Anti-glomerular basement membrane disease with IgA nephropathy: A case report

lNTRODUCTlON

Anti-glomerular basement membrane (GBM) disease is an autoimmune disease with anti-GBM antibody deposition, and the incidence rate of anti-GBM disease in the population is 1 to 2 cases per million population per year in European populations, accounting for 10%-15% of crescentic glomerulonephritis cases[1,2]. The main clinical manifestation is acute progressive nephritis syndrome with or without varying degrees of pulmonary hemorrhage. The disease progresses rapidly, and the prognosis is poor. The main renal pathology is crescentic glomerulonephritis, with Immunoglobulin G (IgG)deposited in a linear pattern along the capillary loop on direct immunofluorescence examination. The coexistence of anti-GBM disease and Immunoglobulin A (IgA) nephropathy is rare. Last year, our hospital diagnosed and treated a patient with concurrent anti-GBM disease and IgA nephropathy. A report of the characteristics of the patient and the disease follows.

CASE PRESENTATlON

Chief complaints

每名赴馬來西亞項目施工的員工，出國之前都必須參加國際工程分公司組織的HSE 培訓班及集團公司的防恐培訓，主要內容包括馬來西亞地理概況、政治宗教、風險管理、公共安全、國外禮儀、突發事件急救、傳染病常識與預防等方面知識的學習，為即將赴海外工作的人員在加強自身安全防護意識方面提供了強有力的保障。

History of present illness

A 49-year-old man was admitted to the nephrology department of Guang'anmen Hospital in November 2020. Nine years before this hospitalization, when the patient underwent a physical examination in the local hospital, the routine urine examination revealed 1+ blood, while urinary protein was negative and serum creatinine was normal. At that time, the patient had no obvious symptoms of discomfort, such as arthralgias, oral ulceration, or photosensitivity. Subsequently, the patient’s annual physical examination showed urinary occult blood fluctuating from 1+ to 3+, but the urinary protein was always negative,and the serum creatinine remained normal. Nearly 2 mo before admission, a routine urine examination showed 3+ blood and 3+ protein, and the patient was administered irbesartan 150 mg once a day. One day before admission, the patient’s urinalysis results revealed 3+ blood and 2+ protein, and the 24-h urine protein result was 5.158 g. In addition, the serum creatinine level was 133 μmol per liter.

History of past illness

Renal ultrasonography revealed that the size of the kidneys was normal and that the echo pattern from the renal cortex was normal.

近年時興埋藏酒。有人把瓶裝好白酒、紅酒和壇裝的糧食酒埋藏在自家陽臺、小院的苗圃，或者寄埋在農家田園，說是要埋它十幾年乃至幾十年，待兒女婚嫁或者自己六十大壽再挖出來開懷暢飲。其實，并非什么酒都是越陳越好，勾兌白酒和許多紅酒，品牌雖好卻不宜久藏。能藏的酒，對溫度、濕度和通風條件亦有嚴格要求。

Personal and family history

The patient had a history of inhaling gasoline and diesel in his working environment and had a long history of smoking and drinking. He had no known allergic reactions to drugs or food. He denied a family history of kidney disease.

Physical examination

The patient’s vital signs were stable, and his blood pressure was 120/78 mmHg. His weight was 67 kg,and his body mass index was 23.2 kg/m

. The patient had mildly depressed edema in both lower limbs.

Laboratory examinations

Methylprednisolone (500 mg) was given intravenously once a day for 3 consecutive days, and then 50 mg prednisolone acetate was given orally once a day. After 2 mo of continuous oral administration, the daily dosage of hormone was decreased by 5 mg per month. In addition, 0.8 g cyclophosphamide was given intravenously once a month.

為證實這一設想，她利用CRISPR/Cas9基因編輯技術，敲除該基因編碼區，被破壞掉編碼區的ZmGRP1就無法正常表達。將經過此處理的植株和正常植株進行比對，發現有一千多個基因的可變剪接受到影響。ZmGRP1就如司令官指揮千軍萬馬一般，調控著這些基因的可變剪接。

Imaging examinations

The patient had a history of hypertension, hyperuricemia, and gout. He had hepatitis A as a child and was later cured.

A greater than 9-year history of hematuria was present, as was a greater than 1-year history of proteinuria.

Approximately 80% of cases of anti-GBM disease show crescents of similar age and activity in renal biopsy findings, reflecting the sudden onset of disease and distinguishing it from ANCA-associated vasculitis, in which a mixture of cellular, fibrocellular and fibrous crescents are often observed[3,10,11].In addition, the proportion of glomeruli containing crescents in IgA nephropathy is usually low[12].However, in this case, approximately 70% of the glomeruli contained crescents, and the multiple crescents seen on this patient’s renal biopsy pathology results were negative for ANCAs. Therefore, it is difficult to determine whether the crescents in this patient resulted from anti-GBM disease or IgA nephropathy. Kojima

[13] previously reported a patient diagnosed with anti-GBM disease during IgA nephropathy progression; in this case, the researchers were also unable to determine whether the anti-GBM disease was primary or secondary because the source of the crescents was unknown.

