ANCA glomerulonephritis characterized by prominent endocapillary prolifer-
(c-ANCA)-positive small-vessel vasculitis with kidney and nerve dam- ation, numerous neutrophils, and diffuse mesangial deposition of
age has been reported in very few cases.5 Members of the Haemophi- immunoglobulin (Ig) G, IgA, IgM, C3, C1q, kappa, and lambda chains.
lus, Actionbacillus, Capnocytophaga, Eikenella, and Kinggella (HACEK) This was accompanied by tubulointerstitial inflammation, moderate
group of bacteria comprise 3% of isolates causing community- tubular necrosis, and tubular cast. Among the 16 examined glomeruli,
acquired infective endocarditis.6 Moreover, renal involvement of the no glomerular sclerosis was observed. A cellular crescent was identi-
HACEK group of bacteria is noted in 26% of patients with endocar- fied in 1 out of 16 glomeruli (6%) without fibrosis. Notably, large
ditis due to Aggregatiacter actinomycetemcomitans.7 electron-dense deposits were present along mesangial basement
We describe a case of glomerulonephritis with renal failure and membranes, resembling subepithelial humps (Figure 1C). After
c-ANCA-positivity finally presenting infective endocarditis in the 19 days of antibiotics, there was no evidence of infection, leading to
bicuspid aortic valve due to Aggregatibacter actinomycetemcomitans. In the initiation of steroid pulse therapy (methylprednisolone 250 mg
the present case, endocarditis with characteristic endocardial vegeta- 3 days and tapering for about 2 weeks) to reduce interstitial and
tion occurred several weeks later after the development of PIGN and tubule inflammation associated with acute kidney injury. At the time
c-ANCA positivity. of discharge, the patient's creatinine level was 1.29 mg/dL. One
month later, it was measured at 1.02 mg/dL (Figure 1A).
Two months after initial discharge from the hospital, the patient
2 | CASE visited the emergency room with exacerbating respiratory failure. Of
note, multiple septic emboli were observed in his palms, soles, and
A 29-year-old man with hypertension suffered fever, myalgia, general trunk (Figure 2A). A subsequent chest x-ray revealed an aggravated
weakness, night sweating, and weight loss up to 20 kg over the past cardiomegaly (Figure 2B). A trans-thoracic echocardiogram showed
few months. On examination, vital signs of the patient were stable severe eccentric aortic regurgitation with suspicious oscillating and
with a blood pressure of 154/64 mmHg, a heart rate of 119 beats per hyperechoic multiple masses attached to the aortic valve, measuring
minute, and a body temperature of 36.0 C. Laboratory tests at the approximately 20  4 mm, along with a left ventricle ejection fraction
time of presentation revealed the following results: white blood cell of 31% compared to 47.7% at the time of initial admission (Figure 2C).
count of 13.32  109/L, hemoglobulin level of 8.7 g/dL, and The patient underwent aortic valve replacement, revealing a large
C-reactive protein level of 119.98 mg/L. Despite extensive tests vegetation and leaflet perforation on the noncoronary cusp and a
including blood cultures and viral studies, all results were negative. small vegetation on the left coronary cusp. The valve specimen did
Medical assessments revealed an enlarged spleen (length: 16.7 cm). A not show bacterial growth. However, it exhibited fibrosis with calcifi-
PET-CT scan highlighted diffuse bone activity, suggesting a possible cation, chronic inflammatory cell infiltration, and focal multinucleated
hematologic malignancy. A bone marrow biopsy yielded no significant giant cells, suggestive of bacterial colonies (Figure 2C). After aortic
findings. valve replacement, the patient received 6 weeks of antibiotic therapy.
Two months later, the patient was hospitalized again for a spleen Thirty-eight days after the surgery, the heart size on chest x-ray
biopsy under suspicion of lymphoma. However, his body temperature returned to normal (Figure 2B) and the creatinine level was 0.95 mg/
was 39.3 C. Aggregatibacter actinomycetemcomitans was identified in dL without proteinuria.
the blood without any evidence of periodontitis. The patient received
antibiotics, specifically piperacillin, tazobactam, cefepime, and ceftri-
axone combined with vancomycin for the entire 23-day hospital stay 3 | DI SCU SSION
(Figure 1A). Within 2 days of starting antibiotics, the blood culture
turned negative. We did transthoracic echocardiogram because of Here we present a very rare case of PIGN with AKI and high titers of
continuous systolic murmur at aortic area in the anterior chest with c-ANCA, which finally progressed to an infective endocarditis caused
fever and identified Aggregatibacter Actinomycetemcomitans bacter- by Aggregatibacter actinomycetemcomitans. The aetiology PIGN is
emia, which showed no vegetation in the bicuspid aortic valve. The known as follows1: glomerular in-situ deposition of bacterial antigens
patient's kidney function severely deteriorated (Figure 1A). As part of with subsequent formation of in-situ immune complexes (IC) by
the evaluation for acute kidney injury, a kidney sonography revealed increased antibody formation, and/or2 glomerular deposition of circu-
enlarged kidneys measuring 15 cm bilaterally with proteinuria (pro- lating immune-complexes.1,2 Therefore, immune-mediated damage
tein/creatinine ratio of 0.56 mg/mg Creatinine) (Figure 1B). Of plays an important role in pathogenesis of PIGN.
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RYOU ET AL. 3

