Continuing Education Activity

Congenital nephrotic syndrome (CNS) is defined when it presents within three months of birth. It consists of heavy proteinuria, edema, hypoalbuminemia, hypogammaglobulinemia, hypercoagulability, and hyperlipidemia. Management is very challenging as patients are prone to complications such as infection, thrombosis, and failure to thrive. This activity outlines the evaluation and treatment of congenital nephrotic syndrome and emphasizes the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Identify the etiology of congenital nephrotic syndrome.
• Review the appropriate evaluation of congenital nephrotic syndrome.
• Outline the management options for congenital nephrotic syndrome.
• Summarize the importance of collaboration amongst the multidisciplinary team to add to the care of patients with congenital nephrotic syndrome.

Introduction

Congenital nephrotic syndrome (CNS) is defined when it presents within three months of birth. It consists of heavy proteinuria, edema, hypoalbuminemia, hypogammaglobulinemia, hypercoagulability, and hyperlipidemia.[1] The infantile nephrotic syndrome presents within 4 to 12 months, and nephrotic syndrome manifesting after one year is called childhood nephrotic syndrome.[2]

Etiology

The etiology of congenital nephrotic syndrome is heterogeneous. The etiology can be divided into genetic, non-genetic, and infectious. 

Most congenital nephrotic syndrome cases are genetic due to monogenic defects of structural proteins that form the kidney filtration barrier.[3] The most common cause is the congenital nephrotic syndrome of the Finnish type (CNF). It is named due to its high incidence in Finland and is inherited as autosomal recessive. Congenital nephrotic syndrome of the Finnish type is caused by a mutation in the gene NPHS1 encoding nephrin, one of the structural proteins that form the kidney filtration barrier.[3] As NPHS1 is expressed exclusively in the kidney podocyte, congenital nephrotic syndrome of the Finnish type does not have extrarenal findings.[4]

Epidemiology

The incidence of congenital nephrotic syndrome is between 1 and 3 per 100,000 live births. Congenital nephrotic syndrome of the Finnish type, CNF, is prevalent in Finland with an incidence of 1 per 8,200 births.[3][5][6]

Pathophysiology

In Congenital nephrotic syndrome of the Finnish type, the primary defect is the loss of proteins in the kidney. Congenital nephrotic syndrome of the Finnish type is due to mutation of the NPHS1 gene on chromosome 19 encoding nephrin, one of the structural proteins that form the kidney filtration barrier. The kidney filtration barrier has three layers of epithelial cell layer composed of (podocyte) with distal foot processes and slit diaphragms (SD) interspersed, glomerular basement membrane (GBM), and fenestrated capillary endothelium. Nephrin localizes to the slit diaphragm, and its defect leads to proteinuria.[2] 

Proteinuria leads to albuminuria, hypoalbuminemia, and edema. Hyperlipidemia is due to the increased lipoprotein synthesis secondary to hypoalbuminemia, which causes increased platelet aggregation and thrombosis. The loss of minerals and vitamins predispose to malnutrition and infections.[6] Hypothyroidism develops due to the loss of thyroid-binding globulin in the urine.[4]

Histopathology

The most typical feature in the histology of congenital nephrotic syndrome of the Finnish type is irregular microcystic dilatation of the proximal tubule.[3] The glomeruli are normal or may show matrix expansion and mesangial hypercellularity.[7]

History and Physical

Prenatal and perinatal history: placental weight below 25% of newborn weight, enlarged prenatal nuchal translucency, fetal edema, increased amniotic fluid alpha-fetoprotein, and oligohydramnios 

Family history: history of congenital nephrotic syndrome, consanguinity, ethnicity, early infantile death,  neurological and kidney diseases of infancy.

Patient history: swelling, poor growth

Physical examination: signs of edema (e.g., pericardial, pleural effusions, and ascites.

Evaluation

Congenital nephrotic syndrome of the Finnish type can be diagnosed prenatally by elevated maternal serum alfa fetoprotein, MSAFP (>2.5 MoM) at the second trimester of pregnancy.

Thyroid-stimulating hormone (TSH) may be normal in the beginning but typically increases during the first month. Free thyroxine (T4) is low.

Blood biochemistry: blood count, levels of sodium, chloride, magnesium, protein, albumin,  creatinine, urea, cholesterol, fasting triglycerides, and glucose.

