bubble_chart Overview

Nephrotic syndrome (NS) is not an independent disease but a group of clinical syndromes in glomerular diseases. Its typical manifestations include massive proteinuria (daily >3.5g/1.73m² body surface area), hypoalbuminemia (plasma albumin <30g/L), edema with or without hyperlipidemia. The diagnostic criteria should be massive proteinuria and hypoalbuminemia. Massive proteinuria is a characteristic of glomerular diseases and is relatively rare in renal vascular diseases or tubulointerstitial diseases. Since hypoalbuminemia, hyperlipidemia, and edema are all consequences of massive proteinuria, it is considered that the diagnostic criteria should primarily focus on massive proteinuria.

bubble_chart Etiology

Many diseases can cause injury to the glomerular capillary filtration membrane, leading to nephrotic syndrome. Two-thirds of adults and most children with nephrotic syndrome have primary causes, including primary glomerulopathy, acute and chronic glomerulonephritis, and rapidly progressive nephritis. Pathological diagnoses mainly include: minimal change disease, membranous glomerulonephritis (membranous nephropathy), mesangial capillary proliferative nephritis (membranoproliferative nephritis), and focal segmental glomerulosclerosis. Their relative incidence and characteristics are shown in Table 1. Secondary causes of nephrotic syndrome include infections, drugs (mercury, organic gold, penicillamine, heroin, etc.), toxins and allergies, tumors (solid tumors of the lung, stomach, colon, breast, and lymphomas, etc.), systemic lupus erythematosus, Henoch-Schönlein purpura, amyloidosis, and diabetes. One-third of adult cases and 10% of childhood cases of nephrotic syndrome can be attributed to secondary factors.

Table 1 Primary Glomerular Diseases Presenting as Nephrotic Syndrome

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	Minimal Change Disease	Focal Glomerulosclerosis	Membranous Nephropathy	Membranoproliferative Nephritis
				Type I	Type II
Incidence
Children	75%	10%	6.0%	10%
Adults	15%	15%	50%	10%
Clinical Features
Age	2–6, adults	2–6, adults	>35	5–15
Gender (Male:Female)	2:1	1.3:1	2:1	1:1
Nephrotic Syndrome	100%	90%	80%	60%
Asymptomatic Proteinuria		10%	20%	40%
Hematuria	20%	60～80%	35%	80%
Hypertension	10%	20%	25%	35%
Prognosis	Non-progressive	10 years	50% in 10～20 years	10～20 years	5～15 years
Serological Findings				C1q, C4, C3～C9 all decreased	C1q, C4 normal, C3～C9↓C3NF↑
HLA	B8, B12	-	DRW3	-	-
Renal Pathology
Light Microscopy	Normal	Focal Segmental Sclerotic Lesions	Diffuse Thickening of GBM	GBM Thickening, Cellular Proliferation, Lobulation
Immunofluorescence	Negative	IgM, C3	Fine Granular IgG, C3	Granular IgG, C3	Only C3
Electron Microscopy	Epithelial Foot Process Fusion	Epithelial Foot Process Fusion	Subepithelial Deposits	Mesangial and Subendothelial Deposits	Intramembranous Dense Deposits
Response to Corticosteroids	90%	15–20%	-	-

bubble_chart Clinical Manifestations

(1) Proteinuria In normal adults, the daily excretion of urinary protein does not exceed 150 mg. The production of massive proteinuria is due to abnormalities in the glomerular filtration membrane. The normal glomerular filtration membrane selectively filters plasma proteins, effectively preventing the majority of plasma proteins from passing through the glomerulus, with only minimal amounts entering the glomerular filtrate. Factors influencing protein filtration may include:

1. **Molecular Size of Proteins** The clearance of a substance by glomerular capillaries is inversely proportional to its effective molecular radius. The larger the molecular weight of a protein, the less it is filtered or completely blocked. Generally, plasma proteins with molecular weights between 60,000 and 70,000 Daltons (e.g., albumin) are filtered sparingly, while those with molecular weights exceeding 200,000 Daltons (e.g., α1-lipoprotein) cannot be filtered. Smaller plasma proteins (less than 40,000 Daltons), such as lysozyme, β2-microglobulin, and immunoglobulin light chains, can pass freely. This selective filtration based on molecular size is termed the **molecular selectivity barrier (mechanical barrier)**, determined by the ultrastructure of the glomerular filtration membrane. The glomerular filtration membrane consists of the endothelium, glomerular basement membrane (GBM), and epithelial layer. The gaps between endothelial cells measure 40–100 nm, allowing all soluble substances (including soluble immune complexes) to pass. The GBM comprises the lamina rara interna, lamina densa, and lamina rara externa, with filtration pores of 3.5–4.2 nm radius, acting as a coarse filter that permits partial passage of albumin (molecular radius 3.7 nm) and transferrin. The epithelial layer features slit diaphragms between podocyte foot processes, with pores of 4×14 nm, forming a fine filter that blocks molecules larger than albumin.

