.
Meng-chao Liua,, Yi-fan Guob,*, Yan-hong Huoc, Tian-peng Xiangb, Zhi-qiang Liub, Wen-jing Zhaoa,#, Bo Lia,d,#
Abstract：Idiopathic Membranous Nephropathy (IMN) has become the leading cause of nephrotic syndrome in adults. At present, IMN is treated mainly by glucocorticoids in combination with alkylation agents, calcineurin inhibitors (CNIs), rituximab, etc. However, these therapies are limited due to high incidences of adverse reactions, high risk of relapse, and high costs. Here, we report two cases of patients who were diagnosed with IMN with kidney failure (KF) in December 2017 and April 2014. They had unsuccessful hormone and immunosuppressive treatments and had experienced severe infections. They achieved complete remission and partial remission, respectively, after the integrated treatment of traditional Chinese medicine (TCM) syndrome differentiation and Western medical symptomatic treatment. So far, their long-term treatment and follow-up has reached 52 and 95 months, their conditions remain stable, and relapse has not occurred. In addition, there is no obvious adverse reaction or complication in either patient, and their symptoms are also alleviated. From this, we conclude that TCM has a certain potential in the treatment of IMN patients with KF, and further studies are needed to confirm the effectiveness and safety of this treatment option.
Keywords: Idiopathic membranous nephropathy (IMN); kidney failure; traditional Chinese medicine (TCM); Chinese herbal medicine; case reports
Introduction
As an autoimmune glomerular disease, idiopathic membranous nephropathy (IMN) has become the leading cause of nephrotic syndrome in adults［１］. According to a large study in China［2］, the proportion of IMN in primary glomerular disease increased from 17% in 2003-2007 to 29% in 2008-2012, which was similar to the findings of several studies［3］［4］. It indicates a rapid increase in the incidence of IMN in China. IMN is pathologically characterised by subepithelial deposition of immune complexes and complement components, followed by new synthesis of the basement membrane that results in thickening of glomerular capillary walls［5］. Although about 30% of patients with IMN will achieve spontaneous remission, 20-40% of these patients will progress to end-stage kidney disease in 5-15 years［6］. Additionally, IMN can cause life-threatening thrombotic complications, making it an essential public health challenge.
In recent years, the discovery of phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) has contributed to crucial breakthroughs in the pathogenesis of IMN［6］,［7］. However, there is still a lack of consensus on the treatment strategy for this disease. Currently, IMN is mainly treated by glucocorticoids in combination with alkylation agents, calcineurin inhibitors (CNIs), rituximab, etc. However, these therapies are limited due to high incidence of adverse reactions, high risk of relapse after discontinuation, and high cost［8］, ［9］. Meanwhile, Traditional Chinese medicine (TCM) has become an important part of complementary and alternative medicine for IMN. As reported in many studies, TCM treatment or an integrated treatment of TCM and Western medicine significantly improved the efficacy of IMN treatment and also reduced the relapse rate［10］. In this study, a combined therapy that integrates traditional Chinese medicine with Western medicine was adopted to benefit patients with IMN with KF who had had unsuccessful hormone and immunosuppressive therapies and experienced severe infection. To the best of our knowledge, this is the first time that a combined therapy was used for such patients. The findings of this study highlight the potential of complementary and alternative medicine and provide evidence for the efficacy of TCM in treating IMN with KF.
Case description
Case 1
In December 2017, a 66-year-old male patient was admitted to our hospital due to intermittent edema for 4 years and elevated serum creatinine (Scr) for 1 year. He had been suffering from type 2 diabetes for 7 years, but denied any history of other diseases or drug abuse. He took amlodipine besylate tablets 5 mg orally every morning, andsubcutaneously injected Novolin R 12, 14 and 14 IU before meals and insulin glargine 10 IU before bedtime. In May 2013, he was found to have positive urine protein and then received his first kidney biopsy in a Grade A tertiary hospital in Beijing. Pathological results were presented as follows: immunofluorescence: 3G, IgM (+), deposited along the mesangial region; negative IgA, IgG, C3 and C1q. Light microscopy: 18G, 2 of which were ischemic sclerosis, diffuse vacuolar degeneration of capillary basement membranes, mild diffuse proliferation of mesangial cells and mesangial matrix, and segmentary sclerosis of some glomerulus, epithelial granules and vacuolar degeneration, and focal atrophy, with small focal mononuclear lymphocyte infiltration with fibrosis in the renal interstitium and slight thickening of the arteriole wall. Based on those examination results, he was diagnosed with focal segmental glomerulosclerosis (FSGS). After a proper amount of methylprednisolone (MP) was administered for initial treatment, his condition gradually improved. However, in October 2013, the patient developed a sudden fever, headache, and confusion, and was diagnosed with cryptococcal meningitis at another Grade A tertiary hospital in Beijing. The dosage of MP was gradually reduced and discontinued in July 2014. In June 2015, this patient had a relapse and was treated with cyclosporin A (CsA) in this hospital. From June 2016 to September 2016, his 24-hour urine protein (24-h UP) increased from 0.72g/d to 2.94g/d, and his serum creatinine (Scr) fluctuated from 1.01mg/dL to 1.08mg/dL. Subsequently, he was treated with the addition of a tripterygium wilfordii polyglycoside tablet (TPT). Nevertheless, his condition continued to deteriorate during treatment. In September 2017, the 24-h UP and Scr of this patient increased to 4.68g/d and 1.48 mg/dL, respectively, and cyclophosphamide (CTX) was added to that hospital one month later. However, the edema in this patient was significantly aggravated. In November 2017, his 24-h UP and Scr were 10.49g/d and 2.40mg/dL, respectively (Figure 1).
