Anti-glomerular basement membrane disease with concomitant myeloperoxidase antibodies in a pediatric patient: a case report of presentation, treatment and outcome a rare disease

Abstract

Anti-glomerular basement membrane disease (anti-GBMD) is a rare small-vessel vasculitis presenting as rapidly progressive glomerulonephritis and/or diffuse alveolar hemorrhage. A third of patients with anti-GBMD have antineutrophil cytoplasmic antibodies and are known as double-positive patients. There are a limited number of pediatric double-positive cases published in the literature. In this case report, we summarize the presentation, treatment, and outcome of a patient with anti-GBMD with both anti-myeloperoxidase and anti-GBM antibodies, highlighting the safe use of rituximab. We also describe atypical complications in our case, including significant weight loss of unclear etiology and development of recurrent episodes of acute pericalcific arthritis.

Introduction

Anti-glomerular basement membrane disease (anti-GBMD) is a rare small-vessel vasculitis that presents with rapidly progressive glomerulonephritis (rapid decline in kidney function over days to weeks, typically requiring dialysis) and/or diffuse alveolar hemorrhage [1-4]. The disease is rare in the pediatric population, with an estimated incidence ranging from 0.60 to 1.79 cases per million children annually [2]. This makes evidence-based treatment challenging, given the limited number of patients and lack of randomized controlled trials. Despite a high overall survival rate (91%) with current therapies, half of pediatric patients with anti-GBMD develop end-stage kidney disease (ESKD) requiring dialysis [5].

Up to one-third of patients with anti-GBMD also have concomitant antineutrophil cytoplasmic antibodies (ANCA) [2,3,5-7]. These patients are referred to as double-positive patients (DPP). Among DPP, most present with acute kidney injury (AKI) at diagnosis and are typically positive for myeloperoxidase (MPO)-ANCA [3]. Outcomes in this group are poor, with only about one-third experiencing renal survival [3]. Moreover, two-thirds of DPP experience disease relapse within 5 years, and 44% are deceased by that time point. Among patients experiencing relapses, ANCA levels are usually elevated [3]. Reports of pediatric cases with anti-GBMD and concurrent ANCA positivity are limited; to date, only 14 cases have been described in the literature [6-18]. These limited data suggest that pediatric DPP have clinical courses and outcomes similar to adults, including poor renal prognosis despite relatively favorable overall survival. This underscores the urgent need for further studies to evaluate and optimize treatment strategies in this high-risk subgroup.

In our brief case report, we summarize the presentation, treatment, and outcome of a patient with anti-GBMD with both anti-MPO and anti-GBM antibodies. We also describe atypical complications in our case, including significant weight loss of unclear etiology and development of pericalcific arthritis.

