There is a gradual unification of understanding in the treatment of nephrotic syndrome, i.e. most clinical scholars recognize that the combination of Chinese and Western medicine is both more effective than any one therapy alone. At present, standard hormone therapy with Chinese medicine is mostly used as a comprehensive treatment method. And refractory nephrotic syndrome is common in clinical practice. It includes frequently relapsing type (including hormone dependent type) and hormone ineffective type nephrotic syndrome. To understand what is refractory nephropathy, we must first understand hormone standard therapy and the responsiveness of nephrotic syndrome to hormones. The so-called standard hormone therapy is based on the conventional hormone therapy for primary nephrotic syndrome without a clear specific pathological diagnosis, which is commonly referred to as “standard hormone therapy”, and is usually carried out in three phases: ① Initial treatment phase: prednisone 1mg/(kg?d), orally, this phase of treatment 8 weeks in total. ② Slow reduction: After 8 weeks of high-dose hormone therapy, the dose should be reduced regardless of the efficacy. Every 1 to 2 weeks, reduce 10% of the original dose, gradually reduce the hormone to a small dose, i.e., about 0.5 mg/(kg?d), and take 2 days’ dose every other day in the morning. For patients with ineffective hormones, reduce the dose by 5 mg per week until it is discontinued. For those in remission, the drug can be continued for 1 to 2 weeks and then reduced by 10% per week to a maintenance dose for 1 to 2 months, and gradually reduced until discontinuation of the drug. (③) Maintenance treatment phase: When prednisone is reduced to a small dose (i.e., about 0.4 mg/(kg?d) every other day), it can be taken for 18 months or longer for frequent relapsers. The so-called refractory nephropathy refers to cases that are either ineffective, hormone dependent, or relapsed after the standard hormone therapy mentioned above (note: especially in pediatric patients, repeated relapses can bring parents to the verge of mental collapse, and most adult patients can barely tolerate it, one patient once said to me: Sun Bo, what have I done in my last life to make me suffer like this? (Hey ……). The frequently relapsing type of renal syndrome refers to those who have relapsed two or more times within six months or three or more times within a year after remission of renal syndrome by treatment; the hormone-dependent type refers to those who have some effect on hormone therapy but relapse during hormone withdrawal or within 14 days of hormone discontinuation; the hormone-ineffective type is those who do not respond to standard hormone therapy. Why do some patients with renal syndrome have good results with hormone therapy while others are “difficult to treat”? There are many reasons why renal syndrome is “difficult to treat”, and Chinese medicine believes that the deficiency of vital energy and the deficiency of both spleen and kidney are related. The course of the disease has been prolonged for a long time, and the origin of the disease is deficiency. The “Treatise on the Origin of Diseases” says: “Water diseases are caused by the deficiency of both spleen and kidney. Under the synergistic effect of pathological factors such as dampness, damp-heat or blood stasis, the disease develops due to the attack of external wind, cold and dampness. Western medicine believes that the following factors are related: (1) Infection factors: renal syndrome due to a large number of immunoglobulin lost from the urine, coupled with malnutrition and the application of hormones and cytotoxic drugs, the body’s immune function is low, the defense capacity is reduced, and caused by a variety of infections, such as viral, bacterial or fungal infections and other factors, induced by the recurrence of renal syndrome. Currently, it is believed that the infection factor is the primary factor for the frequent recurrence of renal syndrome. It may also be the main cause of hormone dependence. (2) Different pathological types, such as microscopic lesion type (MCD) hormone treatment efficiency can be as high as 90% or more, while the hormone efficiency of focal stage glomerulosclerosis (FSGS) is only about 20%. The effectiveness of hormone therapy for membranous nephritis (MN) and membranoproliferative nephritis (MPGN) is also not high. If the patient’s pathological type is FSGS, MN, MPGN, there is a possibility of poor