Treatment of High-Risk Idiopathic Membranous Nephropathy with Huaier Granules and RASi: A Case Series

Abstract

Huaier Granules, an aqueous extract preparation of Trametes robiniophila Murr, has been verified effective in treating various malignant tumors. Many agents used for membranous nephropathy, including cyclophosphamide and rituximab (RTX), were initially developed for cancer therapy. However, no previous studies have explored its application in adult idiopathic membranous nephropathy (IMN). This case series analyzed clinical data of 2 high-risk IMN patients admitted to our hospital from 2023 to 2026. All patients were confirmed by renal biopsy and anti-phospholipase A2 receptor (anti-PLA2R) antibody testing. They received combined therapy of Huaier Granules plus renin-angiotensin system inhibitors (RASi) as the basic treatment. After over 12 months of treatment, laboratory results showed negative anti-PLA2R antibody levels; 24-hour urinary protein, serum albumin and estimated glomerular filtration rate (eGFR) were improved compared with baseline. Case 1 was followed up for 25 months and Case 2 was followed up for 21 months. Case 1 achieved complete clinical remission and Case 2 partial remission. No obvious adverse reactions related to Huaier Granules were observed, with good patient tolerance. This regimen may provide a new adjuvant therapeutic strategy for clinical management of IMN.

Introduction

Membranous nephropathy(MN), a prevalent autoimmune glomerular disease, can affect individuals across all age groups and stands as one of the primary etiologies of nephrotic syndrome in adults. Notably, the identification of phospholipase A2 receptor (PLA2R) as the core target antigen of MN has brought about revolutionary advancements in the precise diagnosis of the disease, optimization of treatment strategies, and disease monitoring, thereby significantly advancing progress in clinical practice and basic research within this field.¹

In clinical testing, anti-PLA2R antibodies can be detected in the serum of the vast majority of membranous nephropathy (MN) patients, and this antibody has become one of the core biomarkers for MN diagnosis.¹

Current clinical evidence indicates that, glucocorticoids, alkylating agents, CNI, and new-generation biological agents targeting CD20-positive lymphocytes have demonstrated favorable efficacy in controlling proteinuria in patients apart from RASis.^2–4 In China, many patients favor traditional Chinese medicine due to their recognition of its clinical efficacy, as it enables them to avoid the adverse effects associated with glucocorticoids, immunosuppressive agents and rituximab (RTX), traditional Chinese medicine also plays a favorable therapeutic role in this regard.^5,6

Huaier Granule is a single-component herbal preparation consisting only of huaier mycelium. The chemical composition of Huaier as a traditional Chinese medicine is complex. Its main active components are proteoglycans and polysaccharides, and it also contains various fungus-derived compounds such as sterols, ketones, alkaloids, and minerals.⁷

Huaier Granules exhibit broad-spectrum immunomodulatory activity on both the innate and adaptive immune systems, acting on a variety of immune cells including macrophages, dendritic cells, natural killer cells, T lymphocytes, and B lymphocytes.⁸ Huaier regulates processes ranging from the expression of damage-associated molecular patterns to the activation and maturation, proliferation and differentiation of immune cells, antibody production, the expression of cytokines and chemokines, and even intracellular signal transduction in terminally differentiated cells.⁸

The case series describes two patients with membranous nephropathy treated with Huaier granules, suggesting that this drug may serve as a potential novel therapeutic option for patients with membranous nephropathy and providing relevant indirect clinical evidence.

We report 2 high-risk MN cases treated with Huaier Granules., accompanied by nearly 2-year follow up.

According to the recommendations of previous KDIGO 2021 guidelines, both patients were classified as high-risk idiopathic membranous nephropathy. All of them had 24-hour urinary protein excretion >3.5 g/d, failed to achieve a ≥50% reduction in proteinuria after RAS inhibitor therapy, and presented with serum albumin <25 g/L.⁹ After receiving a tolerable dose of renin-angiotensin system inhibitors (RASi) for more than 1 month, the nephrotic syndrome of both patients showed no remission.

