Nephrotic syndrome (NS) can be caused by a variety of etiologies and is characterized by a group of clinical syndromes with increased glomerular basement membrane permeability, manifested by massive proteinuria, hypoproteinemia, high edema, and hyperlipidemia.
I. Etiology
There are three major categories: primary, secondary and hereditary. Primary NS belongs to primary glomerular disease and has multiple pathological types of composition.
Classification
Children
Adolescents
Middle-aged and elderly
Primary
Minimal lesion nephropathy
Tegumentary proliferative glomerulonephritis
Microsomal lesion nephropathy
Focal segmental glomerulosclerosis
Mesenteric capillary glomerulonephritis
Membranous nephropathy
Secondary
Allergic purpura nephritis
Hepatitis B virus-associated nephritis
Systemic lupus erythematosus nephritis
Systemic lupus erythematosus nephritis
Allergic purpura nephritis
Hepatitis B virus-associated nephritis
Diabetic nephropathy
Renal amyloidosis
Myelomeningocele nephritis
Lymphoma or solid tumor nephropathy
II. Clinical manifestations
The most basic features of NS are massive proteinuria, hypoproteinemia, (high) edema and hyperlipidemia, the so-called “three highs and one low”, and other metabolic disorders as a group of clinical syndromes.
1. Massive proteinuria
Massive proteinuria is the most important clinical manifestation of NS patients and the most basic pathophysiological mechanism of nephrotic syndrome. Under normal physiological conditions, the glomerular filtration membrane has molecular and charge barriers, resulting in increased protein content in primary urine, and when it far exceeds the proximal tubular reabsorption, large amounts of proteinuria are formed. On this basis, any factors that increase intra-glomerular pressure and lead to high perfusion and high filtration (such as hypertension, high protein diet or large amounts of plasma protein infusion) can aggravate the excretion of urinary protein.
2. Hypoproteinemia
Plasma albumin drops to <30 g/L. A large amount of albumin is lost from the urine in NS, promoting an increase in compensatory hepatic synthesis of albumin and renal tubular breakdown. Hypoalbuminemia occurs when the increase in hepatic albumin synthesis is not sufficient to overcome the loss and catabolism. In addition, hypoalbuminemia is exacerbated in patients with NS by decreased diet, inadequate protein intake, malabsorption, or loss due to gastrointestinal mucosal edema.
In addition to reduced plasma albumin, certain immunoglobulins (e.g. IgG) and complement components of plasma, anticoagulant and fibrinolytic factors, metal-binding proteins and endocrine-binding proteins may also be reduced, especially in massive proteinuria, severe glomerular pathological damage and non-selective proteinuria. Patients are prone to complications such as infection, hypercoagulation, micronutrient deficiency, endocrine disruption and immune deficiency.
3.Oedema
Hypoalbuminemia and decreased plasma colloid osmotic pressure in NS cause water to enter the tissue interstitium from the vascular lumen, which is the basic cause of edema in NS. Recent studies have shown that about 50% of patients have normal or increased blood volume and normal or decreased plasma renin levels, suggesting that certain primary intrarenal sodium and water retention factors play a role in the mechanism of NS edema.
4. Hyperlipidemia
The cause of NS combined with hyperlipidemia has not been fully elucidated. Hypercholesterolemia and/or hypertriglyceridemia, with increased serum concentrations of LDL, VLDL and lipoprotein (alpha), often coexist with hypoproteinemia. Hypercholesterolemia is mainly due to increased hepatic synthesis of lipoproteins, but reduced catabolism in the peripheral circulation also plays a partial role. Hypertriglyceridemia, on the other hand, is primarily due to impaired catabolism, with increased hepatic synthesis as a secondary factor.
III. Diagnosis
1. The diagnostic criteria for nephrotic syndrome (NS) are
(1) Urine protein greater than 3.5g/d;
(2) Plasma albumin less than 30g/L;
(3) edema;
(4) hyperlipidemia. Among them, ①② two are necessary for diagnosis.
2, NS diagnosis should include three aspects
(1) Confirm the diagnosis of NS.
(2) Confirm the etiology: first exclude secondary and hereditary diseases in order to confirm the diagnosis of primary NS; it is best to perform a renal biopsy to make a pathological diagnosis.
(3) Determine the presence or absence of complications.
IV. Differential diagnosis
1.Allergic purpura nephritis
Prevalent in adolescents, with typical cutaneous purpura, often symmetrically distributed in the distal extremities, mostly with hematuria and/or proteinuria 1 to 4 weeks after the rash.
2. Systemic lupus erythematosus nephritis
Prevalent in middle-aged women and adolescents. Immunological examination reveals a variety of autoantibodies, as well as multisystemic damage, which can be clearly diagnosed.