hormone efficacy or even hormone resistance. (3) Irregular hormone administration: The hormone is not administered according to standard hormone therapy. Or the initial dose is insufficient, or the course of treatment is not continuous enough, or the withdrawal and reduction of drugs is too fast and violent, or the usage is improper, such as dividing the hormone into three oral doses, which can cause recurrent attacks or aggravation of renal syndrome. For example, we applied hormones to treat 99 cases of frequently recurring renal syndrome, and the recurrence rates of the high-dose group A (1mk/kg?d) and the low-dose group B (30-60mg/d), treated for 8 weeks, were 28,9% and 67,4% respectively within 1 year, with significant differences between them. Regulating the use of hormone is an effective way to reduce recurrence. (4) Hypercoagulable state and hyperlipidemia: Due to the leakage of large amount of protein from patients with nephrotic syndrome, enhanced synthesis in the liver, increased fibrinogen and factors V, VII, VIII and X, decreased antithrombin III level, decreased protein C and protein S activity, increased blood viscosity due to hyperlipidemia, unreasonable diuresis, and long-term use of large amount of glucocorticoids, patients therefore have a hypercoagulable state. Bed rest increases the possibility of thrombosis in the limbs. Currently, thrombosis and embolism have become one of the serious and fatal complications in patients with nephrotic syndrome. The most common is renal vein thrombosis, and it is also not uncommon to see limb vein thrombosis, inferior vena cava thrombosis, pulmonary vascular thrombosis or embolism, and even cerebrovascular thrombosis and coronary vascular thrombosis. Hyperlipidemia may return to normal with the resolution of proteinuria and the rebound of plasma albumin. Although there is an increase in LDL and cholesterol levels, HDL can sometimes be elevated, which some scholars believe can increase the incidence of cardiovascular complications, but some scholars believe that risk factors and protective factors exist simultaneously, and their effects on the body are difficult to determine. However, hyperlipidemia can increase blood viscosity, lead to thromboembolism, promote glomerular thylakoid cell proliferation and glomerulosclerosis. It leads to poor or ineffective hormone therapy. (5) Adrenocortical hypofunction: long-term repeated unscientific and irregular use of hormones causes adrenocortical hypofunction and decreases compensatory ability after stopping the drug, leading to recurrence of renal syndrome. (6) Other conditions: Those with combined renal tubular and interstitial renal damage usually have poor hormone efficacy. According to our clinical experience, in addition to pathological typing, poor hormone efficacy is usually associated with the following factors: (1) blood inosine >363,6mmol/L and azotemia; (2) persistent hypertension or moderate or higher hypertension; (3) high urinary FDP; (4) non-selective proteinuria; (5) more severe and persistent microscopic hematuria; (6) disease duration of more than 6 months; (7) age Those who are more than 45 years old are more difficult to treat because there are few microscopic lesions and early thylakoid hyperplasia above 45 years old. (1) Hormone and cytotoxic drug therapy (Note: hormone therapy is the most important, the key is in the details) The beginning of treatment: adult prednisone 1mg/(kg?d), weight according to the ideal weight, later on there are also calculated according to the actual weight, in order to emphasize individualized treatment. If the patient has abnormal liver function then treatment is switched to an equivalent dose of prednisolone. The total duration of this phase is 8 weeks. Dose reduction phase: After 8 weeks of high-dose hormone treatment, the dose should be reduced regardless of the efficacy (recently, there are people who believe that high-dose hormone treatment for 12 weeks is only effective). If the efficacy is better in 8 weeks and the disease improves, the hormone should be gradually reduced to a small dose, i.e., about 0.4 mg/(kg?d) for adults, and the 2-day dose should be taken every other day in the morning. Longer-term treatment is possible, usually about 8 months. If the patient has achieved complete remission during the initial treatment phase, the dose should be reduced very carefully and slowly, the smaller the dose, the slower the dose reduction and the longer the duration of