Other factors included in the evaluation include:

• Serum IgG level. Serum levels of  phosphate, ionized calcium, 25(OH) vitamin D3, alkaline phosphatase, and PTH
• Serum urea and creatinine levels are variable. Renal function is often normal for the first months.[2]
• The serum analysis demonstrates hypoalbuminemia (<2.5 mg/dL and low thyroid hormone level.[4]
• The urinalysis demonstrates proteinuria (>2000 mg/L), hematuria, and leukocyturia with a negative urine culture.[4]
• Ultrasound scanning shows kidneys of normal size or larger, and the renal cortex is hyperechogenic.[2] 
• Cardiac ultrasound (effusions and left ventricular mass)

Kidney biopsy demonstrates microcystic dilatation of proximal tubules, increased mesangial hypercellularity, and a mild increase in the mesangial matrix in light microscopy. Electron microscopy demonstrates the effacement of podocyte foot processes. [4]

The modality of choice for precise Congenital nephrotic syndrome of the Finnish type diagnosis is the genetic analysis by detection of mutations in NPHS1.[4]

Treatment / Management

Congenital nephrotic syndrome therapy goals are to control edema, prevent and treat complications including infections and thromboses, and provide optimal nutrition for the child to help grow. Kidney transplantation is the only curative treatment in most cases.[2]

Albumin Infusions

Proteinuria leads to life-threatening complications, including protein malnutrition, edema, and reduced growth.

Protein substitution by parenteral albumin infusions is required for heavy and constant proteinuria (10 to 100 g/L).  Usually (3 to 4 g/kg per day of albumin), 20% albumin solution together with a bolus of intravenous furosemide (0.5 mg/kg) using central venous catheters is given.

Medications 

Angiotensin-converting enzyme (ACE) inhibitors and indomethacin are used to reduce the protein excretion in urine. 

Thyroxine substitution is recommended in congenital nephrotic syndrome patients for low levels of serum thyroid-binding globulin and thyroxine. Thyroxine can be started with 6.25 to 12.5 μg/day and can be adjusted as per TSH levels.

Anticoagulation 

Imbalance of plasma coagulation factor levels due to protein loss in urine results in a risk for thromboses. Aspirin and dipyridamole have been recommended for anticoagulation therapy. 

Nutrition 

Congenital nephrotic syndrome is treated with a high-energy (130 kcal/kg per day) and a high-protein (3 to 4 g/kg per day) diet. First, Breast milk and milk formulas are used. Excessive protein is used as a  casein-based protein. A mixture of rapeseed and sunflower oils is given as lipid supplementation. Vitamin D2 (400 IU/day), magnesium (50 mg/day) and calcium (500 to 1,000 mg/day) are given. Daily water intake is 100 to 130 mL/kg. 

Nephrectomy  

One approach is to do a unilateral nephrectomy to reduce protein loss and decrease the frequency of the albumin infusion. Another approach is to do an early bilateral nephrectomy and start peritoneal dialysis. When the baby is 7 kg of weight, bilateral nephrectomy is done, and start peritoneal dialysis.[8] Renal transplantation with the extraperitoneal placement of the kidney graft is performed later when the child weighs more than 9 kg. The third approach is to perform early, preemptive kidney transplantation with an intraperitoneal placement and removing the nephrotic kidneys at the same operation.

Renal transplantation

Congenital nephrotic syndrome children are usually transplanted at 1 to 2 years of age

Treatment Summary

Differential Diagnosis

The Finnish type's genetic form of congenital nephrotic syndrome can be divided as autosomal dominant or  (AD) autosomal recessive (AR).[3]

Denys-Drash syndrome (DDS) is characterized by male pseudo-hermaphroditism, Wilms tumor, and early-onset nephrotic syndrome that progress rapidly to end-stage renal disease.[9] Renal biopsy mostly reveals diffuse mesangial sclerosis (DMS) of glomeruli.[2]

Frasier syndrome (FS) is characterized by progressive glomerulopathy, male pseudo-hermaphroditism, and gonadoblastomas. Proteinuria is usually detected between 2 and 6 years of age. The disease has a slower progression to end-stage renal disease than DDS. Renal biopsy shows FSGS.[9]

Pierson's syndrome is characterized by congenital nephrotic syndrome/diffuse mesangial sclerosis, microcoria (small pupils), impairments of vision, and muscular hypotonia. Children with Pierson syndrome usually die from renal failure within days or weeks after birth.[3]

Nail-patella syndrome is characterized by dysplastic or absent finger- and toenails, small or absent patellar, and kidney involvement ranging from mild proteinuria to end-stage renal failure.[10] 

Galloway Mowat syndrome (GMS) is characterized by microcephaly with various central nervous system anomalies and early-onset nephrotic syndrome.[3] Other additional findings include microphthalmos, epicanthic folds, a narrow slopping forehead, a highly arched palate, large low-set floppy ears, a small midface, a beaked nose, thin lips, clenched hands, and arachnodactyly.[11]