3. Hepatitis B virus-associated nephritis
Most commonly seen in children and adolescents, the main clinical manifestation is proteinuria or NS, and the common pathological type is membranous nephropathy. Diagnosis is based on: ① positive serum HBV antigen; ② glomerulonephritis, and exclude secondary glomerulonephritis; ③ renal biopsy sections to find HBV antigen.
4.Diabetic nephropathy
Prevalent in middle-aged and elderly, commonly in diabetic patients with a disease duration of more than 10 years. The history of diabetes mellitus and characteristic fundus changes can help in the differential diagnosis.
5. Renal amyloidosis
Renal amyloidosis is a part of systemic multi-organ involvement. Primary amyloidosis mainly involves the heart, kidney, digestive tract (including the tongue), skin and nerves; secondary amyloidosis is often secondary to chronic septic infection, tuberculosis, malignant tumors and other diseases, mainly involving the kidney, liver and spleen and other organs. Renal amyloidosis often requires renal biopsy to confirm the diagnosis.
6.Myelomeningocele nephropathy
Patients may have characteristic clinical manifestations of multiple myeloma, such as bone pain, increased serum monoclonal globulin, positive protein electrophoresis M band and urine periprotein, and abnormal proliferation of plasma cells (more than 15% of nucleated cells) with qualitative changes in bone marrow image. NS can be seen in multiple myeloma involving glomeruli, and the above characteristic manifestations of myeloma are helpful for differential diagnosis.
V. Complications
Complications of NS are important factors affecting the long-term prognosis of patients and should be actively prevented and treated.
1.Infection
It is usually not necessary to apply antibiotics to prevent infection during hormone therapy, otherwise it will not only fail to achieve the purpose of prevention, but may induce fungal secondary infection. Once the infection is found, the antibiotics that are sensitive to the causative organism, strong and non-nephrotoxic should be used to actively treat the infection, and those with clear foci of infection should be removed as soon as possible. When severe infection is difficult to control, the reduction or discontinuation of hormone should be considered, but it should be decided according to the specific situation of the patient.
2.Complications of thrombosis and embolism
It is generally believed that when plasma albumin is less than 20g/L (less than 25g/L in idiopathic membranous nephropathy) anticoagulation treatment can be given by subcutaneous injection of sodium heparin (low molecular heparin can also be used) or oral warfarin. Anticoagulation can be supplemented with antiplatelet agents, such as dipyridamole or aspirin orally. Urokinase or streptokinase should be given as early as possible (best within 6 hours, but still expected to be effective within 3 days) for systemic or local thrombolysis, along with anticoagulation, which should generally be continued for more than six months. Both anticoagulation and thrombolytic therapy should be used to avoid bleeding due to drug overdose.
3.Acute renal failure
Acute renal failure complicated by NS can be life-threatening if not handled properly, but most patients can be expected to recover if given the right treatment in time. The following measures can be taken.
(1) Loop diuretics should be given in larger doses to flush out the blocked tubular pattern of the kidney if loop diuretics are still effective;
(2)If hemodialysis diuresis is ineffective and dialysis indication has been reached, hemodialysis should be given to maintain life and appropriate dehydration after supplementation of plasma products to reduce interstitial renal edema;
(3) Treatment of primary pathology should be actively treated because of its pathological type, which is mostly microscopic nephropathy;
(4) Alkalinization of urine can be done orally with sodium bicarbonate to reduce the formation of tubular type.
4.Disorders of protein and fat metabolism
It is often difficult to completely correct metabolic disorders before NS remission, but the amount and structure of protein and fat in the diet should be adjusted to strive to minimize the effects of metabolic disorders. Currently, a number of drugs are available for the treatment of protein and fat metabolism disorders. For example, ACEI and angiotensin II receptor antagonists can reduce urinary protein; some studies suggest that the Chinese herbal medicine Astragalus can promote hepatic albumin synthesis, and may also have the effect of reducing hyperlipidemia. Lipid-lowering drugs can be chosen from cholesterol-lowering-based hydroxymethylglutarate monoacyl coenzyme A (HMG-CoA) reductase inhibitors, such as lovastatin and other statins; or triglyceride-lowering-based clofibrates, such as fenofibrate, etc. If hyperlipidemia can be naturally relieved after NS remission, there is no need to continue drug treatment.
VI. Treatment
(I) General treatment
Anyone with severe edema and hypoproteinemia needs bed rest. After the edema disappears and the general condition improves, you can get up and move around.