2. **Protein Charge** The inner and outer layers of the GBM, the endothelial and epithelial surfaces of glomerular capillaries, and the mesangial matrix are rich in glycosaminoglycans (e.g., heparan sulfate) and sialic acid, which confer a negative charge to the glomerular filtration membrane, creating an **electrostatic barrier**. Through the principle of like-charge repulsion, negatively charged proteins exhibit the lowest clearance, while positively charged ones have the highest. Studies show that in glomerular diseases, reduced sialic acid content in the GBM leads to increased filtration of negatively charged albumin, resulting in proteinuria. Beyond its electrostatic role, the glomerular negative charge field also maintains cellular morphology and capillary structure. Thus, pure electrostatic barrier loss is rare clinically, often accompanied by structural and functional abnormalities.

3. **Protein Shape and Flexibility** Due to the glomerular mechanical barrier, molecules with loose, linear conformations pass more readily than tightly packed, spherical ones.

4. **Hemodynamic Changes** The permeability of the glomerular filtration membrane is closely related to intraglomerular pressure and renal blood flow. Reduced plasma flow in the afferent arteriole and compensatory increases in hydrostatic pressure across the membrane are common hemodynamic adjustments in glomerular injury. This elevates the single-nephron filtration fraction, raising protein concentration at the efferent end above normal levels and increasing plasma protein diffusion across the glomerular capillary wall. Elevated intrarenal angiotensin II causes efferent arteriole constriction, raising intraglomerular capillary pressure and further promoting protein extravasation.

Charge barrier abnormalities (such as minimal change disease) primarily lead to albumin fistula disease, manifesting as selective proteinuria. Under light microscopy, the glomerular structure appears normal, but special staining techniques reveal a significant reduction in anions on the glomerular capillary wall. The increased albumin clearance fraction reflects the degree of charge barrier defect. Mechanical barrier abnormalities, such as membranous nephritis, membranoproliferative nephritis, or glomerular diseases accompanied by GBM generation and transformation, as well as structural changes like those seen in diabetes or hereditary nephritis, can exhibit significant structural alterations. These changes result in increased filtration of all plasma proteins, presenting as non-selective proteinuria.

(II) Hypoalbuminemia Hypoalbuminemia is observed in most patients with nephrotic syndrome, defined as a serum albumin level below 30g/L. The primary cause is the loss of albumin in the urine, but the two are not entirely parallel, as plasma albumin levels reflect the balance between albumin synthesis and catabolism. This is mainly influenced by the following factors: ① Increased hepatic synthesis of albumin. In cases of hypoalbuminemia and a reduced albumin pool, the absolute rate of albumin catabolism remains normal or even decreases. The liver compensates by increasing albumin synthesis. If the diet provides sufficient protein and calories, the liver can synthesize over 20g of albumin daily. Constitutionally robust individuals or those consuming a high-protein diet may not develop hypoalbuminemia. Some suggest that plasma colloid osmotic pressure may play a significant role in regulating hepatic albumin synthesis. ② Enhanced tubular catabolism of albumin. Normally, 10% of albumin synthesized by the liver is metabolized in the renal tubules. In nephrotic syndrome, due to increased uptake and catabolism of filtered proteins by the proximal tubules, intrarenal metabolism can rise to 16–30%. ③ Severe edema and reduced gastrointestinal absorption often lead to a negative nitrogen balance in nephrotic syndrome patients. Age, disease duration, chronic liver disease, and malnutrition can also affect plasma albumin levels. In nephrotic syndrome patients, a high-protein diet may increase urinary protein excretion without significantly raising plasma albumin levels, except in cases of severe malnutrition where concomitant use of angiotensin-converting enzyme inhibitors (reducing glomerular hyperfiltration) may allow a high-protein diet to increase plasma albumin concentration. Conversely, protein restriction reduces urinary protein excretion but has little to no effect on plasma albumin levels. This has led to a new perspective on dietary protein intake management for nephrotic syndrome patients.

Due to hypoalbuminemia, drug binding to albumin decreases, leading to elevated levels of free drugs in the blood, which can cause toxic reactions even at conventional doses. In hypoalbuminemia, reduced binding of arachidonic acid to plasma proteins promotes platelet aggregation and increases thromboxane (TXA₂), which exacerbates proteinuria and renal damage.