Case report

A 17-year-old female presented in August 2023 with 1 week of non-bloody diarrhea and vomiting, abdominal pain, decreased appetite, fatigue, and an 8-pound (approximately 3.6 kg) weight loss. The patient was not hypertensive or edematous at presentation and did not report grossly bloody urine. The initial laboratory evaluation demonstrated an AKI with serum creatinine of 2.82 mg/dL. Urinalysis was significant for 2+ protein, 3+ blood, 11–20 white blood cells per high-power field (HPF), and >100 red blood cells per HPF. White blood cell and platelet counts in peripheral blood were normal. Renal ultrasound showed mildly increased echogenicity, consistent with medical renal disease. Patient underwent urine and stool culture on presentation that did not show infection. She was not evaluated for inflammatory bowel disease. She was hospitalized for intravenous (IV) hydration for AKI. Despite IV fluids, serum creatinine continued to rise during admission, and this was associated with onset of edema and oliguria. Further evaluation given the worsening AKI included an antinuclear antibody (ANA) panel with a positive ANA of 1:320 and normal complements. Elevated inflammatory markers were noted including a C-reactive protein of 21.1 mg/dL and elevated erythrocyte sedimentation rate of 85 mm/hr. Despite IV fluids, creatinine rose to 4.06 mg/dL, which prompted renal biopsy. Preliminary biopsy results were consistent with crescentic glomerulonephritis with 80% to 100% crescents (Fig. 1). Five days after presentation, on day 12 of illness, she was administered IV methylprednisolone (IVMP) pulse of 1,000 mg given findings of cellular crescents. Following this initial pulse, the patient had symptomatic improvement but continued to have elevated creatinine ultimately peaking at 9.19 mg/dL. Given oliguric AKI and fluid overload, the patient required initiation of hemodialysis 1 week after presentation. Anti-GBM antibodies were positive at 115 AU/mL (upper limit of normal, 25 AU/mL), as well as anti-MPO antibodies at 67 AU/mL (upper limit of normal, 26 AU/mL). Computed tomography (CT) of the chest did not show pulmonary involvement. Initial rheumatology evaluation revealed left knee arthritis. A presumptive diagnosis of anti-GBMD was made. Final pathology findings showed predominantly cellular crescentic (47 of 50 glomeruli) glomerulonephritis with fibrinoid necrosis. There was diffuse interstitial chronic inflammation comprised of lymphocytes and plasma cells. Immunofluorescence showed linear immunoglobulin G (IgG) and complement component 3 (C3) GBM staining. Electron microscopy showed markedly thickened, wrinkled GBMs, as well as variable foot process effacement, with no electron dense deposits and no tubular reticular inclusions (Fig. 1). Prior to completion of final pathology findings, a decision was made to start plasma exchange (PLEX) due to the presence of anti-GBM antibodies and rapidly progressive glomerulonephritis, and the patient received a total of 5 sessions. Anti-MPO and anti-GBM antibody titers were not repeated at the end of the PLEX sessions. The patient remained stable on room air during most of the initial admission but had episodes of desaturation associated with a facial rash during blood transfusion in her third PLEX treatment that required nasal cannula. Repeat chest CT identified left lower lobe atelectasis and pleural effusion, but no hemorrhage. The patient was treated for presumed community-acquired pneumonia. She was then treated with 3 doses of cyclophosphamide: 1,000 mg (729 mg/m²) for first dose, 750 mg for second dose (adjusted for dialysis), and 640 mg for third dose (adjusted for neutropenia requiring filgrastim). She received a total of 4 IVMP pulses (1,000 mg) and transitioned to prednisone (60 mg daily oral weaned over 8.5 months). She also received 2 doses of rituximab during induction and every 6 months as maintenance doses. The decision to initiate rituximab was based on the presence of positive ANCA serology in the setting of severe kidney disease requiring dialysis. It is the practice in our center to use a combination of cyclophosphamide and rituximab for severe kidney disease in ANCA vasculitis. The risk of increased immunosuppression with combination therapy was felt to be justified given the patient’s severe presentation. Treatment details are summarized in Fig. 2. Ten days after initiation of immunosuppressive medication, she developed a yeast infection treated with fluconazole. With completion of cyclophosphamide and rituximab induction therapy, normalization of inflammatory markers, anti-GBM and anti-MPO antibodies was achieved. Despite immunosuppressive therapies, she did not attain renal recovery after 3 months and has remained dependent on hemodialysis with future renal transplant anticipated. Her course was complicated by significant weight loss in the setting of recurrent vomiting, abdominal pain and poor appetite, despite being on prolonged steroids. Patient underwent an abdominal and pelvic CT with contrast that did not show vasculitis or superior mesenteric artery syndrome. Six months after initiation of therapy, she was admitted for moderate malnutrition and underwent multiple studies that did not identify an etiology of weight loss including Helicobacter pylori testing, upper gastrointestinal (GI) radiologic evaluation, gastric emptying studies, brain CT, and GI endoscopy. Patient was discharged with prescription for cyproheptadine, stool softeners, and daily use of Renastep (Nestlé Health Science). Patient continued to have weight loss as well as daily vomiting and abdominal pain. Given that the patient had a negative work up for structural causes of vomiting and weight loss, anxiety and depression were considered as possibly contributing to her symptoms. Mirtazapine was prescribed and resulted in complete resolution of vomiting with stabilization of weight. In addition to patient’s GI complications, an episode of acute right thumb swelling occurred 10 months after diagnosis. Radiographs detected periarticular calcification of the first, second, and fifth metacarpophalangeal joints. Due to suspicion for pericalcific arthritis, she was started on prednisone 20 mg daily with tapering which resulted in symptom improvement. Two months later, swelling of her left 5th finger was associated with calcifications in the left 4th and 5th metacarpophalangeal joints, 2nd proximal interphalangeal joint, 3rd distal interphalangeal joint, and the dorsal surface of the proximal carpal row (Fig. 3), treated with a repeat course of oral steroids. At her most recent pediatric rheumatology visit, she was clinically inactive with a Birmingham Vasculitis Activity Score of 0. Anti-GBM and anti-MPO antibodies were both undetectable. She was transitioned to adult rheumatology without complication. After transitioning to adult care, the patient was diagnosed with latent tuberculosis and treated with 6 months of isoniazid.

Fig. 1.

