INTRODUCTION

Idiopathic membranous nephropathy (IMN) is an uncommon cause of nephrotic syndrome (NS) in children, with an incidence of less than 5%[1]. The diagnosis of IMN depends on renal biopsy. IMN is an organ-specific (kidney) autoimmune disease, and its pathogenesis involves circulating antibodies binding to the intrinsic antigen on podocytes, which leads to subepithelial deposits of immune complexes[2]. To date, phospholipase A

receptors (PLA

Rs) on podocytes have been considered to be the primary antigen, and the rate of PLA

R positivity in the renal tissue of children with IMN is nearly 32%[3]. Circulating autoantibodies to PLA

R have been confirmed in approximately 80% of adults with IMN and are seldom detected in secondary MN[4]. Some studies have indicated that the titer of anti-PL A

R antibodies reflects disease activity and urinary protein levels. A high titer of antibodies is correlated with a great risk of deterioration in renal function and minimal chance of remission[5]. Although the possibility of spontaneous remission in children with IMN is greater than that in adults, personalized therapy must be adopted because there is no evidence-based standard treatment for IMN in children. Steroids and immunosuppressant drugs are popular treatment options for this disease; however, which immunosuppressant drug should be used and for how long still need to be determined[6].

There were no reports of tacrolimus in the treatment of idiopathic nephropathy in children. Here, we describe a child with IMN who presented with NS and was followed for a long period of time. Initially, high-dose methylprednisolone pulse therapy followed by prednisone therapy failed to eliminate the presence of urinary proteins. Renal biopsy and other specific tests were performed to confirm the diagnosis of IMN. Consequently, tacrolimus was added, and the therapeutic effect was satisfactory. By reviewing the literature on the therapeutic strategies for and prognosis of IMN in children, we aimed to better manage this disease.

CASE PRESENTATION

Chief complaints

A 7-year-old boy was admitted to our hospital (West China Second University Hospital of Sichuan University, Chengdu, Sichuan, China) in August 2020 with “repeated edema over the past 6 mo”.

History of present illness

Six months prior to admission, the patient developed facial edema and was diagnosed with idiopathic NS due to nephrotic proteinuria (24-h urinary protein 2.51 g), hypoproteinemia (albumin 20 g/L), and hyperlipidemia (serum cholesterol 6.29 mmol/L). At the same time, hematuria and leukocyturia were observed, without hypertension or abnormal renal function. Initially, the patient was treated with oral prednisone (2 mg/kg?d) and captopril (0.5-1.0 mg/kg?d) for 4 wk in another hospital (The First People’s Hospital of Sichuan Liangshan Yi Autonomous Prefecture, Liangshan Yi Autonomous Prefecture, Sichuan, China). However, the presence of urinary proteins persisted. Subsequently, the urinary protein fluctuated between 1+ and 3+ after methylprednisolone pulse therapy (20 mg/kg?d) for 3 d followed by oral prednisone (2 mg/kg?d) for 2 wk. Captopril (1 mg/kg?d) was prescribed as maintenance therapy for the patient. Early-onset steroid resistance was considered; consequently, immunosuppressant drugs were added. The doctor administered cyclophosphamide (CTX) pulse therapy (8 mg/kg, used for two consecutive days, every 2 wk), and the prednisone was gradually tapered by 5-10 mg every 4 wk. After six CTX treatments, the urinary protein results remained positive. Because of the poor therapeutic effects, the patient was transferred to our hospital and was admitted to the Nephrology Department on October 28, 2020.

