Nephrotic syndrome (NS) is a common pediatric kidney disease, characterized by increased permeability of the glomerular basement membrane due to various disease causes, leading to significant protein loss in urine. The main features include massive proteinuria, hypoalbuminemia, severe edema, and hypercholesterolemia. Based on clinical manifestations, it is classified into three types: simple nephrosis, nephritic nephrosis, and congenital nephrosis. In children under 5 years old, the pathological type of nephrotic syndrome is mostly minimal change disease, while in older children, non-minimal change types (including mesangial proliferative glomerulonephritis, focal segmental sclerosis, etc.) are more common.

bubble_chart Pathogenesis

Not yet elucidated. Minimal change disease may be related to T-cell immune dysfunction. Membranous nephropathy and membranoproliferative glomerulonephritis may be associated with immune complex formation.

bubble_chart Pathological Changes

Primary nephrotic syndrome in children can present with various pathological changes, but the majority are dominated by certain lesions. The reported proportions of these changes vary and may differ based on factors such as the patient's age, source (i.e., whether they are non-selective cases or referred cases with difficult diagnoses and treatments), and indications for renal biopsy.

Unlike adults, children primarily exhibit minimal change disease. Additionally, the results differ depending on the source of the patients. In non-selective cases, minimal change disease predominates (76.4%), but among referred cases—which often include corticosteroid-resistant or recurrent refractory cases—the proportion of minimal change disease decreases, while non-minimal change cases increase. According to pediatric data in China, membranoproliferative lesions are more common. For example, a report from the Pediatric Hospital of Shanghai Medical University on 72 children with nephrotic syndrome who underwent biopsy showed that membranoproliferative lesions were the most frequent (31.9%), followed by minimal change disease (26.3%). Reports from other regions are roughly similar.

The age of onset and gender show a peak incidence in preschool-aged children. The age of onset for simple cases tends to be younger, while for tense cases, it is relatively later. The condition is more common in males than females, with a male-to-female ratio of approximately 1.5–3.7:1.

Edema is the most common clinical manifestation, often first noticed by parents. It typically begins in the eyelids and face, gradually spreading to the limbs and the entire body. The edema is pitting and may also involve serous membrane effusions such as pleural effusion or ascites. Boys often exhibit significant scrotal edema. Body weight may increase by 30–50%. In severe cases of edema, white or purple striae may appear on the inner thighs, upper arms, and abdominal skin. The severity of edema is usually unrelated to prognosis. Concurrently with edema, reduced urine output is often observed.

In addition to edema, children may develop protein malnutrition due to prolonged protein loss, presenting as pale complexion, dry skin, brittle and shallow yellow hair, white transverse lines on fingernails and toenails, and weakened ear cartilage and nasal cartilage. Affected children may appear lethargic, fatigued, and have reduced appetite, sometimes accompanied by diarrhea, which may be related to intestinal mucosal edema and/or concurrent infections. Prolonged or recurrent episodes may lead to developmental delays. Children with nephritis may exhibit elevated blood pressure and hematuria.

bubble_chart Auxiliary Examination

1. Urinalysis: Significant increase in urinary protein, qualitative ≥ (+++), 24-hour urinary protein quantification ≥ 0.1g/kg. Microscopic examination of urine sediment reveals hyaline casts and a few granular casts. In children with nephritis, red blood cells may also be observed, along with renal epithelial cells and cellular casts. A reduction or disappearance of urinary protein is an indicator of clinical improvement.
2. Plasma proteins: Total plasma protein is below normal, with albumin showing a more pronounced decrease, often <25～30g/L，有時低於10g/L，並有白蛋白、球蛋白比例代倒置。球蛋白中α2、β-球蛋白和纖維蛋白原增高，γ-球蛋白下降。IgG和IgA水平降低，IgE和IgM有時升高。血沉增快。
3. Serum cholesterol: Mostly significantly elevated, and other lipids such as triglycerides and phospholipids may also increase. Due to elevated lipid levels, the serum may appear milky.

