bubble_chart Overview

Nephrotic syndrome is a clinical syndrome caused by various {|###|}disease causes{|###|} that lead to increased permeability of the glomerular filtration {|###|}membrane{|###|} to plasma proteins, resulting in massive loss of plasma proteins in the urine. It is characterized by four main features:

1. Massive proteinuria. Urine protein qualitative test shows +++ or ++++, with a quantitative measurement of >100mg/kg per day, persisting for more than 2 weeks. In recent years, some have proposed standards of >50mg/kg or >40mg/(m²‧h).
2. Hypoalbuminemia, with plasma albumin levels below 30g/L.
3. Hypercholesterolemia, with blood cholesterol >5.72mmol/L (220mg/dl).
4. Edema.

Among these, (1) and (2) are essential diagnostic criteria. Clinically, the syndrome is divided into primary and secondary categories. Primary cases are further classified into:

1. Simple type: meeting the criteria for nephrotic syndrome without {|###|}hematuria{|###|}, hypertension, azotemia, or hypocomplementemia.
2. Nephritic type: in addition to the four main features of nephrotic syndrome, it also includes one or more of the following manifestations: recurrent urinary red blood cells >10 per high-power field; repeated hypertension, with school-age children >17.3/12.0kPa (130/90mmHg) and preschool children >16.0/10.7kPa (120/80mmHg), excluding cases caused by corticosteroid use; persistent azotemia, with blood urea nitrogen >10.71 mmol/L (30mg/dl), excluding cases due to hypovolemia or prerenal causes; and decreased total complement or C3 levels.
3. Congenital type (onset within 6 months of birth).

Secondary cases are most commonly seen in pediatric clinical practice in lupus nephritis, Henoch-Schönlein purpura nephritis, and hepatitis B virus-associated nephritis. Primary nephrotic syndrome can manifest in various pathological forms, including:

1. Minimal change disease;
2. Mesangial proliferation;
3. Focal segmental glomerulosclerosis;
4. {|###|}Membrane{|###|} proliferative glomerulonephritis;
5. {|###|}Membrane{|###|} nephropathy.

Clinical classification and pathological manifestations often correlate to some extent, such as the simple type mostly presenting with minimal change disease; however, the two cannot substitute for each other.

bubble_chart Auxiliary Examination

Perform renal biopsy for refractory nephropathy or cases with significant disease progression during the course. Make pathological diagnosis based on light microscopy, immunofluorescence, and electron microscopy examinations.

bubble_chart Diagnosis

Based on the aforementioned four major clinical features, particularly the presence of massive proteinuria and hypoalbuminemia, a diagnosis of nephrotic syndrome can be made. If secondary causes are excluded based on medical history, physical examination, and laboratory tests, it is classified as primary nephrotic syndrome. Further differentiation into nephritic or simple types is made based on the presence or absence of hematuria, azotemia, hypertension, and low serum complement levels. Given that glucocorticoids (referred to as "hormones") are the first-line treatment for pediatric nephrotic syndrome, and their response to an 8-day course of full-dose therapy often indicates prognosis and serves as a crucial reference for subsequent treatment planning, it is advisable to document the hormonal response at the time of clinical diagnosis. Typically, the response to an 8-day course of full-dose glucocorticoid therapy is categorized as follows:

1. **Complete response**: Hormone-sensitive, edema resolved, urine protein negative;
2. **Partial response**: Partially hormone-sensitive, edema resolved, urine protein ≤++;
3. **No response**: Hormone-resistant, urine protein ≥+++.

Clinically, cases of hormone resistance, hormone dependence (defined as hormone-sensitive initially, with remission upon treatment but relapse within 2 weeks of dose reduction or discontinuation, and responsiveness to re-treatment, recurring three or more times), and frequent relapsers (defined as relapse within six months or two recurrences, or three or more recurrences within one year) are collectively termed "refractory nephrotic syndrome."

bubble_chart Treatment Measures

(1) General Treatment

During the edema phase, bed rest is required, and sodium intake should be restricted. For those without edema, strive to maintain a lifestyle and diet as close to normal as possible. Ensure adequate calcium and vitamin intake. Minimize visits to public places to reduce the risk of infection. In case of concurrent infection, active treatment should be initiated.

