Nephrotic syndrome aetiology is mostly idiopathic. Factors such as genetic, environmental, haematologic, metabolic, systematic conditions and infections have all been implicated in the aetiology of the syndrome (Table 1). 

Table 1: Aetiology and risk factors of nephrotic syndrome

Idiopathic

Minimal change NS (MCNS), Focal segmental glomerulosclerosis (FSGS), membranous nephropathy, IgM nephropathy, membranous proliferative glomerulonephritis (MPGN), C1q nephropathy

Genetic

Finnish-type (NPHS1), familial FSGS (NPHS2), Denys-Drash syndrome (WT1), Pierson syndrome (LAMB2), isolated diffuse mesangial sclerosis (PLCE 1) and podocin gene (NPHS2)

Infections

Schistosomiasis, congenital syphilis, cytomegalovirus (CMV), Hepatitis B & C, HIV, Malaria, Filariasis and toxoplasmosis

Metabolic

Fabry’s disease, glutaric acidaemia, glycogen storage, mitochondrial cytopathies

Haematologic and Oncologic

Leukaemia, Lymphoma, sickle cell disease

Drugs

NSAIDs, gold, penicillamine, ACEIs, interferon, Mercury, Lithium

Systemic

Diabetes mellitus, lupus nephritis, amyloidosis, reflux nephropathy, Henoch Schoenlein purpura,

Others

Bee sting, fo

od allergies, pregnancy

Nephrotic syndrome can be classified based on aetiology as: (i) Congenital Nephrotic Syndrome (ii) Primary or Idiopathic Nephrotic Syndrome (iii) Secondary Nephrotic Syndrome. It can also be classified based on histological characteristics into: (i) Minimal change disease (ii) Focal segmental glomerulosclerosis (iii) Membranoproliferative glomerulonephritis (iv) Mesangial proliferative glomerulonephritis (v) Membranous nephropathy.

While congenital nephrotic syndrome manifests within the first 3 months of life, idiopathic nephrotic syndrome starts later and is most common between the ages of 2 and 7 years with a male preponderance. It is often heralded by a minor infection or allergic reactions including bee stings. It usually starts as a periorbital oedema usually worse in the morning. The oedema is also gravity dependent localized to the lower extremities in the standing position and to the dorsal part of the body in lying position. With time, the oedema becomes generalized, with the development of ascites, pleural effusions, and genital oedema.

Occurrence before 3 months of life and history of large placenta will suggest a congenital nephrotic syndrome. Other relevant history for the other forms include: bee sting, recent illness, drug and exposure to heavy metals, urine colour and volume as well as body rashes, and joint pains.

A general physical examination to identify the extent of oedema. Ascites is also a common abdominal finding. Blood pressure is usually normal with normal urine output.  Extrarenal features, e.g., dysmorphic features or ambiguous genitalia or eye abnormalities (microcoria, aniridia), rash, arthritis. Other systemic examinations can be done to identify complications such as pleural effusion, pulmonary oedema from fluid accumulation.

Conditions that have a similar presentation to NS include acute or chronic glomerulonephritis, protein-losing enteropathy, oedematous severe acute malnutrition, congestive heart failure and hepatic failure.

H, Complications

Complications of nephrotic syndrome could be due to the disease or due to the complications following medications as indicated in Table 2 and 3 below.

Table 2: complications due to nephrotic syndrome

Infectious

Spontaneous bacteria peritonitis usually due to organisms such as Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae, and Klebsiella spp. Viral infections and tuberculosis may be observed in patients receiving corticosteroids or immunosuppressive agents, cellulitis, urinary tract infection and disseminated varicella infection can also occur.