History of past illness

Minimal change disease (MCD) is a common cause of NS in children and has a good prognosis. However, IMN is rare and has a poor prognosis in children. Especially in children with IMN who present with NS, it is necessary to carefully evaluate and select a reasonable therapeutic strategy as early as possible to improve the prognosis. Due to the lower morbidity of IMN in children, there are few relevant data on therapeutic strategies for and evaluation of children with IMN, and there is a notable lack of large-sample randomized controlled trials (RCTs). Most of the current studies were retrospective studies or case reports. IMN in children is more common in men and in adolescents. Studies indicated that the most prominent clinical manifestation was NS, which was accompanied by various degrees of edema, hyperlipidemia, hypoalbuminemia, and nephrotic proteinuria[7]. Hypertension, hematuria, and renal injury were also observed[9]. All reported cases were resistant to hormones[10,11]. In children with MN, PLA

R-associated MN appears to be common. PLA

R antibody levels are closely associated with disease activity, whereas PLA

R antibody-negative patients often have a good prognosis[4]. MCD in children is common in male preschool children. NS is the main clinical manifestation, and it can be mitigated by hormone therapy in 90%-95% of cases[12]. We summarize the differences between IMN and MCD to better identify and address IMN at the early stage, as shown in Table 3.

The patient did not have any relevant family history.

The authors declare that they have no conflicts of interest to disclose.

Personal and family history

“這么說，是拾寶撿漏去了？難怪坊間將尋寶人稱作‘拾寶猴子’，他呀，的確比猴子還精?！贬舅臓斝Φ?，“是不是嗅到什么寶貝了？”

怒江大峽谷國(guó)家公園位于云南省怒江傈僳族自治州，總面積35.88萬(wàn)公頃，國(guó)家公園由怒江大峽谷西岸的高黎貢山和東岸的碧羅雪山兩部分組成。怒江大峽谷全長(zhǎng)約600公里，向境外延長(zhǎng)可達(dá)700公里，是世界上最長(zhǎng)的峽谷，也是世界上少有的縱向嶺谷區(qū)。特殊的地理環(huán)境條件不僅形成了獨(dú)特的自然奇觀，而且造就了豐富的生物多樣性和文化多樣性，怒江大峽谷因此成為中國(guó)生物多樣性保護(hù)的關(guān)鍵地區(qū)。2003年7月，包括怒江流域山脈在內(nèi)的“三江并流”自然景觀，就被聯(lián)合國(guó)教科文組織列入《世界自然遺產(chǎn)名錄》。

Physical examination

The patient’s temperature, arterial pressure, weight, height, respiration rate, and heart rate were 36.5 °C, 110/65 mmHg, 26 kg, 115.9 cm, 22 times per minute, and 95 times per minute, respectively. A moon face and eyelid edema were observed on October 28, 2020.

Laboratory examinations

The laboratory test results revealed heavy proteinuria, hypoproteinemia, hyperlipidemia, leukocyturia, hematuria, and pathological casts (Table 1). The blood count, complement protein levels, and renal function were normal on October 28, 2020.

Imaging examinations

The computerized tomography (CT) scan was normal. Urinary ultrasound showed a slightly enhanced echo in the bilateral renal parenchyma on October 28, 2020.

Pathological examination

To further evaluate if the patient was steroid-resistant, renal biopsy was performed on October 30, 2020. No glomerulosclerosis, segmental sclerosis, or crescents was found. Obvious diffuse thickening of the basement membrane with several spiky formations, subepithelial deposition of fuchsinophilic protein, and vacuolar and granular degeneration in the renal tubular epithelial cells, without wire-loop lesions, were revealed by light microscopy. Irregular thickening of the basement membrane, along with electron-dense deposits in the subepithelial and intrabasal areas, and diffuse fusion of the foot processes of epithelial cells were suggested based on electron microscopy. The immunofluorescence results were as follows: Immunoglobulin A (IgA) -, IgG +++, IgM +, C

+, complement C

q -, and fibrinogen -. Immunohistochemical staining for IgG subtypes indicated deposition of IgG

and IgG

along the glomerular capillary wall, with PLA

R + and thrombospondin type-1 domain-containing 7A -, as shown in Figure 1.

Further diagnostic work-up

To exclude secondary MN, we performed analyses of anti-streptolysin O, autoantibodies, antineutrophil cytoplasmic antibodies, and complement proteins, tested for the hepatitis virus, syphilis, acquired immunodeficiency syndrome, and tuberculosis, and performed a urine culture, sputum culture, and plain chest CT scan, which were all negative.

