I. Treatment of the primary disease causing nephrotic syndrome
1.Glucocorticoid treatment
Glucocorticoids are used in kidney diseases mainly for their anti-inflammatory effects. It can reduce the exudation in acute inflammation, stabilize the lysosomal membrane, reduce fibrin deposition, reduce capillary permeability and reduce urinary protein leakage; in addition, it can also inhibit the proliferative reaction in chronic inflammation, reduce fibroblast activity and mitigate fibrosis due to tissue repair. The efficacy response of glucocorticoids in nephrotic syndrome depends to a large extent on its pathological type, and it is generally believed that only the efficacy of microscopic lesions nephropathy is most certain.
The hormone preparations are short-acting (half-life 6-12 hours): hydrogenated prednisone (20 mg); medium-acting (12-36 hours): prednisone (5 mg), prednisolone (5 mg), methylprednisolone (4 mg), fluoxyprednisolone (4 mg); long-acting (48-72 hours): dexamethasone (0.75 mg), betamethasone (0.60 mg). The hormone can be absorbed rapidly through the gastrointestinal tract, so tablets are the most commonly used dosage form. The first treatment dose is usually 1mg/(kg・d) of prednisone and 1.5-2mg/(kg・d) for children. After 8 weeks of treatment, those who are effective should be maintained, and then the dose should be gradually reduced, generally by 0%-20% of the original dose every 1-2 weeks, and the smaller the dose, the smaller the decreasing amount and the slower the speed.
The maintenance amount and maintenance time of hormone varies from case to case, and the minimum dose used without clinical symptoms is the degree, and less than 15mg/d is satisfactory. The hormone dosage is adjusted in case of weight change, infection, surgery and pregnancy during the maintenance phase. In cases where regular treatment is ineffective after more than 8 weeks, factors affecting the efficacy, such as infection, weight gain due to edema and renal vein thrombosis, need to be excluded and should be diagnosed and treated as promptly as possible. For patients with poor response to oral hormone therapy, high edema affecting the absorption of hormone in the gastrointestinal tract, severe nephrotic syndrome caused by systemic diseases (such as systemic lupus erythematosus); patients with obvious pathological changes such as interstitial lesions, diffuse glomerular hyperplasia, crescent formation and vascular fibrinoid necrosis, intravenous hormone shock therapy can be given.
The dose of shock therapy is 0.5-1g/d of methylprednisolone for 3-5 days, but according to clinical experience, a small to medium dose therapy is generally used, i.e. 240-480mg/d of prednisolone for 3-5 days, and then changed to oral dose after 1 week. This can reduce the side effects such as infection caused by high-dose hormone shock, and the clinical effect is not affected. The corresponding dose of dexamethasone shock is 30-70mg/d, but attention should be paid to side effects such as aggravated water and sodium retention and hypertension.
Long-term application of hormones can produce many side effects, sometimes quite serious. The high protein catabolic state caused by hormones can aggravate azotemia, contribute to the increase of blood uric acid, trigger gout and aggravate renal hypoperfusion. High doses can sometimes exacerbate hypertension and promote heart failure. The symptoms of infection may not be obvious when hormones are applied, which can especially delay the diagnosis and spread the infection. Long-term application of hormones can aggravate the bone disease of nephrotic syndrome and even produce aseptic ischemic necrosis of femoral neck.
2.Cytotoxic drugs
Nephrotic syndrome that is ineffective in hormone therapy, or hormone-dependent or recurrent type, and difficult to continue medication due to intolerance of hormone side effects can be treated with cytotoxic drugs on a trial basis. Since these drugs have the risk of gonadotoxicity, reducing human resistance and inducing tumors, they should be carefully controlled in terms of indications and course of treatment. If focal segmental glomerulonephritis responds poorly to cytotoxic drugs, it should not be used. CTX is administered at a dose of 2-3 mg/(kg・d) for 8 weeks and is prone to gonadotoxicity when the cumulative total exceeds 300 mg/kg. Phenylbutyrate 0.1mg/(kg・d), divided into 3 oral doses, for 8 weeks, is prone to toxic side effects when the cumulative total amount reaches 7-8mg/kg. The second dose is not recommended for those who have relapsed after remission to avoid poisoning. For nephrotic syndrome caused by lupus nephritis and membranous nephritis, some people advocate the use of CTX shock therapy at a dose of 12mg-20mg/(kg/time) once a week for 5-6 times, and later extend the dosing interval according to the patient’s tolerance, and the total dose can be 9-12g. The purpose of shock therapy is to reduce the amount of hormone, reduce the complications of infection and improve the efficacy, but it should be selected according to The dose should be chosen according to the glomerular filtration function or contraindicated.