Give normal amount of 0.8-1.0g/(kg・d) of high quality protein (animal protein rich in essential amino acids is the main source) diet. Calories should be sufficient, not less than 30-35kcal per kg of body weight per day. although patients lose a large amount of urinary protein, high protein diet increases glomerular hyperfiltration, which can aggravate proteinuria and promote the progression of renal lesions, so it is generally no longer advocated.
A low-salt (<3g/d) diet should be used in the case of edema. To reduce hyperlipidemia, a diet rich in saturated fatty acids (animal fats) should be consumed sparingly, and a diet rich in polyunsaturated fatty acids (e.g. vegetable oils, fish oils) and soluble fiber (e.g. beans) should be consumed more frequently.
(II) Symptomatic treatment
1.Diuretic and anti-swelling
(1) Thiazide diuretics mainly act on the thick-walled segment of the ascending branch of the medullary loop and the anterior segment of the distal convoluted tubule, and diuretic by inhibiting the reabsorption of sodium and chloride and increasing the excretion of potassium. Long-term use should prevent hypokalemia and hyponatremia.
(2) Potassium retention diuretics mainly act on the posterior segment of the distal convoluted tubule, excreting sodium and chloride, but retaining potassium, and are suitable for patients with hypokalemia. The diuretic effect is not significant when used alone, and can be used in combination with thiazide diuretics. Aminopterin or the aldosterone antagonist spironolactone are commonly used. Long-term use is required to prevent hyperkalemia, and should be used with caution in patients with renal insufficiency.
(3) Loop diuretics mainly act on the ascending branch of the medullary loop and have a strong inhibitory effect on the reabsorption of sodium, chloride and potassium. Furosemide (tachyphylaxis) or bumetanide (butanuric acid) (40 times stronger than furosemide at the same dose) is commonly used, and is given orally or intravenously in divided doses. It is more effective when given immediately after the application of an osmotic diuretic. When applying loop diuretics, it is necessary to prevent hyponatremia and hypokalemia and hypochlorhydria alkalosis.
(4) Osmotic diuretics increase the plasma colloid osmotic pressure transiently, which allows water to be absorbed back into the blood from the tissues. In addition, they pass through glomerular filtration, resulting in a hypertonic state of intrarenal tubular fluid, reducing the reabsorption of water and sodium and diuresis. Sodium-free dextran 40 (low-molecular dextran) or starch-substituted plasma (706-substituted plasma) (both with a molecular weight of 25-45,000) is commonly used intravenously by drip. Subsequent addition of loop diuretics may enhance the diuretic effect. However, these drugs should be used with caution in patients with oliguria (urine volume <400ml/d), because they tend to form tubular patterns with Tamm-Horsfall protein secreted by the renal tubules and albumin filtered by the glomerulus, blocking the renal tubules and causing degeneration and necrosis of the renal tubular epithelium due to their hypertonic effect, inducing "osmotic nephropathy" This can lead to acute renal failure.
(5) improve plasma colloid osmotic pressure plasma or plasma albumin and other intravenous infusion can improve plasma colloid osmotic pressure, promote water absorption in tissues and diuresis, such as the use of furosemide in glucose solution slowly intravenous drip, sometimes can get a good diuretic effect. However, since the protein input will be excreted in urine within 24-48 hours, it can cause glomerular hyperfiltration and tubular hypermetabolism, resulting in damage to the glomerular dirty layer and tubular epithelial cells and promoting interstitial fibrosis, which may affect the efficacy of glucocorticoids and delay the remission of disease in mild cases, or damage the renal function in severe cases. Therefore, the indications should be strictly controlled. For NS patients with severe hypoproteinemia, high edema and oliguria (urine volume <400ml/d), use should be considered only when diuresis is necessary, but excessive frequency and excess should also be avoided. It should be used with caution in patients with heart failure.
The principle of diuretic treatment for NS patients is that it should not be too fast and too vigorous, so as not to cause blood volume deficiency, aggravate the tendency of blood hypercoagulation and induce thrombosis and embolism complications.
2.Reduce urine protein
Persistent large amount of proteinuria itself can lead to glomerular hyperfiltration, aggravate tubular-interstitial injury and promote glomerulosclerosis, which is an important factor affecting the prognosis of glomerulopathy. Reducing urinary protein has been shown to be effective in delaying the deterioration of renal function.
Angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor antagonists (ARB), in addition to effectively controlling hypertension, can have an effect on reducing urinary protein independent of lowering systemic blood pressure by lowering glomerular intracellular pressure and directly affecting the permeability of the glomerular basement membrane to macromolecules. When lowering urinary protein with ACEI or ARB, the dose used should generally be larger than the conventional antihypertensive dose in order to obtain good efficacy.