(2) Symptomatic Treatment

Diuretics should be administered for significant edema. Oral hydrochlorothiazide is commonly used, with spironolactone added for long-term use. For severe edema with oliguria, furosemide (Lasix) can be administered orally or via injection at 1–2 mg/kg per dose, or bumetanide (Bumex) can be given intravenously at 0.5–1.0 mg for adults, with adjusted doses for children. For patients with markedly low albumin and potential hypovolemia, low-salt human serum albumin can be infused intravenously first, followed by furosemide. Alternatively, low-molecular-weight dextran can be used for volume expansion (5–10 ml/kg) before administering furosemide once daily for several days. Significant diuresis may lead to water-electrolyte imbalances, particularly hypokalemia, which should be corrected if necessary. For patients with elevated blood pressure, antihypertensive drugs should be given (see the Hypertension chapter).

(3) Hormone Therapy

This is the first-line treatment, with prednisone being the most commonly used. Prednisone is administered at 1.5–2.0 mg/(kg·d) (total daily dose generally not exceeding 60 mg), divided into three oral doses, for 4–8 weeks (no less than 4 weeks, or 3 weeks after urine protein turns negative). Then, switch to 2–3 mg/kg administered as a single morning dose every other day, followed by gradual tapering. The total course lasts 6–9 months or longer; for initial treatment, 6 months is usually sufficient. For relapses, a medium-to-long course is often adopted. For steroid-dependent cases, the lowest effective dose to maintain remission should be given for an extended period. For steroid-resistant cases, especially those with some degree of renal injury, intravenous methylprednisolone pulse therapy may be used at 15–30 mg/kg per dose (total dose not exceeding 1 g/day), diluted in 100–200 ml of glucose solution and infused intravenously once daily or every other day, with three doses constituting one course. Prednisone is resumed 48 hours after pulse therapy, administered as a single morning dose every other day. Note that pulse therapy may occasionally cause hypertension or severe infections.

(4) Other Immunosuppressants

Indications for adding or switching to these agents include refractory nephrotic syndrome and/or significant steroid toxicity.

Cyclophosphamide: Oral dose is 2–2.5 mg/(kg·d) for 8–12 weeks. Potential short-term side effects include leukopenia, alopecia areata, liver dysfunction, and hemorrhagic cystitis. Long-term side effects include gonadal injury and infertility, so caution is advised for prepubertal and adolescent boys. Intravenous pulse therapy has also been used in recent years, with 8–12 mg/kg per dose infused intravenously over two days as one course, repeated every 15–30 days for a total of six courses.
1. Chlorambucil: Oral dose is 0.2 mg/(kg·d) for no longer than 8 weeks, with a total dose preferably <10mg/kg。副作用白細胞及血小板減少，對病毒感染的易感性增加，青春期前男孩用藥也可能有性腺損傷。
2. 6-Thioguanine (6-TG): Dose is 1.5–2.0 mg/(kg·d), with the optimal course duration yet to be determined. Side effects include leukopenia and thrombocytopenia.
3. Cyclosporine A: 5 mg/(kg·d), preferably with blood concentration monitoring for dose adjustment. Toxicities include prerenal azotemia (early stage), tubulointerstitial injury (long-term use), hirsutism, gingival hyperplasia, hypomagnesemia, and elevated alkaline phosphatase.

(5) Adjunctive Therapy

For patients with a hypercoagulable state, anticoagulant therapy may be administered, such as oral alginic sodium diester, dipyridamole, or Salvia miltiorrhiza. Alternatively, ancrod or heparin therapy may be used.

For patients prone to infections, immunostimulants such as levamisole may be added.

Chinese medicinals: For the side effects of hormone toxicity, use medicines that nourish yin and reduce fire (Unprocessed Rehmannia Root, Anemarrhena, Moutan Bark, Poria, Alisma, Raw Licorice, etc.). During the hormone reduction process, tonify qi and nourish the kidneys using Astragalus Root, Prepared Liquorice Root, Epimedium Herb, Dodder Seed, Psoralea, etc.

bubble_chart Differentiation

The main purpose is to exclude secondary causes, which often requires testing for blood complement, antinuclear antibodies, hepatitis B virus infection markers, and other laboratory tests, along with a thorough review of medical history and relevant family history.