AD

bubble_chart Diagnosis

The diagnosis of nephrotic syndrome is primarily based on clinical manifestations. It is characterized by massive proteinuria (24-hour urinary protein excretion >0.1g/kg or >3.5g/kg), severe edema, hypercholesterolemia (>5.7mmol/L or >220mg%), and hypoalbuminemia (<30g/L,<3Gg%）均可診為腎病綜合徵。典型病例血清蛋白電泳多提示α2↑↑，而γ↓。部分病兒可有低補體血症，鏡下或肉眼血尿、氮質血症或高血壓，學齡前兒童>1610.6kPa (120/80mmHg), and >17.3/12kPa (130/90mmHg) in school-aged children, it is classified as nephritic nephrosis. Nephrotic syndrome that is steroid-resistant (no response or partial response after 8 weeks of full-dose steroid therapy), frequently relapsing or recurring (≥2 relapses within 6 months or ≥3 relapses within 1 year), or steroid-dependent is termed refractory nephrotic syndrome. Refractory nephrotic syndrome is one of the indications for renal biopsy, which can clarify the pathological type and severity of renal lesions to guide treatment. Children with a hypercoagulable state may exhibit shortened prothrombin time, elevated plasma fibrinogen levels, and platelet counts above normal. During steroid therapy, sudden onset of lumbago accompanied by hematuria, elevated blood pressure, worsening edema, or deteriorating renal function may indicate renal vein thrombosis. Additionally, analysis of the underlying disease can aid in treatment. Among these criteria, massive proteinuria and hypoalbuminemia are essential for diagnosis.

bubble_chart Treatment Measures

Adopt a comprehensive treatment combining traditional Chinese and Western medicine, primarily based on adrenocortical hormones. The treatment includes controlling edema, maintaining water and electrolyte balance, providing adequate nutrition, preventing and controlling accompanying infections, and the correct use of adrenocortical hormones. For recurrent cases or those resistant to hormones, immunosuppressants are combined. Currently, Chinese medicinals focus on strengthening the spleen and tonifying the kidneys, while mitigating the side effects of Western drugs.

(1) Rest and lifestyle: Except for cases with severe edema or concurrent infections, absolute bed rest is generally unnecessary. Activity levels can gradually increase after the condition improves. After 3–6 months of remission, patients may gradually resume studies but should avoid overexertion.

(2) Diet: A low-salt diet is recommended. Salt should be avoided in cases of severe edema or high blood pressure. Children with severe edema and/or oliguria should have their water intake moderately restricted, but salt and fluids should be appropriately supplemented during significant diuresis, diarrhea, or vomiting with salt loss.

2. Symptomatic Treatment Generally, most children begin diuresis and edema reduction within 7–14 days of hormone therapy, so diuretics are often unnecessary. However, diuretics are often required for severe edema, concurrent skin infections, hypertension, or hormone-insensitive cases.

3. Adrenocortical Hormone (hereinafter referred to as hormone) Therapy Despite certain side effects and unresolved recurrence issues, clinical practice has proven that hormones remain the most effective drugs for inducing proteinuria remission and are the first-line treatment for nephrosis. The mechanism is not fully understood but may involve: (1) Immunosuppression; (2) Improving the permeability of the glomerular filtration membrane, reducing proteinuria; (3) Diuretic effects (via impacts on glomerular filtration rate and renal tubules).

Principles of medication: (1) Medium-acting preparations with a biological half-life of 12–36 hours (e.g., prednisone) are preferred, as they induce remission quickly and are suitable for intermittent therapy. (2) Initial treatment should be administered in sufficient doses, divided into multiple doses, to rapidly induce proteinuria remission. (3) During the maintenance phase after proteinuria remission, a single morning dose every other day is recommended. Since adrenal cortisol secretion follows a circadian rhythm (high in the morning, low at night), this method minimizes suppression of the hypothalamic-pituitary-adrenal (HPA) axis. (4) Maintenance therapy should not be too short; discontinuation should occur only after stable remission to reduce recurrence and facilitate re-remission if proteinuria reappears.

(1) Initial treatment plans: Two types: (1) Medium-to-long-term therapy: Commonly used in China. Prednisone 2 mg/kg/day (max 60 mg), divided into 3 doses. If proteinuria resolves within 4 weeks, consolidate for at least 2 weeks before tapering, switching to 2 mg/kg every other morning for 4 weeks, then reducing by 2.5–5 mg every 2–4 weeks until discontinuation (6-month course). If proteinuria persists at 4 weeks, continue until remission + 2 weeks (usually 8 weeks, max 12 weeks), then switch to 2 mg/kg every other day for 4 weeks, tapering as above (9–12-month course). (2) Short-term therapy: Common in Western countries. Start with 60 mg/m²/day (max 60–80 mg), divided doses for 4 weeks, then 40 mg/m² every other day for 4 weeks before stopping. Recently, 12-week or slightly longer courses have been used.