(C) The main treatment (suppression of immune and inflammatory response)
1.Glucocorticoid therapy
Glucocorticoids (hereinafter referred to as hormones) 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 of glucocorticoid response to disease depends largely on its pathological type, with the most rapid and definite efficacy in microscopic lesions. The principles and programs of use are generally as follows: (1) starting with a full dose: the commonly used drug is prednisone, which is taken orally for 8 weeks, and can be extended to 12 weeks if necessary; (2) slow reduction; after full treatment, the original dosage is reduced by 10% every 2-3 weeks, and when the symptoms are easily recurring when reduced to about 20 mg/d, the dosage should be reduced more slowly; (3) long-term maintenance: finally, the minimum effective dose is maintained for several months to six months. The hormone can be taken as a full daily dose or as a dose every other day during the maintenance period to reduce the side effects of hormone. In case of severe edema, hepatic impairment or poor efficacy of prednisone, prednisolone may be replaced by oral or intravenous drip.
According to the patients’ response to glucocorticoid treatment, they can be divided into “hormone-sensitive” (NS remission within 8-12 weeks), “hormone-dependent” (relapse after hormone reduction to a certain extent) and “hormone-resistant” (hormone treatment is ineffective). There are three types of hormone resistance (hormone therapy is ineffective), and the further treatment for each of them is different.
Patients with long-term hormone application may experience side effects such as infection, drug-related diabetes and osteoporosis, and in a few cases, aseptic ischemic necrosis of the femoral head may occur, which needs to be monitored and handled in a timely manner.
2.Cytotoxic drugs
Hormone therapy is ineffective, or hormone dependent or recurrent type, cytotoxic drugs can assist in treatment. Since these drugs have gonadal toxicity, liver damage and the risk of tumor induction at high doses, they should be carefully controlled in terms of indications and treatment course. Currently, cyclophosphamide (CTX) and benzoylecgonine (CB1348) are more commonly used in clinical practice.
3.Immunosuppressants
The immunosuppressants commonly used in clinical practice are cyclosporine A, tacrolimus (FK506), mescaline and leflunomide.
Previously, immunosuppressants are often used in combination with glucocorticoids to treat many different pathological types of nephrotic syndrome. In recent years, it is also recommended that some patients who are relatively contraindicated or intolerant to glucocorticoids (such as uncontrolled diabetes, psychiatric factors, severe osteoporosis), and some patients who do not want to accept glucocorticoid treatment regimens or have contraindications, can be treated with immunosuppressants alone (including as Certain pathological types of nephrotic syndromes, such as focal segmental glomerulosclerosis, membranous nephropathy, microscopic nephropathy, etc., may be treated with immunosuppressive agents alone (including as an initial regimen).
In principle, it is appropriate to enhance the efficacy while minimizing side effects. Whether to apply hormone therapy, the duration of treatment, and whether to use and what kind of immunosuppressive drugs (cytotoxic drugs) should be selected should be treated differently according to the pathological type of glomerulopathy, age, renal function and whether there are relative contraindications, etc. According to the target of immunosuppressive drugs, individualized treatment plans should be formulated. In recent years, according to the research results of evidence-based medicine, the corresponding treatment plan is proposed for different pathological types.
VII. Prognosis
The prognosis of NS varies greatly among individuals. The main factors that determine prognosis include.
1.Pathological type
In general, the prognosis of microscopic nephropathy and mild tegumentary hyperplastic glomerulonephritis is good. Some patients with microscopic lesion nephropathy can spontaneously remit with a high remission rate with treatment, but are prone to relapse after remission. Early-stage membranous nephropathy still has a high rate of therapeutic remission. Although it is difficult to achieve therapeutic remission in advanced stages, most of the disease progresses slowly and renal failure occurs later. The prognosis is poor, and the disease enters chronic renal failure relatively quickly. The most important factor affecting the prognosis of focal segmental glomerulosclerosis is the degree of urine protein and response to treatment. The 10-year kidney survival rate is 90% for non-NS patients and 50% for NS patients in the natural course of the disease; while the 10-year kidney survival rate for NS patients in remission to hormone therapy is more than 90%, and only 40% for those who are ineffective.
2.Clinical factors
Large amounts of proteinuria, hypertension and hyperlipidemia can promote glomerulosclerosis, and the above factors, if not controlled for a long time, become an important factor of poor prognosis.
3, the presence of recurrent infections, thromboembolic complications often affect the prognosis.
Nephrotic syndrome (NS) can be caused by a variety of etiologies, with a group of clinical syndromes that manifest as massive proteinuria, hypoproteinemia, high edema, and hyperlipidemia due to increased glomerular basement membrane permeability.