3.Cyclosporine A (CyA)
CyA is an effective cellular immunosuppressant, which has been used in the treatment of various autoimmune diseases in recent years. At present, the clinical efficacy of CyA is more certain in microscopic lesions, membranous nephropathy and membranoproliferative nephritis. Compared with hormones and cytotoxic drugs, the biggest advantage of CyA is that it is reliable in reducing proteinuria and improving hypoproteinemia, and does not affect growth and development and inhibit hematopoietic cell function. However, this drug also has a variety of side effects, the most serious of which are nephrotoxicity and hepatotoxicity. The incidence of nephrotoxicity is 20%-40%, and long-term application can lead to interstitial fibrosis. Individual cases are prone to relapse after discontinuation of the drug. The therapeutic dose of CyA is 3-5mg/(kg・d), and the trough value of blood concentration is 75-200μg/ml (whole blood, HPLC method), and it usually takes 2-8 weeks to take effect, but individual patients need longer time to take effect. If the blood creatinine rises during the course of treatment, the patient should be alerted to the possibility of CyA toxicity. The course of treatment is usually 3-6 months, and it can still be effective for relapse.
4.Chinese medicine comprehensive treatment
As some nephrotic syndrome does not respond well to immunosuppressive therapy, a large amount of protein is continuously lost from the urine. For these patients, in addition to symptomatic treatment, Chinese medicine can be tried. According to the theory of Chinese medicine, in the edema stage, the main manifestation is the deficiency of both spleen and kidney and the accumulation of water and fluid in the interstitial tissue, which is a manifestation of the original deficiency and the actual symptoms. The treatment is based on the following principles
(1) Spleen and kidney yang deficiency type, the treatment is to warm the kidney and strengthen the spleen, and at the same time to promote water. The formula can be added and reduced by Zhen Wu Tang and Ji Sheng Kidney Qi Wan.
(2) Spleen and kidney qi deficiency type: the treatment is to benefit qi, strengthen the spleen and warm the kidney, the formula can be used to strengthen the spleen drink or Fangji Fu Ling Tang with Ginseng and Atractylodes.
(3) Deficiency of both yin and yang in the kidney: the treatment is to tonify both yin and yang, and the formula can be Ji Sheng Kidney Qi Pill and Di Huang Drink plus or minus.
Symptomatic treatment
1.Treatment of hypoalbuminemia
(1) Diet therapy: Patients with nephrotic syndrome usually have a negative nitrogen balance, and if they can consume a high protein diet, it is possible to turn to a positive nitrogen balance. However, the intake of high protein in patients with nephrotic syndrome will lead to an increase in urinary protein and aggravate glomerular damage without an increase in plasma albumin level. Therefore, the recommended daily protein intake is 1 g/kg, plus the amount of protein lost in the urine daily, and for every 1 g of protein intake, 138 kJ (33 kcal) of non-protein calories must be consumed at the same time. The protein supplied should be high-quality protein, such as milk, eggs and fish, meat.
(2) Intravenous drip albumin: Since intravenous input of albumin is lost from urine via kidney in 1-2 days, and it is expensive. In addition, large amounts of intravenous application of albumin have side effects such as immunosuppression, hepatitis C, induced heart failure, delayed remission and increased relapse rate, so when applying intravenous albumin should strictly grasp the indications for.
①In patients with severe systemic edema and intravenous tachyphylaxis cannot achieve diuretic effect, intravenous tachyphylaxis (120mg of tachyphylaxis, added to 100-250ml of glucose solution and slowly dripped for 1 hour) immediately after intravenous albumin can often achieve good diuretic effect even for those who were not effective in tachyphylaxis.
