- The syndrome is characterized by heavy proteinuria, hypoalbuminemia, edema, hypercholesterolemia, and normal renal function
Nephrotic 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 (e.g. systemic lupus erythematosus [SLE], rheumatoid arthritis, polyarteritis nodosa)
- Henoch-Schönlein purpura
- Hereditary nephritis
- Sickle cell disease
- Diabetes mellitus
- Malignancy (e.g. leukemia, lymphoma, Wilms tumor, pheochromocytoma)
- Toxins (e.g. bee sting, poison ivy and oak, snake venom)
- Medications (e.g. 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
- Viral infections (e.g. 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
- 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 secondary congenital nephrotic syndrome include intrauterine infections (e.g. 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
- 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.
- 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.
- 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.
- Acute management
- With good parental and patient education and close outpatient follow-up care, hospitalization is not usually necessary. Hospitalization should be considered if a patient has generalized edema severe enough to cause respiratory distress, if a patient has tense scrotal or labial edema, if a patient is experiencing complications (eg, bacterial sepsis, peritonitis, pneumonia, thromboembolic phenomenon, failure to thrive), and if patient or family compliance with treatment is in doubt.
- Diuretics and intravenous albumin may be needed. Furosemide (1 mg/kg/d) and spironolactone (2 mg/kg/d) are not always indicated but may help when fluid retention is severe, provided no signs of renal failure or volume contraction are evident. Achieving a satisfactory diuresis is difficult when the patient’s serum albumin level is less than 1.5 g/dL. An effective regimen is to give salt-poor albumin at 1 g/kg, followed by intravenous furosemide. Close monitoring is obligatory to prevent pulmonary edema. Some evidence suggests that albumin may delay the response to steroids and may even induce more frequent relapses, probably by causing severe glomerular epithelial damage. The time required for remission is prolonged with a longer duration of administration and larger volumes of infused albumin. Fluid removal and weight loss remain transient unless proteinuria remits.
- With regard to infection, oral penicillin can be prescribed as prophylaxis for children with gross edema. Abdominal paracentesis should be performed if the patient develops signs of peritonitis, and any bacterial infection should be treated promptly. A nonimmune patient with varicella should receive zoster immunoglobulin therapy if exposed to chickenpox, and acyclovir therapy should be administered if the patient develops chickenpox.
- Among the nephropathies causing nephrotic syndrome, only minimal-change disease is treatable. Most patients with minimal-change disease are steroid-sensitive, especially children