F I G U R E 1 (A) Clinical course timetable of the patient from initial admission to 2nd admission. AVR, aortic valve replacement; CRO,
ceftriaxone; CRRT, continuous renal replacement therapy; FEP, cefepime; MEM, meropenem; TZP, piperacillin/tazobactam; VAN, vancomycin.
(B) Renal sonography shows both enlarged kidneys up to 15 cm in length. (C) Kidney biopsy findings. Light microscopy of the renal biopsy shows
severe tubulointerstitial fibrosis and inflammatory cell infiltration and endocapillary proliferation (periodic acid-Schiff; 50 and 400,
respectively). Immuofluorescence demonstrating by +4 granular mesangial and glomerular endocapillary wall staining for C3 (400).
Electromicroscopic finding shows irregular subepithelial humps in the glomerular basement membranes (10.000).

In our case, interestingly, the patient initially showed B-symptoms and crescentic GN and endocapillary proliferative GN.10 In this case,
with elevated titers of c-ANCA or anti-PR3.8,9 In addition to glomeru- on the other hand, the renal biopsy showed that, in addition to promi-
lonephritis caused by Aggregatibacter actinomycetemcomitans. A previ- nent endocapillary proliferation, a characteristic feature of PIGN, the
ous report has suggested the possibility that certain epitopes on tubulointerstitial compartment exhibited acute tubular injury and
Aggregatibacter actinomycetemcomitans may trigger ANCA production acute tubular inflammation with mononuclear and neutrophilic infiltra-
by acting as a molecular mimic of bacterial/permeability-increasing tion, suggesting that active tubulointerstitial inflammation was the pri-
protein (BPI), which is a 55-kDa cationic protein involved in host mary cause of AKI and c-ANCA vasculitis. After continuous antibiotics
defences against Gram-negative bacteria and endotoxin which acts treatment, steroid therapy was initiated concurrently, leading to the
intracellularly in polymorphonuclear leukocytes.4 Furthermore, the restoration of normal kidney function.
presence of a low C3 level with a normal level of C4 is linked to role However, during the initial admission, no biopsy was conducted
of alternative complement pathway in the pathogenesis of PIGN apart from those of the bone marrow and kidney, primarily to assess
caused by Aggregatibacter actinomycetemcomitans. In the present the possibility of an early lymphoma diagnosis. No other extra-renal
patient, alternative complement pathway activation might have signs were observed, and the renal biopsy did not reveal typical fea-
caused glomerulonephritis with heavy deposition of IC in the glomeru- tures of ANCA associated vasculitis (AAV). Nevertheless, given the
lar subepithelial spaces (Figure 1C), which might have triggered com- relation between positivity of c-ANCA and renal injury, three possibili-
plement activation. These ICs are subsequently broken down by ties can be considered. Firstly, infective endocarditis could potentially
phagocytic cells, leading to the residual presence of C3, followed lead to false positivity.11 Since systemic infections can cause ANCA
by the occurrence of C3 deposits.2 It has been known that most com- positivity, some argue that the threshold should be raised during an
mon biopsy findings in endocarditis-associated PIGN are necrotizing infection. However, in this case, a titre 3.75 times higher than the
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4 RYOU ET AL.