(②After the use of tachypnea diuresis, clinical manifestations of plasma volume deficiency appear.
③Those with acute renal failure due to interstitial edema.
2.Treatment of edema
(1) Sodium-restricted diet: edema itself indicates excessive sodium in the body, so it is important to limit salt intake in patients with nephrotic syndrome. The daily salt intake of normal people is 10g (containing 3.9g of sodium), but patients often lose their appetite due to tasteless diet after sodium restriction, which affects the intake of protein and calories. Therefore, the sodium-restricted diet should be tolerated by the patient without affecting his appetite, and the salt content of the low-salt diet is 3-5 g/d. In chronic patients, a prolonged sodium-restricted diet can lead to intracellular sodium deficiency, which should be noted.
(2) Application of diuretics: According to different action sites, diuretics can be divided into.
(1) collaterals diuretics: the main mechanism of action is to inhibit the reabsorption of chloride and sodium in the ascending branches of the medullary collaterals, such as enzymes (tachyphylaxis) and bumetanide (butanuric acid) are the most powerful diuretics. The dose is 20-120mg/d for tachyphylaxis and 1-5mg/d for butralamide.
②Thiazide diuretics: mainly act on the thick-walled segment of the ascending branch of medullary collaterals (cortical part) and the anterior segment of the distal convoluted tubule, achieving diuretic effect by inhibiting the reabsorption of sodium and chloride and increasing the excretion of potassium. The usual dose of dihydrochlorperazine is 75-100mg/d.
(iii) Sodium retention diuretics: mainly act on the distal tubules and collecting ducts, and are aldosterone antagonists. The usual dose of Anserine is 60-120mg/d. The effect of such drugs alone is poor, so they are often used in combination with potassium-retention diuretics.
④ Osmotic diuretic: It can be freely filtered by the glomerulus without being reabsorbed by the renal tubules, thus increasing the osmotic concentration of the renal tubules and preventing the reabsorption of water and sodium by the proximal and distal tubules to achieve diuretic effect. The usual dose of low molecular dextran is 500Ml/2-3d and mannitol 250Ml/d. Note that it is used with caution in patients with impaired renal function. Tachyphylaxis is the preferred diuretic drug for patients with nephrotic syndrome, but the dose varies greatly among individuals; intravenous medication is more effective by adding 100mg of tachyphylaxis to 100Ml of glucose solution or 100ml of mannitol and slowly administering it for 1 hour; tachyphylaxis is a potassium-removal diuretic, so it is often used in combination with ambrisentin. After long-term application of tachyphylaxis (7-10 days), the diuretic effect is weakened, and sometimes it is necessary to increase the dose, and it is better to change to intermittent dosing, i.e. after 3 days of discontinuation. It is recommended to choose the combination of diuretics with different action sites alternatively for severe edema.
3.Treatment of hypercoagulable state
Patients with nephrotic syndrome are in a hypercoagulable state due to changes in coagulation factors, especially when plasma albumin is lower than 20-25g/L, which means there is a possibility of venous thrombosis. Currently, the following anticoagulant drugs are commonly used in clinical practice.
(1) heparin: mainly through the activation of antithrombin III (ATIII) activity. Commonly used dose of 50-75mg/d IV, so that ATIII vital units in more than 90%. Some literature reported that heparin can reduce proteinuria and improve renal function in nephrotic syndrome, but its mechanism of action is not clear. Of note is that heparin (MW65600) can cause platelet aggregation. Small molecular weight heparin is still available for subcutaneous injection once daily.
(2) Urokinase (UK): directly activates fibrinogen, leading to fibrinolysis. The commonly used dose is 20-80,000 U/d. Start with a small dose and use it with heparin as an intravenous dose. Monitor the time of euglobulin lysis so that it is between 90-120 min. the main side effects of UK are allergy and bleeding.
(3) Warfarin: inhibit the synthesis of vitamin K-dependent factors II, VII, IX and X in hepatocytes. commonly used dose 2.5mg/d orally, monitor the prothrombin time so that it is between 50%-70% of normal.