Figure 1: The medical history and current information timeline of this visit (Case 1)
Subsequently, the patient was admitted for systematic treatment. His blood pressure at admission was 151/81 mmHg, and there was moderate edema in both lower extremities. He underwent a series of laboratory examinations, with the results presented as follows: serum albumin (sALB), 19.9g/L; Scr, 1.96mg/dL; blood urea nitrogen (BUN), 12.77mmol/L; 24-h UP, 5.18g/d; anti-PLA2R antibody titer, 474.37RU/ml. Therefore, this patient received a kidney biopsy again. Pathological results were presented as follows. Immunofluorescence: IgG (3+), PLA2R (+), C3 (2+), IgG1 (3+), IgG3 (2+), IgG4 (3+), HBcAg (+-), κ (2+), and λ (3+) were deposited on the capillary wall. Light microscopy: there was mild proliferation of mesangial cells and stroma, infiltration and thickening of basement membranes, of fuchsinophilic proteins deposition under the epithelium, and formation of segmental spikes. The epithelial cells of renal tubules were extensively vacuolated and granular in shape, with multiple foci of brush edge ablated, and foci of atrophy accompanied by some protein tubules. In addition, renal interstitial edema, focal lymphatic, and monocyte infiltration with fibrosis were manifested. Congo red staining was negative in the results. These findings were consistent with stage II membranous nephropathy (MN) accompanied by subacute tubulointerstitial nephritis (TIN). The reasons for the difference in pathological results may be that the glomerular diameter was not reported on the first pathological examination, and obesity-related FSGS could not be excluded. In addition, the latest pathological examination may miss some glomerular indications of segmental sclerosis. But in any case, the latest pathological findings are very definitive for the diagnosis of IMN. This patient was classified into the high-risk group based on the assessment of the MN risk of the KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases［11］. Without effective intervention, he was prone to end-stage kidney disease (ESKD) in a short period of time.
In addition to antihypertensive (amlodipine besylate), hypoglycemic, lipid-lowering and other symptomatic therapies, the patient also received TCM treatment at the same time. He suffered from edema on both lower limbs, fatigue, chills, dry mouth and poor appetite, as well as with a slightly pale tongue, white tongue coating and stringy pulses. Syndrome differentiation revealed spleen and kidney deficiency, and retained dampness in the body. The patient received an herbal decoction to treat IMN, as listed in Table 1.
表1 中草藥處方 (案例1)
| 标准名 | 中药名 | 剂量（g） |
| Astragali Radix | 黄芪 | 60 |
| Atractylodis Macrocephalae Rhizoma | 白术 | 20 |
| Poria | 茯苓 | 30 |
| Ephedrae Herba | 麻黄 | 9 |
| Mori Cortex | 桑白皮 | 20 |
| Arecae Pericarpium | 大腹皮 | 15 |
| Rubi Fructus | 覆盆子 | 30 |
| Smilacis Glabrea Rhizoma | 土茯苓 | 30 |
| Hedyotis Corymbosa | 白花蛇舌草 | 30 |
| Cinnamomi Ramulus | 桂枝 | 15 |
| Aconiti Lateralis Radix Praeparata | 附子 | 10 |
| Curcumae Rhizoma | 莪术 | 30 |
| Euonymi Alati Ramulus | 鬼箭羽 | 20 |
| Cuscutae Semen | 菟丝子 | 20 |
| Maydis Seigma | 玉米须 | 10 |
| Polyporus | 猪苓 | 20 |
The medical history and current information timeline of this visit (Case 1)
After 2 weeks of treatment, the decoction was adjusted for the treatment of the patient’s dry mouth by removing Aconiti Lateralis Radix Praeparata (Fuzi) and adding 20g of Sinomenii Caulis (Qingfengteng). From this, the decoction was fine-tuned according to the patient’s symptoms. After 2 months of treatment, the patient’s edema decreased, fatigue, chills, and dry mouth improved, and he gradually regained appetite. More importantly, he achieved partial remission and complete remission in the 4th and 26th months after treatment, respectively. The patient’s condition continues to remain stable. Furthermore, after long-term monitoring of blood routine and liver function, there have been no obvious adverse reactions (Figure 2).