the drug. If the first 8 weeks of high-dose hormone treatment does not provide any remission or even worsens, the dosage should be gradually reduced or even stopped. Switch to Chinese herbal medicine treatment. During the hormone reduction phase, due to the presence of Yin and Yang deficiency symptoms, the Yin and Yang deficiency type prescriptions in Chinese medicine can be used for the treatment. Continuing treatment phase: Depending on the response of the initial treatment phase, there are two types of continuing treatment: a) For those who only get partial remission with high-dose hormone treatment, prednisone can be taken for 8 months or longer when it is reduced to a small dose. If complete remission is obtained during the course of low-dose maintenance therapy, the original amount is taken for another 4 weeks after remission, and then slowly and regularly reduced to the maintenance amount (about 0.2mg/(kg?d) every other day for adults), and then gradually reduced to discontinuation after a period of discretionary maintenance depending on changes in the disease; if complete remission is still not achieved, cyclophosphamide (CTX) 0,2 is often added to 20ml of saline for intravenous injection every other day at this time The cumulative amount is ≤150mg/kg body weight. Or, add benzodiazepine (CLB) 0.2mg/(kg?d), divided into two oral doses, the cumulative amount ≤ 10mg/kg body weight. At this stage, due to the effect of CTX or CLB, the patient also shows the clinical manifestation of kidney yang deficiency and yin blood deficiency, we often add Chinese herbal medicines such as Xian Ling Spleen, Semen Cuscutae, Huang Jing, Chicken Blood Vine, Agaricus, etc. to warm the kidney and nourish the blood at the same time. b) After the initial treatment has achieved complete remission, prednisone is reduced to the maintenance level (this level is very easy for the patient to relapse), that is, every other morning 0.4mg/(kg?d) for a period of time, and then reduce the dosage very slowly until the drug is stopped. The whole course of treatment can be 2 to 3 years. The following basic principles should be followed in hormone therapy: ①The starting amount is sufficient. According to the initial treatment amount, i.e., about 1mg/(kg?d) for adults, the drug should be used for 8 to 12 weeks. If an adult is in remission for less than 8 weeks, the dosage can be reduced after 1 to 2 weeks of medication. ②Take off the drug slowly. Effective cases are reduced by 10% of the original dosage every 2-3 weeks, and when reduced to 20mg/d, it is easy to rebound and must be reduced carefully. ③The maintenance time should be long enough. When it is reduced to about 0.2mg/(kg?d), take it again for six months or longer. For abnormal liver function, prednisolone may be given, and the usage is the same as prednisone. Depending on the type of pathology and the degree of lesion, methylprednisolone shock therapy can also be used for the treatment of this disease. Cytotoxic drugs: ①Cyclophosphamide (CTX): It is the most commonly used cytotoxic drug at the dose of 100mg/d, 1 to 2 times orally. Or 200mg intravenously once every other day, or 1,0g intravenously, once a month. The cumulative dose is ≤150mg/(kg?d). It is believed that oral administration can still be effective when intravenous administration is not effective, which can be referred to. Side effects include gonadal suppression, bone marrow suppression, liver damage, hair loss, hemorrhagic cystitis, etc. ②Nitrogen mustard hydrochloride: It is still a cytotoxic drug with better efficacy in the treatment of nephrotic syndrome, but due to the side effects, this drug is now used sparingly. The dosage of nitrogen mustard hydrochloride is 1mg for the first time, after that, every other day, each increment of 1mg to 5mg each time, no more increase, and changed to 2-3 times a week, the cumulative total of the course of treatment is 1.5-2mg/kg, pay attention to check the blood picture during the use of the drug, when the white blood cells are lower than 4.0×109/L, promptly stop the drug. The common dosage of azelaic acid benzoate (CLB) is 0.1~0.2mg/(kg?d) orally at the beginning. The main side effects are bone marrow suppression, sperm deficiency, and chemical cystitis. Cyclosporin A: This drug can selectively inhibit T helper cells and T cytotoxic effector cells, and can be tried in refractory nephrotic syndrome where hormone and cytotoxic drugs are ineffective. The dosage is 5mg/(kg?d), divided into 2 