Introduction
Background
Nephrotic syndrome is not a disease. The term nephrotic syndrome was coined by Calvin and Goldberg. The syndrome is characterized by heavy proteinuria, hypoalbuminemia, edema, hypercholesterolemia, and normal renal function.Because other eMedicine articles emphasize different glomerulopathies encountered in adults (eg, see Glomerulonephritis, Acute; Glomerulonephritis, Chronic; Glomerulonephritis, Crescentic; Glomerulonephritis, Diffuse Proliferative; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Glomerulonephritis, Nonstreptococcal Associated with Infection; Glomerulonephritis, Poststreptococcal; or Glomerulonephritis, Rapidly Progressive), this article mainly focuses on pediatric nephrotic syndrome.
ClassificationNephrotic syndrome can be primary, occurring as part of a recognized systemic disease, or secondary, resulting from some evident cause.
Primary causes include the following:
- Postinfectious etiologies
- Collagen vascular disease (eg, systemic lupus erythematosus [SLE], rheumatoid arthritis, polyarteritis nodosa)
- Henoch-Schönlein purpura
- Hereditary nephritis
- Sickle cell disease
- Diabetes mellitus
- Amyloidosis
- Malignancy (eg, leukemia, lymphoma, Wilms tumor, pheochromocytoma)
- Toxins (eg, bee sting, poison ivy and oak, snake venom)
- Medications (eg, probenecid, fenoprofen, captopril, lithium, warfarin, penicillamine, mercury, gold, trimethadione, paramethadione)
- Heroin use
Secondary causes are related to postinfectious causes and include the following:
- Group A beta-hemolytic streptococci
- Syphilis
- Malaria
- Tuberculosis
- Viral infections (eg, varicella, hepatitis B, HIV type 1, infectious mononucleosis)
Nephrotic syndrome can be classified further according to histological findings. According to the International Study of Kidney Diseases in Childhood (ISKDC), 84.5% of all children have minimal-change nephrotic syndrome (MCNS), 9.5% have focal segmental glomerulosclerosis (FSGS), 2.5% have mesangial proliferation, and 3.5% have membranous nephropathy or other etiologies. Increasing trends of FSGS incidence in children with idiopathic nephrotic syndrome are being reported, but MCNS remains the most important cause of chronic renal disease in children. MCNS is a disorder of primary T lymphocyte dysfunction, where the lymphocytes are altered with IL2 expression during a relapse, resulting in increased vascular and glomerular basement membrane (GBM) permeability, leading to the typical clinical features seen in nephrotic syndrome.
The histological classifications of glomerular lesions associated with primary and secondary nephrotic syndrome are minimal-lesion nephrotic syndrome, diffuse mesangial hypercellularity, focal glomerulosclerosis, membranous glomerulonephritis, fibrillary glomerulosclerosis, and membranoproliferative glomerulonephritis.
The classifications of primary congenital nephrotic syndrome include infantile microcystic disease (Finnish type), infantile microcystic disease (non-Finnish type), diffuse mesangial sclerosis, minimal-lesion nephrotic syndrome, and FSGS.
The classifications of secondary congenital nephrotic syndrome include intrauterine infections (eg, toxoplasmosis, cytomegalovirus, rubella, syphilis), gonadal dysgenesis, nail-patella syndrome, and Lowe syndrome.
From a therapeutic perspective, nephrotic syndrome may be classified as steroid sensitive, steroid resistant, steroid dependent, or frequently relapsing.
Pathophysiology
Filtration of low molecular weight anionic plasma proteins across the glomerular basement membrane is normally prevented by a negatively charged filtration barrier, which consists of proteoglycan molecules of heparan sulfate. In persons with nephrotic syndrome, the concentration of heparan sulfate mucopolysaccharide in the basement membrane is lower, and large amounts of protein cross the barrier and are excreted.
High glomerular permeability leads to hyperalbuminuria and, eventually, to hypoalbuminemia. In turn, hypoalbuminemia lowers the plasma colloid osmotic pressure, causing greater transcapillary filtration of water and the development of edema.