Figure 2: 24-hour urine protein, albumin and serum creatinine follow-up results (case 1)
Case 2
In April 2014, a 68-year-old male patient was admitted to our hospital due to aggregated edema. He had hypertension for 10 years and denied other medical conditions.
In February 2012, he received examinations in a Grade A tertiary hospital in Beijing, with the 24-h UP and Scr being 8g/24h and 1.36-1.47mg/dL, respectively. He also underwent a kidney biopsy and the results were presented as follows: immunofluorescence: IgG (4+), C3 (2+), deposited along GBM. Light microscopy: there were 17 glomeruli, 2 of which presented global sclerosis, focal segmental mild hyperplasia of the mesangial cells and stroma, thin basement membranes, fine capillary loop opening, renal tubular epithelial cells, interstitial fibrosis and chronic inflammatory cell infiltration, and thickening of small vessel walls. Based on those findings, this patient was diagnosed with early MN. In April 2012, he began treatment with MP as his condition worsened. During that period, he received the treatment of intravenous CTX, with the cumulative amount of CTX being 2.6g. However, his kidney function and urinary protein condition did not improve, and Scr gradually increased to more than 4mg/dL. In September 2013, he was treated with tacrolimus (TAC) due to poor outcomes. In December 2013, MP was discontinued and TAC was also discontinued in March 2014 after the patient had aggravated edema and fatigue, with Scr increasing to 6.28mg/dL. During treatment, he suffered from a severe bout of pneumonia (Figure 3).
Figure 3: The medical history and current information timeline of this visit (case 2)
This patient was referred to our hospital in April 2014, and Scr, sALB and 24-h UP were 5.52mg/dL, 2.23g/dL and 4.53g/d, respectively, at admission. The physical examination showed BP 153/79mmHg, with edema in both eyelids and lower limbs. Since there was no rheumatic immune disease, infectious disease, tumor and other diseases that may be secondary to MN, he was eventually diagnosed with IMN. Of note, he developed renal insufficiency at the onset of the disease 2 years ago. After being treated with hormones, cyclophosphamide, and tacrolimus, his condition did not improve and the Scr continued to increase. When this patient was referred to our hospital, he had stage 5 chronic kidney disease (CKD) and a poor prognosis.
This patient refused renal replacement therapy and began to receive TCM decoctions in addition to the symptomatic treatment of hypotension, lipid reduction, diuretic, anticoagulation, anemia correction, and acidosis correction. His symptoms mainly included edema, fatigue, lumbago, occasional dizziness, loss of appetite, stomach distension, cough, and sticky stools. Additionally, he presented with a pale and white tongue, thin tongue coating, and heavy and thin pulses. Syndrome differentiation also revealed spleen and kidney deficiency, with retained dampness in the body. A similar decoction to that of Case 1 was also provided, as listed in Table 2.
表2 中草藥處方 (案例2)
| 标准名 | 中药名 | 剂量（g） |
| Astragali Radix | 黄芪 | 30 |
| Atractylodis Macrocephalae Rhizoma | 白术 | 20 |
| Poria | 茯苓 | 30 |
| Ephedrae Herba | 麻黄 | 6 |
| Mori Cortex | 桑白皮 | 20 |
| Arecae Pericarpium | 大腹皮 | 20 |
| Rubi Fructus | 覆盆子 | 40 |
| Smilacis Glabrea Rhizoma | 土茯苓 | 30 |
| Hedyotis Corymbosa | 白花蛇舌草 | 30 |
| Codonopsis Radix | 党参 | 15 |
| Citri Reticulatae Pericarpium | 陈皮 | 20 |
| Bambusae Caulis In Taenias | 竹茹 | 12 |
| Amomi Fructus | 砂仁 | 10 |
| Glycyrrhizea Radix Et Rhizoma | 炙甘草 | 15 |
| Zingiberis Rhizoma | 干姜 | 15 |
Note: Take orally, one dose (400ml) per day, twice a day.
After 2 weeks of treatment, his cough and stomach distension were significantly relieved and his appetite improved. Subsequently, the decoction was adjusted to tonify the kidney and blood circulation by removing Citri Reticulatae Pericarpium (Chenpi), Bambusae Caulis In Taenias (Zhuru) and Amomi Fructus (Sharen) and adding 20g of Nelumbinis Stamen (Lianxu), Rehmanniae Radix Praeparata (Shudihuang) and Wenyujin Rhizoma Concisum (Pianjianghuang), respectively. After 1 month of treatment, his edema and lumbago were significantly relieved, and stools became smooth and not sticky; in addition, his strength was substantially restored. Subsequently, with the improvement of the disease, the patient’s diuretics and anticoagulants were gradually reduced until they were finally stopped. The drugs of anemia correction and acidosis correction were also adjusted according to the regular follow-up checks of each indicator. Antihypertensive drugs and lipid-lowering drugs continue to be used today. Finally, we observed that his disease achieved partial remission in the 14th month after treatment, and Scr decreased to less than 3mg/dL in the 20th month after treatment. The patient was followed for more than 7 years without recurrence (Figure 4).