Cardiovascular

Hypertension, hyperlipidaemia, coronary artery disease

Respiratory

Pleural effusion and pulmonary embolism

Haematologic

Venous (more common) or arterial (less common) thrombosis (thrombo-embolic events due to urinary losses of Antithrombin III, Protein S and C. Also, haemoconcentration and immobilization) and anaemia (due to erythropoietin and transferrin loss)

Gastrointestinal

Intussusception

Renal

Acute kidney injury (usually pre-renal) and renal vein thrombosis

Endocrinologic

Reduced bone mineral density and hypothyroidism

Neurologic

Cerebral venous thrombosis

Table 3: Complications of nephrotic syndrome due to medications

Medications

Complications / side effects

Steroids

Growth impairment, avascular necrosis of femoral bone, posterior capsular cataract and

Alkylating agents

Haemorrhagic cystitis, dose related oligospermia, premature ovarian failure and increased risk of malignancy

Calcineurin agents

Gingival hyperplasia, hirsutism, hyperkalaemia, encephalopathy

MMF

Nausea, vomiting, diarrhoea, constipati

on, dose related leukopaenia and headache

A good history makes it easy to diagnose nephrotic syndrome. Previous history of body swelling, description of urine and presence of risk factors assist in coining on the diagnosis. Routine investigations are urinalysis, urine protein: creatinine ratio, serum protein/albumin and fasting lipids. Complete blood count and serum electrolytes, urea and creatinine will serve as ancillary investigations.

The kidney disease improving global outcome (KDIGO) 2024 treatment guideline is still relevant for NS management. However, key interventions before definitive treatment include:

Pneumococcal vaccine should be given if child will be admitted, also confirm status of exposure to varicella if to be treated in an open ward. Diet should entail increased protein intake, at least 120-140% protein of daily recommended allowance for age, with hypovolaemia give rapid infusion of plasma (20 ml/kg) or albumin 20% (1 g/kg) over 4 hours. Salt restriction is necessary for massive oedema (To approximately 2 g of sodium per day). Fluid restriction should be implemented when serum Na is < 125meq/l. Diuretics (frusemide, hydrochlothiazide and spironolactone) are relevant when there is massive oedema and child is not hypovolaemic. Give empirical antibiotics once blood count suggests presence of infections.

Treatment of NS with steroid is the mainstay of treatment. To understand this in line with the KDIGO guideline there is a need to define the terms used as outlined below:

1. Remission: negative/ trace dipstick on ≥ 3 consecutive occasions.

2. Relapse: Urine dipstick ≥ 3+ (≥300 mg/dl) or UPCR ≥ 200 mg/mmol (≥ 2 mg/mg) on a spot urine sample on 3 consecutive days, with or without reappearance of oedema in a child who had previously achieved complete remission

3. Steroid-sensitive nephrotic syndrome (SSNS): Complete remission within 4 weeks of prednisone at standard dose (60 mg/m2 /day or 2 mg/kg/day, maximum 60 mg/day).

4. Steroid-resistant nephrotic syndrome (SRNS): Lack of complete remission within 4 weeks of treatment with prednisone at standard dose

 5. Confirmation period: Time period between 4 and 6 weeks from prednisone initiation during which responses to further oral prednisone are ascertained in patients achieving only partial remission at 4 weeks. A patient not achieving complete remission by 6 weeks, although partial remission was achieved at 4 weeks, is defined as Steroid resistant nephrotic syndrome (SRNS).

6. SSNS late responder: A patient achieving complete remission during the confirmation period (i.e. between 4 and 6 weeks of prednisone therapy) for new onset NS.

7. Relapse: Urine dipstick ≥3+ (≥300 mg/dl) or UPCR≥200 mg/mmol (≥2 mg/mg) on a spot urine sample on 3 consecutive days, with or without reappearance of oedema in a child who had previously achieved complete remission.

8. Frequently relapsing nephrotic syndrome (FRNS): ≥ 2 relapses in the first 6-months following remission of the initial episode or ≥ 3 relapses in any 12 months.

9. Steroid-dependent nephrotic syndrome (SDNS): A patient with SSNS who experiences 2 consecutive relapses during recommended prednisone therapy for first presentation or relapse within 14 days of its discontinuation.