Renal biopsy

Immunofluorescence staining showed linear deposition of IgG, kappa, and lambda along the capillary wall. IgG1 and IgG4 were the main subtypes of IgG, and granular and bolus-type deposits of IgA and C3 were seen in the mesangial area.

Light microscopy demonstrated glomerulosclerosis and ischemic sclerosis, and approximately 70% of glomeruli contained crescents, including small-cell crescents, small cellular fibrous crescents, cellular fibrous crescents, and fibrous crescents with sclerosis, accompanied by seriously damaged glomerular capillary loops and partial destruction of Bowman's capsules. In addition, the glomerular mesangial cells and matrix were slightly proliferative. Renal interstitial inflammatory cell infiltration was accompanied by fibrosis. In addition, there were vacuoles and granular degeneration of renal tubular epithelial cells, the hair margin of the small focus brush had deteriorated, and multiple lesions showed atrophy. Immunohistochemistry revealed granular deposition of C4d in the capillary wall, mesangial area, and arteriole wall.

Electron microscopy showed massive electron-dense deposits in the mesangial area. The pathological results were consistent with a diagnosis of type I crescentic nephritis with IgA nephropathy (Figure 1).

FlNAL DlAGNOSlS

A diagnosis of anti-GBM glomerulonephritis and IgA nephropathy was confirmed.

TREATMENT

The novel coronavirus nucleic acid test was negative, and the novel coronavirus IgM antibody and IgG antibody tests were negative. The hepatitis B virus antigen, hepatitis C antibody, syphilis, and HIV tests were also negative. The other laboratory examination results are shown in Table 1. Subsequently, a positive anti-GBM antibody result was obtained at a titer of 68 RU/mL, though anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies were absent.

金鉆明，長得白白凈凈，待人謙遜有禮。他一開腔說自己是上海人時，一楞后一喜，我們趕緊問他是上海哪里人？答曰：浦東楊家宅。坐落于如今浦東最繁華地段陸家嘴地區的楊家宅屬浦東沿江地帶，這和上海的開埠歷史幾乎是同時的。1986年出生的小金回憶，從懂事起，耳畔不時傳來的就是機器的打樁聲，以及拆房者、建樓者的身影。談及兒時的成長，他最大的感受是自己居住地周圍的環境一直在變，念書學校的場地也換了幾次。這就是當年浦東大開發的速度。這段經歷也讓金鉆明成了浦東開發開放的親歷者。

OUTCOME AND FOLLOW-UP

After two months of treatment, the anti-GBM antibody result turned negative. On May 31, 2021, the dosage of corticosteroids was adjusted to 20 mg every day, and the cumulative amount of cyclophosphamide was 4.8 g. Subsequently, the patient’s serum creatinine fluctuated between 105 μmol/L and 123 μmol/L after discharge, the 24-hour urine protein quantity decreased from 5.16 g to 1.68 g, and the urine red blood cell count decreased from 45.09/HPF to 10.6/HPF under a high-power microscope(Table 1).

從某種意義上說，基于ICT的成人參與學習本質是有效使用ICT，是人們發展與ICT的關系以及能夠獲得有用的教育資源。在思考ICT對成人參與學習的價值時，既不能以“技術決定論”為導向過分夸大ICT技術在教育與社會發展中的角色，亦不可以“社會決定論”為導向僅賦予ICT為中性技術工具的內涵，而誤解其所涵蓋的社會文化特性［17］。因此，如何面對使用ICT過程中所產生的來自心理、教育、社會等復雜因素交織而成的障礙，學習個體、教育機構、決策組織乃至關聯企業的應對之策，均至關重要。

原題：The 1906earthquake and a century of progress in understanding earthquakes and their hazards

DlSCUSSlON

Anti-GBM disease is a rare systemic vasculitis mediated by autoantibodies produced against antigens in the glomerular and alveolar basement membrane that is often characterized by a rapid decline in renal function and alveolar hemorrhage[3,4]. Although the patient in this case did not show obvious pulmonary-renal syndrome symptoms, the anti-GBM antibody titer in the serum increased, and immunofluorescence analysis showed linear deposition of IgG along the capillary wall. Therefore, the diagnosis of anti-GBM disease was clear. In addition, IgA nephropathy was diagnosed in this patient because immunofluorescence analysis demonstrated IgA deposited along the mesangial area.

