lNTRODUCTlON

IgA nephropathy (IgAN) is one of the most common forms of primary nephritis and is characterized by mesangial proliferation and diffused IgA deposition in the mesangium[1]. In China, IgAN accounts for 45.26% of primary glomerulonephritis cases[2]. To date, corticosteroids, immunosuppressive agents, and symptomatic treatment have been the main therapeutic strategies, but the long-term treatment efficacy and safety need to be improved[3]. Preserving the renal function remains a major challenge for nephrologists[4]. A new target, sodium-dependent glucose transporters 2 (SGLT2), has reportedly shown efficacy in IgAN, but the high incidence of urinary tract infections has limited the use of SGLT2 inhibitors[5]. Resultingly, increasing attention has been paid to traditional Chinese medicine (TCM).

TCM has a long history in the treatment of kidney diseases in Eastern Asia[6]. Over recent decades, the efficacy and safety of TCM in treating kidney diseases have improved considerably[7,8], as documented studies have confirmed[9,10]. TCM thus has the potential to become an alternative treatment for IgAN[11,12]. However, high quality studies remain scarce. Professor Yan-Qin Zou, a National Chinese Medicine Master and the fourth-generation heir of the Bo-Xiong Fei family, is a wellknown nephrology expert in TCM. Professor Zou has been engaged in clinical work for nearly 60 years and has accumulated rich and unique experience in treating nephropathy using TCM methods[13].

Two pretty little naked men came: Most correctly, the little men are brownies (German: Heinzelm?nnchen), not elves, but the earliest translations of the tale into English designated the men as elves and thus they have stayed, however innaccurately over the years

When Sonali came home from school, I let her play for an hour before I told her the news. I wanted to savor8 the innocence9 of her not knowing Daddy was dead. When she heard Alan s plane had crashed and he was not coming home, she wailed10 a cry so deep and heartbreaking, a cry I pray I will never hear again from any living being. She sobbed11 for an hour straight, and then she looked me in the eyes and said, I am so sad. But I m not the saddest girl in the world. Some children have lost their mommy and their daddy, and I still have you.

Therapies that successfully delay the progression of IgAN remain limited. Once the condition has progressed to renal failure, there are no effective methods to stop the decline of kidney function[14]. This case report describes a patient suffering from renal failure due to IgAN. He received TCM treatment with improvement in renal function, thus demonstrating Professor Zou’s therapeutic strategy for treating IgAN. We hope this report could provide a valuable reference for the treatment of IgAN with TCM.

CASE PRESENTATlON

Chief complaints

Under light microscopy, a renal biopsy sample contained 25 glomeruli, among which there were 15 glomeruli with global sclerosis and no crescent. The remaining glomeruli were enlarged with approximately 90-110 cells/glomerulus. There were some mesangial areas with severe matrix hyperplasia with 2-3 cells/mesangium. The basement membrane was normal and the structure of capillary loop remained open. Complete sclerosis was seen in some glomeruli. Masson Stain was negative.

History of present illness

A 28-year-old man had positive urinary protein (++) and elevated Scr (149 μmol/L) test results in 2014. He underwent renal biopsy in February 2015 and was diagnosed with “IgAN, mesangial proliferative glomerulonephritis with sclerosis”. Since then, the patient had been taking losartan (100 mg daily) and ketosteril (α-ketoacid tablets; 2.52 g/3 times daily). He first visited the outpatient department at our hospital on June 1, 2017. At this visit, malaise, waist soreness, acid reflux, and bubbles in the urine were the main clinical manifestations. The patient also complained of frequent urination at night. His tongue was light red with a yellow coating, his pulse was slippery (meaning that his pulse was beating freely and smoothly like the movement of abacus beads), and his pharynx was red.

The patient visited the outpatient department again on August 2, 2017. At this visit, waist soreness and fatigue were resolved. The patient’s stomach discomfort was also alleviated. However, he still had a sore throat and spermatorrhea.

At his 3visit on September 28, 2017, serological indexes were stable. Clinical manifestations such as waist soreness, fatigue, pharynx discomfort, spermatorrhea, and epigastric discomfort were unchanged.

At the 4visit on October 26, 2017, serological indexes had decreased significantly. The patient’s epigastric discomfort had improved, but waist soreness remained.

At the patient’s 5visit on November 23, 2017, his clinical symptoms including waist soreness, fatigue, spermatorrhea, and epigastric discomfort were all resolved, and the serological indexes had also decreased.