Crescentic glomerulonephritis associated with anti-GBM antibodies and ANCA. (A) Representative glomerulus with cellular crescent and prominent interstitial chronic inflammatory infiltrate (hematoxylin and eosin stain, ×400). (B) Periodic acid Schiff (PAS) staining highlights the glomerular membranes and mesangium of residual glomerulus surrounded by cellular crescent that abuts glomerular capsule. Also note adjacent tubules with atrophic features (PAS stain, ×400). (C) Immunoglobulin G (IgG) immunofluorescence highlights GBMs (IgG antibody by immunofluorescence, ×400). (D) Ultrastructural features of glomerulus with loss of foot processes, moderately thickened and focally wrinkled GBM with no electron dense deposits with membranes or mesangium (electron microscopy, ×1,000). GBM, glomerular basement membrane; ANCA, antineutrophil cytoplasmic antibodies.

Fig. 2.

This figure shows a summary of the patient’s treatment. PLEX, plasma exchange; HD, hemodialysis. ^a)The originally planned dose was 40 mg, but patient was taking 3/4 of a 50 mg tablet instead. ^b)An additional 20 mg prednisone taper was administered from weeks 43–48 and weeks 52–56 for episodes of recurrent acute pericalcific arthritis.

Fig. 3.

This X-ray was obtained during the patient’s second episode of acute pericalcific arthritis. The red arrow points towards calcifications in the left fourth and fifth metacarpophalangeal joints as well as the left third distal interphalangeal joint and second proximal interphalangeal joint.

Discussion

Anti-GBMD is a rare, life-threatening small-vessel vasculitis which most commonly affects kidneys and lungs [2,8]. It accounts for 12.8% of patients with crescentic glomerulonephritis [2]. When looking at all anti-GBMD patients, survival at 1 year is relatively high at 76% of patients, and two-thirds go on to develop ESKD [2,3]. A third of anti-GBMD patients also have concomitant ANCA [2,3,5-7]. DPP have similar rates of renal and pulmonary involvement as those with single antibodies, but have some unique features when compared to single antibodies such as a higher percentage of extra-renal and extra-pulmonary involvement and higher relapse rates [3]. Our patient had extra-renal manifestations of arthritis at presentation. We believe that her initial symptoms of diarrhea, vomiting, and abdominal pain were likely prodromal symptoms of vasculitis which has been described previously in patients with anti-GBMD [8].

Despite the available reports of DPP highlighting some unique features, the clinical significance of this dual positivity remains unclear, as studies have reported conflicting outcomes. While some suggest that the presence of both antibodies is associated with more severe disease, others indicate that mortality risk and renal outcomes are comparable to those of patients with anti-GBMD alone [2,3]. Furthermore, most of the information on DPP is derived from adult studies, and thus it is unclear if the same principles can be applied to children. Although the patient has dual antibodies, it is likely that the pathogenesis of the patient’s kidney disease is primarily driven by the presence of anti-GBM antibodies given the presence of linear basement membrane IgG and C3 on immunofluorescence with no glomerular electron dense deposits which is characteristic for anti-GBMD [1].

A recent review of all of the published pediatric anti-GBMD cases included 12 DPP [8], which represents 25% of cases. Among all pediatric anti-GBMD in this review, 34% achieved normal renal function, 34% developed ESKD, 12.7% developed chronic kidney disease, and 8% died [8]. Table 1 summarizes pediatric cases with concomitant anti-GBM antibod­ies and ANCA in the literature [6-18], including the current patient. One-third of patients achieved normal renal function, while six cases (40%) progressed to ESKD, one case (7%) developed chronic kidney disease, and four cases (27%) resulted in mortality. This suggests that pediatric DPP have a higher risk of mortality, but a lower risk of ESKD than pediatric patients with only anti-GBM antibodies. This case report contributes information on the presentation, treatment, and outcome of pediatric patients with double-positive anti-GBMD, given the limited number of such cases reported in the literature. There is a paucity of information on pediatric anti-GBMD treatment. The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend treating anti-GBMD with glucocorticoids, PLEX and cyclophosphamide [4]. In patients without diffuse alveolar hemorrhage but with advanced kidney failure, conservative treatment is recommended. However, recommendations for anti-GBMD are based on limited evidence and often extrapolated from adult studies.

Table 1.