Based on a literature analysis, anti-GBM disease is closely related to genetic and environmental factors[5]. In terms of genetic susceptibility, anti-GBM disease is closely related to the HLA-DRB1 × 1501 allele and is also associated with genes of the KLK and FCGR families[6]. The patient in this case had no family history of kidney disease. In terms of environmental factors, anti-GBM disease is often associated with cigarette smoking or hydrocarbon inhalation, such as inhalation of gasoline, diesel, or paint, which may trigger exposure of cryptic collagen epitopes in the alveolar basement membrane, inducing the formation of anti-basement membrane antibodies and leading to nephritis and hemorrhage through cross-reaction with the GBM[5,7,8]. In contrast to the hemoptysis of most patients with a history of hydrocarbon inhalation, only small nodules were found on lung CT in this case[9].

Chest high-resolution computed tomography (CT) showed small solid nodules in the lower lobe of the left lung.

In regard to treatment, plasma exchange (PE) is often the first choice to eliminate existing anti-GBM antibodies, followed by administration of corticosteroids and cyclophosphamide to suppress inflammation and reduce renal damage[11]. After analyzing some similar case reports in recent 5 years searching from PubMed (https://pubmed.ncbi.nlm.nih.gov/) (Table 2), we found that although the patients had rapidly decreasing renal function and positive anti-GBM antibody, the disease could be improved without PE. Even if PE was used, the patients might not get rid of dialysis[13-16]. For this patient, considering that there was no rapid and progressive increase in serum creatinine and that the serum anti-GBM antibody titer was not high, PE was not used. After 2 mo of treatment with corticosteroids and cyclophosphamide, the patient's serum anti-GBM antibody result turned negative. After half a year of follow-up, the patient's serum creatinine remained relatively stable, and the hematuria and proteinuria were improved.

A relevant literature review showed that the prognosis of concurrent anti-GBM disease and IgA nephropathy seems to be better than that of simple anti-GBM disease; This improved prognosis with concomitant disease may be due to the deposition of immune complexes associated with IgA nephropathy, which can result in changes in the composition of the GBM[15-17]. In the case reports summarized (Table 2), four of five cases showed rapidly decreasing kidney function at the beginning,but four of five cases showed improvement after treatment and did not rely on dialysis[13-16].However, more clinical and laboratory data are needed to further confirm the prognosis of this coexisting disease.

5.英語對每一個小學生來說都是一門新的課程，但是很多家長或教師在態度上沒有正確對待，例如，經常因為成績加以批評，使學生在學校時常常存在抵觸心理。這也是教學領域中表現得尤為突出的問題。

CONCLUSlON

This is a case report of anti-GBM disease coexisting with IgA nephropathy. The patient had a history of hydrocarbon inhalation and smoking, which are environmental factors associated with anti-GBMdisease. Fortunately, there was no pulmonary hemorrhage or rapidly progressive glomerulonephritis.After combined administration of corticosteroids and cyclophosphamide, the patient's anti-GBM antibody result turned negative, and serum creatinine remained relatively stable. The origin of the crescents and the relationship between IgA nephropathy and anti-GBM nephropathy in this patient are worthy of further study and analysis.

ACKNOWLEDGEMENTS

We would like to thank the patient and the medical staff of the Nephrology Department of Guang'anmen Hospital, China Academy of Chinese Medical Sciences. We thank the Institute of Nephrology of Peking University First Hospital for providing renal pathology pictures and pathological diagnosis. We thank Dr. Yang ΧF for his constructive comments.

FOOTNOTES

Guo C analyzed this case and wrote the manuscript; Ye M and Li S guided the discussion part;Zhu TT provided follow-up data of the patient; Rao ΧR provided treatment and directed the writing of the manuscript; all authors have read and approve the final manuscript.

The patient signed a written informed consent form.

The authors declare that they have no conflicts of interest.

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

China

Chuan Guo 0000-0002-9566-7929; Ming Ye 0000-0002-0936-9598; Shen Li 0000-0002-4079-557Χ; Ting-Ting Zhu 0000-0003-4662-1155; Χiang-Rong Rao 0000-0001-5309-9719.

Χing YΧ

結構方程模型中包括兩個基本部分：測量模型和結構模型。測量模型表示潛變量和觀測變量之間的關系為x=Λxξ+δ及y=Λyη+ε。結構模型表達潛變量之間的關系為η=Bη+Гξ+ζ。

A

Χing YΧ

1 McAdoo SP, Pusey CD. Anti-Glomerular Basement Membrane Disease. Clin J Am Soc Nephrol 2017 ; 12 : 1162 -1172 [PMID: 28515156 DOI: 10 .2215 /CJN.01380217 ]

2 Canney M, O'Hara PV, McEvoy CM, Medani S, Connaughton DM, Abdalla AA, Doyle R, Stack AG, O'Seaghdha CM,Clarkson MR, Griffin MD, Holian J, Dorman AM, Niland A, Keogan M, Wallace EM, Conlon NP, Walsh C, Kelly A,Little MA. Spatial and Temporal Clustering of Anti-Glomerular Basement Membrane Disease.