For SSNS it is recommended that oral prednisone be administered as a single daily dose starting at 60mg/m2 /d or 2mg/kg/d to a maximum 60 mg/d daily for 4–6 weeks, followed by alternate-day medication as a single daily dose starting at 40 mg/m2 or 1.5 mg/kg (maximum 40 mg on alternate days) for 2–5 months with tapering of the dose in the last month. All parents must be seen by the renal nurse / Paediatric Nephrologist for counselling details will include how, why and when to do urine dipstick testing, what a relapse is, what to do in the case of a relapse, understand the relapsing nature of nephrotic syndrome and learn about prednisolone, its dosing and side-effects. Following this treatment, 20% of children have no further episodes, 80% will relapse at least once and 50% will become frequent relapsers or steroid resistant.

For infrequent relapses of SSNS in children be treated with a single-daily dose of prednisone 60 mg/m2 or 2 mg/kg (maximum of 60 mg/d) until the child has been in complete remission for at least 3 days. After achieving complete remission, children be given prednisone as a single dose on alternate days (40mg/m2 per dose or 1.5mg/kg per dose: maximum 40mg on alternate days) for at least 4 weeks.

For steroid dependent or frequent relapsers, suitable steroid-sparing agents such as levamisole, alkylating agents or calcineurin inhibitors (CNIs). These medications are given along with low dose of prednisolone (20mg/m2 on alternate day for 3months). Levamisole is recommended to be given at a dose of 2.5 mg/kg on alternate days for at least 12 months. Alkylating agents (cyclophosphamide 2mg/kg over 2months with total maximum cumulative dose of 168mg/kg or chlorambucil 0.1-0.2mg/kg/day for 8weeks with cumulative dose of 11.2mg/kg). Calcineurin inhibitors (cyclosporin at 4–5mg/kg/d (starting dose) in two divided doses or tacrolimus at 0.1 mg/kg/d (starting dose) given in two divided doses) for at least 6 months. CNIs monitoring and alkylating agents for toxicity is very important.

For SRNS, it is highly recommended that corticosteroids treatments should be for a minimum of 8 weeks also administration of 3 doses of pulsatile doses of methyl prednisolone before finalizing on the diagnosis. A re-evaluation entailing a diagnostic kidney biopsy, evaluation of kidney function by GFR or eGFR and quantitation of urine protein excretion. Thereafter, administration of one of these three medications is advocated for SRNS:

1. Immunosuppressive (Calcineurin inhibitors, Mycophenolate mofetil, Rituximab)

2. Immune stimulatory: Levamisole

3. Non immunosuppressive: ACEi, ARBs and Vitamin E.

Renal biopsy should be done in steroid resistance children, other indications include children less than 1 year or more than 10 years of age, gross hematuria, sustained hypertension despite treatment, persistent renal insufficiency, low C3 component of complement, family history of renal failure and deafness as well as presence of extra-renal symptoms (Skin, Joints etc.).

Avoiding triggers or associations such as use of mercury, allergens (bee sting, house dust)

Control of infections: Reducing the burden of infections through vaccination, vector control (for malaria), and HIV prevention can help reduce secondary nephrotic syndrome.

Early diagnosis: Prompt and early recognition of signs and symptoms of nephrotic syndrome can improve outcomes.

Genetic counselling: For congenital nephrotic syndrome and families with a history of nephrotic syndrome, especially FSGS, genetic counselling may be useful in high-risk populations.

Childhood nephrotic syndrome in sub-Saharan Africa presents significant challenges due to limited healthcare resources and delayed access to medical care. Early diagnosis and proper management are crucial to prevent complications such as infections and kidney damage. Treatment typically includes corticosteroids, but recurrent relapses and steroid resistance can complicate the prognosis. Improved access to healthcare, early intervention, and better education for caregivers about the condition are essential to improving outcomes for children with nephrotic syndrome in the region.