Materials and Methods

Criteria for Complete Remission: 24-hour urinary protein <0.3 g/day, normal serum albumin, and stable renal function. Criteria for Partial Remission: 24-hour urinary protein reduced to <3.5 g/day or decreased by ≥50% from the peak level, accompanied by improved or normal serum albumin and stable renal function.

Immunological remission was defined as anti-PLA2R antibody levels < 14 RU/mL, while seronegativity was set at antibody concentrations < 2 RU/mL.

Test results were obtained for Case 1 at baseline and at 2, 4, 6, 8, 11, 23, and 25 months; Test results were obtained for Case 2 at baseline and at 2, 6, 13, 16,18 and 21 months.

Dosage Regimen: One packet (10 g) three times daily: 10 g per administration, 3 times daily. Medications were dispensed according to the follow‑up schedule. Huaier Granules were administered for 25 months in Case 1 and 21 months in Case 2.

Results

The baseline characteristics of the two cases are shown in Table 1.

Table 1.

Baseline Clinical and Pathological Characteristics of MN Patients (N=2)

Patient No.	Case 1	Case 2
Age at renal biopsy, yrs	61	52
MN Grading	Early MN	Early MN
Age at Huaier Granule initiation, yrs	61	52
Sex	Male	Male
SBP, mmHg	140	132
DBP, mmHg	85	95
BMI, kg/m2	24.2	21.8
eGFR, mL/min per 1.73 m2	102.46	117.06
UTP, g/d	6.24	7.31
Alb, g/L	24.9	24.2
Hb, g/L	148	165
Total duration of Huaier application, month	25	21
PLA2R Ab (IgG), RU/mL	43.1	51.4
Observation period, month	25	21
RASi	Valsartan	Candesartan cilexetil tablets

Information of Case 1

Medical History

Male, 61 years old. He was diagnosed with early-stage membranous nephropathy by renal biopsy on October 25, 2023. He had a 6-year history of hypertension, with the highest blood pressure reaching 180/100 mmHg. There was no history of diabetes or coronary heart disease. He suffered a lumbar compression fracture 2 years ago. No family hereditary diseases were reported.

Clinical Findings of Case 1

This 61-year-old male patient was admitted to the hospital on October 24, 2023 due to bilateral lower extremity edema for 2 months. Two months ago, the patient developed bilateral lower extremity edema without obvious inducement, accompanied by increased foamy urine. There was no hematuria, frequent urination, urgent urination, or painful urination. No nausea, vomiting, chest distress, dyspnea, fever, arthralgia, photosensitivity, alopecia, or oral ulcer was observed.

Assistant Examinations and Diagnostic Assessment of Case 1

Pre admission assistant examination showed urinary immunoglobulin kappa light chain: 385 mg/L, urinary immunoglobulin lambda light chain: 236 mg/L, total protein: 45.4 g/L, albumin: 24 g/L, urea: 8.40 mmol/L, creatinine: 62 μmol/L, uric acid: 288 μmol/L, immunoglobulin G: 5.15 g/L, immunoglobulin A: 2.49 g/L, immunoglobulin M: 1.09 g/L, serum immunoglobulin kappa light chain: 1.52 g/L, serum immunoglobulin lambda light chain: 0.87 g/L, and anti-phospholipase A2 receptor antibody (IgG): 8.9 RU/mL. He was diagnosed with early-stage membranous nephropathy by renal biopsy on October 25, 2023.

Therapeutic Intervention of Case 1

After October 28, 2023, he continued regular medication treatment, including valsartan and amlodipine, atorvastatin, and calcium carbonate D3. He started taking Huaier Granules around November 24, 2023 after 1 month of treatment with RASi.