(III) Edema The presence and severity of edema correlate positively with the degree of hypoalbuminemia, though exceptions are not uncommon. The body has inherent mechanisms to counteract edema formation, regulated as follows: ① When plasma albumin concentration and colloid osmotic pressure decrease, lymphatic drainage of tissue fluid increases significantly, removing proteins from the interstitial fluid and lowering its colloid osmotic pressure, thereby maintaining a normal gradient between the two. ② Increased tissue fluid volume raises hydrostatic pressure, causing precapillary vasoconstriction, which reduces blood flow perfusion and capillary bed area, thereby lowering intracapillary hydrostatic pressure and inhibiting fluid extravasation into the interstitium. ③ Fluid leakage into the interstitium dilutes tissue fluid protein concentration while increasing plasma protein concentration. However, the lymphatic system's capacity to drain tissue fluid proteins is limited. When plasma colloid osmotic pressure drops further, the colloid osmotic pressure of tissue fluid cannot adjust accordingly, and the gradient between the two fails to remain normal, leading to edema.

Most patients with nephrotic syndrome edema have normal or even increased blood volume, which is not necessarily reduced. Plasma renin levels are normal or low, suggesting that sodium retention in nephrotic syndrome is due to impaired renal regulation of sodium balance, rather than activation of the renin-angiotensin-aldosterone system by hypovolemia. The occurrence of nephrotic syndrome edema cannot be explained by a single mechanism. Changes in blood volume may contribute to water and sodium retention and aggravate edema in some patients, but this does not account for all cases of edema. The exact underlying mechanism remains unclear and is likely related to dysfunction of certain intrarenal regulatory mechanisms.

(4) Hyperlipidemia The characteristics of lipid metabolism abnormalities in nephrotic syndrome include an increase in almost all plasma lipoprotein components, with significant elevations in total cholesterol (Ch) and low-density lipoprotein cholesterol (LDL-Ch), as well as increases in triglycerides (TG) and very-low-density lipoprotein cholesterol (VLDL-Ch). High-density lipoprotein cholesterol (HDL-Ch) concentrations may be elevated, normal, or decreased; the distribution of HDL subtypes is abnormal, with HDL3 increasing and HDL2 decreasing, indicating impaired maturation of HDL3. During the disease course, the increase in various lipid components occurs at different times, with Ch elevation typically appearing first, followed by phospholipids and TG. In addition to quantitative changes, qualitative changes in lipids also occur, with the ratios of cholesterol/phospholipid and cholesterol/triglyceride increasing in various lipoproteins. Apolipoproteins also often show abnormalities, such as a significant increase in ApoB and grade I elevations in ApoC and ApoE. The duration and severity of lipid abnormalities are closely related to the disease course and relapse frequency, and long-term hyperlipidemia may persist even after nephrotic syndrome enters the stage of convalescence. The mechanisms of lipid metabolism abnormalities in nephrotic syndrome include: ① Increased hepatic synthesis of Ch, TG, and lipoproteins. ② Impaired lipid clearance due to altered activity of lipid-regulating enzymes or changes in LDL receptor activity or number. ③ Increased urinary loss of HDL. In nephrotic syndrome, 50–100% of HDL's ApoA-I may be lost in the urine, and patients exhibit increased plasma HDL₃ and decreased HDL₂, indicating that HDL₃ is lost in the urine before it can transform into larger HDL₂ particles. The impact of hyperlipidemia in nephrotic syndrome patients on the incidence of heart blood vessel diseases depends mainly on the duration of hyperlipidemia, the LDL/HDL ratio, history of hypertension, smoking, and other factors. Long-term hyperlipidemia, especially with elevated LDL and decreased HDL, can accelerate the occurrence of coronary stirred pulse atherosclerosis and increase the risk of acute myocardial infarction. In recent years, the effects of hyperlipidemia on the kidneys have attracted considerable attention from researchers. The role of lipids in causing glomerulosclerosis has been confirmed in studies on endogenous hyperlipidemia. The mechanisms and influencing factors of glomerular injury caused by lipid metabolism disorders are complex and may involve the following: lipoprotein deposition in the glomeruli, lipoprotein deposition in the tubulointerstitium, LDL oxidation, monocyte infiltration, lipoprotein-induced cytotoxicity leading to endothelial cell injury, the effects of lipid mediators, and increased matrix synthesis due to lipids.