Capillary hydrostatic pressure and the gradient of plasma to interstitial fluid oncotic pressure determine the movement of fluid from the vascular compartment to the interstitium. The oncotic pressure is mainly determined by the protein content, and the interstitial fluid has a protein concentration of 25-50% that of plasma. Fluid that is not absorbed back into the vascular system until it has reached the venous end of the capillary bed is usually absorbed by the lymphatics and returned back to the vascular space. In a steady state, the flux of water across the capillary wall can be expressed by the following formula:
Qw = K ([Pc - Pi] - [p p - [p i]
In this formula, Qw is net flux of water, K is the capillary filtration coefficient, Pc is plasma fluid hydrostatic pressure, and Pi is the interstitial fluid hydrostatic pressure. Also, p p is the plasma oncotic pressure, and p i is the interstitial fluid oncotic pressure. When the fall of D p is wide, the amount of fluid filtered exceeds the maximal lymphatic flow, and edema occurs. In most patients with nephrotic syndrome, this causes a reduction in plasma volume. A hyperreninemic state ensues, resulting in increased sodium and water retention by the kidney.
An alternate hypothesis is that a condition of renal sodium retention occurs because of the proteinuria, but this is not related to intravascular volume or serum protein concentration. The evidence supporting this hypothesis is (1) sodium retention is observed even before the serum albumin level starts falling; (2) intravascular volume is normal or even increased in most patients with nephrotic syndrome; (3) Starling forces are unchanged in nephrotic syndrome until late in the disease course because p i remains equivalent to p p; and (4) the sites of renal sodium retention are predominantly in the distal nephron, not in the proximal nephron, as is expected by changes in Starling forces.
Hypoalbuminemia results mainly from increased catabolism and is not caused only by urinary loss of albumin; however, no evidence of decreased albumin synthesis exists in patients with nephrotic syndrome.
The structural changes believed to be responsible for causing proteinuria are (1) damage to the endothelial surface, causing loss of the negative charge; (2) damage to the glomerular basement membrane; and (3) effacement of the foot processes.
The foot processes are firmly attached to the visceral surface of the glomerular basement membrane. The space between the bases of the foot processes form the filtration slits, and this space constitutes the site for the convective forces that govern the filtration through the visceral epithelium. The podocyte forms a cover to the filtration slits. To date, they seem to have receptors for vasoactive agents such as endothelin, atrial natriureteric peptide, nitrous oxide, and, possibly, angiotensin II. Recently, congenital nephrotic syndrome of the Finnish type has been determined to be caused by mutations in the gene known as NPHS1. This gene codes for a cell adhesion protein called nephrin, which is synthesized by podocytes.
The role of nephrins in acquired kidney diseases in not known; however, nephrin and another podocyte protein called podocin are associated with the development of proteinuria, at least in the congenital type of nephrotic syndrome and in experimental models of glomerular disease.
Recently, the tandem endocytic receptors megalin and cubilin in the luminal membrane of proximal tubule cells have been shown to play an important role in endocytosis of albumin and low molecular weight proteins that may be filtered in the glomerulus. The presence of these receptors likely serves to protect the tubules from the toxic effects of undegraded albumin. These receptors are not specific for albumin. Therefore, proteinuria is now believed to be at least partly due to inhibition of albumin retrieval and degradation pathways.
Urinary immunoglobulin losses lower the patient's resistance to infections and increase the risk of serious sepsis and peritonitis. The loss of antithrombin III and plasminogen via urine and the simultaneous increase in clotting factors, especially factors I, VII, VIII, and X, increases the risk for arterial thrombosis, venous thrombosis, and pulmonary embolism, which occurs in 5% of children with nephrotic syndrome.
High glomerular permeability causes the excretion of vitamin D–binding protein and complexes in the urine, leading to (1) malabsorption of calcium and development of bone disease (eg, osteitis fibrosa cystica) because of enhanced parathyroid hormone production and (2) osteomalacia because of impairment in mineralization.
In the nephrotic state, levels of almost all serum lipids are elevated. Two pathogenic processes are operative, including (1) hypoproteinemia stimulating generalized protein synthesis in the liver, including the lipoproteins, and (2) diminution of lipid catabolism caused by reduced plasma levels of lipoprotein lipase.