(2) Recurrent cases: Extend the every-other-day dosing period (i.e., medium-to-long-term therapy). For ≥2 recurrences, consider adding immunosuppressants.

(3) Hormone-dependent cases: Based on medication history and recurrence patterns, identify the minimal every-other-day dose to maintain remission, continuing for at least 6 months before attempting tapering. Generally, prednisone 1.4 mg/kg every other day causes no significant side effects. Immunosuppressants may also be added.

(4) For those resistant to hormones: Prolonging the dosing interval and/or adding immunosuppressants may lead to partial or complete remission in some cases and potentially slow the progression of renal function decline. Since these cases are mostly non-minimal change types, a renal biopsy is recommended to clarify the pathological type and determine the treatment plan. When hormone resistance occurs, other influencing factors should also be considered, such as concurrent infections, tubulointerstitial changes, renal vein thrombosis, or the concurrent use of drugs that affect hormone efficacy, such as phenytoin sodium or rifampicin.

(5) Methylprednisolone intravenous pulse therapy: High-dose intravenous administration has more potent immunosuppressive and anti-inflammatory effects, enabling faster induction of urinary protein negativity. Although this method can be used for initial treatment, it is more commonly employed in China for refractory nephrotic syndrome, i.e., in cases of steroid resistance or those requiring high-dose maintenance with significant steroid side effects. The dose is 15–30 mg/kg (total dose not exceeding 100 mg), diluted in 100–200 ml of 5–10% glucose and infused intravenously over 1–2 hours. Administered once daily or every other day, 3 doses constitute one course, with repetition after one week if necessary. After 48 hours of pulse therapy, oral steroids are resumed on an alternate-day schedule. Side effects include occasional facial flushing, tremor, nausea, and altered taste during infusion, as well as transient hypercoagulability, hypertension, arrhythmia, and gastrointestinal ulcer bleeding.

(6) Observation of steroid therapy efficacy:

1) Short-term efficacy: A child’s sensitivity to steroids is related to their disease type. According to clinical classification data in China, 78.9% of cases with simple sexually transmitted disease show complete response, while only 34.3% of nephritic-type cases do. In terms of histopathological types, the International Study of Kidney Disease in Children (ISKDC) reported that among 471 pediatric cases of primary nephrotic syndrome, 368 (78.1%) responded to steroids. Among these responsive cases, 93.1% had minimal change disease, 29.7% had focal segmental glomerulosclerosis, 55.6% had mesangial proliferative disease, and only 6.9% had membranoproliferative glomerulonephritis. The Pediatric Department of Peking University First Hospital treated 123 cases, with 96 (78%) showing steroid response over an 8-day cycle, consistent with ISKDC findings.

2) Long-term efficacy: Sensitivity to steroid therapy but a tendency to relapse is a common phenomenon. Foreign reports indicate that only 23% of cases do not relapse after initial remission. The duration of initial treatment appears to influence relapse rates. Foreign data show relapse rates within 12 months of 81%, 61%, and 36% for 4-week, 8-week, and 12-week treatment courses, respectively. The Pediatric Department of Peking University First Hospital followed 80 steroid-responsive cases treated with medium- to long-term therapy for 2 years: at 6 months, 32 cases (40%) had no relapse, 38 (47.5%) were infrequent relapsers, and 19 (23.7%) were frequent relapsers. Among relapsed cases, 80% occurred within 2 years, though some children relapsed even after years of remission. Frequent relapses within the first six months of treatment may predict a pattern of frequent relapses. Frequent relapsers often remain in an active disease state long-term, with a few developing varying degrees of renal insufficiency. Due to prolonged steroid use, side effects are common. About 20% of frequent relapsers may have a disease course lasting 10–15 years, though disease activity tends to weaken over time. Generally, steroid-sensitive cases remain sensitive despite multiple relapses, though a few may transition from steroid sensitivity to resistance.

For relapsed cases, intermittent therapy may be extended to 1–several years, and immunosuppressants may be added after 1–2 relapses.

As mentioned earlier, steroid-resistant cases are mostly non-minimal change disease. In recent years, a long-term alternate-day administered at draught regimen has been used for membranoproliferative glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, and steroid-resistant minimal change disease. Prednisone 1.5–2.0 mg/kg is administered at draught every other morning for 0.5–3 years, gradually tapered to 0.5–1.0 mg/kg every other morning for 3–5 years. This approach can lead to varying degrees of improvement, achieving remission or partial remission while preserving renal function.

