Introduction
Congenital nephrotic syndrome (CNS) begins soon after birth and typically progresses to end-stage renal disease. The symptoms of the condition appear within three months of birth. It is primarily caused due to genetic mutations causing damage to the kidneys' filtration barrier, resulting in excessive loss of plasma protein in the urine. Early diagnosis is essential to prevent mortality. With proper treatment, it is found to show good results.
What Is Congenital Nephrotic Syndrome?
It is a genetic condition characterized by heavy proteinuria (protein in the urine) and edema (collection of fluid in the interstitial spaces) of body parts that typically leads to end-stage renal disease.
What Is the Inheritance Pattern of Congenital Nephrotic Syndrome?
CNS is found to show autosomal recessive inheritance patterns in which both parents carry one copy of the mutated gene, and both genes should be mutated to cause the disease in an individual.
What Is the Etiology of Congenital Nephrotic Syndrome?
Studies have shown that most cases of congenital nephrotic syndrome occur due to the mutation in NPHS1 (nephrin gene) and NPHS2 (podocin gene), which are found in podocytes of glomeruli. Other reported causes include:
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LamB2 (Laminin subunit Beta 2) gene mutations.
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PLCE1 (Phospholipase C Epsilon1) gene mutations.
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LMX1B (LIM homeobox transcription factor 1-beta) mutations.
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LamB3 (Laminin 332) gene mutations.
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Mitochondrial myopathies (a neuromuscular disease caused by damage to the mitochondria).
It may occur secondary to the following:
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Congenital syphilis is a disease that occurs when a mother with syphilis passes the infection to her baby during pregnancy.
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Toxoplasmosis is a disease caused due to infection of the Toxoplasma gondii parasite.
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Viral infections.
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Maternal systemic lupus erythematosus is the systemic lupus erythematosus affecting women during pregnancy.
What Are the Types of Congenital Nephrotic Syndrome?
Congenital nephrotic syndrome is of three types based on the gene mutation causing the disease:
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NPHS1 CNS or Finnish Type of CNS - Caused due to mutation in NPHS1 or nephrin gene, most common in the Finnish population and hence the name.
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NPHS2 CNS or Childhood CNS - Caused due to mutation in NPHS2 or podocin gene
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Other Genetic Forms - Caused due to mutation in other genes (LAMB2, LAMB3, LMX1B, etc.)
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Nongenetic Type of CNS - Caused due to reasons other than genetic.
What Is the Epidemiology of Congenital Nephrotic Syndrome?
NPHS1 type is predominantly found in the Finnish population; studies report that it affects 1 in 10,000 children in Finland. In general, CNS affects 1 to 3 per 1,00,000 children worldwide.
What Is the Pathogenesis of Congenital Nephrotic Syndrome?
The NPHS1 and NPHS2 genes found in the podocyte cell surface produce proteins that regulate the function of the slit diaphragm. The slit diaphragm is the area between two podocytes, called the filtration barrier, as it arrests proteins from the blood from being excreted and allows sugar and salts to be excreted in the urine. The mutation of NPHS1 and NPHS2 genes will result in defective protein production, which alters the functional capacity of the slit diaphragm. With the defective or nonfunctional slit diaphragm, more molecules, including protein and blood cells, pass through the kidney abnormally. This, in turn, affects the kidneys' filtering capacity, which starts from birth and typically results in renal failure.
What Are the Symptoms of Congenital Nephrotic Syndrome?
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Generalized Edema - This refers to fluid collection in the interstitial spaces causing swelling of the body parts.
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Ascites - Fluid collection in the abdomen leading to abdominal distension.
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Pulmonary Edema - This fluid collection in the lungs leads to coughing in children.
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Foamy Appearance of the Urine - Due to excess leakage of protein in the urine.
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Widened Fontanelles - Cranial structures and fontanelles appear widened due to fluid retention.
How Is Congenital Nephrotic Syndrome Diagnosed?
The steps in diagnosis involve:
Medical and Family History:
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Medical and family history will help understand the symptoms and the possible genetic link in patients with the underlying disease.
Clinical Examination:
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Clinical examination of the patient would reveal generalized body swelling due to fluid retention. In addition, high blood pressure, abnormal heart sounds, and signs of malnutrition may be appreciated.
Urine Analysis:
Urinalysis will reveal the presence of,
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Proteinuria - Protein in the urine decreases during the initial stages and increases as the disease progresses.
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Blood Cells in Urine - Small amounts of red blood cells (RBC) and white blood cells (WBC) will be present in the urine.
Blood Examination:
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Hypoproteinemia - Decreased serum protein levels, especially albumin, due to increased loss in urine.
Kidney Function Test:
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Renal function may appear normal for the first few months, after which renal failure develops faster.
Kidney Ultrasound:
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The kidneys may appear normal or larger than normal with the hypoechogenic renal cortex.
Kidney Biopsy:
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Though microscopic findings do not help in finding the cause of the disease, it helps in treatment planning. Light microscopic findings reveal the presence of focal segmental glomerulosclerosis and mesangial expansion. In addition, the stroma may show fibrosis and inflammation.
Genetic Analysis:
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Genetic analysis helps in understanding the etiology of the disease, which assists in managing the disorder. Therefore, analysis for the mutation in the NPHS1 and NPHS2 genes is indicated in all cases of CNS. If this appears negative, tests for other gene mutations should be considered.
Prenatal Testing:
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It is carried out during pregnancy in families with a known history of CNS. NPHS1 mutation can also be detected prenatally with increased alpha-fetoprotein levels in the amniotic fluid and maternal serum.
What Are the Complications of Congenital Nephrotic Syndrome?
The possible complications of congenital nephrotic syndrome include:
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Malnutrition.
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Frequent infections.
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Poor growth.
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Renal failure.
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Thromboses.
How Is Congenital Nephrotic Syndrome Managed?
Unlike other genetic disorders of the kidney, the congenital nephrotic syndrome does not respond to immunosuppressants and corticosteroids. Therefore, the main aim of the treatment is to reduce the loss of protein in the urine and edema to prevent complications and promote the child's proper growth.
The steps in management include:
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Protein Substitution - 20% albumin infusion to compensate for the protein loss.
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ACE Inhibitors - Angiotensin-converting enzyme inhibitors can be given to reduce protein loss in the urine.
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Thyroxine Substitution - Given to compensate for the low levels of serum thyroid binding protein and thyroxine.
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Nutrition - Children affected with CNS should be treated with a high protein and high energy diet. Breast milk, formula milk, and casein-based protein products can be given. Glucose polymers, vitamin D2, and multivitamin supplements can be given according to the recommended dietary allowances.
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Nephrectomy - In some cases, unilateral nephrectomy is performed to reduce the amount of protein loss from the body. An early bilateral nephrectomy is performed in a few cases, and the patient is put under peritoneal dialysis to avoid complications. Later kidney transplantation is performed.
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Kidney Transplantation - It is the most preferred treatment method in CNS. After transplantation, adequate hydration is necessary to maintain the blood flow to the heart and the kidneys, as reduced blood flow may cause damage to the grafted kidneys.
Conclusion
Congenital nephrotic syndrome is a rare but serious condition affecting children. Excessive protein loss and generalized edema will result in complications and rapidly developing kidney failure. Early diagnosis and treatment are mandatory to prevent complications. The prognosis of patients after kidney transplantation is good, and the five-year survival rate is 90 %.
