Kidney disease that affects a kidney’s filtering system is the most common cause of nephrotic syndrome in children. Other causes can include diseases that affect other parts of the body, infections, some medicines, and genetics.

Primary nephrotic syndrome

Four types of kidney disease can cause primary nephrotic syndrome in children and adolescents.

• Minimal change disease (MCD). MCD is the most common cause of nephrotic syndrome in young children. The disease causes very little change to the glomeruli or nearby kidney tissue. The changes in the kidney can only be seen using an electron microscope, which shows tiny details. Although the cause of MCD is unknown, some health care professionals think the immune system may be involved.
• Focal segmental glomerulosclerosis (FSGS). This disease can cause some of the kidney’s glomeruli to become scarred. FSGS may be caused by genetic variants, or changes in genes present at birth.
• Membranous nephropathy (MN). MN is an autoimmune disease that causes immune proteins to build up in the kidney’s glomerular basement membrane. As a result, the membrane becomes thick and does not work properly, allowing too much protein to pass into the urine.

Other causes of primary nephrotic syndrome are uncommon.

Secondary nephrotic syndrome

Causes of secondary nephrotic syndrome in children include

• diseases that involve many organs or the whole body, called systemic diseases. Examples include IgA vasculitis (also known as Henoch-Schönlein purpura) and lupus.
• infections, including hepatitis B and C, HIV, and malaria.
• diseases of the blood, such as leukemia, lymphoma, and sickle cell disease.
• some medicines and drugs, such as nonsteroidal anti-inflammatory drugs, and some medicines used to treat mood disorders, bone loss, or cancer.

Congenital nephrotic syndrome

Among newborns and infants younger than 12 months old, the two most common causes of nephrotic syndrome are

• genetic variants, which account for most cases of congenital nephrotic syndrome
• infections present at or before birth, such as syphilis and toxoplasmosis

Pathophysiology

The pathogenesis of focal segmental glomerular sclerosis (FSGS) involves a complex interplay of several cell types including podocytes, endothelial cells, and the basement membrane. Podocytes are terminally differentiated cells that provide structural support to the glomerulus and are essential in maintaining an intact glomerular filtration barrier essential to prevent nephrotic range proteinuria. Injury and loss of podocytes result in podocyte hypertrophy of remaining podocytes to cover the glomerular capillary surface resulting in effacement and protein loss.

Histopathology

Histologically, focal segmental glomerular sclerosis (FSGS) is characterized by sclerosis, hyalinosis, adhesions/synechiae formation, resulting in segmental obliteration of glomerular capillaries. On EM, foot process effacement is the predominant finding without significant basement membrane abnormalities. Immunofluorescence shows staining for IgM and C3 in sclerotic areas. Juxtamedullary nephrons are affected first and hence inadequate sampling may miss focal lesions.

Histologically, FSGS is classified into five variants: perihilar, tip, cellular, collapsing and NOS (not otherwise specified).

Perihilar: The sclerosing lesion is located at the vascular pole of the glomerulus. This is commonly seen in adaptive FSGS due to increased pressure in the glomerulus which is in close proximity to the afferent arteriole. Foot process effacement is mild, resulting in subnephrotic proteinuria and relatively normal serum albumin levels.

Tip: The segmental lesion involves the tubular pole of the glomerulus. This is commonly seen in Caucasians, presenting with diffuse foot process effacement and abrupt onset of nephrotic syndrome. These patients have lower baseline creatinine, have an excellent response to treatment, and the lowest rate of progression.

Cellular: This is the least common variant of FSGS, characterized by hypercellular glomerulus including endocapillary and glomerular epithelial cell hyperplasia. It presents with diffuse foot process effacement and full-blown nephrotic syndrome.

Collapsing:- This is characterized by hyperplasia and hypertrophy of visceral glomerular epithelial cells leading to the collapse of the glomerular tuft. This is commonly seen in viral (parvovirus B19, CMV, HIV) and drug-associated forms of FSGS (IFN, pamidronate) and presents with diffuse effacement of foot processes, heavy proteinuria with the lowest rate of remission, and the worst prognosis.