Summary of previously reported patients with ANCA and anti-GBM antibodies

No.	Author (year)	Age (yr)/sexa)	Kidney	Lung	Other manifestations	% crescents	Max Cr (mg/dL)	Anti-GBM titer (reference range)	ANCA type and titer (with normal reference)	CTX	RTX	Other TX	No. of PLEX sessions	Outcome	FU time (mo)
1	Current study	17/F	Y	N	Knee arthritis	94 (47/50 AC)	9.19	115 AU/mL (<25 AU/mL)	MPO 67 AU/mL (<26 AU/mL)	Y	Y	IVIG	5	ESRD	16
2	Echcharii et al. (2024) [8]	9/M	Y	N	N	64 (9/14 AC)	3.79	680 IU/mL (<6 IU/mL)	MPO 1:80	Y	Y	N	11	Normal	24
3	Helander et al. (2021) [9]	2/F	Y	N	N	100 (6/11 GS, 5 /11 AC); + rupture of BC	5.27	6.3 U (<1 U)	MPO 54.1 U (<20 U)	Y	Y	AZA	15	ESRD, KT	25
4	Timmermans et al. (2020) [10]	15/F	Y	Y	Hemorrhagic blisters	64 (7/11 AC)	1.09	258 U/mL (<7 U/mL)	MPO 25 IU/mL (<3.5 IU/mL)	Y	Y	NA	14 dayb)	Normal	24
5	Agarwal and Al-Ghitany (2017) [11]	11/M	Y	N	N	73 (8/11 AC)	7.90	590 U/mL (<7 U/mL)	p-ANCA	Y	N	NA	22	Normal	NA
6	Xie et al. (2015) [12]	6/F	Y	N	N	100 (36/38 AC or FC, 2/38 GS)	9.40	119 RU/mL (<20 RU/mL)	MPO 69 RU/mL (<20 U/mL)	Y, IV x2	N	N	8	ESRD	NA
7	Bogdanovic et al. (2013) [13]	10/F	Y	Y	Leg pain	16 (4/25 AC)	0.53	19.7 RU/mL (<20 RU/mL)	MPO 57.2 U/mL (<5 U/mL)	Y, IV x6	N	MMF	NA	Normal	10
8	Williamson et al. (2011) [6]	8/F	Y	Y	NA	83	7.70	0 AU/mL	MPO 182 AU/mL	N	N	N	NA	Death	NA
9	Poddar et al. (2010) [14]	9/M	Y	Y	NA	NA	8.80	1,514 U/mL	MPO	Y	N	N	21	ESRD, death	2
10	Naidoo and Waller (2009) [15]	4/F	Y	N	NA	95 (7/21 GS, 13/21 AC)	2.68	220 U/mL (<10 U/mL)	MPO 53 U/mL (<9 U/mL)	Y	N	N	11	Normal	9
11	Hijosa et al. (2005) [16]	12/M	Y	Y	LCV, arthritis, seizures, demyelinating lesions on visual nerves	60 (AC, no number)	7.40	1.6 OD (<0.1 OD)	MPO between 100–120 μmol/mL (<10)	Y	N	IVIG 2 g/kg, MMF	10	CKD	18
12	Paueksakon et al. (1999) [17]	12/F	Y	Y	LCV on feet, biopsy confirmed	35 (2/23 AC)	1.20	211 SLI	MPO 215 EIA units	Y	N	N	7	Death	NA
13	Fanburg et al. (1993) [18]	17/F	Y	Y	Necrotic lesions of spleen	90 (Fibrotic)	12.5	NA	MPO	Y	N	N	NA	Death	NA
14	Jayne et al. (1990) [7]	13/M	Y	Y	Rash, sinusitis	NA	NA	NA	NA	Y	N	N	NA	ESRD	NA
15	Jayne et al. (1990) [7]	17/F	Y	N	N	20	NA	NA	NA	Y	N	AZA	NA	ESRD	NA

ANCA, antineutrophil cytoplasmic antibodies; GBM, glomerular basement membrane; Cr, creatinine; CTX, cyclophosphamide; RTX, rituximab; TX, treatment; PLEX, plasma exchange; FU, follow up; F, female; M, male; Y, yes; N, no; NA, data not reported; LCV, leukocytoclastic vasculitis; AC, cellular crescents; BC, Bowman's capsule; FC, fibrocellular crescents; GS, globally sclerotic; OD, optical density; SLI, standard light units; MPO, myeloperoxidase; p-ANCA, perinuclear antineutrophil cytoplasmic antibody; EIA, enzyme immunoassay; IVIG, intravenous immune globulin; AZA, azathioprine; MMF, mycophenolate mofetil; ESRD, end-stage renal disease; KT, kidney transplant; CKD, chronic kidney disease.

^a)Biological sex is reported as written in the publication.

^b)In the text it states PLEX was continued for 14 days but does not specify actual number of sessions.