Frequency
United States
The incidence of nephrotic syndrome is reportedly 2-7 cases in children per 100,000 children per year. However, in adults, the frequency varies significantly in different regions. Because of a much higher prevalence of diabetic nephropathy, which varies significantly from region to region, the incidence of nephrotic syndrome tends to be higher in the southern region compared to the northern region.
Mortality/Morbidity
- Although most adult patients have a glomerulopathy that is secondary to a systemic disease process (eg, diabetes mellitus, hypertension, SLE), primary or idiopathic glomerulonephritis is not uncommon.
- In most patients, the mortality rate is directly related to the primary disease process; however, once nephrotic syndrome manifests, the prognosis worsens because of (1) the increased incidence of renal failure and the complications secondary to nephrotic syndrome (eg, thrombotic episodes, hypoalbuminemia, hyperlipidemia) or (2) the treatment-related conditions (eg, increased incidence of infection from steroid therapy and blood dyscrasia from other immunosuppressive medications).
Race
- Because diabetes is now emerging as a major cause of nephrotic syndrome, American Indians, Hispanic persons, and African Americans have a clearly higher incidence of nephrotic syndrome compared to white persons.
Sex
- Incidence varies according to the type of glomerular disease.
Age
- Nephrotic syndrome is 15 times more common in children than in adults. Most cases of primary nephrotic syndrome are in children and are due to minimal-change disease. The age at onset varies with the type of nephrotic syndrome.
- In adults, the most common form of glomerulopathy causing nephrotic syndrome is membranous glomerulonephritis, followed by FSGS. In certain countries and in certain regions of the same country, diabetic nephropathy is emerging as a major cause of nephrotic syndrome.
Clinical
History
- The first sign in children is usually swelling of the face; periorbital edema is a common presentation. This is followed by swelling of the entire body.
- Adults can present with edema of dependent parts. In most cases, this includes the ankles or legs.
- Facial swelling or anasarca can be the presenting symptom.
- In certain instances, patients notice frothy urine, which leads to investigations that reveal evidence of nephrotic syndrome.
- A hypercoagulable state leading to thrombotic complications, such as deep vein thrombosis of the calf veins or the renal vein, may be the first clue indicating nephrotic syndrome.
Physical
- Patients present with increasing edema over a few days or weeks, lethargy, poor appetite, weakness, and occasional abdominal pain.
- The initial episode and the subsequent relapses may follow an apparent viral upper respiratory tract infection.
- Edema is the predominant feature and initially develops around the eyes and lower extremities. With time, the edema becomes generalized and may be associated with an increase in weight, the development of an ascitic or pleural effusion, and a decline in urine output.
- Hematuria and hypertension are unusual but manifest in a minority of patients.
Causes
- Nephrotic syndrome reportedly has a familial cause in 2-8% of patients, and most familial cases involve siblings.
- Congenital nephrotic syndrome of the Finnish type is inherited in an autosomal recessive fashion. Recently, the gene responsible for this disease entity has been identified (ie, NPHS1).
- For the other causes, see Classification in Background.
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Further Reading
Keywords
nephrosis, nephropathy, heavy proteinuria, hypoalbuminemia, hypercholesterolemia, pediatric nephrotic syndrome, collagen vascular disease, systemic lupus erythematosus, SLE, rheumatoid arthritis, polyarteritis nodosa, Henoch-Schonlein purpura, hereditary nephritis, sickle cell disease, diabetes mellitus, amyloidosis, malignancy, leukemia, lymphoma, Wilms tumor, pheochromocytoma, toxins, bee sting, poison ivy, poison oak, snake venom, snake bite, heroin group A beta-hemolytic streptococci, syphilis, malaria, tuberculosis, viral infection, varicella, hepatitis B, HIV, human immunodeficiency virus, infectious mononucleosis, minimal-lesion nephrotic syndrome, diffuse mesangial hypercellularity, focal glomerulosclerosis, membranous glomerulonephritis, fibrillary glomerulosclerosis, membranoproliferative glomerulonephritis, infantile microcystic disease, Finnish type infantile microcystic disease, diffuse mesangial sclerosis, focal segmental glomerulosclerosis, FSGS, intrauterine infections,toxoplasmosis,cytomegalovirus, rubella, gonadal dysgenesis, nail-patella syndrome, Lowe syndrome