(7) Side effects and complications of steroid therapy: There are two categories.

1) It is caused by the effects of long-term supraphysiological doses of hormones on the body: such as fat metabolism disorders, manifested as obesity, abnormal body fat distribution, and Cushingoid appearance; due to enhanced protein catabolism, negative nitrogen balance, muscle atrophy and weakness, and poor wound healing occur; glucose metabolism disorders can lead to hyperglycemia and glycosuria; due to water and electrolyte imbalances, water and sodium retention and hypertension occur; calcium and phosphorus metabolism disorders result in hypercalciuria and osteoporosis. The gastrointestinal tract may develop peptic ulcers or even perforation. Neuropsychiatric effects include euphoria, excitement, insomnia, and in severe cases, psychosis and epileptic seizures. Due to the suppression of antibody formation, infections or the activation and spread of latent infections (such as subcutaneous nodular disease) can easily occur. Long-term medication can also lead to cataracts, femoral head avascular necrosis. In children during their growth period, their growth, especially height, may be affected.

2) Another category is acute adrenocortical insufficiency and withdrawal syndrome caused by hormones: large amounts of exogenous corticosteroids feedback-inhibit the hypothalamic-pituitary-adrenal system, leading to reduced secretion, functional decline, and even glandular atrophy of the adrenal cortex. If the medication is suddenly discontinued or if the body encounters stress conditions such as infection or surgery, the adrenal cortex may produce a relative or absolute insufficiency of secretion, resulting in symptoms of acute adrenocortical insufficiency, manifested as nausea, vomiting, abdominal pain, pre-shock, or even shock.

4. Immunosuppressive Therapy Indications: For refractory nephrotic syndrome and/or cases with severe hormone side effects, immunosuppressants may be added or substituted.

(1) Cyclophosphamide: Can reduce relapses and prolong the stage of remission; for patients partially sensitive to hormones, its addition may induce complete remission; for hormone-resistant cases, it may sometimes improve the child's response to hormones. The dose is 2–2.5 mg/(kg·d), with a treatment course of 8–12 weeks and a total dose of 200–250 mg/kg. Repeated use within one year is contraindicated. Side effects: Short-term effects may include gastrointestinal reactions, liver function impairment, alopecia areata, bone marrow suppression, hemorrhagic cystitis, and increased susceptibility to bacteria and viruses. Long-term effects on gonads have recently gained attention, as its use in adolescent or pre-adolescent boys may affect testicular spermatogenic function, leading to infertility. Gonadal injury is dose-related, so indications and dosage should be carefully considered when using this drug.

(2) Chlorambucil: Can reduce relapses in hormone-sensitive patients. The usual dose is 0.2 mg/kg daily, with a treatment course of 6–8 weeks and a total dose not exceeding 10 mg/kg. Side effects are similar to cyclophosphamide, with some gonadal injury. There have also been reports of leukemia and solid tumors.

(3) Nitrogen Mustard: Administered via rapid intravenous drip or slow intravenous push every other day, with 10–20 doses constituting one treatment course. Start with a small dose (1–2 mg for the first dose) and gradually increase up to 0.1 mg/kg. Side effects include gastrointestinal symptoms, which can be prevented by administering sedatives beforehand. Additionally, local venous irritation may occur, so the drug should be administered through larger veins.

(4) Cyclosporine A: This drug specifically inhibits the activation and proliferation of helper T cells and cytotoxic T cells without affecting B cells or granulocytes. The dose is 6–8 mg/kg daily, and blood concentration monitoring is often required to adjust the dosage. The treatment course is 8 weeks. Its efficacy for nephrotic syndrome can be summarized as follows: patients responsive to hormones often respond to this drug as well. For such patients, when hormone toxicity is severe, this drug may be substituted, though relapse may occur after discontinuation, and reuse remains effective. For hormone-resistant cases, early application may induce remission in some patients. Among its toxic side effects, nephrotoxicity is the most prominent. Acute nephrotoxicity manifests as pre-renal azotemia, generally reversible and dose-related. Chronic nephrotoxicity involves structural changes in renal tissue, presenting as interstitial and tubular lesions. Clinically, it may cause hypertension, hyperuricemia, sodium retention, hyperkalemia, and decreased creatinine clearance. Beyond nephrotoxicity, it may also cause hirsutism, gingival hyperplasia, and hypomagnesemia.