This case highlights the poor prognosis previously reported in pediatric patients with anti-GBMD. The current patient developed ESKD, despite aggressive therapy with cyclophosphamide, rituximab and PLEX, and normalization of anti-GBM and anti-MPO antibodies. There were likely several factors that contributed to the poor renal outcome seen in our patient. First, our patient had several risk factors for development of ESKD in anti-GBMD that have been reported in the literature including oligoanuria, higher baseline serum creatinine, higher percentage of crescents, and initial need for renal replacement therapy [3,4]. Additionally, our patient had a high percentage of glomeruli with crescents (94%), whereas a higher percentage of normal glomeruli on initial biopsy has been found to be a protective factor [2]. Lastly, anti-GBM antibody titers were not repeated following the patient’s final PLEX session. Fig. 4 summarizes antibody titers for our patient showing significant decrease following induction but continued low titers until they became undetectable at week 28. According to KDIGO guidelines, PLEX should be performed until anti-GBM antibody titers are no longer detectable [4], and the American Society for Apheresis (ASFA) recommends continuing therapeutic plasma exchange (TPE) for 10–20 days or until titers fall to undetectable [19]. However, both KDIGO and ASFA note that the benefit of TPE may be limited in patients who are dialysis-dependent at presentation, have serum creatinine ≥5.7 mg/dL, and biopsy findings of 100% crescents or extensive glomerulosclerosis [4,19]. In our patient, the number of PLEX sessions was limited to 5, based on these considerations—specifically, her peak serum creatinine of 9.19 mg/dL, dialysis dependence at presentation, and 94% crescentic involvement—reflecting a poor renal prognosis and a decision to weigh risks versus expected benefit in this context.

Fig. 4.

Levels of anti-GBM and anti-MPO antibodies beginning from presentation. The solid arrows represent PLEX, dotted arrows cyclophosphamide doses, and arrowheads rituximab doses. Both anti-GBM and anti-MPO antibody levels have remained 0 since week 28. GBM, glomerular basement membrane; MPO, myeloperoxidase; PLEX, plasma exchange.

This case highlights the benefit of rituximab in addition to PLEX for induction of anti-GBMD therapy, as previously reported [8-10]. Although the current patient did not attain renal recovery, she has remained clinically inactive. This is remarkable considering the higher risk of flare in DPP [3,7]. In a large review of DPP 61% were on maintenance therapy with the most common agents including azathioprine (69%) [3]. Moreover, suppression of ANCA may help in preventing or lessening progression of arthritis in this patient. Overall, the current patient tolerated the immunosuppressive regimen quite well. Although the patient experienced severe neutropenia following her second cyclophosphamide dose, this improved with filgrastim and did not occur afterwards with appropriate dose reduction. She was found to have a positive purified protein derivative without pulmonary tuberculosis manifestations. Although not having active vasculitis, the patient experienced significant weight loss and GI symptoms with a negative work up for structural causes. A meta-analysis of patients with both anti-GBM antibodies and ANCA reported GI manifestations in 2.7% of cases [3]. The patient’s improvement with mirtazapine highlights the importance of adequate mental health evaluation and support for these patients, and suggests that mirtazapine is a safe option for both improving appetite and treating depression and anxiety in patients with ESKD and vasculitis when dosed for dialysis. Finally, this case report highlights the efficacy of steroids in the management of acute flares of pericalcific arthritis, a rare complication in patients with ESKD. Acute calcific periarthritis is caused by the deposition of calcium hydroxyapatite crystals in joints [20]. It most often occurs with the shoulder joint, and when present in the hand, it mostly involves metacarpal phalangeal and interphalangeal joints. It presents as pain, swelling and erythema of the affected joints and resolves with conservative management, including nonsteroidal anti-inflammatory drugs and splinting [20]. Pericalcific arthritis should be considered in patients with vasculitis and ESKD who experience joint swelling.

In summary, this case emphasizes the critical importance of initiating prompt treatment with immunomodulation and PLEX to facilitate clearance of anti-MPO and anti-GBM antibodies in pediatric anti-GBMD who are DPP and who have high-risk features for ESKD, including oligoanuria, elevated baseline serum creatinine, a high percentage of crescents, and initial need for dialysis. Despite the predominance of cellular crescents and minimal fibrosis, our patient progressed to ESKD, illustrating the poor renal prognosis associated with this illness. Additionally, our case supports the safety of rituximab for both induction and maintenance therapy in pediatric anti-GBMD. Finally, it emphasizes the need for comprehensive evaluation of extra-renal and extra-pulmonary manifestations as well as the importance of addressing mental health in pediatric patients facing severe chronic illness.

Funding Statement

None.

Data availability statement

Data sharing is not applicable as no new data were created or analyzed in this study.