(5) Changes in Other Plasma Protein Concentrations In nephrotic syndrome, the concentrations of various plasma proteins may change. For example, serum protein electrophoresis shows elevated α2 and β globulins, while α1 globulin may be normal or decreased. IgG levels may significantly decline, whereas IgA, IgM, and IgE levels are often normal or elevated, though immunoglobulin changes are related to the primary disease. Deficiency of complement factor B in the alternative pathway can impair the body's opsonization of bacteria, which is one reason for the increased susceptibility to infections in nephrotic syndrome patients. Fibrinogen and coagulation factors V, VII, and X may increase; platelets may also show grade I elevation; antithrombin III may be severely reduced due to urinary loss; protein C and protein S concentrations are often normal or elevated, but their activity is decreased; increased platelet aggregation and elevated β-thromboglobulin may be signs of latent spontaneous thrombosis.

bubble_chart Treatment Measures

(1) Treatment of Primary Diseases Causing Nephrotic Syndrome

1. Glucocorticoid Therapy Glucocorticoids are used in kidney diseases primarily for their anti-inflammatory effects. They can reduce exudation during acute inflammation, stabilize lysosomal membranes, decrease fibrin deposition, and reduce capillary permeability, thereby lessening proteinuria. Additionally, they inhibit proliferative responses in chronic inflammation, lower fibroblast activity, and mitigate fibrosis caused by tissue repair. The therapeutic response of glucocorticoids in nephrotic syndrome largely depends on the pathological type, with minimal change nephropathy generally considered the most responsive.

Glucocorticoid preparations include: - Short-acting (half-life 6–12 hours): Hydrocortisone (20mg); - Intermediate-acting (12–36 hours): Prednisone (5mg), Prednisolone (5mg), Methylprednisolone (4mg), Triamcinolone (4mg); - Long-acting (48–72 hours): Dexamethasone (0.75mg), Betamethasone (0.60mg). Glucocorticoids are rapidly absorbed through the gastrointestinal tract, making tablets the most common dosage form. The initial dose is typically prednisone 1mg/(kg·d) for adults and 1.5–2mg/(kg·d) for children. After 8 weeks of treatment, responders should continue maintenance therapy with gradual dose reduction, usually by 10–20% of the original dose every 1–2 weeks. The lower the dose, the smaller and slower the reduction should be. The maintenance dose and duration vary by case, with the minimal dose that avoids clinical symptoms being ideal, preferably below 15mg/d. Adjustments are needed during maintenance for factors like weight changes, infections, surgery, or pregnancy. For cases unresponsive after 8 weeks of standard therapy, factors affecting efficacy (e.g., infections, edema-induced weight gain, renal vein thrombosis) should be excluded and promptly addressed. Intravenous glucocorticoid pulse therapy may be considered for patients with poor oral response, severe edema impairing absorption, severe nephrotic syndrome due to systemic diseases (e.g., SLE), or significant pathological findings (e.g., interstitial lesions, diffuse glomerular proliferation, crescent formation, fibrinoid necrosis). Pulse therapy doses: - Methylprednisolone: 0.5–1g/d for 3–5 days (clinically, smaller doses like prednisolone 240–480mg/d for 3–5 days are often used, switching to oral doses after 1 week). - Dexamethasone: 30–70mg/d (but beware of worsened fluid retention and hypertension).

Long-term glucocorticoid use can cause many side effects, sometimes severe. Glucocorticoid-induced protein catabolism may worsen azotemia, elevate uric acid, trigger gout, and accelerate renal decline. High doses may exacerbate hypertension or precipitate heart failure. Infections may present atypically, delaying diagnosis and allowing spread. Chronic use can worsen nephrotic syndrome-related bone disease, even causing avascular necrosis of the femoral head.

2. Cytotoxic Drugs For nephrotic syndrome that is unresponsive to hormone therapy, hormone-dependent, or recurrent, and where continued medication is difficult due to intolerance to the side effects of hormones, cytotoxic drug therapy may be attempted. Since such drugs often carry risks of gonadal toxicity, reduced immune resistance, and potential tumor induction, careful consideration should be given to the indications and treatment duration. For example, focal segmental glomerulosclerosis responds poorly to cytotoxic drugs and should not be selected. Among the commonly used drugs in clinical practice, cyclophosphamide (CTX) and chlorambucil (CB1348) are the most reliable in terms of efficacy. The dose of CTX is 2–3 mg/(kg·d), with a treatment course of 8 weeks. When the cumulative total dose exceeds 300 mg/kg, gonadal toxicity is more likely to occur. Chlorambucil is administered at 0.1 mg/(kg·d), divided into three oral doses, with an 8-week treatment course. A cumulative total dose of 7–8 mg/kg increases the risk of toxic side effects. For patients who relapse after remission, a second course of treatment is generally not recommended to avoid toxicity. For nephrotic syndrome caused by lupus nephritis or membranous nephritis, some advocate the use of CTX pulse therapy, with a dose of 12–20 mg/(kg·dose) administered once weekly for 5–6 doses. Subsequent dosing intervals are extended based on the patient’s tolerance, with a total cumulative dose of up to 9–12 g. The goal of pulse therapy is to reduce hormone dosage, lower infection complications, and improve efficacy, but the dose should be adjusted or avoided based on glomerular filtration function.