(4) Pansentine: a platelet antagonist, commonly used dose is 100-200mg/d. The general hypercoagulable state of intravenous anticoagulation for 2-8 weeks, later changed to warfarin or pansentine orally.
In the presence of venous thrombosis.
(1) Surgical removal of thrombus.
(2) Interventional thrombolysis. A one-time injection of UK 240,000 U into the renal artery via interventional radiation to dissolve the renal vein thrombus, this method can be repeated.
(3) Systemic intravenous anticoagulation. That is, heparin plus urokinase, the course of treatment for 2-3 months.
(4) Oral warfarin until the nephrotic syndrome is relieved to prevent thrombus re-formation.
4.Treatment of hyperlipidemia
Patients with nephrotic syndrome, especially those with multiple relapses, have a long duration of hyperlipidemia, which persists even after the nephrotic syndrome is in remission. In recent years, the influence of hyperlipidemia on the progression of renal disease has been recognized, and some drugs for the treatment of nephrotic syndrome, such as adrenocorticosteroids and diuretics, can aggravate hyperlipidemia, so the use of lipid-lowering drugs for hyperlipidemia in nephrotic syndrome is now mostly advocated. The optional lipid-lowering drugs are.
(1) fibric acid drugs (fibricacids): fenofibrate (fenofibrate) 3 times a day, 100mg each time, gemfibrozil (gemfibrozil) 2 times a day, 600mg each time, its lowering blood triglyceride effect is stronger than cholesterol. This drug occasionally has gastrointestinal discomfort and elevated serum transaminases.
(2) Hmg-CoA reductase inhibitors: lovastatin (Meldonium), 20mgBid, simvastatin (Sulforaphane), 5mgBid; these drugs mainly make intracellular Ch decrease, lower plasma LDL-Ch concentration, reduce hepatocyte production of VLDL and LDL.
(3) Angiotensin-converting enzyme inhibitor (ACEI): The main effects are to reduce plasma Ch and TG concentration; to increase plasma HDL, and its main apolipoproteins ApoA-Ⅰ and ApoA-Ⅱ are also increased, which can accelerate the removal of Ch from surrounding tissues; to reduce the infiltration of LDL into the intima of arteries, and to protect the arterial wall. In addition, ACEI can also reduce the effect of proteinuria to varying degrees.
5.Acute renal failure treatment
The treatment of nephrotic syndrome combined with acute renal failure varies depending on the cause. For those with hemodynamic factors, the main treatment principles include: reasonable use of diuretics, adrenocorticosteroids, correction of hypovolemia and dialysis therapy. Hemodialysis not only controls azotemia and maintains electrolyte-acid-base balance, but also removes water retention in the body more quickly. Acute renal failure due to interstitial edema can recover more quickly after the above treatment.
When using diuretics, attention should be paid to.
(1) Timely use of diuretics: in nephrotic syndrome with acute renal failure with severe hypoproteinemia, the use of high-dose diuretics without plasma protein supplementation will aggravate hypoproteinemia and hypovolemia and worsen renal failure. Therefore, diuretics should be administered after plasma albumin supplementation (10-50 g of human albumin intravenously daily). However, an excessive amount of plasma albumin supplementation without timely diuretics may lead to pulmonary edema.
(2) Appropriate use of diuretics: Since patients with nephrotic syndrome have a tendency to relative blood volume deficiency and hypotension, diuretics should be used at a daily urine volume of 2000-2500ml or a daily weight loss of about 1kg.
(3) In patients with increased plasma renin level, the use of diuretics will make the plasma renin level higher after the decrease of blood volume, and diuretic treatment will not only be ineffective but also aggravate the disease. Only after correction of hypoproteinemia and hypovolemia can diuretics be used in these patients to help restore renal function.
Nephrotic syndrome combined with acute renal failure is generally reversible, and most patients gradually recover renal function with increased urine output under treatment. In a few patients, acute renal failure occurs several times in the course of the disease and can be recovered. The prognosis is related to the etiology of acute renal failure, generally speaking, the prognosis of acute glomerulonephritis and renal vein thrombosis is poor, while the prognosis of those associated with nephrotic syndrome alone is better.