(5) Tripterygium Wilfordii Polyglycoside: An extract from the root of Tripterygium wilfordii (a plant of the Celastraceae family), it has immunosuppressive effects. The dose is 1 mg/kg daily, with a maximum of 30 mg daily divided into three doses. The treatment course is 3 months. Side effects include leukopenia, gastrointestinal reactions, skin pigmentation, and potential effects on gonadal function (manifested as menstrual disorders or amenorrhea in females, and reduced sperm motility or count in males).

5. Other Treatments

(1) Use of Anticoagulants: Nephrotic syndrome often presents with a hypercoagulable state, so some advocate the addition of anticoagulants or antiplatelet agents such as heparin, dipyridamole, or blood-activating and stasis-resolving Chinese herbs like Salvia.

(2) Levamisole: An immunomodulator. It is generally used as an adjunctive therapy to hormones, especially for frequently relapsing or hormone-dependent cases often accompanied by infections. The dose is 2.5mg/kg, administered every other day. After use, it can reduce concurrent respiratory infections and decrease the dosage of hormones in hormone-dependent patients.

(3) Captopril: As an angiotensin II converting enzyme inhibitor, it has been suggested in recent years to improve glomerular hemodynamics, thereby reducing urinary protein excretion. It can be used as an adjunct to hormone therapy, especially in patients with hypertension.

6. Chinese Herbal Medicine Treatment In addition to treating edema through pattern identification, it can also address the side effects caused by hormones and immunosuppressants. For edema and oliguria, Plantain Herb, Christina Loosestrife, Grass of Common Knotgrass, and corn silk can be used. For symptoms of blood stasis, add Salvia, Sichuan Lovage Rhizome, Chinese Angelica, motherwort herb, and Shiny Bugleweed leaves. For cases of spleen qi deficiency and kidney deficiency, tonify the spleen and strengthen the kidney with herbs such as Astragalus Root, Tangshen, Poria, White Atractylodes Rhizome, Chinese Yam, Psoralea, Epimedium Herb, Cuscuta Seeds, and Barbary Wolfberry Fruit. During hormone induction, if symptoms such as red tongue texture, wiry pulse, and flushed excitement appear, prescribe yin-nourishing and fire-reducing herbs. The basic formula includes Anemarrhena, Scrophularia, Unprocessed Rehmannia Root, Moutan Bark, Alisma, Raw Liquorice Root, Phellodendron Bark, and Gentian. During hormone dose reduction, if qi deficiency or kidney deficiency manifests, add qi-tonifying and kidney-nourishing herbs. The basic formula consists of Astragalus Root, Prepared Liquorice Root, Cuscuta Seeds, and Schisandra Fruit. For yang deficiency, add Psoralea and Epimedium Herb; for yin deficiency, add glossy privet fruit and Yerbadetajo Herb, along with Six-Ingredient Rehmannia Pill. If leukopenia occurs during immunosuppressant therapy, administer qi and blood tonics such as Solomonseal Rhizome, Chinese Angelica, Suberect Spatholobus Stem, Motherwort Herb, and Hairyvein Agrimonia Herb.

bubble_chart Prognosis

Over the past half-century, the advent of effective antibacterial drugs, adrenocortical hormones, and immunosuppressants has significantly improved the prognosis of childhood nephrotic syndrome. The five-year mortality rate has decreased from 60–70% in the era without antibacterial drugs to about 10% with the use of prednisone, and further declined with the application of immunosuppressants, especially in cases of minimal change disease. It should be noted that the prognosis of this syndrome is closely related to its pathological type. According to Habib et al. (1971), in a 1–18 year follow-up study, the rates of progression to chronic kidney failure or death were 7% for minimal change disease, 38% for focal segmental sclerosis, and 8% and 41.5% for membranous nephropathy and membranoproliferative glomerulonephritis, respectively.

bubble_chart Complications

1. Infection is the most common complication and the leading cause of death; according to the 1984 statistics from the International Study of Kidney Disease in Children (ISKDC), 70% of deaths in children with nephrotic syndrome were directly or indirectly caused by infection. Infection is also a frequent trigger for relapse and/or exacerbation of the condition and can affect the efficacy of corticosteroid therapy.