Figure 2: Patient’s 24-hour follow-up results of urine protein, albumin, and serum creatinine (Case 2)
Discussion
IMN is an autoimmune disease and there is still a lack of effective and safe treatment. The current treatment mainly uses glucocorticoids combined with alkylating agents, CNIs, rituximab, and other drugs. However, the efficacy of these therapies for IMN remains controversial. Corticosteroids and cytotoxic drugs have the side effects of potential bone marrow toxicity, infection, cancer and thrombosis［12］. CNIs have a high recurrence rate, a low long-term remission rate, and some obvious adverse reactions［12］. In recent years, rituximab has gained prominence as a first-line drug owing to its high response rate and relatively few side effects. However, in addition to its high cost, its application is also limited to some extent by its 35-40% non-response rate［13］,［14］, 19% recurrence rate［15］, 28% allergic reaction rate［16］, as well as the low probability of immune remission in patients with anti-PLA2R antibody titer higher than 152RU/ml［17］. Therefore, these treatments still have certain limitations. For the two cases in this study, they used hormones, CTX and CNIs, but IMN did not achieve prolonged remission, and the patients gradually deteriorated and even developed KF. Beyond that, another crucial problem was that they all developed serious infections during immunosuppressive therapy, which on the one hand, could be life-threatening, and on the other hand, raised barriers to their immunosuppressive or molecularly targeted therapy. For such patients, finding a safer treatment may have had longer-term benefits.
Recent trials have shown the efficacy and safety of TCM in the treatment of IMN. A meta-analysis showed that TCM combined with immunosuppression significantly reduced the incidence of adverse effects such as infection, insomnia, gastrointestinal discomfort, and Cushings syndrome compared with immunosuppression alone［10］. An open-label, multicenter, parallel, randomized, controlled clinical trial involving 190 patients with nephrotic syndrome with biopsy-confirmed IMN found that TCM was analogous to standard prednisone and cyclophosphamide in enhancing 24-h UP excretion rates, and also showed good protection against renal function［18］. These results suggested that TCM has great potential in clinical application and good safety in patients with ineffective or limited immunosuppressive therapy.
IMN belongs to the category of “edema disease” in TCM, and is generally considered to be based on a deficiency of the spleen and kidney, potentially also mixed with wind-evil syndrome, water-dampness syndrome, damp-heat syndrome, blood stasis syndrome, etc. According to TCM, the spleen is the foundation of acquired life and the kidney is the foundation of nature. Deficiency of the spleen and kidney can lead to further aggravation of solid-evil, which can further affect the operation of Qi, blood, and water, which, in turn, aggravates the deficiency of the spleen and kidney. Therefore, tonifying the spleen and kidney and eliminating solid pathogens are crucial in the treatment of IMN. In this study, the differentiation of the syndrome reveals that both patients have spleen and kidney deficiency, as well as retained dampness in the body. Therefore, the prescriptions in the two cases included Astragali Radix (Huangqi), Atractylodis Macrocephalae Rhizoma (Baizhu), Poria (Fuling), and Rubi Fructus (Fupenzi) to nourish the spleen and kidney, Hedyotis Corymbosa (Baihuasheshecao), Arecae Pericarpium (Dafupi) and Smilacis Glabrea Rhizoma (Tufuling) to reduce dampness and turbidity, supplemented by Curcumae Rhizoma (Ezhu), Alati Ramulus (Guijianyu), Cinnamomi Ramulus (Guizhi) to promote Qi and blood circulation, which was conducive to the smooth flow of the sanjiao, thus, invigorating spleen and kidney and removing dampness and turbidity. According to the different conditions of the patients, the first case was focused on promoting blood circulation and the elimination of edema, while the second case was focused on relieving cough and reducing phlegm, both cases remaining consistent with the essence of the differentiation and treatment.
Despite the two different conditions, there are some common Chinese herbs in both decoctions. As the monarch medicine in both decoctions, Astragali Radix (Huangqi) has the functions of immune system regulation, anti-oxidation, anti-inflammation, and anti-aging［19］. Astragaloside IV can restore the loss of podocyte morphology and cytoskeleton induced by the complement membrane attack complex, and reduce the phosphorylation of JNK and ERK1/2 induced by the complement membrane attack complex, which may be the key mechanism for its efficacy in the treatment of IMN［20］. The extract of Atractylodis Macrocephalae Rhizoma (Baizhu), Poria (Fuling), and Hedyotis Corymbosa (Baihuasheshecao) has immunomodulatory effects［21-23］. Atractylodis Macrocephalae Rhizoma (Baizhu) can also inhibit inflammation, prevent cancer, and promote gastrointestinal movement［23］. Poria (Fuling) has anti-inflammatory and antioxidant activity, and it can also protect liver and 〖JP3〗kidney functions［22］. Ephedrae Herba (Mahuang) has antitussive diuretic, anti-inflammatory, and antiviral functions［24］. Mori Cortex (Sangbaipi) can resist inflammation and reduce proteinuria［25］. Arecae Pericarpium (Dafupi) can resist thrombosis and promote gastrointestinal movement［26］. Smilacis Glabrea Rhizoma (Tufuling) has the anti-inflammatory and analgesic effects, and it can also reduce the level of uric acid［27］.
