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CASE REPORT
Pulmonary-Renal Syndrome During COVID-19 Pandemic Revealed a Rare Case of Anti-GBM Disease
Aglaia Chalkia1, Christos Koutsianas2, Emelina Stampolliou1, Panagiota Giannou1, Harikleia Gakiopoulou3, Dimitrios Vassilopoulos2, Dimitrios Petras1
1Nephrology Department, Hippokration General Hospital, Athens, Greece, 22nd Department of Medicine and Laboratory, Clinical Immunology - Rheumatology Unit, National and Kapodistrian University of Athens School of Medicine, Hippokration General Hospital, Athens, Greece, 31st Department of Pathology, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
ABSTRACT
Anti-GBM disease is a rare, life-threatening small vessel vasculitis caused by circulating anti-GBM antibodies resulting to rapidly progressive glomerulonephritis and/or pulmonary haemorrhage. The gold standard for the diagnosis is the renal biopsy with the pathognomonic finding of linear deposition of IgG along the glomerular capillaries. Early diagnosis and intervention are key determinants of the response to therapy and long-term prognosis of these patients. However, during COVID-19 pandemic recognizing a pulmonary-renal syndrome caused by autoimmune diseases has become challenging. Herein, we aimed to describe a rare case of anti-GBM disease with pulmonary haemorrhage and rapidly progressive glomerulonephritis in a young man in a tertiary referral hospital in Greece, while COVID-19 pandemic was at its peak. Although the patient presented high level of creatinine and crescents, the early diagnosis and start of treatment resulted to favourable renal prognosis.
Mediterr J Rheumatol 2023;34(2):252-6 https://doi.org/10.31138/mjr.34.2.256
Article Submitted: 15 Jan 2023; Revised Form: 16 Feb 2023; Article Accepted: 21 Feb 2023; Available Online: 30 Jun 2023
Keywords: anti-GBM disease, rapidly progressive glomerulonephritis, pulmonary haemorrhage
INTRODUCTION
Anti-GBM disease is a rare, life-threatening small vessel vasculitis. Circulating antibodies are directed against glomerular basement membrane (GBM), resulting to rapidly progressive glomerulonephritis as well as alveolar
basement membrane (ABM) resulting to alveolar hemorrhage.1 Anti-GBM nephritis accounts for approximately 15 percent of all cases of crescentic glomerulonephritis according to case se-ries.2 Younger patients
usually present pulmonary haemorrhage, compared to older people who more often present only nephritis. However, <10% of the patients will present only pulmonary haemorrhage. The principal target for the anti-GBM antibodies is the NC1 domain of the alpha-3 chain of type IV collagen (alpha-3[IV] chain), one of six genetically distinct gene products found in basement membrane collagen and these antibodies are usually IgG.3 Recently, it has been described a rare variant of anti-GBM disease, described as "atypical anti-GBM nephritis" without pulmonary haemorrhage and undetectable antibodies.4 During the COVID-19 pandemic, recognising a pulmonary-renal syndrome caused by autoimmune diseases has become challenging. Herein, we aimed to describe a rare case of anti-GBM disease with pulmonary haem-
Corresponding Author:
Aglaia Chalkia
Nephrology Department, Hippokration General Hospital
Vasilissis Sofias 108, 11527, Athens, Greece
Tel.: +30 694 441 9653 E-mail: aglaia.chalkia@gmail.com
252 Cite this article as: Chalkia A, Koutsianas C, Stampolliou E, Giannou P, Gakiopoulou H, Vassilopoulos D, Petras D. Pulmonary-Renal Syndrome During COVID-19 Pandemic Revealed a Rare Case of Anti-GBM Disease. Mediterr J Rheumatol 2023;34(2):252-6.
orrhage and rapidly progressive glomerulonephritis in a young man in a tertiary referral hospital in Greece, while COVID-19 pandemic was at its peak.
CASE PRESENTATION
A 21-years-old healthy male and smoker from Iran was presented at the emergency room complaining of fever and fatigue. Physical examination showed peripheral capillary oxygen saturation (Sp02) was 98%, blood pressure 120/80 mmHg, heart rate of 100 beats per minute, and body temperature 38 0C. A chest x-ray showed diffuse alveolar pulmonary infiltrates and the chest computed tomography scan showed ground-glass opacities. As he was admitted during the period of COVID-19 pandemic, he was first transferred to the infectious diseases' unit, and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV-2 on nasal and oro-
Table 1. Initial and post-treatment laboratory findings.