History of past illness

The patient has no history of a relevant illness.

The Tsar bade them bring her before him and when he saw the linen he was struck with astonishment52 at its fineness and beauty. What wilt thou take for it, old woman? he asked.

Personal and family history

The patient has no family history of a similar illness.

Physical examination

Delaying the Progression of Renal Failure in Chronic Κidney Disease Project, No. JD2019SZ10 and Jiangsu Chinese Medicine Science and Technology Development Projects, No. YB201913.

Laboratory examinations

The serological and urinary indexes are shown in Table 1.

ONCE upon a time there was a poor husbandman1 who had many children2 and little to give them in the way either of food or clothing.3 They were all pretty, but the prettiest of all was the youngest daughter,4 who was so beautiful that there were no bounds to her beauty.5

Imaging examinations

Renal ultrasound showed no obvious abnormality.

Pathological analysis

The patient’s chief complaint was positive urinary protein and elevated serum creatinine (Scr) levels.

Now this strange friendship was observed by the Tanuki, a wicked, quarrelsome beast, who hated the peasant, and was never tired of doing him an ill turn

There were moderate lesions in the tubulointerstitium with indistinct tubular structure, no tubular atrophy, some swollen and degenerated tubular epithelial cells and some vacuolar degeneration. Focal fibrosis (40%) and more inflammatory cell infiltration could be seen in the interstitial area.

Immunofluorescence showed classic prominent IgA deposits.

FlNAL DlAGNOSlS

The patient’s TCM prescription included the following:(1) Taizishen () 15 g; (2) Shenghuangqi () 30 g; (3) Chaobaizhu (fried) 10 g; (4) Shengyiyiren () 30 g; (5) Fuling () 30 g; (6) Fushen () 30 g; (7) Jiangcan () 15 g; (8) Niubangzi () 10 g; (9) Huangshukuihua () 30 g; (10) Shiwei () 20 g; (11) Chuanduan () 15 g; (12) Sangjisheng () 15 g; (13) Yinchen () 30 g; (14) Tufuling () 30 g; (15) Shengpuhuang () 30 g; (16) Danshen () 20 g; (17) Chishao () 15 g; (18) Honghua () 10 g; (19) Wulingzhi () 30 g; (20) Shudahuang (cooked) 12 g; (21) Cheqianzi () 30 g; (22) Donglingcao () 10 g; (23) Yumixu () 30 g; (24) Bixie () 20 g; and (25) Walengzi () 40 g. A dose of Chinese medicinal herbs is decocted twice, and the juice is mixed. The herbs were taken twice a day.

TREATMENT

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Accordingly, the patient was diagnosed with IgAN (mesangial proliferative glomerulonephritis with sclerosis), Hass Ⅲ[15], M0E0S0T1[16].

At the patient’s 2visit, his clinical symptoms were resolved, and the serological indexes were improved. Professor Zou strengthened the therapy of clearing damp-heat and turbidity along with relieving pharynx discomfort and detoxifying in accordance with the abovementioned treatment principles. The patient’s prescription included the prescription from visit 1, but the amount of Tufuling () was increased to 50 g, Shudahuang (cooked) was increased to 20 g, and the following were added:(1) Zisuye () 30 g; (2) Tusizi () 15 g; (3) Xuanshen () 10 g; (4) Jinyinhua () 10 g; and (5) Baihuasheshecao () 30 g.

At the patient’s 3visit, Professor Zou strengthened the therapy of tonifying the kidney while maintaining the power of discharging turbidity and detoxifying. In addition to the initial prescription, Duzhong () 15 g; Huainiuxi () 10 g; Nvzhenzi () 20 g and Gouqizi () 20 g were added to tonify both kidney Yin and kidney Yang. Jixuecao () 30 g; Baihuasheshecao () 30 g and Shenggancao () 6 g were added to purge turbidity and aid detoxification, which are effective for reducing creatinine. Jiangcan (); niubangzi (); Donglingcao (); Bixie () and Walengzi () were removed when the abovementioned drugs were added at the third visit. Because Shudahuang (cooked) can also help to quicken the blood, transform stasis, and free the vessels, Chishao () and Honghua () were removed because there was enough power to promote blood circulation in the previous treatment.

Zhang YY wrote the paper; Chen YL and Yi L helped to collect the patient’s information; Gao Κ supervised Zhang YY while writing the paper and helped to revise the manuscript.