In this study, after continuous TCM treatment and follow-up for these two patients for 52 and 95 months respectively, they finally achieved partial or complete remission, and their conditions remained stable, free from relapse so far. In addition, there is no obvious adverse reaction or complication in either patient, and their symptoms are also alleviated. For these two patients, integrated therapy with TCM has been notably effective.
However, there are some limitations to this study. Specifically, because these two patients were admitted to the hospital many years ago, rituximab was expensive and had not been recommended as a first-line drug. Although they had been treated with various hormones and immunosuppressants, neither of them could receive rituximab. In addition, although the kidney biopsy reports of these two patients are presented in Grade A tertiary hospitals in Beijing with high credibility, it is difficult to obtain clear color images, and only the detailed content of the official pathological reports could be obtained. Furthermore, due to the limitation of a case report, the conclusions need to be verified by high-quality clinical studies with a large sample size.
It is worth noting that these findings support that TCM is effective in the treatment of IMN complicated with KF, and no significant adverse reactions occured after a long time of TCM treatment. It suggests that a TCM decoction with an appropriate herbal dosage is relatively safe and has great potential as the representative of complementary and alternative medicine in the treatment of IMN.
Author contributions:M.L. and Y.G. drafted the manuscript and followed up with the patient. Y.H., T.X. and Z.L. participated in the collection of the patients’ diagnosis and treatment data, as well as searched the literature. W.Z. contributed to the design, treated, and evaluated the patients. B.L. put forward research ideas and participated in the revision of the paper. All authors read and approved the final manuscript for publication.
Conflict of interest: The authors declare that they have no conflict of interest.
Data availability statement:All data generated or analysed during this study are included in this published article.
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中西醫結合治療特發性膜性腎病合併腎功能衰竭——驗案2則