Follow-Up and Outcomes of Case 1

The PLA2R antibody was 43.1 RU/mL at baseline and basically turned negative after 11 months. The serum albumin (ALB) was 24.9 g/L at baseline. After 11 months of treatment, the serum albumin returned to normal within one year. The 24-hour urinary protein was 6.24 g/day at baseline and remained at a low level and eventually decreased to 0.53 g/day after 25 months. The estimated glomerular filtration rate (eGFR) remained at a relatively high level throughout the course. All results were shown in Figure 1.

Figure 1.

From baseline of case 1, the changes in plasma PLA2R antibody (phospholipase A2 receptor antibody), serum albumin (ALB), 24-hour urinary protein (UTP), and estimated glomerular filtration rate (eGFR) were assessed over time (months) with the combination of Huaier granules and RASi treatment. The first dashed line indicates the initiation time of Huaier Granule.

Information of Case 2

Medical History

Male, 52 years old. On June 7, 2024, he underwent renal biopsy at a local hospital, which confirmed early Idiopathic Membranous Nephropathy (IMN). He also had simple right renal cyst, fatty liver, abnormal diagnostic imaging findings of the lungs, and a history of upper limb injury surgery.

Clinical Findings of Case 2

The 52-year-old male patient was admitted to the hospital on May 24, 2024 due to facial edema for half a month and bilateral lower extremity edema for 3 days. Half a month ago, the patient developed facial edema without obvious cause or predisposing factors. The patient had no other discomfort, so he ignored it and did not seek medical treatment. Three days ago, he noticed bilateral lower extremity edema accompanied by increased foamy urine, with no joint pain, no skin rash, and no decreased urine output.

Assistant Examinations and Diagnostic Assessment of Case 2

Routine urine examination revealed 4+ proteinuria and 3+ occult blood. Serum albumin was 24.4 g/L, and total cholesterol was 8.2 mmol/L. On June 7, 2024, he underwent renal biopsy at a local hospital, which confirmed early Idiopathic Membranous Nephropathy (IMN).

Therapeutic Intervention of Case 2

He started to take Huaier Granules on August 14, 2024 after treatment of RASi for more than 1 month. His medication list included candesartan cilexetil tablets, furosemide, compound amino acid capsules, probucol, dipyridamole tablets, vitamin D tablets, and Huaier Granules.

Follow-Up and Outcomes of Case 2

The PLA2R antibody was 51.4 RU/mL at baseline and antibody basically turned negative after 13 months. The serum albumin (ALB) decreased (around 20 g/L at baseline) and reached 28.8 g/L after 16 months. After 21 months, the albumin level rose to 33.2 g/L. During the treatment period, the 24-hour urinary protein was 7.31 g/day at baseline. It reached 6.15 g/day after 16 months. After 21 months, the 24-hour urinary protein decreased to 3.46 g/day. The increase in serum albumin and the decrease in 24-hour urinary protein excretion was synchronous with the seroconversion of anti-PLA2R antibody to negative. The estimated glomerular filtration rate (eGFR) remained stable during the whole period fluctuating from above 100 mL/min/1.73m² before October 14, 2024 to 95.08 mL/min/1.73m². After 21 months, the estimated glomerular filtration rate (eGFR) reached 98.32 mL/min/1.73m². All results were shown in Figure 2.

Figure 2.

From baseline of case 2, the changes in plasma PLA2R antibody (phospholipase A2 receptor antibody), serum albumin (ALB), 24-hour urinary protein (UTP), and estimated glomerular filtration rate (eGFR) were assessed over time (months) with the combination of Huaier granules and RASi treatment. The first dashed line indicates the initiation time of Huaier Granule.

Safety

No adverse reactions occurred in either of the two cases in this study; the only complaint from both patients was the bitter taste of the medication. During the entire follow-up period, the patients did not develop any complications of nephrotic syndrome, such as acute kidney injury, thrombosis and embolism, or severe infection.

