- Nephrotic Syndrome is a clinical syndrome that can be initiated by a number of distinct etiologies that lead to a shared pathogenic sequence.
- Nephrotic syndrome is characterized by massive proteinuria of more than 3.0g/day and resultant hypoalbuminemia, the pathogenesis of which is discussed below. In addition, patients display hyperlipidemia. It is thought that compensatory synthesis of albumin by the liver to replace urinary losses is accompanied by hepatic synthesis of lipids, resulting in the hyperlipidemia. In contrast to nephritic syndrome, hematuria and pyuria are less pronounced or non-existent in patients with nephrotic syndrome.
- Primary Defect: Proteinuria
- The primary defect in nephrotic syndrome is an insult to the glomerulus which results in loss of glomerular filtration barrier selectivity. Recall from glomerular filtration that the barrier is normally highly selective in preventing filtration of plasma proteins. This selectivity is lost in nephrotic syndrome, allowing substantial filtration of plasma proteins which cannot undergo tubular resorption and are thus excreted in the urine, hence causing massive proteinuria.
- Secondary Defect: Reduced Plasma Protein Concentration
- Chronic excretion of plasma proteins reduces the concentration of albumin in the plasma, resulting in hypoalbuminemia. Decreased concentration of plasma proteins also results in reduced plasma oncotic pressure, which yields derangement of vascular Starling Forces. The result is increased filtration of fluid into the ECF from systemic capillaries, often manifesting as generalized edema.
- Tertiary Spiral: Compensatory Salt Retention
- Chronic loss of plasma fluids to the ECF reduces the systemic arterial pressure and in consequence activates the Renin-Angiotensin-Aldosterone System (RAAS). The activated RAAS then enhances tubular sodium and water resorption in an attempt to boost blood volume with the expectation that this will enhance systemic arterial pressure. However, the proteinuria of nephrotic syndrome results in a reduction in blood oncotic pressure and thus deranged Starling Forces in which additional retained ECF volume is not proportionally added to the blood volume. Consequently, systemic arterial pressure and ECF volume become dissociated, resulting in renaly resorbed sodium and water simply leaking into the interstitial fluid rather than remaining within the vascular space and boosting arterial pressure (See: "Sodium Regulation" section of ECF Volume Regulation). Because systemic arterial pressure remains deficient, chronic activation of the RAAS can lead to retention of large amounts of sodium and water, sufficient to generate clinically apparent generalized edema.