劉夢超 郭弋凡 霍延紅 向湉芃 劉志強 趙文景 李博
摘要：特發性膜性腎病（idiopathic membranous nephropathy，IMN）是一種自身免疫性腎小球疾病，是成人腎病綜合徵的主要原因。目前，IMN主要是通過糖皮質激素聯合烷化劑、鈣調神經磷酸酶抑製劑（calcineurin inhibitors，CNIs）、利妥昔單抗等進行治療。然而，由於其不良反應發生率高、停藥後的複發風險高或價格昂貴等原因導致應用受限。在這項研究中，我們報告了2例在2017年12月和2014年4月應用激素和免疫抑制治療失敗，並經歷了嚴重感染的IMN合併腎功能衰竭（kidney failure，KF）患者。經中醫（traditional Chinese medicine，TCM）辨證治療和西醫對症治療後，分別達到完全緩解和部分緩解。到目前為止，2例患者長期治療和隨訪時間分別達到了52個月和95個月，病情穩定且均未復發，無明顯不良反應或併發症，提示中醫藥在治療IMN合併KF患者方面具有一定的潛力，需要進一步研究來證實該治療方案的有效性與安全性。
關鍵詞:特發性膜性腎病 腎功能衰竭 中醫 中藥 病例報告
特發性膜性腎病（idiopathic membranous nephropathy，IMN）是一種自身免疫性腎小球疾病，是全球成人腎病綜合徵的主要原因［1］。一項中國人群的大型調查研究顯示［2］，IMN在原發性腎小球疾病中的比例從 2003-2007 年期間的17%升到2008-2012年的29%。另有多項研究顯示了類似結果，提示IMN在中國的發病率明顯增加［3］［4］。 IMN的病理特徵是腎小球基底膜上皮細胞下免疫複合物沉積伴基底膜瀰漫增厚［5］。 IMN約30%會獲得自發緩解，但仍有20-40%的患者會在5-15年內發展為ESKD［1］。此外，IMN可導致危及生命的血栓栓塞並發症，已成為一項重要的公共衛生挑戰。
近年來，足細胞磷脂酶A2受體（PLA2R）、抗凝血酶反應蛋白1型結構域7A（THSD7A）的發現為IMN的發病機製做出了重大突破［6］［7］，但其治療策略仍然存在爭議。目前，IMN主要採用糖皮質激素聯合烷化劑、鈣調神經磷酸酶抑製劑、利妥昔單抗等藥物治療，但由於其不良反應發生率高、停藥後的複發風險高或價格昂貴等原因導致應用受限［8］［9］。中醫藥是補充與替代醫學的重要組成部分，已有多項研究表明中醫或中西醫結合療法顯著提高了IMN總有效率，降低了復發率［10］。本研究採用中西醫結合聯合治療，使激素和免疫抑制治療失敗且感染嚴重的IMN合併KF患者獲益。據我們所知，這是首次報導聯合治療此類患者的病例報告。本研究結果突出了補充與替代醫學的潛力，為中醫治療IMN的療效提供了依據。
案例描述
案例1
2017年12月，一名66歲男性患者，因“間斷水腫4年，血肌酐升高1年”就診。既往2型糖尿病7年，否認其他疾病史及家族史。每天口服苯磺酸氨氯地平片5 mg，三餐前皮下注射諾和靈R 12-14-14 IU，睡前註射甘精胰島素10IU。2013年5月患者因水腫發現蛋白尿，於北京某三甲醫院接受了第一次腎活檢，病理結果如下：“免疫熒光：3G，IgM（+），沿系膜區沉積；IgA、IgG、C3、C1q均（-）。光鏡可見18個腎小球，2個缺血性硬化，其餘腎小球毛細血管基底膜瀰漫空泡變性，系膜細胞與系膜基質輕度瀰漫性增生，部分腎小球節段性硬化；腎小管上皮顆粒及空泡變性，小灶狀萎縮；腎間質小灶狀單核淋巴細胞浸潤伴纖維化，小動脈壁輕度增厚”。根據結果回報，診斷為局灶性節段性腎小球硬化（focal segmental glomerulosclerosis，FSGS）。在給予適量的甲基潑尼松龍（methylprednisolone，MP）進行初始治療後，病情逐漸好轉。 2013年10月患者出現發熱、頭痛、意識不清，於另一三甲醫院診斷為“隱球菌腦膜炎”，隨後MP逐漸減量，至2014年7月停服。 2015年6月患者病情復發（具體不詳），開始口服環孢素A（cyclosporin A，CsA）治療。 2016年6月至2016年9月，患者24小時尿蛋定量（24-hour urine protein，24h-UP）由0.72g/d升至2.94g/d，血肌酐（serum creatinine，Scr）波動於1.01-1.08mg/dL，予加用雷公藤多苷片（tripterygium wilfordii polyglycoside tablet，TPT）治療。然而，在治療期間該患者病情繼續惡化。 2017年9月，患者24h-UTP升至4.68g/d，Scr升至1.48mg/dL，2017年10月再次加用CTX治療。然而，該患者水腫持續加重，2017年11月查24h-UP 10.49g/d，Scr 2.40mg/dL（圖1）。
圖1：本次就診病史及當前信息時間軸（案例1）