Parameters Initial value Post 6month value Normal ranges
Hb 6.9 11.4 12-18 g/dL
urea 91 25 18-55 mg/dL
creatinine 2.1 1.1 0.72-1.25 mg/dL
Sodium 137 138 136-145 mmol/L
Potassium 5 3.5 3.5-5.1 mmol/L
Glucose 150 82 70-105 mg/dL
Calcium 8.7 9.2 8.4-10.2 mg/dL
Albumin 3.3 3.8 3.5-5 g/dL
AST 9 21 5-34 U/L
ALT 6 11 0-55 U/L
CRP, mg/L 3.25 1.13 0-5 mg/L
WBC count, 11.66 8.34 5.2-12.4 x x10e3/uL
Platelet count, 371 290 130-400 x x10e3/uL
Lymphocyte count, 0.97 2.22 0.9-5.2x x10e3/uL
IgG 549 654 700-1600 mg/dL
IgM 27 78 40-230 mg/dL
IgA 102 116 70-400 mg/dL
C3 110 152 75-180 mg/dL
C4 35 55 10-40 mg/dL
Proteinuria 3.320 930 <150 mg/24h
Urine RBC/ HPF 100-120 50-70 0-1
Urine WBC/ HPF 18-20 2-3 0-5
Hb: hemoglobulin; AST: Aspartate transaminase; ALT: alanine aminotransferase; CRP: C-reactive protein; WBC: White blood cells; IgG: Immunoglobulin G; IgM: Immunoglobulin M; IgA: Immunoglobulin A; C3: complement 3; C4: complement 4; RBC: red blood cells; WBC: white blood cells; HPF: high power field.
pharyngeal swabs test were performed and antibiotics were given.
The laboratory results at the time of admission are detailed in Table 1. The patient presented with Acute kidney injury (AKI) stage 2 (according to the KDIGO classification, without previous baseline serum Creatinine) and severe anaemia (hb=6.9 g/L). To further evaluate the cause of AKI, a renal ultrasound was performed which showed normal-sized kidneys and morning urine test which showed microscopic haematuria (dysmorphic RBCs 75%) and proteinuria nephrotic range (ACR 300mg/g). Although, the patient did not complain of breathless or haemoptysis, he started pulses of intravenous glucocor-ticoids considering as a possible pulmonary-renal syndrome. He remained in the infectious diseases' unit for 2 days until two PCR for SARS-COV-2 proved negative and then transferred to the Nephrology Unit.
After two days, the cre-atinine level was further increased at 4.5mg/dl. The fourth day, a kidney biopsy was performed to determine the cause of a possible crescentic glomerulonephritis. In the meantime, further investigation was performed to exclude possible autoimmune diseases including, serologic testing for hepatitis B, hepatitis C, and HIV, cryoglobulins, serum complement for C3 and C4, antinuclear antibody, anti-double-stranded DNA, ANCA, anti-GBM antibodies. Although the patient had already received three pulses of corticosteroids, he presented dyspnoea with low SpO2 and further reducing hemoglobulin, without clinical sign of haemoptysis and therefore plasmapheresis regimen was added, as rescue treatment for possible pulmonary haemorrhage. According to the biopsy results, light microscopy revealed crescentic glomerulonephritis with 92% cellular crescents, 8% normal glomeruli and
Figure 1. Light microscopy-cellular crescent formation (silver stain, original magnification x 200).
Figure 3. Light microscopy-cellular crescent formation and segmental necrosis (yellow arrow) (Masson stain, original magnification x 400).
Figure 2. Light microscopy-cellular crescent formation (Masson stain, original magnification x200).
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Figure 4. Immunofluorescence-linear deposition of IgG along the glomerular capillaries in a crescent formation.
the immunofluorescence demonstrated the virtually pathognomonic finding of linear deposition of IgG along the glomerular capillaries and occasionally the distal tubules, indicating anti-GBM nephritis. (Figures 1-4) The anti-GBM antibodies were found positive [level 86 (positive>30 ELISA method)] whereas the antineutrophil cytoplasmic antibodies were negative. Overall, the patient received intravenous pulses with cyclophosphamide and plasmapheresis regimen (prescription: 4 litres exchanges with fresh frozen plasma daily for 15 procedures), and the anti-GBM antibodies became negative (10 days after the initiation of the plasmaphere-sis). He continued cyclophosphamide for 3 months and
started tapering of glucocorticoids for 6 months. We continued to monitor anti-GBM antibody levels monthly for 6 months and they remained negative After, 6 months the patient presents normal renal function with creatinine level 0.8mg/dL, persistent microscopic haematuria, proteinuria <1gm/24H and negative anti-GBM antibodies.
DISCUSSION
This case report highlights a rare case of renal-pulmonary syndrome, which every physician should consider in patient with evidence of pulmonary haemorrhage, even without clinical sign of haemoptysis, and rapidly progressive glomerulonephritis. Especially, during the
15
30
Days
90
ISO
period of COVID-19 when the most patients with fever or dyspnoea and ground glass in CT lung concurrently quite often with AKI would be considered as SARS-CoV-2 infection, further evaluation of the cause of AKI with urine assessment should be performed and in cases with active urine sediment high suspicion of anti-GBM, amongst other autoimmune diseases such as ANCA associated vasculitis, IgA or cryoglobulinemic vasculitis, SLE as well as infection-related glomerulonephritis, is essential. The gold standard for the diagnosis is the renal biopsy with the pathognomonic finding of linear deposition of IgG along the glomerular capillaries, because the anti-GBM antibodies could also be present in other conditions, for example ANCA associated vasculitis or could be false negative dependent on the commercial ELISA assays or as a rare variant described as "atypical anti-GBM nephritis" and therefore renal biopsy should not be delayed. According to the literature, the majority patients with anti-GBM are smokers, and the most common symptom that leaded them to the medical consultation was fatigue at 33%, while fever, dyspnoea, or haemoptysis were found under 10%.5 Likewise, the systemic complaints and signs when are present, are usually experienced for only a few weeks. In our case the systemic symptoms (fever and fatigue) had driven the patient to the emergency without complaining of haemoptysis or breathless. Furthermore, while our patient did not present dual ANCA positivity, it could be found in one third of the patients with anti-GBM disease.
