An Overview of Nephrotic Syndrome

Pediatric Nephrotic syndrome is defined by the presence of:

• nephrotic proteinuria > 1 g/m2/day,
• hypoproteinemia – albumin usually < 25 g/l, based on protein loss to urine,
• hypercholesterolemia – based on increased lipoprotein synthesis (caused by hypoproteinemia),
• edema – based on increased naturism resorption in tubules.

Nephrotic syndrome is a constellation of clinical findings that is the result of massive renal losses of protein. Thus, nephrotic syndrome is not a disease itself, but the manifestation of many different glomerular diseases.

Minimal Change DiseaseMinimal Change Disease (also known as lipoid nephrosis) is a disease of the kidney that causes nephrotic syndrome and usually affects children (peak incidence at 2–3 years of age).

Pathophysiology
Nephrotic syndrome is a nonspecific disorder in which thekidneys are damaged, causing them to leak large amounts of protein from the blood into the urine.

Kidneys affected by nephrotic syndrome have small pores in the podocytes, large enough to permit proteinuria (and subsequently hypoalbuminemia, because some of the protein albumin has gone from the blood to the urine.

NS is believed to have an immune pathogenesis. Evidence of the immune-mediated nature of NS is demonstrated by the fact that immunosuppressive agents, such as corticosteroids and alkylating agents, can result in remission of nephrotic syndrome.

Pathology of Edema in Nephrotic Syndrome
The classical explanation for edema formation is a decrease in plasma oncotic pressure, as a consequence of low serum albumin levels, causing an extravasation of plasma water into the interstitial space. The resulting contraction in plasma volume (PV) leads to stimulation of the renin-angiotensin-aldosterone axis and antidiuretic hormone. The resultant retention of sodium and water by the renal tubules contributes to the extension and maintenance of edema.

A more recent theory of edema formation posits that massive proteinuria leads to tubulointerstitial inflammation and release of local vasoconstrictors and inhibition of vasodilation. This leads to a reduction in single-nephron glomerular filtration rate and sodium and water retention.

Thrombosis
Patients with nephrotic syndrome are at increased risk for thrombosis.

Various factors play a role in the increased incidence of thrombosis. Abnormalities described in INS include the following:

• Increased platelet activation and aggregation
• Elevation in levels of factors V, VII, VIII, and XIII and fibrinogen
• Decreased antithrombin III, proteins C and S, and factors XI and XII
• Increased activities of tissue plasminogen activator and plasminogen activator inhibitor-1.

Infections
Patients with NS are at increased risk of infection. Peritonitis and sepsis are the most common and serious infections.Risk of infection may be increased in NS because of low immunoglobulin (Ig)G levels, which do not appear to be the result of urinary losses. Instead, low IgG levels seem to be the result of impaired synthesis, again pointing to a primary disorder in lymphocyte regulation in NS.

Pathology in Minimal Change Disease
For years pathologists found no changes when viewing specimens under light microscopy; hence the name minimal change disease. With the advent of electron microscopy, the changes now known as the hallmarks for the disease were discovered. These are diffuse loss of visceral epithelial cells (podocyte) foot processes, vacuolation, and growth of microvilli on the visceral epithelial cells.

The pathology of minimal change disease is unclear and is currently considered idiopathic. The pathology does not appear to involve immune complex deposition. Rather, an altered cell-mediated immunologic response leads to reduced production of anions in the glomerular basement membrane, thereby increasing the glomerular permeability to serum albumin through a reduction of elecrostatic repulsion. The loss of anionic charges is also thought to favor foot process fusion. The etiological agent is somewhat of a mystery but viruses have been implicated.

Causes
Nephrotic syndrome has many causes and may either be the result of a disease limited to the kidney, called primary nephrotic syndrome, or a condition that affects the kidney and other parts of the body, called secondary nephrotic syndrome.

Signs and Symptoms

• Edemas have sudden beginning, localization: eyelids, ankles, scrotum or anasarca.
• Ascites might be presented too. It is connected with weight gain.
• In some cases edema can be presented by diarrhea (intestinal edema) or pulmonary edema or pulmonary effusion.
• Blood pressure is usually normal.
• The child seems to be more tired & more irritable, eating less and pale looking.

Diagnosis
The diagnosis can be made by a

• complete history and physical examination (previous pharyngitis ? PSAGN, gastroenteritis ? HUS, present edema, petechiae, hypertension …)
• confirmation of presence proteinuria (if necessary repeat urinalysis)
• protein/creatinine ratio (from first morning urine sample), if P/C ratio is > 0,5, other evaluation is necessary:
• serum electrolytes analysis, creatinine clearance, serum levels of cholesterol, total protein, albumin
• streptozyme, C3, C4, ASLO analysis
• renal ultrasonography.

Prognosis
Since the introduction of corticosteroids, the overall mortality of INS has decreased dramatically from over 50% to approximately 2-5%.

Despite the improvement in survival, NS is usually a chronic, relapsing disease and most patients experience some degree of morbidity, including the following:

• Hospitalization, in some instances
• Frequent monitoring both by parents and by physician
• Administration of medications associated with significant adverse events
• A high rate of recurrence (relapses in >60% of patients)
• The potential for progression to chronic kidney failure and end-stage kidney failure (ESKD)

Additionally, NS is associated with an increased risk of multiple complications, including edema, infection, thrombosis, hyperlipidemia, acute kidney failure, and possible increased risk of cardiovascular disease.

The prognosis varies, depending on whether the nephrotic syndrome is steroid responsive or steroid resistant.