隨後，患者於我院接受系統治療。入院時血壓為151/81 mmHg，雙下肢中度水腫。實驗室檢查結果如下：血清白蛋白（serum albumin，sALB）19.9g/L，Scr 1.96mg/dL，血尿素氮（blood urea nitrogen，BUN）12.77mmol/L，24h-UP 5.18g/d，抗PLA2R抗體 474.37RU/ml。隨後，該患者接受重複腎活檢，病理結果如下：“免疫熒光：IgG（3+), PLA2R(+), C3（2+），IgG1（3+），IgG3（2+），IgG4（3+), HBcAg（+-），κ（2+），λ（3+）於毛細血管壁呈顆粒樣沉積；腎小球系膜細胞及基質輕度增生，基底膜浸潤增厚，上皮下嗜复紅蛋白沉積，節段釘突形成。腎小管上皮細胞廣泛空泡及顆粒狀變性，多灶狀刷狀緣脫落，灶狀萎縮伴部分蛋白管型。腎間質水腫，灶狀淋巴、單核細胞浸潤伴纖維化。剛果紅染色陰性。符合II期膜性腎病伴亞急性腎小管間質腎病。”兩次病理結果存在差異的原因可能是第一次未報導腎小球直徑，不能排除與肥胖相關的FSGS。此外，最新的病理檢查可能會錯過一些FSGS的腎小球指徵。但是，最新的病理髮現對IMN的診斷是非常明確的。根據KDIGO 2021腎小球疾病管理臨床實踐指南［11］的MN風險評估，該患者為高危組，若無有效干預患者在短期內發展至ESKD（end-stage kidney disease，ESKD）可能性很大。
該患者除降壓（苯磺酸氨氯地平）、降糖、降脂等對症治療外，主要予中藥治療。患者雙下肢水腫，乏力，畏寒，口乾，食慾不振，舌質暗苔白，脈弦。辨病為水腫病，辨證為脾腎陽虛、水濕內停證，具體中藥處方見表1。
表1 中草藥處方 (案例1)
| 标准名 | 中药名 | 剂量（g） |
| Astragali Radix | 黄芪 | 60 |
| Atractylodis Macrocephalae Rhizoma | 白术 | 20 |
| Poria | 茯苓 | 30 |
| Ephedrae Herba | 麻黄 | 9 |
| Mori Cortex | 桑白皮 | 20 |
| Arecae Pericarpium | 大腹皮 | 15 |
| Rubi Fructus | 覆盆子 | 30 |
| Smilacis Glabrea Rhizoma | 土茯苓 | 30 |
| Hedyotis Corymbosa | 白花蛇舌草 | 30 |
| Cinnamomi Ramulus | 桂枝 | 15 |
| Aconiti Lateralis Radix Praeparata | 附子 | 10 |
| Curcumae Rhizoma | 莪术 | 30 |
| Euonymi Alati Ramulus | 鬼箭羽 | 20 |
| Cuscutae Semen | 菟丝子 | 20 |
| Maydis Seigma | 玉米须 | 10 |
| Polyporus | 猪苓 | 20 |
注：口服，每日一劑（400ml），每日兩次。
治療2週後，患者輕度口乾，去黑順片，加青風藤20g。治療2個月後，患者水腫減輕，乏力、畏寒、口乾症狀改善，食慾逐漸恢復。更重要的是，該患者在治療後第4個月和第26個月獲得了部分和完全緩解，至今病情平穩。長期監測血常規、肝功能等，無明顯不良反應發生。 （圖2）。
圖2：患者24小時尿蛋白、白蛋白和血肌酐隨訪結果（案例1）
案例2
2014年4月，一位68歲的男性因水腫加重就診。既往高血壓10年，否認其他病史。
2012年2月患者因水腫於北京某三甲醫院查尿常規：PRO3+，24hUTP 8g/24h，Scr 1.36-1.47mg/dL，腎活檢病理：“免疫熒光：IgG（4+），C3（2+），沿GBM沉積，光鏡下顯示17個腎小球，2個全球性硬化，系膜細胞和基質有局灶節段性輕度增生，基底膜不厚，毛細血管袢開放尚好，腎小管上皮細胞有顆粒變性，伴有間質的纖維化和慢性炎細胞浸潤，小血管壁增厚。符合膜性腎病早期”。 〖JP2〗2012年4月，由於病情惡化，他開始接受MP治療，予強的松40mg qd口服1個半月後逐漸減量，期間曾予環磷酰胺靜脈治療，累積量2.6g，腎功能及蛋白尿均無改善，Scr逐漸增加到4mg/dL以上。 2013年9月，因預後不佳患者接受了他克莫司（tacrolimus，TAC）治療。 2013年12月，患者停用MP。 2014年3月Scr升至6.28mg/dL，停用他克莫司。在治療期間，患者還經歷了一次重症肺炎（圖3）。
圖3：本次就診病史及當前信息時間軸（案例2）
表2 中草藥處方 (案例2)
| 标准名 | 中药名 | 剂量（g） |
| Astragali Radix | 黄芪 | 30 |
| Atractylodis Macrocephalae Rhizoma | 白术 | 20 |
| Poria | 茯苓 | 30 |
| Ephedrae Herba | 麻黄 | 6 |
| Mori Cortex | 桑白皮 | 20 |
| Arecae Pericarpium | 大腹皮 | 20 |
| Rubi Fructus | 覆盆子 | 40 |
| Smilacis Glabrea Rhizoma | 土茯苓 | 30 |
| Hedyotis Corymbosa | 白花蛇舌草 | 30 |
| Codonopsis Radix | 党参 | 15 |
| Citri Reticulatae Pericarpium | 陈皮 | 20 |
| Bambusae Caulis In Taenias | 竹茹 | 12 |
| Amomi Fructus | 砂仁 | 10 |
| Glycyrrhizea Radix Et Rhizoma | 炙甘草 | 15 |
| Zingiberis Rhizoma | 干姜 | 15 |
