Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Glomerulonephropathies and Disorders of Tubular Function
Key Points
-
Nephrotic syndrome (NS) comprises persistent heavy proteinuria, hypoalbuminemia, edema, and hyperlipidemia.
-
Genetic abnormalities of structural or regulatory proteins within the glomerular basement membrane and/or podocyte lead to primary congenital NS (CNS).
-
Treatment of CNS does not involve immunosuppression and is aimed at minimizing symptoms and preventing serious complications.
-
Infections causing secondary NS include human immunodeficiency virus, syphilis, toxoplasmosis, hepatitis B, malaria, rubella, and cytomegalovirus.
-
Renal tubular acidosis (RTA) causes a non-anion gap metabolic acidosis. It is important to evaluate for other sources of bicarbonate (HCO 3 − ) loss before initiating a work-up for RTA and to note that immature tubular function in premature infants may cause a self-limited moderate metabolic acidosis in the first 2 weeks of life.
-
Inherited renal tubulopathies are rare and can be distinguished from each other in part by differences in serum potassium levels, presence of metabolic acidosis or alkalosis, presence of hypertension, and urine findings.
-
Fanconi syndrome is a condition of diffuse proximal tubule dysfunction resulting in polyuria and wasting of HCO 3 − , amino acids, uric acid, phosphate, glucose, and low-molecular-weight proteins. Fanconi syndrome may be due to an isolated defect or can be a part of a broader genetic syndrome.
-
Primary nephrogenic diabetes insipidus may present during pregnancy as polyhydramnios. In the newborn period, treatment should focus on maintaining adequate fluid balance.
Glomerulonephropathies
Generally, glomerulonephropathies are considered when nephrotic syndrome (NS)—the constellation of persistent heavy proteinuria, hypoalbuminemia, edema, and hyperlipidemia—is present. Greater than 40 mg/m 2 body surface area per hour of protein excretion on a 24-hour urine collection is consistent with nephrotic range proteinuria. Alternately, an untimed “spot” urine protein-to-creatinine ratio can be used when a 24-hour urine collection is impractical. In this setting, nephrotic range proteinuria is defined as a ratio of ≥2 mg protein/mg creatinine.
Congenital Nephrotic Syndrome
Congenital nephrotic syndrome (CNS) is defined as NS onset within the first 3 months of life. Infantile NS refers to NS onset within the first year of life. Both congenital and infantile NS can be divided into primary and secondary causes, with primary being the most common. Genetic abnormalities of structural or regulatory proteins within the glomerular basement membrane and/or podocyte lead to primary CNS. Podocytes are cells with extensive foot processes that wrap around the capillaries of the glomerulus to prevent loss of proteins from the capillary into the urinary space. They are anchored in place by many proteins that make up the slit diaphragm, located between podocytes ( Fig. 79.1 ). When there are abnormalities of the podocyte or slit diaphragm proteins, large molecules (such as proteins) may leak into the urinary space leading to proteinuria. Secondary CNS can be a presentation of congenital or perinatal infections or related to underlying metabolic disease. Diagnosis may be made prenatally when a positive family history is present or because of an elevated amniotic fluid alpha fetoprotein indicating fetal proteinuria. In infants, clinical concerns (e.g., edema, failure to thrive, developmental delay) or NS complications, such as thromboembolism or infection, may lead to work-up and diagnosis. Genetic screening identifies the genetic abnormality in greater than 85% of CNS patients. Renal biopsy is not generally recommended due to success and availability of genetic screening, and because biopsy findings are commonly nonspecific. The most common light microscopy findings are mesangial hypercellularity and sclerosis, dilated proximal tubules, microcystic changes, or focal segmental glomerular sclerosis (FSGS), but these are not pathognomonic. Electron microscopy demonstrates diffuse foot process effacement. Although most children with CNS require kidney transplant at a young age, there are case reports of CNS with spontaneous resolution or delayed progression, likely related to mild genetic mutations.
Primary Congenital Nephrotic Syndromes
Finnish-Type Congenital Nephrotic Syndrome (MIM #256300)
Mutations in the nephrin protein encoding gene NPHS1 are the most common cause of autosomal recessive (AR) CNS. It is referred to as CNS of the Finnish type (CNF), owing to an incidence of approximately 1 in 8000 live births in the Finnish population. Nephrin is an essential component of the podocyte slit diaphragm. The classic presentation includes placental enlargement, premature delivery, and proteinuria. Patients may have microscopic hematuria in addition to massive proteinuria, and typically present at birth or within the first 3 months of life. Cardiac abnormalities, such as pulmonary stenosis or patent ductus arteriosus, have been reported in patients with NPHS1 mutations, although severity and frequency are not well defined. Renal ultrasound images demonstrate large echogenic kidneys with poor corticomedullary differentiation. These imaging findings are similar among all forms of congenital and infantile NS.
Congenital Nephrotic Syndrome Type 2 (MIM #600995)
Podocin protein mutations in the NPHS2 gene lead to the second most common form of AR CNS. This is the most common gene implicated in CNS in central European populations. Podocin is essential for targeting nephrin to the slit diaphragm of the podocyte, and protein absence leads to early onset, severe NS. Clinical presentation is often slightly later than for NPHS1 mutations, with NS commonly presenting between 4 months and 1 year of age. Additionally, progression to end-stage kidney disease (ESKD) is thought to occur more gradually, with a mean time of 6.6 years from diagnosis to development of ESKD. Ultrasound findings are similar to other forms of congenital and infantile NS.
Wilms Tumor Suppressor Gene Mutation Syndromes (MIM #194072, 136680, 194080)
Mutations of the Wilms tumor suppressor gene ( WT1 ) may result in isolated diffuse mesangial sclerosis or be part of a syndrome associated with CNS such as Wilms tumor, aniridia, genitourinary abnormalities, and intellectual disabilities (WAGR), Frasier, or Denys-Drash syndrome. On average, ESKD occurs at 3 years of age but can occur in infancy, and disease severity is partially dependent on mutation type. Patients with WT1 mutations are at risk for Wilms tumors and gonadoblastomas and should be screened for these malignancies. Patients should also be screened with karyotype testing and, possibly, further genitourinary imaging, as they may have ambiguous genitalia or other genitourinary tract anomalies such as cryptorchidism in males or uterine abnormalities in females.
Pierson Syndrome (MIM #609049)
Pierson syndrome is an AR disorder caused by mutations in LAMB2 , which codes for the beta 2 chain of laminin, a basement membrane protein integral to the glomerular and ocular basement membranes, retina, and neuromuscular junctions. Children with Pierson syndrome classically present with NS and ophthalmic findings (often microcoria) and neurodevelopmental abnormalities such as hypotonia. Age of presentation varies depending on the mutation type, but many present within the first 3 months of life.
Other Primary Causes of Congenital Nephrotic Syndrome (MIM #251300, 161200)
Galloway-Mowat syndrome is a rare AR condition in patients with NS and central nervous system anomalies, primarily microcephaly, with a genetic defect in the WDR73 , or OSGEP , TP53RK , TPRKB , and LAGE3 genes. Case studies of other conditions such as nail–patella syndrome (an autosomal dominant [AD] condition associated with LMX1B mutations) may present with renal involvement, nail dysplasia, glaucoma, and bony anomalies classically identified by the presence of iliac horns. Though significant proteinuria may be present, this is not typically a presentation of NS.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here