NOS: This is the most common subtype of FSGS and does not fit into any other morphological forms of FSGS. It presents with a variable degree of effacement and proteinuria.

Histopathology may sometimes resemble nodular sclerosis as in diabetes and other conditions.

History and Physical

Children with focal segmental glomerular sclerosis (FSGS) typically present with the full-blown nephrotic syndrome (edema, massive proteinuria, hypoalbuminemia, hypercholesterolemia). Adults can have nephrotic or sub-nephrotic proteinuria, hypertension, microscopic hematuria, or present with renal insufficiency. Patients with primary FSGS often have profound hypoalbuminemia and edema, but these are rare in secondary forms.

It is essential to obtain an extensive history including birth history (low birth weight/premature birth, congenital renal malformations), family history, medical comorbidities, pre-existing renal disease, exposure to drugs/toxins, recent viral illnesses, and family history to identify secondary causes of FSGS.

Evaluation

1. Basic laboratory tests including metabolic panel, lipid panel, serum albumin

2. urinalysis with microscopy

3. 24-hour urine collection for protein quantification

4. Hepatitis and HIV serology

5. Complement levels

6. Serum and urine protein electrophoresis in elderly to rule out paraproteinemias

Ultimately, a kidney biopsy is required to confirm the diagnosis of FSGS.

Treatment / Management

Glucocorticoids (daily or every other day) are the first line of treatment in children and adults with focal segmental glomerular sclerosis (FSGS). Patients who are resistant or intolerant to steroids are treated with immunosuppressive therapy with calcineurin inhibitors (CNI), mycophenolate mofetil, or rituximab.

• Oral prednisone: 2 mg/kg/day for 6 weeks followed by 1 mg/kg/day on alternate days for 6 weeks in children and 1mg/kg/day for 3 to 6 months in adults

• CNI: Tacrolimus (0.2 to 0.3 mg/kg/day) or cyclosporine (3 to 5 mg/kg/day) for 6 to 12 months

• MMF: 25 to 35 mg/kg/day +/- dexamethasone

In patients with subnephrotic proteinuria, adaptive FSGS, a trial of RAS inhibition, and sodium restriction can be tried. In other secondary forms of FSGS, removing the offending agent or treating the underlying disorder is recommended. Optimization of blood pressure, treatment of edema with diuretics, statin therapy for hypercholesterolemia and anticoagulation in select patients at risk for thrombosis/embolization are indicated.

Children respond within a few weeks, but adults may take months to respond. Glucocorticoids are associated with a remission rate of approximately 30% compared to about 50% in patients treated with CNI. Rituximab, mTOR inhibitors, and plasmapheresis have been tried in select patients with varied results.

Differential Diagnosis

• Hematuria

• Mesangial proliferative glomerulonephritis

• Membranoproliferative glomerulonephritis

• Nephrotic syndrome

• Nephropathy

• Systemic lupus erythematosus

Prognosis

Several features predict outcome in FSGS including, race (Blacks have worse outcomes), degree of proteinuria, presence of renal insufficiency, histological variant (tip variant had the best outcome and collapsing variant had the worst outcome), degree of IFTA (interstitial fibrosis/tubular atrophy) and response to treatment with patients attaining partial or complete remission having better prognosis. Also, patients with primary FSGS did worse when compared to those with adaptive/secondary causes of FSGS.

Enhancing Healthcare Team Outcomes

Focal segmental glomerular sclerosis (FSGS) is a frequently encountered cause of nephrotic syndrome, accounting for 40% of cases in adults and 20% in children. Because of the numerous causes and varied presentation, the condition is best managed by an interprofessional team that includes a nephrologist, pharmacist, internist, and pathologist.

Several features predict outcome in FSGS including, race (Blacks have worse outcomes), degree of proteinuria, presence of renal insufficiency, histological variant (tip variant had the best outcome and collapsing variant had the worst outcome), degree of IFTA (interstitial fibrosis/tubular atrophy) and response to treatment with patients attaining partial or complete remission having better prognosis. Also, patients with primary FSGS did worse when compared to those with adaptive/secondary causes of FSGS. (Level V)