Discussion

We firstly describe two patients with high-risk membranous nephropathy who achieved immunological and clinical remission after treatment with Huaier Granule. Immunological remission in membranous nephropathy is typically observed within 6 months. Current randomized controlled trials for MN, including the MENTOR, RI-CYCLO, and STARMEN studies, have reported immunological remission at approximately 3 to 6 months, with a follow-up duration of 2 years for each study.^10–12In contrast, as our treatment approach is based on traditional Chinese medicine, immunological remission was achieved after month 11 in Case 1 and month 13 in Case 2. We have also followed up these MN patients for 2 years, and the follow-up is still ongoing.

Case 1 nearly achieved complete clinical remission, while Case 2 attained partial clinical remission, demonstrating some evidence of efficacy and safety with Huaier Granules. Spontaneous remission is mostly observed in patients with low‑to‑intermediate risk membranous nephropathy (MN), characterized by proteinuria below 4–6 g/day and PLA2R antibody levels below 40 RU/mL. In contrast, our patients were classified as high‑risk, with proteinuria > 6 g/day and antibody levels above 40 RU/mL. Additionally, serum albumin levels were less than 25 g/L. Since no reduction in proteinuria to less than 50% of baseline was observed within six months, the likelihood of spontaneous remission was extremely low. Meanwhile, both patients had high-risk membranous nephropathy and showed no remission during the first year. It is highly unlikely that the effect was attributable to RAS inhibitors.

In addition, urinary protein in membranous nephropathy itself is characterized by considerable fluctuations. Nevertheless, serum albumin remained stable with an overall upward trend, and both patients ultimately achieved clinical remission.

High safety and good tolerability. Huaier Granules is a traditional Chinese medicine preparation with a low incidence of side effects. Mild gastrointestinal reactions (such as nausea and abdominal distension) are occasionally reported, and most of these reactions can resolve spontaneously without the need for drug discontinuation. Compared with other immunomodulatory drugs, it has less impact on liver and kidney function, making it suitable for long-term treatment. It is particularly suitable for patients with weak physical conditions who cannot tolerate high-dose Western medicines.⁸ No adverse reactions occurred in either of the two cases in this study; the only feedback from the patients was the bitter taste of the medication.

Meanwhile, previous studies have also shown that Huaier possesses potential anticancer effects and has been confirmed to inhibit the growth of cancer cells in various types of cancer.¹³ Additionally, Huaier can suppress the proliferation of breast cancer stem cells, induce programmed cell death, and reverse the characteristics of breast cancer stem cells by regulating multiple key signaling pathways.¹³ The efficacy of Huaier Granules, an aqueous preparation of Huaier extract, has been evaluated in the treatment of various cancers, such as hepatocellular carcinoma and gastric cancer.¹³

Many agents used for membranous nephropathy, including cyclophosphamide and rituximab (RTX), were initially developed for cancer therapy. Prior to this, there were no reports of Huaier Granules being used in the treatment of IMN. This case series is the first to report the therapeutic effects of Huaier Granules in two MN patients, demonstrating its efficacy and safety to a certain extent. Neither of the two patients developed complications such as thrombosis, embolism, infection, or acute kidney injury during the entire course of treatment, which may be related to the immunomodulatory effect of Huaier Granules.

Limitations

In the future, the approach may be attempted in high‑risk IMN patients, but confirmation through larger, well‑designed prospective studies is warranted.

Conclusion

Huaier Granules exhibit potential therapeutic effects that warrant further investigation in the treatment of high-risk MN without serious adverse effects.

Funding Statement

This study received no financial support.

Data Sharing Statement

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Ethical Approval

It has been reviewed and approved by the Ethics Committee of Qilu Hospital of Shandong University. The ethical review approval number is: Ethical Approval No. S2020-409-03. No additional institutional approval is required for the publication of the details of this case series.

Informed Consent

The patients provided written informed consent for the publication of the cases report and all accompanying images. Copies of the written consent documents can be provided to the Editor-in-Chief for review if required.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no conflicts of interest in this work.