3. Cyclosporin A (CyA) CyA is a potent cellular immunosuppressant that has been used in recent years for the treatment of various autoimmune diseases. Currently, its efficacy is relatively well-established in clinical settings for minimal change disease, membranous nephropathy, and membranoproliferative glomerulonephritis. Compared to hormones and cytotoxic drugs, the greatest advantages of CyA are its reliable effectiveness in reducing proteinuria and improving hypoalbuminemia, without affecting growth and development or suppressing hematopoietic cell function. However, this drug also has several side effects, the most severe being renal and hepatic toxicity. The incidence of nephrotoxicity ranges from 20% to 40%, and long-term use can lead to interstitial fibrosis. Some cases may relapse after discontinuation of the drug. Therefore, it is not advisable to use CyA for long-term treatment of nephrotic syndrome, nor should it be easily considered as a first-line drug. The therapeutic dose of CyA is 3–5 mg/(kg·d), with the target trough blood concentration maintained at 75–200 μg/ml (whole blood, HPLC method). The drug usually takes effect within 2–8 weeks after administration, though individual responses vary significantly, and some patients may require a longer time to respond. Once efficacy is observed, the dose should be gradually reduced. During treatment, an increase in serum creatinine should raise suspicion of CyA toxicity. The treatment course typically lasts 3–6 months, and relapses may still respond to retreatment.

4. Traditional Chinese Medicine (TCM) Comprehensive Treatment Due to the poor response of some nephrotic syndrome cases to immunosuppressive therapy, with persistent massive proteinuria, TCM treatment may be considered for these patients in addition to symptomatic management. According to TCM theory, nephrotic syndrome during the edema stage primarily manifests as spleen-kidney deficiency and fluid retention in the interstitium, presenting as a deficiency in the root and excess in the branch. Therefore, treatment should focus on both attacking and supplementing, i.e., promoting diuresis and reducing swelling based on warming the kidneys and strengthening the spleen. Pattern identification and treatment include: ① Spleen-kidney yang deficiency type: Treatment principles involve warming the kidneys and invigorating the spleen, combined with promoting diuresis. Formulas such as True Warrior Decoction or Life-Relieving Kidney Qi Pill with modifications may be used. ② Spleen-kidney qi deficiency type: Treatment principles involve tonifying qi, strengthening the spleen, and warming the kidneys. Formulas such as Spleen-Strengthening Decoction or Stephania and Poria Decoction with comprehensive pulse and complexion analysis, along with White Atractylodes Powder, may be modified. ③ Kidney yin and yang deficiency type: Treatment principles involve dual supplementation of yin and yang. Formulas such as Life-Relieving Kidney Qi Pill or Rehmannia Decoction may be modified.

(II) Symptomatic Treatment

1. Treatment of Hypoalbuminemia

(1) Dietary Therapy: Patients with nephrotic syndrome are typically in a state of negative nitrogen balance. If a high-protein diet is consumed, it may shift to positive nitrogen balance. However, a high-protein intake in nephrotic syndrome patients can increase proteinuria, exacerbate glomerular damage, without raising plasma albumin levels. Therefore, the recommended daily protein intake is 1 g/kg, plus the amount of protein lost in urine daily. For every 1 g of protein consumed, 138 kJ (33 kcal) of non-protein calories must also be ingested. The protein provided should be high-quality, such as milk, eggs, fish, and meat.

(2) Intravenous Albumin Infusion: Since intravenously administered albumin is excreted in urine within 1–2 days and is costly, its use should be strictly indicated. Additionally, large doses of intravenous albumin carry side effects such as immunosuppression, hepatitis C, heart failure induction, delayed remission, and increased relapse rates. Indications for intravenous albumin include: ① Severe generalized edema unresponsive to intravenous furosemide. Administering albumin followed by furosemide (120 mg in 100–250 ml glucose solution, infused slowly over 1 hour) may restore diuretic efficacy in previously unresponsive patients. ② Clinical signs of hypovolemia after furosemide diuresis. ③ Acute renal failure due to renal interstitial edema.

2. Treatment of Edema

(1) Sodium-restricted diet: Edema itself indicates excessive sodium in the body, so restricting salt intake is of great significance for patients with nephrotic syndrome. The daily salt intake for normal individuals is 10g (containing 3.9g of sodium). However, since patients often experience loss of appetite due to bland food after sodium restriction, this affects their intake of protein and calories. Therefore, sodium restriction should be tailored to the patient's tolerance and should not compromise their appetite. A low-salt diet typically contains 3–5g of salt per day. For chronic patients, prolonged sodium restriction may lead to intracellular sodium deficiency, which should be noted.