2016 ; 11 : 1392 -1399 [PMID: 27401523 DOI: 10 .2215 /CJN.13591215 ]

3 Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int 2003 ; 63 : 1164 -1177 [PMID: 12631105 DOI:10 .1046 /j.1523 -1755 .2003 .00843 .x]

4 McAdoo SP, Pusey CD. Antiglomerular Basement Membrane Disease. Semin Respir Crit Care Med 2018 ; 39 : 494 -503 [PMID: 30404116 DOI: 10 .1055 /s-0038 -1669413 ]

5 Cui Z, Zhao MH. Advances in human antiglomerular basement membrane disease. Nat Rev Nephrol 2011 ; 7 : 697 -705 [PMID: 21769105 DOI: 10 .1038 /nrneph.2011 .89 ]

6 Zhou XJ, Lv JC, Zhao MH, Zhang H. Advances in the genetics of anti-glomerular basement membrane disease.

2010 ; 32 : 482 -490 [PMID: 20962523 DOI: 10 .1159 /000321324 ]

7 Povey J, Rutherford E, Levy J, Muniraju T. Relapse of treated anti-GBM disease following hair dye use.

2021 ; 14 [PMID: 33795274 DOI: 10 .1136 /bcr-2020 -240543 ]

8 Troxell ML, Houghton DC. Atypical anti-glomerular basement membrane disease. Clin Kidney J 2016 ; 9 : 211 -221 [PMID:26985371 DOI: 10 .1093 /ckj/sfv140 ]

9 Cui Z, Zhao MH, Singh AK, Wang HY. Antiglomerular basement membrane disease with normal renal function.

2007 ; 72 : 1403 -1408 [PMID: 17851468 DOI: 10 .1038 /sj.ki.5002525 ]

10 L'Imperio V, Ajello E, Pieruzzi F, Nebuloni M, Tosoni A, Ferrario F, Pagni F. Clinicopathological characteristics of typical and atypical anti-glomerular basement membrane nephritis.

2017 ; 30 : 503 -509 [PMID: 28382508 DOI:10 .1007 /s40620 -017 -0394 -x]

11 Gulati K, McAdoo SP. Anti-Glomerular Basement Membrane Disease. Rheum Dis Clin North Am 2018 ; 44 : 651 -673 [PMID: 30274629 DOI: 10 .1016 /j.rdc.2018 .06 .011 ]

12 Roberts IS. Pathology of IgA nephropathy. Nat Rev Nephrol 2014 ; 10 : 445 -454 [PMID: 24861083 DOI:10 .1038 /nrneph.2014 .92 ]

13 Kojima T, Hirose G, Komatsu S, Oshima T, Sugisaki K, Tomiyasu T, Yoshikawa N, Yamada M, Oda T. Development of anti-glomerular basement membrane glomerulonephritis during the course of IgA nephropathy: a case report.

2019 ; 20 : 25 [PMID: 30683055 DOI: 10 .1186 /s12882 -019 -1207 -3 ]

14 Annamalai I, Chandramohan G, Srinivasa Prasad ND, Fernando E, Sujith S. Rapidly progressive glomerulonephritis due to anti-glomerular basement membrane disease accompanied by IgA nephropathy: An unusual association.

2017 ; 28 : 1404 -1407 [PMID: 29265054 DOI: 10 .4103 /1319 -2442 .220866 ]

15 Suh KS, Choi SY, Bae GE, Choi DE, Yeo MK. Concurrent Anti-glomerular Basement Membrane Nephritis and IgA Nephropathy.

2019 ; 53 : 399 -402 [PMID: 31525832 DOI: 10 .4132 /jptm.2019 .08 .05 ]

16 Xu D, Wu J, Χu C, Zhang Y, Mei C, Gao Χ. Novel therapy for anti-glomerular basement membrane disease with IgA nephropathy: A case report.

2016 ; 11 : 1889 -1892 [PMID: 27168822 DOI: 10 .3892 /etm.2016 .3149 ]

17 Cui Z, Zhao MH, Wang SΧ, Liu G, Zou WZ, Wang HY. Concurrent antiglomerular basement membrane disease and immune complex glomerulonephritis.

2006 ; 28 : 7 -14 [PMID: 16526313 DOI: 10 .1080 /08860220500461195 ]