At the 5visit, the patient’s clinical symptoms were resolved, and the serological indexes were also decreased. Over the following 5 mo, Professor Zou prescribed the original treatment principles (Invigorating the spleen and tonifying the kidney, removing dampness and clearing turbidity, quickening the blood and transforming stasis, and freeing vessels and regulating collaterals).

OUTCOME AND FOLLOW-UP

The patient’s symptoms and discomfort were resolved. As shown in Figure 1, during the 1-year followup, renal function was improved as evidenced by the stable level of BUN, Scr, serum cystatin C and UA. As shown in Figure 2, urinary red blood cell remained negative, and urinary protein maintained negative or trace findings.

DlSCUSSlON

A typical clinical manifestation of IgAN is hematuria with or without proteinuria, hypertension, and impaired renal function[1]. Some patients with IgAN gradually progress to chronic renal failure 10-20 years after their diagnosis[17]. The efficacy of conventional therapy is limited because of side effects. Treatment using TCM is worth considering because it has shown good safety and therapeutic effects.

Wounded to death, he crept back through the village, and no man knew the old, old man to be the strong handsome youth who had run down the street an hour before

TCM pathogenesis and IgAN therapy

IgAN is in the edema and hematuria category in TCM[18]. In ancient times, doctors had a comprehensive theory on pathogenesis, diagnosis, and therapy for kidney diseases, as recorded in the Yellow Emperor’s Canon of Medicine Plain Conversation:“All dampness, swelling and turgidity is ascribed to the spleen.” Professor Zou proposes that IgAN pathogenesis is a mixture of deficiency and excess. Patients with IgAN are susceptible to outer pathogen infection because of lung Qi deficiency, in accordance with TCM theory. Qi deficiency in the kidney, spleen, and lung is the internal basis that contributes to damp-heat production as a pathological factor throughout the course of IgAN. Additionally, the long-term existence of the dampness pathogen suppresses Qi and leads to Qi stagnation. Qi stagnation makes it difficult for blood to circulate smoothly. In summary, the main cause of IgAN is derived from kidney, spleen and lung deficiency, which is accompanied by dampness, damp-heat, blood stasis and wind-pathogen. Improving deficiency and eliminating excess pathogenic factors constituted Professor Zou’s main clinical therapeutic strategy.

Case study

In this case, Professor Zou initially distinguished between deficiency syndrome and excess syndrome, giving consideration to both improving the deficiency and expelling pathogenic factors. The patient was treated on the basis of the disease stage and its course. In the early stage of therapy, pathogenic factors were prominent. Professor Zou strengthened the therapy of purging turbidity and detoxifying to gradually eliminate the damp-heat and blood stasis from the body. Malaise and waist soreness in the morning indicated kidney and spleen deficiency, while acid reflux, increased Scr and UA levels and bubbles in the urine demonstrated turbidity and dampness. She used treatment measures to tonify the kidney and spleen, purge turbidity and clear dampness, promote blood circulation and remove blood stasis. After the first treatment, the waist and stomach symptoms were relieved and serology indexes were improved. However, the patient’s throat discomfort and an increase in spermatorrhea demonstrated persisting kidney deficiency. At the following visits, the deficiency syndrome was the main target. Professor Zou strengthened the therapy of invigorating the kidney, spleen and lung to improve Qi. Throughout the disease treatment, Professor Zou focused on tonifying the kidney and spleen and clearing away damp-heat. After almost 6 mo of treatment, the patient’s symptoms were resolved, and Scr and UA levels were significantly lower. There was an increase in the UA level on January 18, 2018, which may have resulted from the previous cold or the patient’s overeating. These were not recorded and overall, the UA level trended downwards. Over the subsequent follow-up, renal function remained stable.

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Common compatibility and dosage