(2) Application of diuretics: Based on their different sites of action, diuretics can be classified into: ① Loop diuretics: The primary mechanism of action is inhibiting the reabsorption of chloride and sodium in the ascending limb of the loop of Henle. Examples include furosemide (Lasix) and bumetanide, which are the most potent diuretics. The dose is 20–120 mg/d for furosemide and 1–5 mg/d for bumetanide. ② Thiazide diuretics: These mainly act on the thick ascending limb (cortical portion) of the loop of Henle and the early distal convoluted tubule, achieving diuretic effects by inhibiting the reabsorption of sodium and chloride while increasing potassium excretion. The usual dose of hydrochlorothiazide is 75–100 mg/d. ③ Potassium-sparing diuretics: These primarily act on the distal tubule and collecting duct and function as aldosterone antagonists. The typical dose of spironolactone is 60–120 mg/d. Since the efficacy of these drugs alone is relatively poor, they are often combined with potassium-excreting diuretics. ④ Osmotic diuretics: These can freely filter through the glomerulus without being reabsorbed by the renal tubules, thereby increasing the osmotic concentration in the tubules and inhibiting the reabsorption of water and sodium in the proximal and distal tubules to achieve diuresis. The usual dose of low-molecular-weight dextran is 500 mL every 2–3 days, and mannitol is 250 mL/d. Caution is advised in patients with renal impairment. For nephrotic syndrome patients, furosemide is the diuretic of choice, though the dose varies significantly among individuals. Intravenous administration is more effective: dissolve 100 mg of furosemide in 100 mL of glucose solution or 100 mL of mannitol and infuse slowly over 1 hour. Since furosemide is a potassium-excreting diuretic, it is often combined with spironolactone. Prolonged use of furosemide (7–10 days) may reduce its diuretic effect, sometimes necessitating an increased dose. It is advisable to switch to intermittent dosing, such as discontinuing for 3 days before resuming. For severe edema, it is recommended to combine and alternate diuretics with different sites of action.

3. Treatment of Hypercoagulable State

Patients with nephrotic syndrome are in a hypercoagulable state due to changes in clotting factors, especially when plasma albumin levels fall below 20–25 g/L, increasing the risk of venous thrombosis. Commonly used anticoagulants in clinical practice include:

(1) Heparin: Primarily activates antithrombin III (AT III). The usual dose is 50–75 mg/d via intravenous infusion, maintaining AT III activity above 90%. Some studies report that heparin may reduce proteinuria and improve renal function in nephrotic syndrome, though the mechanism remains unclear. Notably, heparin (MW 65600) can induce platelet aggregation. Low-molecular-weight heparin is also available for subcutaneous injection once daily.

(2) Urokinase (UK): Directly activates plasminogen, leading to fibrinolysis. The usual dose is 20,000–80,000 U/d, starting with a low dose and possibly co-administered with heparin via intravenous infusion. Monitor euglobulin lysis time, keeping it between 90–120 minutes. The main side effects of UK are allergic reactions and bleeding.

(3) Warfarin: Inhibits the synthesis of vitamin K-dependent factors II, VII, IX, and X in hepatocytes. The usual dose is 2.5 mg/d orally, with monitoring of prothrombin time to maintain it at 50–70% of normal levels.

(4) Dipyridamole: A platelet antagonist, with a usual dose of 100–200 mg/d. Generally, intravenous anticoagulation for hypercoagulable states lasts 2–8 weeks, after which warfarin or dipyridamole is administered orally.

For patients with venous thrombosis: ① Surgical removal of the thrombus. ② Interventional thrombolysis: A single injection of 240,000 U of UK into the renal vein via interventional radiology to dissolve the thrombus; this method can be repeated. ③ Systemic intravenous anticoagulation: Heparin combined with urokinase for 2–3 months. ④ Oral warfarin until nephrotic syndrome remission to prevent thrombus recurrence.

4. Treatment of Hyperlipidemia

Patients with nephrotic syndrome, especially those with multiple relapses, often experience prolonged hyperlipidemia, which persists even after the remission of nephrotic syndrome. In recent years, the impact of hyperlipidemia on the progression of kidney disease has been recognized. Additionally, some medications used to treat nephrotic syndrome, such as corticosteroids and diuretics, can exacerbate hyperlipidemia. Therefore, it is now widely recommended to use lipid-lowering drugs for hyperlipidemia in nephrotic syndrome. The available lipid-lowering drugs include: ① Fibric acids: Fenofibrate, 100mg three times daily; Gemfibrozil, 600mg twice daily. These drugs are more effective in lowering blood triglycerides than cholesterol. Side effects may occasionally include gastrointestinal discomfort and elevated serum transaminase levels. ② HMG-CoA reductase inhibitors: Lovastatin (Mevacor), 20mg twice daily; Simvastatin (Zocor), 5mg twice daily. These drugs primarily reduce intracellular cholesterol, lower plasma LDL-cholesterol levels, and decrease the production of VLDL and LDL by liver cells. ③ Angiotensin-converting enzyme inhibitors (ACEIs): Their main effects include reducing plasma cholesterol and triglyceride concentrations, increasing plasma HDL levels, and elevating the major apolipoproteins ApoA-I and ApoA-II, which accelerates the clearance of cholesterol from peripheral tissues. They also reduce LDL infiltration into the arterial intima and protect the arterial walls. Furthermore, ACEIs may reduce proteinuria to varying degrees.