oral doses, and the dosage is reduced after 2-3 months for about half a year. The high price and side effects have limited its application, especially the nephrotoxicity of this drug, such as causing interstitial nephritis and relapse after discontinuation of the drug, have also attracted attention. ④ Mycophenolate mofetil (primaquine): It is a new type of immunosuppressant used in clinical practice in recent years, with small side effects and insufficient clinical experience. The recommended usage is 1~2g/d, which is reduced to 0,5~1g/d after six months, and then used for six months with good efficacy. Due to its high price, its application is limited to some extent. Other drugs such as azathioprine and vincristine are still available, but they are less effective and have more side effects. Cytotoxic drugs are only used for microscopic lesion type and thylakoid recurrent and and type nephrotic syndrome, with hormone can improve the remission rate, if not contraindicated by hormone, generally do not prefer and apply cytotoxic drugs alone. (2) Symptomatic treatment Diuretic treatment: Select appropriate diuretics according to different clinical manifestations. For example, furosemide, anisodone, etc. Anticoagulation and lipid-lowering therapy: short-term application of small doses of heparin subcutaneously, especially for those with plasma albumin below 20g/L, routine application of heparin anticoagulation. In recent years, the clinical tendency is to apply low-molecular heparin. It has been found that low-molecular heparin not only has the anticoagulation, inhibition of thylakoid cell proliferation and slowing down of glomerular fibrosis effects of heparin, but also its side effects of causing bleeding are significantly lower than those of heparin. Aspirin can also be used for treatment, 50mg each time, 3 times a day. Or Pansentine 25-50mg each time, 3 times a day treatment. Once the complication of thromboembolism occurs, high-dose urokinase or streptokinase should be given promptly for thrombolytic therapy. Lipid-lowering therapy includes dietary therapy and drug therapy. The drugs are divided into four categories: statins, fibrates, bile acid binding resins and propofol. Studies have proved that statins have improved effects on various experimental nephropathies, inhibiting the proliferation of thylakoid cells, epithelial cells and thylakoid stroma; reducing the secretion of type IV collagen; reducing monocyte-macrophage infiltration and the expression of various inflammatory cytokines; significantly reducing proteinuria and delaying renal decompensation. It can also be added to the use of Chinese medicine to activate blood circulation and lower lipids and blood circulation. Reduction of proteinuria: Angiotensin converting enzyme inhibitors (ACEI) can be used, which can reduce proteinuria and have a protective effect on the kidney. Captopril (mercaptopropionic acid) 25mg 3 times a day can be used. Perindopril (Yashida) 4mg once a day. Benadryl (Lodinexin), 10mg once daily. (Note: When we wrote this article in 2001, we already recognized the nephroprotective effect of ACEI and the anti-protein effect, and our later experience is that Lodinexin is better than other drugs, of course, it is only personal experience) (3) Chinese medicine evidence-based treatment: For refractory kidney disease, it is mostly advocated to combine Western medicine treatment with Chinese medicine treatment. It can be treated according to different stages and clinical manifestations. For patients whose hormones are ineffective, Chinese medicine alone can be used for treatment. We observe that Chinese medicine can slow down the progression of the disease. Spleen and kidney yang deficiency: Dampness and turbidity are in the internal stagnation type. The symptoms include shaking white face, swelling all around the body, or accompanied by abdominal distension like a drum, chest tightness and shortness of breath, unfavorable urination or shortage of urine, cold form and limbs, poor appetite and loose stools, pale tongue, fat tongue, white greasy or thin white coating, and sunken and thin pulse. Most often seen in those who have not been treated with hormone therapy or in the initial stage of hormone therapy. The treatment is to warm the spleen and kidney, induce diuresis and reduce swelling. The formula is Zhen Wu Tang with Five Peel Drink plus and minus. Poria 12g, Rhizoma Atractylodis Macrocephalae 10g, Radix et Rhizoma Atractylodis 6g, Radix