FINAL DIAGNOSIS

Written informed consent was obtained from the patient for publication of this report and any accompanying images.

對(duì)福建省某一級(jí)達(dá)標(biāo)校高二年級(jí)四個(gè)教學(xué)平行班學(xué)生施以“高中學(xué)生‘基因’概念表征水平的問卷調(diào)查”、“高中學(xué)生‘有氧呼吸’概念表征水平的問卷調(diào)查”兩份概念水平問卷，調(diào)查學(xué)生對(duì)創(chuàng)設(shè)型概念的表征水平。

TREATMENT

In view of the patient’s poor response to steroids and CTX, we changed the therapeutic strategy to include tacrolimus (0.07 mg/kg?d), and at the same time, prednisone was gradually decreased referencing 2019 Kidney Disease Improving Global Outcomes.

OUTCOME AND FOLLOW-UP

On January 4, 2021, after 49 d of treatment using tacrolimus and prednisone, the urine protein results and urinary pathologic casts were negative. The red blood cell count in the urine decreased to 59 cells/μL, and the white blood cell count in the urine decreased to 10 cells/μL. Throughout a 5-mo follow-up period, the patient showed an uneventful clinical course, and the steroids were progressively decreased. Kidney function remained normal in the patient during follow-up. The urinalysis results during the follow-up are shown in Table 2.

DISCUSSION

IMN is a rare cause of NS in children. Here, we report the case of a school-age boy with steroid-resistant NS. IMN was diagnosed by renal biopsy, with PLA

R +. The therapeutic effect of tacrolimus plus prednisone was satisfactory. In this article, we described a 7-year-old boy with stage II IMN confirmed by renal biopsy and other laboratory tests. Initially, prednisone and CTX were given for several months, but remission was not achieved. After tacrolimus was substituted for CTX, the proteinuria gradually became negative. IMN patients who present with NS need to receive steroid therapy for several weeks initially. If the therapeutic effect is not satisfactory, immunosuppressant drugs should be added to the treatment regimen for these patients. However, which immunosuppressant drug should be used and for how long are still unclear. Alkylating agents remain the only agents proven to be effective in preventing end-stage renal disease or death[6]. Rituximab may be considered for children who do not respond to hormonal or immunosuppressant therapy[6]. Other studies have reported that tacrolimus and CTX are superior to other immunosuppressant drugs in terms of complete remission rate, and tacrolimus monotherapy is also the safest and most effective choice for IMN with stable renal function[7]. A regimen of prednisone plus tacrolimus could undoubtedly yield a higher remission rate and long-term safety. More than 60% of patients can reach complete remission or partial remission in 24 mo, and relapse is rare[8]. In terms of other immunosuppressant drugs, the remission rate associated with the use of glucocorticoids and CTX in IMN is only 58.6%[9].

“兩票制”的執(zhí)行，使藥品的供應(yīng)鏈更為簡(jiǎn)化，以往常見的底價(jià)代理、層層加價(jià)分銷的模式逐漸退出供應(yīng)鏈主流，而藥品出廠價(jià)接近中標(biāo)價(jià)格的高開自營(yíng)和高開代理模式將占居市場(chǎng)的主導(dǎo)地位，個(gè)別專營(yíng)或兼營(yíng)“過票”的藥品批發(fā)企業(yè)，喪失了原有的商業(yè)價(jià)值。同時(shí)，“兩票制”與“營(yíng)改增”和藥監(jiān)部門“飛行檢查”多管齊下，有力地打擊了“掛靠”、“走票”等違法行為，“過票”企業(yè)必將被市場(chǎng)淘汰[3，4]。

The patient had no history of other illnesses and no known allergies.

CONCLUSION

IMN is rare in children. The main clinical manifestations are edema and NS. The diagnosis depends on renal biopsy. PLA

R antibody should be used to monitor treatment and follow-up. There is little evidence-based data on the treatment of IMN in children. Therefore, large-sample RCTs need to be performed. Individualized treatment should be used to improve the prognosis of the disease. In the future, for children who are not simple NS, we hope to detect serum PLA

R antibody to early predict MN and its prognosis.