5. Acute kidney failure treatment

When nephrotic syndrome is complicated by acute kidney failure, the treatment methods vary depending on the disease cause. For cases caused by hemodynamic factors, the main treatment principles include: rational use of diuretics, adrenal corticosteroids, correction of hypovolemia, and dialysis therapy. Hemodialysis not only controls azotemia and maintains electrolyte and acid-base balance but also rapidly eliminates water retention in the body. Acute kidney failure caused by renal interstitial edema shows faster recovery of renal function after the above treatments. When using diuretics, the following points should be noted: ① Timely use of diuretics: For nephrotic syndrome patients with acute kidney failure and severe hypoalbuminemia, using high-dose diuretics without replenishing plasma protein may worsen hypoalbuminemia and hypovolemia, further deteriorating renal failure. Therefore, diuretics should be administered only after replenishing plasma albumin (10–50g of human albumin intravenously per day). However, excessive replenishment of plasma albumin without timely use of diuretics may lead to pulmonary edema. ② Appropriate use of diuretics: Since nephrotic syndrome patients tend to have relative hypovolemia and hypotension, the use of diuretics should aim for a daily urine output of 2000–2500ml or a daily weight loss of around 1kg. ③ For patients with elevated plasma renin levels, the use of diuretics may further increase plasma renin levels after reducing blood volume, rendering the diuretic treatment ineffective and even worsening the condition. For such patients, diuretics should only be used after correcting hypoalbuminemia and hypovolemia to facilitate renal function recovery.

Nephrotic syndrome complicated by acute kidney failure is generally reversible. Most patients gradually recover renal function with treatment as urine output increases. A few patients may experience multiple episodes of acute kidney failure during the course of the disease but can still recover. The prognosis depends on the disease cause of acute kidney failure. Generally, rapidly progressive glomerulonephritis and renal vein thrombosis have a poorer prognosis, while cases solely related to nephrotic syndrome have a better prognosis.

bubble_chart Complications

(1) Infection The primary reasons for the decreased resistance to infection in patients with nephrotic syndrome are: ① Loss of large amounts of IgG in the urine. ② Deficiency of factor B (a component of the alternative complement pathway), leading to impaired immune opsonization of bacteria; ③ Malnutrition weakens the body's nonspecific immune response, resulting in compromised immune function. ④ Significant loss of transferrin and zinc in the urine. Transferrin is essential for maintaining normal lymphocyte function, and zinc ion concentration is related to thymosin synthesis. ⑤ Local factors. Pleural effusion, ascites, skin rupture due to severe edema, and dilution of local humoral factors with weakened defense mechanisms are all predisposing factors for infections in nephrotic syndrome patients. Before the Suwen era, bacterial infections were one of the leading causes of death in nephrotic syndrome patients, with severe infections mainly occurring in children and the elderly, while being less common in adults. Clinically common infections include primary peritonitis, cellulitis, respiratory infections, and urinary tract infections. Once an infection is diagnosed, immediate treatment should be initiated.

(2) Hypercoagulable State and Venous Thrombosis Nephrotic syndrome is associated with a hypercoagulable state, primarily due to alterations in blood clotting factors. These include decreased levels of factors IX and XI, and increased levels of factors V, VIII, X, fibrinogen, β-thromboglobulin, and platelets. Platelet adhesion and aggregation are enhanced, while antithrombin III and antiplasmin activity are reduced. Thus, the increase in procoagulant and proaggregatory factors, the decrease in anticoagulant and antiaggregatory factors, and impaired fibrinolysis mechanisms contribute to the hypercoagulable state in nephrotic syndrome. The use of antibiotics, hormones, and diuretics exacerbates venous thrombosis, as hormones act through coagulation proteins, while diuretics concentrate the blood and increase its viscosity.