F I G U R E 2 (A) The physical examination shows that multiple septic emboli are noticed in the patient's palm, sole and trunk. (B) Cardiac
enlargement is noted on chest PA at 2nd admission (preoperative; pre-OP), which returns to a normal sized heart after aortic valve replacement
(postoperative; post-OP). (C) Aortic vegetation approximately 20 cm in diameter, which was absent at the 1st admission, is observed at the 2nd
admission on the trans-thoracic echocardiogram. The aortic valve shows a large vegetation and leaflet perforation on the noncoronary cusp and a
small vegetation on the left coronary cusp in view during surgery.

threshold cannot exclude the possibility of AAV-related renal injury. Usually, the beginning of the infection route is a buccal focus. The
Secondly, in the renal biopsy, the presence of diffuse immune com- course of EAA is usually subacute and chronic. In rare cases, it can be
plex deposition without necrotizing features was not a typical mani- diagnosed after several months.13 This case report raises the question
festation of vasculitis, but rather suggested PIGN combined with of whether a patient could acquire EAA during antibiotic and immuno-
acute interstitial nephritis. However, it is possible for characteristics suppressive therapy for PIGN or whether subclinical Aggregatiacter
of interstitial nephritis to appear when only the renal medulla is actinomycetemcomitans infection might precede and possibly precipi-
involved, without affecting the vesseles. Lastly, there is a discrepancy tate the full development of endocarditis. Interestingly, in the present
between the serum ANCA titre and the immunofluorescense results patient, serum creatinine and c-ANCA levels elevated as early as
of renal biopsy. Despite the absence of signs of vasculitis, the pres- 2 months of systemic symptoms, whereas endocardial vegetation as a
ence of positive serum ANCA, particularly at a high titre, three times marker of endocarditis was prominent 2 months later, suggesting that
higher than normal, indicates a high likelihood of kidney disease devel- PIGN might be an early manifestation of endocarditis as it was not
opment later on.12 In this regard, we could emphasize the association seen in the initial echocardiogram. A recent study has shown that the
between a high ANCA titre and kidney injury. risk of incidence of infective endocarditis in patents with bicuspid aor-
Two months after renal function normalized, the patient suddenly tic valve is increased 12-fold compared with that in the general popu-
developed a full-blown form of infective endocarditis. Endocarditis lation.14 Consequently, infective endocarditis due to HACEK,
caused by Aggregatiacter actinomycetemcomitans (EAA) is character- including Aggregatibacter actinomycetemcomitans, should be suspected
ized by gradual and hidden nature of endocarditis. Therefore, the in a patient with underlying heart abnormality with or without evi-
infective endocarditis outbreak in the present patient might have two dence of chronic periodontitis.15
potential causes. First, reinfection of Aggregatibacter actinomycetem- In summary, we present a rare case of PIGN with AKI due to
comitans might be the cause during immunosuppressive therapy as tubulointerstitial nephritis and c-ANCA-positivity appearing later as
there was no change in oral microbiome of the patient. Second, latent an infective endocarditis due to Aggregatibacter actinomycetemcomi-
activation of asymptomatic Aggregatibacter actinomycetemcomitans tans. Hence, it is imperative to give heightened consideration to PIGN
endocarditis might have occurred, subsequently leading to the devel- resulting from Aggregatibacter actinomycetemcomitans particularly in
opment of full-blown endocarditis. EAA distinguishes itself from typi- patients with valvular heart disease, and to promptly address it with
cal endocarditis as it does not necessarily entail cardiac abnormalities. appropriate treatment for those with infective endocarditis.
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RYOU ET AL. 5

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