For herb selection, Professor Zou prefers mild and gentle herbs to invigorate the kidney and spleen because warm and hot drugs can easily hurt Yin, and greasy drugs can easily cause dampness stagnation. She uses drugs such as:(1) Taizishen (); (2) Shenghuangqi (); (3) Chaobaizhu (fried); (4) Shengyiyiren (), (5) Fuling (); and (6) Fushen (). Furthermore, the mechanism of kidney diseases in TCM theory is the disorder of Yin and Yang in the lower abdomen (Xia-jiao), and it is difficult for the herbs to reach the disease center because Xia-jiao is located in the lower part of the body[19]. However, the course of kidney disease is often long and persistent. Professor Zou used a combination of herbs and larger drug doses to balance Yin and Yang in the lower abdomen. The following herbs are often used for purging turbidity and detoxifying:(1) Huangshukuihua (); (2) Shiwei (); (3) Yinchen (); (4) Tufuling (); (5) Shudahuang (cooked); (6) Cheqianzi (); (6) Donglingcao (); (7) Yumixu (); (8) Bixie (); (9) Baihuasheshecao (); (10) Xuanshen (); and (11) Jinyinhua (). For proteinuria, drugs such as:(1) Jiangcan (); (2) Niubangzi (); and (3) Huangshukuihua () are commonly used[20-22]. Modern pharmacological research suggests that the major effects of herbal medicine are related to anti-inflammatory, antioxidative, antifibrotic and immunomodulatory pathways[6,12,23].

Characteristics and comparison with similar treatment

Most TCM practitioners consider that Qi and Yin deficiencies are the leading causes of IgAN and propose that the treatment of IgAN should be based on reinforcing Qi and replenishing Yin[24]. In contrast to the general TCM treatment, Professor Zou suggests that kidney deficiency is the most fundamental internal factor in the occurrence of IgAN and the treatment of IgAN should be based on tonifying the kidney and harmonizing other viscera. In addition, the spleen also plays an important role in the pathogenesis of IgAN. In TCM theory, the spleen governs the transportation and transformation of nutrients and water and it controls the function of spleen-qi to elevate food nutrients[17]. Tonifying the spleen is conducive to controlling proteinuria and improving metabolism. Recently, some powerful drugs, such as Leigongteng (), have been proven to be protective against kidney diseases[25]. However, although these powerful drugs may have obvious short-term effects, they may easily hurt healthy Qi. Professor Zou advocates mild drugs to gradually dissipate the pathogenic factors without side effects. Unique academic thought and exquisite herbal selection reflect the power of Professor Zou as a National Chinese Medicine Master.

Limitations

Herein, we report only one case, which has limited reference value to reflect Professor Zou’s treatment experience. However, we followed the patient for nearly 1 year and did not observe any subsequent disease relapse. Finally, 24-hour urine protein quantification is also an important laboratory indicator for IgAN, but we did not have access to these results because the patient did not undergo this test in the outpatient setting.

CONCLUSlON

IgAN is a prevalent type of glomerular disease in most Western and Asian countries. TCM therapy uses natural medicines that can reduce proteinuria and Scr and improve symptoms such as back pain in a long-term regimen. Professor Zou is a TCM specialist in treatment of IgAN. Her main therapeutic strategies for treating this disease focus on improving deficiency and eliminating excess pathogenic factors. This case provides a specific method and an effective reference for clinical application of TCM to treat IgAN. Our findings indicate that TCM can play an important role in the treatment of IgAN and is worth consideration as a worldwide treatment option.

The symptoms that were present at the patient’s first visit are described in TCM as kidney and spleen deficiency, dampness, turbidity, blood stasis, and collateral disharmony. After differentiation, Professor Zou initiated TCM therapy, namely by invigorating the spleen and tonifying the kidney, removing dampness and clearing turbidity, quickening the blood and transforming stasis, and freeing vessels and regulating collaterals.

We thank Li W for editing the English text of a draft of this manuscript and Sun PC for helping to revise the manuscript.

At the 4visit, Professor Zou strengthened the therapy to tonify the kidney and clear the pharynx, adding Duanlonggu () 40 g; Duanmuli () 40 g; Gouji () 20 g and Tusizi () 15 g to the last prescription.

On admission, the patient’s blood pressure was 120/80 mmHg, and no abnormalities were detected during the physical examination, including the cardiopulmonary system. There was no edema in either lower limb.

Informed written consent was obtained from the patient’ parents for publication of this report and any accompanying images.

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The authors declare that they have no conflict of interest.

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8. Threw him with all her might against the wall: The earliest versions of the story have the princess committing an act of violence which breaks the spell instead of the now famous kiss. Most often the frog is thrown against the wall, but in some versions he is beheaded or his skin is burnt. Sometimes, simply sleeping in the princess bed is sufficient to break the spell. Maria Tatar notes that passion rather than compassion34 leads to a happy ending to this tale (Tatar 1988).

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

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Ying-Yu Zhang 0000-0002-6684-3989; Yan-Lin Chen 0000-0002-7663-729X; Lan Yi 0000-0002-7600-3000; Kun Gao 0000-0003-3236-4944.

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