In nephrotic syndrome, when plasma albumin falls below 2.0 g/dL, the risk of renal vein thrombosis increases. It is widely believed that thrombosis initially forms in small veins and then extends, eventually involving the renal vein. The incidence of renal vein thrombosis can be as high as 50% in membranous nephropathy patients, while in other pathological types, it ranges from 5–16%. Acute renal vein thrombosis may present as sudden onset of lumbago, hematuria, leukocyturia, increased proteinuria, and renal function deterioration. Chronic cases may be asymptomatic, but post-thrombotic renal stasis often worsens proteinuria or reduces treatment responsiveness. Due to thrombus detachment, extrarenal embolism symptoms, such as pulmonary embolism, are common. Tubular dysfunction, such as glycosuria, aminoaciduria, and renal tubular acidosis, may also occur. Definitive diagnosis requires renal venography, though noninvasive tests like Doppler ultrasound, CT, and MRI are also helpful. Elevated plasma β-thromboglobulin suggests underlying thrombosis, and increased α₂-antiplasmin is also considered a marker of renal vein thrombosis. The incidence of peripheral deep vein thrombosis is approximately 6%, commonly occurring in the deep veins of the calf, with only 12% showing clinical symptoms and 25% detectable by Doppler ultrasound. Pulmonary embolism occurs in 7% of cases, with 12% remaining asymptomatic. Other venous involvement is rare. Arterial thrombosis is even rarer, but in children, although the overall incidence of thrombosis is low, arterial involvement is as common as venous involvement.

(3) Acute kidney failure Acute kidney failure is the most severe complication of nephrotic syndrome and often requires dialysis treatment. Common disease causes include: ① Hemodynamic changes: Nephrotic syndrome is often accompanied by hypoproteinemia and vascular lesions, especially in elderly patients who frequently have renal arteriolosclerosis, making them highly sensitive to decreases in blood volume and blood pressure. Therefore, acute blood loss, vomiting, diarrhea leading to fluid loss, surgical injury, ascites, excessive diuresis, or the use of antihypertensive drugs can further lower blood pressure, causing a sudden reduction in renal perfusion. This leads to a decline in glomerular filtration rate (GFR) and, due to acute ischemia, results in swelling, degeneration, and necrosis of tubular epithelial cells, ultimately causing acute kidney failure. ② Renal interstitial edema: Hypoproteinemia can cause edema in surrounding tissues and similarly lead to renal interstitial edema. This edema compresses the renal tubules, increasing the hydrostatic pressure in Bowman's capsule of the proximal tubules and reducing GFR. ③ Drug-induced acute interstitial nephritis. ④ Bilateral renal vein thrombosis. ⑤ Vasoconstriction: Some nephrotic syndrome patients exhibit elevated renin levels during hypoproteinemia, which causes renal arteriole constriction and a decline in GFR. This condition is more common in elderly individuals with vascular lesions. ⑥ Concentrated protein casts obstructing the distal renal tubules: This may contribute to one of the mechanisms of acute renal failure in nephrotic syndrome. ⑦ Nephrotic syndrome is often accompanied by widespread fusion of glomerular epithelial foot processes and the disappearance of slit pores, significantly reducing the effective filtration area. ⑧ Rapidly progressive glomerulonephritis. ⑨ Urinary tract obstruction.

(4) Renal Tubular Dysfunction In nephrotic syndrome, renal tubular dysfunction is more common in children. The mechanism is believed to be due to the massive reabsorption of filtered proteins by the renal tubules, which damages the tubular epithelial cells. It often manifests as glycosuria, aminoaciduria, hyperphosphaturia, renal tubular potassium loss, and hyperchloremic acidosis. The presence of multiple renal tubular function defects often indicates a poor prognosis.

(5) Bone and Calcium Metabolism Abnormalities In nephrotic syndrome, the vitamin D-binding protein (Mw 65,000) and vitamin D complexes in the blood circulation are lost in the urine, leading to decreased levels of 1,25(OH)₂vitamin D₃ in the blood. This results in impaired intestinal calcium absorption and bone resistance to PTH. Consequently, nephrotic syndrome often presents with hypocalcemia, and sometimes osteomalacia or fibrous cystic osteitis caused by hyperparathyroidism. The bone dystrophy complicating renal failure in the progression of nephrotic syndrome is generally more severe than that caused by non-nephrotic uremia.

(6) Endocrine and Metabolic Abnormalities In nephrotic syndrome, thyroid-binding globulin (TBG) and corticosteroid-binding globulin (CBG) are lost in the urine. Clinically, thyroid function may appear normal, but serum TBG and T₃ levels are often decreased, while free T₃ and T₄, as well as TSH levels, remain normal. Due to the reduction of both CBG and 17-hydroxycortisol in the blood, the ratio of free to bound cortisol may change, and the tissue response to pharmacological doses of cortisol may differ from normal. Because ceruloplasmin (Mw 151,000), transferrin (Mw 80,000), and albumin are lost in the urine, nephrotic syndrome often leads to decreased serum concentrations of copper, iron, and zinc. Zinc deficiency can cause impotence, taste disorders, impaired wound healing, and compromised cell-mediated immunity. Persistent transferrin reduction may result in microcytic hypochromic anemia that is resistant to iron therapy. Additionally, severe hypoalbuminemia can lead to persistent metabolic alkalosis. For every 10 g/L decrease in plasma protein, plasma bicarbonate decreases by approximately 3 mmol/L.