et Rhizoma Cao Guo 10g, Radix ginger 10g, Radix et Rhizoma Macrocephalae 15g, Radix et Rhizoma Mulberry 9g, Radix et Rhizoma Ginger 10g, Radix et Rhizoma Bupleurum 20g, Radix et Rhizoma Glycyrrhiza 5g. For those with shortness of breath and weakness, add 15g of Radix Codonopsis Pilosulae and 30g of Radix Astragali; if proteinuria is high, add 30g of Radix Astragali, 10g of Goldenseal and 10g of Sangchuan. Yin deficiency and fire type: mild swelling, excitement and agitation, insomnia and night sweating, flushing of both cheekbones, hairiness, acne, irritable heat in the five hearts, dry mouth and throat, red tongue with little fluid and fine pulse. Most often seen in the stage of extensive hormone therapy. Nourishing Yin and lowering fire. This formula is based on Er Zhi Wan combined with Da Yin Tonic Pill plus or minus. Radix et Rhizoma Drynariae 15g, Radix Rehmanniae 24g, Fructus Lycii 15g, Radix Medlar 15g, Fructus Chasteberry 12g, Radix et Rhizoma Bone 15g, Radix Zhi Mu 30g, Radix Tortoise (first decoction) 30g, Radix Phellodendron 10g. For heavy edema, add Radix et Rhizoma Bupleurum 30g, Radix Phellodendron 12g, Poria 12g, Radix Zedoariae 9g; for damp-heat, add Radix Phellodendron 9g, Radix Gentianae 12g, Radix Rehmanniae 9g, Radix Phellodendron 15g, Radix Phellodendron 10g. For Yin deficiency and heat toxicity, skin sores, add 15g of Panax notoginseng and 9g of Phellodendron. Yin and Yang deficiency: Floaters are prolonged and do not subside over time, with recurrent attacks, unfavorable urination, soft waist and knees, dizziness and tinnitus, dry mouth, bitterness and dryness of the throat, five hearts are hot, the limbs are not warm, the face is white, insomnia and night sweats, dreaming and spermatorrhea, the tongue is light with white fur, and the pulse is thin or late. Most often seen in prolonged illness and hormone reduction treatment stage. The treatment is to tonify both yin and yang and consolidate astringent and astringent sperm. This formula is based on Jisheng Kidney Qi Pill with Dihuang Drink. Radix Rehmanniae 24g, Rhizoma Dioscoreae 12g, Cornu Cervi Pantotrichum 12g, Poria 9g, Radix et Rhizoma Polygonati 6g, Plantago ovata 15g, Radix Achyranthes Bidentatae 15g, Radix Cistanches 12g, Rhizoma Bidentatae 15g, Semen Spleen 15g, Radix Bidentatae 12g, Radix Astragali 30g, Rhizoma Polygonati 10g. For heavy Yin deficiency, Radix et Rhizoma Polygonati can be removed and Radix Lycii 15g can be added; for blood stasis, Radix Salviae Miltiorrhizae 20g, Radix Safflower 10g, Rhizoma Chuanxiong 12g. 10g, Chuanxiong 12g. Spleen and kidney Qi deficiency type: withered face, swelling around the body, or edema is light, less breath and lazy speech, less food and loose stools, soreness and weakness of the waist and knees, short urine, light fat tongue with tooth marks on the side, white greasy or white smooth coating, sunken and weak pulse. This type is mostly seen in the maintenance treatment phase of hormone and the consolidation treatment phase of frequently recurrent nephrotic syndrome. The treatment is to tonify the spleen and benefit the kidney, and to resolve dampness by diuresis. The formula is Ginseng and Atractylodes Macrocephalae combined with Right Return Pill. Radix Codonopsis Pilosulae 15g, Atractylodes Macrocephala 15g, Poria Cocos 15g, Semen Coicis 20g, Lentil 15g, Rhizoma Polygonati 20g, Radix Rehmanniae 12g, Cortex Eucommiae 15g, Cornu Cervi Pantotrichum 12g, Fructus Lycii 15g, Semen Cuscutae 12g. In case of high urinary protein, Radix et Rhizoma Polygonati 10g, Rhizoma Polygonati 12g, Radix Astragali 30g; in case of blood stasis, Radix Safflower 10g, Radix Astragali 15g, Radix Salviae Miltiorrhizae 10g, Radix Angelicae Sinensis 12g. Liver and Kidney Yin deficiency: swelling of the face and lower limbs, soreness and weakness of the waist and knees, dizziness and tinnitus, sleeplessness, dry mouth and throat, short urine, dry stool, red or reddish tongue, thin white greasy or thin yellow coating, thin pulse or thin strings. The treatment is to nourish the liver and kidney, clear heat and promote water retention. The formula is Liu Wei Di Huang Wan with Pig Ling Tang. For patients with combined yang deficiency, add Duzhong 15g, Cuscuta 12g, Bupleurum 9g. For patients with ineffective hormones, the above-mentioned TCM treatment can be applied alone. For patients with effective hormones, the use of Chinese herbal medicine with treatment can improve the efficacy and reduce the recurrence of the disease.