注：口服，每日一劑（400ml），每日兩次。
治療2週後，患者咳嗽、胃脹明顯減輕，納食改善，去陳皮、竹茹、焦三仙等，加蓮鬚20g、鹿角磅20g、熟地黃20g、莪朮20g增強補腎活血之功。治療1個月後，患者水腫、腰痛明顯緩解，大便正常，體力明顯恢復。隨著病情改善，患者利尿劑和抗凝劑逐漸減少，直到停用。根據各指標的定期隨訪檢查，調整貧血糾正和酸中毒糾正的藥物。降壓藥和降脂藥持續使用至今。我們觀察到患者病情在治療後第14個月達到了部分緩解，而在治療後第20個月Scr下降到低於3mg/dL。患者被隨訪7年以上未復發（圖4）。
圖2：患者24小時尿蛋白、白蛋白和血肌酐隨訪結果（案例2）
討論
IMN是一種自身免疫性疾病，目前仍缺乏有效且安全的治療方法。西醫主要使用糖皮質激素聯合烷基化劑、CNIs、利妥昔單抗等藥物治療。然而，這些藥物治療IMN的療效仍存在爭議。糖皮質激素和細胞毒性藥物聯用有產生骨髓毒性、感染、癌症和血栓形成風險的副作用［12］。 CNIs復發率高，長期緩解率低，並有一些明顯的不良反應［12］。近年來，利妥昔單抗因其高反應率和相對較少的副作用而成為一線藥物。但除用藥成本昂貴外，利妥昔單抗有35-40% 無反應率［13］［14］，約19%的複發率［15］，約28%的過敏反應［16］，及對PLA2R抗體滴度高於152 IU/ml患者免疫緩解的可能性小等缺點［17］。因此，這些治療方法仍有一定局限性。本研究中的兩例患者均使用了激素，CTX和CNIs，但MN沒有達到長期緩解，病情逐漸惡化，甚至發展為KFI。除此之外，另一個關鍵的問題是他們在免疫抑製過程中均出現了嚴重感染，一方面可能危及生命，另一方面也對免疫抑製或分子靶向治療帶來限制。對於這類患者，尋找一種更安全的治療方法可能會有更遠期的獲益。
近年來多項臨床試驗證實了中醫藥治療IMN的有效性和安全性。一項薈萃分析顯示，與單純免疫抑制相比，中藥聯合免疫抑制顯著降低了感染、失眠、胃腸道不適、庫欣綜合徵等不良反應的發生率［10］。一項開放標籤、多中心、平行、隨機、對照臨床試驗在190名活檢確診的IMN腎病綜合徵患者中發現中藥在改善24h-UP排泄率方面與強的松環和磷酰胺標準療法相當，且表現出良好的腎功能保護作用［18］。提示在免疫抑制治療無效或受限的患者中，中醫藥具有相當的臨床應用潛力和良好的安全性。
IMN屬於中醫“水腫病”範疇，一般認為以脾腎兩虛為本，可與風邪、水濕、濕熱、血瘀等兼夾。脾為後天之本，腎為先天之本。脾腎虧虛可導致實邪加重，進而影響氣、血、水的運行，實邪存在進一步加重脾腎虧虛。因此，補益脾腎，清除實邪是治療IMN的關鍵。在本研究中，兩名患者都有脾腎陽虛，水濕內停證。因此，兩名患者的處方包括生黃芪、白朮、茯苓、覆盆子補益脾腎；白花蛇舌草、大腹皮、土茯苓利濕洩濁；輔以莪朮、鬼箭羽、桂枝促進氣血運行，暢達三焦，助脾腎袪濕洩濁。根據患者自身差異，第1例增加活血利水之品，第2例加止咳化痰之品，符合辨證論治的特點。
在這兩個處方中均有一些常用的中草藥。黃芪是本方的君藥，具有調節免疫系統、抗氧化、抗炎、抗衰老等作用［19］。黃芪甲苷可以恢復補體膜攻擊複合物誘導的足細胞形態和細胞骨架丟失，並減少補體膜攻擊複合物誘導的JNK和ERK1/2的磷酸化，這可能是其可治療IMN的關鍵機制。白朮、茯苓、白花蛇舌草提取物具有免疫調節作用［21］［22］［23］。白朮提取物具有抗炎、抗腫瘤、促進胃腸運動等活性［23］。茯苓具有抗炎、抗氧化的作用，還能保護肝腎功能［22］。麻黃具有利尿、抗炎和抗病毒的作用［24］。桑白皮具有降糖、抗炎、減少蛋白尿的作用，還可改善STZ誘導的肥胖小鼠認知障礙和神經元損傷［25］。大腹皮可抗血栓形成，促胃腸運動［26］。土茯苓具有抗炎鎮痛作用，還能降低尿酸水平［27］。
在本研究中，2例患者持續中醫治療，分別隨訪52個月和95個月，最終獲得部分或完全緩解，病情穩定，至今無復發，無明顯不良反應或併發症。由此可得，給予這兩例患者中醫藥治療是有益的。然而，本研究也存在一定局限性。
首先，由於這兩名患者是多年前入院的，利妥昔單抗價格昂貴，且當時並沒有被推薦為一線藥物。儘管患者均接受了激素和多種免疫抑製劑治療，但均未接受過利妥昔單抗治療。此外，雖然2例患者的腎活檢均在北京三甲醫院完成，具有較高的可信度，但難以獲得清晰的彩色圖像，只能獲取其病理報告的詳細內容。此外，由於病例報告的局限性，這些結論需要通過大樣本量的高質量臨床研究進行證實。
值得注意的是，這些發現支持了中醫藥治療IMN合併KF是有效的，且經過長期的中藥治療後未出現明顯的不良反應。體現了補充與替代醫學的代表——中醫藥在IMN臨床應用的巨大潛力。
作者貢獻：#共同第一作者劉夢超和郭弋凡對這項工作的貢獻相同。劉夢超和郭弋凡起草稿件並對患者進行隨訪。霍延紅、向湉芃、劉志強參與了患者診斷和治療資料的收集，並進行了文獻檢索。趙文景參與了患者的治療和預後評估。李博提出了研究思路，並參與了論文修改。所有作者都閱讀並批准了最終稿件以供出版。
倫理聲明：作者對工作的所有方面負責，以確保與工作的任何部分的準確性或完整性相關的問題得到適當的調查和解決。本研究中進行的所有程序都符合機構和/或國家研究委員會的倫理標準和《赫爾辛基宣言》（2013年修訂）。本報告和任何相關圖片的發表均獲得了患者的書面知情同意。
數據可用性聲明：在本研究中產生或分析的所有數據均包含在本文中。