Infectious causes of congenital nephrotic syndrome are congenital syphilis, toxoplasmosis, or viral infections as cytomegalovirus. The prognosis is good.[3]

Congenital syphilis causes congenital nephrotic syndrome commonly in developing countries. Congenital syphilis presents with fever, anemia, persistent rhinitis, hepatitis, hepatosplenomegaly, neurosyphilis, desquamations, and erythematous patches with superficial bullae. Renal involvement varies from microscopic hematuria to nephrotic syndrome. The nephrotic syndrome usually appears between 2 and 3 months. Membranous nephropathy is a common finding in renal biopsy. The immune system is involved in the pathogenesis, as evidenced by immune deposits in the region of the glomerular basement membrane. Prognosis is good as antimicrobial therapy. Usually, penicillin is curative.[3]

Congenital toxoplasmosis is a rare cause of nephrotic syndrome. It is usually caused by intrauterine toxoplasmosis infection in the mother. Congenital toxoplasmosis is associated with massive proteinuria, hypoalbuminemia, anasarca, and positive IgM serum antibody for toxoplasmosis.  In congenital nephrotic syndrome caused by toxoplasmosis, diffuse mild increase in mesangial cells and extensive glomerulosclerosis is a common finding in renal biopsy.[3] After spiramycin treatment for three weeks, proteinuria is negative, and serum toxoplasmosis IgM antibody titer vanish. 

In western countries, cytomegalovirus infection is one of the common causes of congenital infections. Incidence varies between 0.15% and 2%. Cytomegalovirus infection presents with anemia, thrombocytopenia, pulmonary infection, and congenital nephrotic syndrome. Diagnosis is confirmed by the detection of viral DNA by quantitative PCR assay. Diffuse mesangial sclerosis (DMS) is often seen on histological examination on renal biopsy. Tubular cells and glomeruli may show cytomegalic inclusion bodies.[3] Clinical response to ganciclovir therapy for 3 weeks is excellent.[12]

Non-genetic causes of congenital nephrotic syndrome are neonatal alloimmunization, renal vein thrombosis, maternal systemic lupus erythematosus, and mercury poisoning.[3]

Neonatal alloimmunization Mother has mutations in the metallomembrane endopeptidase gene, which encodes the podocyte protein neutral endopeptidase (NEP). Pathogenesis involves the absence of the neutral endopeptidase (NEP) in the mother that induces an alloimmunization process against the NEP of fetal cells. Pregnant mothers with a deficiency of neutral endopeptidase (NEP) produce anti–neutral endopeptidase (NEP) antibodies resulting in fetal podocyte insult and nephron loss.[3]

Prognosis

The course of the congenital nephrotic syndrome of the Finnish type is progressive, leads to end-stage renal disease by 2-3 years of age. Prognosis is worse in NPHS1 gene mutations compared with NPHS2 gene mutations. Prognosis is different in patients with different ethnic backgrounds. Female patients with NPHS1 mutations have longer survival than their male counterparts.[3] Kidney transplantation is the only curative treatment in most cases. Overall, the results of kidney transplantation in congenital nephrotic syndrome are quite good. The patient's 5-year survival rate is over 90%, and the graft survival rate is over 80%.[2]

Complications

Congenital nephrotic syndrome is more susceptible to infection with encapsulated organisms such as Haemophilus influenzae, Escherichia coli, and Streptococcus due to losses of alternative complement pathway components into the urine.[4]

Thromboembolism due to urinary loss of antithrombin III and increased synthesis of procoagulant factors by the liver. Types of thrombosis include central sinus thrombosis, deep vein thrombosis, renal vein thrombosis, and pulmonary embolism.[4]

Failure to thrive, protein malnutrition, and vitamin deficiency.

Low levels of thyroxin and serum thyroid-binding globulin due to protein excretion.[2]

Enhancing Healthcare Team Outcomes

Congenital nephrotic syndrome (CNS) is defined when it presents within three months of birth. It consists of heavy proteinuria, edema, hypoalbuminemia, hypogammaglobulinemia, hypercoagulability, and hyperlipidemia.[1] Management is very challenging as patients are prone to complications such as infection, thrombosis, and failure to thrive. 

The recommendation is that patients with congenital nephrotic syndrome require referral to tertiary pediatric nephrology center and treatment by an interprofessional team that includes pediatric nephrologists, pediatric nephrology nurses, pediatric hemodialysis nurses, pediatric peritoneal dialysis nurses, pediatric renal dieticians, pediatric renal transplant surgeons, renal pharmacists, neonatologist and child psychologists and social workers. Through interprofessional care coordination, open communication, and information sharing, patients will have a better chance at improved outcomes. [Level 5]