Case series with anti-GBM disease revealed that creatinine level >5.6mg/dL, percentage of crescents >75%, or
lower percentage of normal glomeruli have been proved as negative prognostic factors for renal prognosis. 6,7In contrary, even though our patient presented high level of creatinine at diagnosis (peak level of 6 mg/dL) and significantly increased percentage of crescents in the renal biopsy (>90%) and few normally glomeruli, he presented favourable renal prognosis (at 6 months normal renal function). Presumably, this may reflect the immediate start of the combination treatment (immunosuppressive and plasmapheresis) to our patient and points out the unmet need for high suspicion given that anti-GBM is a life-threatening disease, and the usage of plasmapheresis has been found to be beneficial for the patients [HR 0.29 95% CI (0.08-0.98), p=0.046].5 Large prospective studies have not been carried out due to the rarity of the cases. Immunosuppressive treatment consisted of corticosteroids and cyclophosphamide have been used for 3 months, as anti-GBM disease has described as monophasic disease with rare relapses.8 Rituximab has been used in resistant disease.9 Our patient received 15 plasma exchanges and 3 doses of intravenous cyclophosphamide, and the anti-GBM antibody levels remained consistently negative after the tenth day of plasmapheresis.
Consequently, most patients with anti-GBM disease present clinical features of rapidly progressive glomeru-lonephritis and around the half of them with concomitant alveolar haemorrhage. Anti-GBM antibodies should be work out in every clinical suspicion, and kidney biopsy should not be delayed. Therefore, the diagnosis of anti-GBM disease could be challenging and high suspi-
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cion of the physicians is an unmet need, because early diagnosis and intervention could drive to a favourable outcome.
AUTHOR CONTRIBUTIONS
AC wrote the final manuscript whose final version was approved by all the authors; CK, ES and PG actively participated in the treatment of the described patient; HG performed the histopathological analysis; DV and DP supervised the findings of this work.
ETHICS APPROVAL
Not applicable.
CONSENT TO PARTICIPATE
Not applicable.
CONSENT FOR PUBLICATION
Written informed consent was obtained.
CONFLICT OF INTEREST
The authors declare no competing interests.
REFERENCES
1. McAdoo SP, Pusey CD. Anti-Glomerular Basement Membrane Disease. Clin J Am Soc Nephrol 2017 Jul 7;12(7):1162-1172. doi: 10.2215/CJN.01380217
2. Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int 2003 Mar;63(3):1164-77. doi: 10.1046/j.1523-1755.2003.00843.x
3. Kalluri R, Wilson CB, Weber M, Gunwar S, Chonko AM, Neilson EG, et al. Identification of the A3 Chain of Type IV Collagen as the Common Autoantigen in Antibasement Membrane Disease and Goodpasture Syndrome. J Am Soc Nephrol 1995 Oct;6(4):1178-85. doi: 10.1681/ASN.V641178.
4. Nasr SH, Collins AB, Alexander MP, Schraith DF, Herrera Hernandez L, Fidler ME, et al. The clinicopathologic characteristics and outcome of atypical anti-glomerular basement membrane nephritis. Kidney International 2016;89(4):897-908. doi: 10.1016/j. kint.2016.02.001.
5. Marques C, Carvelli J, Biard L, Faguer S, Provôt F, Matignon M, et al. Prognostic Factors in Anti-glomerular Basement Membrane Disease: A multicenter study of 119 patients. Front Immunol 2019; Jul 18;10:1665. doi: 10.3389/fimmu.2019.01665.
6. Van Daalen EE, Jennette JC, McAdoo SP, Pusey CD, Alba MA, Poulton CJ, et al. Article Predicting Outcome in Patients with Anti-GBM Glomerulonephritis. Clin J Am Soc Nephrol 2018;13:63-72. doi: 10.2215/CJN.04290417.
7. Alchi B, Griffiths M, Sivalingam M, Jayne D, Farrington K. Predictors of renal and patient outcomes in anti-GBM disease: Clinicopathologic analysis of a two-centre cohort. Nephrol Dial Transplant 2015;30(5):814-821. doi: 10.1093/ndt/gfu399
8. Levy JB, Turner AN, Rees AJ, Pusey CD. Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med 2001 Jun 5;134(11):1033-42. doi: 10.7326/0003-4819-134-11-200106050-00009.
9. Jain R, Dgheim H, Bomback AS. Rituximab for Anti-Glomerular Basement Membrane Disease. Kidney Int Rep 2018 Dec 17;4(4):614-618. doi: 10.1016/j.ekir.2018.12.002