The reasons for the susceptibility to infection in this syndrome include: (1) impaired humoral immune function (loss of immunoglobulins in urine, reduced synthesis, increased catabolism); (2) frequent accompanying deficiencies in cellular immune function and complement system activity; (3) protein malnutrition and edema leading to impaired local circulation; (4) common use of corticosteroids and immunosuppressants.

Among bacterial infections, pneumococcal infections were predominant in the past, but infections caused by bacilli (e.g., large intestine bacilli) have increased in recent years. Common infections include respiratory infections, urinary tract infections, skin erysipeloid, and primary peritonitis. Prophylactic antibiotic use is generally not recommended due to unreliable efficacy and the risk of promoting resistant bacterial strains and microbial imbalance; however, prompt and aggressive treatment is necessary once an infection occurs.

Children are also more susceptible to viral infections, particularly during corticosteroid and immunosuppressant therapy. Complications such as chickenpox, measles, and herpes zoster tend to be more severe than in typical cases. For those with a history of exposure, corticosteroids and immunosuppressants may be temporarily reduced, and γ-globulin injections administered. There have been isolated reports of temporary remission of nephrotic syndrome following measles infection.

2. Hypercoagulability and Thromboembolic Complications In nephrotic syndrome, the coagulation and fibrinolytic systems may undergo the following changes: (1) increased fibrinogen; (2) elevated levels of coagulation factors V and VIII; (3) decreased antithrombin III; (4) reduced plasminogen activity; (5) possible increase in platelet count, along with enhanced adhesion and aggregation. These changes can lead to a hypercoagulable state and thromboembolic complications, with renal vein thrombosis being of particular clinical concern. Acute cases present with sudden-onset gross hematuria and abdominal pain, accompanied by costovertebral angle tenderness and a renal mass; bilateral involvement may result in acute renal impairment. Chronic renal vein thrombosis often has subtle clinical manifestations, such as worsening edema and persistent proteinuria. Imaging may reveal an enlarged kidney and ureteral notching. B-mode ultrasound can sometimes detect it, but renal venography is definitive if needed. Besides renal veins, thromboembolic complications may occur in other veins or arteries, such as the femoral vein, femoral artery, pulmonary artery, mesenteric artery, coronary artery, and intracranial arteries, with corresponding symptoms. Clinically, if blood is found to clot easily during venipuncture, hypercoagulability should be suspected. The simplest screening tests are fibrinogen levels and platelet counts, with further tests conducted if feasible.

3. Calcium and Vitamin D Metabolic Disorders In nephrotic syndrome, vitamin D-binding protein (VDBP, molecular weight 59,000) is lost in the urine, leading to vitamin D deficiency, impaired intestinal calcium absorption, and secondary hyperparathyroidism. Clinical manifestations include hypocalcemia, insufficient circulating vitamin D, and poor bone calcification. These changes are particularly pronounced in growing children.

4. Hypovolemia Due to hypoalbuminemia and reduced plasma colloid osmotic pressure, this syndrome is often associated with hypovolemia. In some cases, prolonged inappropriate salt restriction exacerbates the risk. With acute fluid loss (e.g., vomiting, diarrhea, high-dose diuretic use, or large-volume ascites drainage), symptoms of hypovolemia may arise, ranging from orthostatic hypotension and prerenal azotemia to shock.

5. Acute renal impairment Transient grade I azotemia is not uncommon during the acute onset. Acute renal impairment may occasionally occur during the course of the disease. The causes include: (1) hypovolemia and inappropriate massive necrosis. (2) Severe renal interstitial edema, with renal tubules obstructed by protein casts, leading to increased hydrostatic pressure in the renal capsule and proximal tubules and reduced glomerular filtration. (3) Drug-induced tubulointerstitial lesions. (4) Complicated bilateral renal vein thrombosis.

6. Renal tubular dysfunction May manifest as glycosuria, aminoaciduria, potassium and phosphorus loss in urine, and impaired concentrating ability.

7. Stirred pulse Atherosclerosis Occasionally occurs in children with persistent hyperlipidemia. When coronary stirred pulse is involved, symptoms may include chest tightness, colicky pain, ECG changes, and even sudden death.

8. Children may occasionally experience neurological symptoms such as headache, spasm, and visual disturbances, which may be caused by various factors including hypertensive encephalopathy, cerebral edema, dilutional hyponatremia, hypocalcemia, and hypomagnesemia.