Meng-chao Liu^a,, Yi-fan Guo^b,*, Yan-hong Huo^c, Tian-peng Xiang^b, Zhi-qiang Liu^b, Wen-jing Zhao^a,#,

Bo Li^a,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)

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)

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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