官竅，泛指器官和孔竅。官指耳、目、口、鼻、舌五個(gè)器官，簡(jiǎn)稱五官。五官分屬于五臟，為五臟之外候。除五官之外，咽喉也屬于官之范疇。七竅是頭面部（眼二、耳二、鼻孔二和口）七個(gè)竅的合稱。頭面部的七竅，又稱清竅，是人體清陽(yáng)之氣出入的通道，與之相應(yīng)，前后二陰（前陰尿道口和后陰肛門），是人體尿便排出的通道，稱為濁竅。頭部七竅及前后二陰統(tǒng)稱為“九竅”。五臟的精氣分別通于官竅，五臟有病，往往從官竅變化中反映出來(lái)。每一官竅不僅同與其相應(yīng)的臟腑有著特定的聯(lián)系，而且與其他臟腑也有密切的關(guān)系。

ACKNOWLEDGEMENTS

建筑信息化模型(BIM)技術(shù)以建筑工程項(xiàng)目的各項(xiàng)相關(guān)信息數(shù)據(jù)作為模型基礎(chǔ)，建立建筑模型，從根本上改變了從業(yè)人員依靠圖紙符號(hào)文字進(jìn)行項(xiàng)目建設(shè)和運(yùn)營(yíng)管理的工作方法[1]，對(duì)實(shí)現(xiàn)項(xiàng)目的高精度、高效益建造具有重大意義。

FOOTNOTES

Cui KH collated the patient data and drafted the manuscript; Zhang H analyzed the patient’s clinical course and outcomes, interpreted the findings, and critically reviewed the manuscript; Tao YH helped modify the manuscript; all authors read, critically reviewed, and provided feedback on the manuscript; and all authors approved the final manuscript.

Renal biopsy confirmed the pathological diagnosis of stage II IMN. The pathological changes of IMN include thickened glomerular basement membranes under a light microscope, with immunofluorescence examination showing granular staining for IgG, IgM, C

and PLA

R along the periphery of glomerular capillary loops, and electron-dense subepithelial deposits under an electron microscope. After ruling out other immunological and infectious diseases relevant to secondary MN with other laboratory tests, IMN was identified.

A、B、D三類酶均可存在于可以水平移動(dòng)的可移動(dòng)耐藥元件中，通過接合，轉(zhuǎn)化，轉(zhuǎn)導(dǎo)，轉(zhuǎn)座等方式在不同菌株之間水平傳播，從而導(dǎo)致耐藥菌株的流行。結(jié)合各個(gè)國(guó)家和地區(qū)的研究文獻(xiàn)和相關(guān)報(bào)道我們得知KPC，OXA-48，VIM和NDM這4種酶可以引起全世界范圍內(nèi)的廣泛傳播，而其他碳青霉烯酶如IMP，GES，PER，SME，SIM等引起的感染則具有相對(duì)獨(dú)特的地域性。

We sincerely thank the Department of Nephrology and Renal Pathology.

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

3．4 ELBWI的消化系統(tǒng)合并癥 ELBWI的腸內(nèi)營(yíng)養(yǎng)在早產(chǎn)兒管理中至關(guān)重要，其難度遠(yuǎn)高于1 500g以上的早產(chǎn)兒，本研究資料中分別有2例消化道出血，1例消化道穿孔死亡。ELBWI胃腸道發(fā)育極不成熟，目前提倡早期腸道內(nèi)微量喂養(yǎng)，以促進(jìn)腸道發(fā)育，恢復(fù)胃腸道動(dòng)力以及消化酶的分泌；對(duì)腹脹、嘔吐、胃潴留患兒可予胃腸減壓、暫停喂奶及應(yīng)用促胃腸動(dòng)力藥。

Kun-Hua Cui 0000-0002-5696-8075; Hui Zhang 0000-0002-0650-4396; Yu-Hong Tao 0000-0001-8074-4170.

Wang JJ

Wang TQ

Wang JJ

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