Pathogenesis of nephrotic syndrome

Triggering the pathological cascade: proteinuria

All manifestations of nephrotic syndrome begin with a single event — damage to the glomerular filter. Normally, the basement membrane and podocytes do not allow large protein molecules to pass through. When the glomeruli are damaged (e.g., in glomerulonephritis, amyloidosis, or diabetic nephropathy), this barrier is destroyed.

Massive proteinuria occurs — a huge amount of protein, primarily albumins, is lost in the urine (more than 3.5 g per day). This is the initial and main link from which all other systemic disorders stem.

Mechanism of edema development

Protein loss rapidly depletes its reserves in the blood, leading to hypoproteinemia (decreased total protein) and hypoalbuminemia. Because of this, plasma oncotic pressure drops — the force that keeps the liquid part of the blood within the vascular bed.

The pathogenesis of nephrotic edema includes the following stages:

1. Fluid leaves the vessels into the interstitium along the pressure gradient (oncotic edema develops).
2. The circulating plasma volume decreases, resulting in hypovolemia.
3. Cardiac output decreases and the blood supply to the kidneys themselves worsens (hypoperfusion).
4. In response, the kidneys activate the renin-angiotensin-aldosterone system (RAAS).
5. Secondary aldosteronism occurs — sodium and water retention, which creates a vicious circle and increases edema up to anasarca with body cavity effusions (ascites, hydropericardium, pleurisy).

Note: the secretion of natriuretic factor does not increase in this case, since venous return to the heart is reduced.

Hyperlipidemia and fatty degeneration of the kidneys

The body tries to compensate for the drop in blood oncotic pressure. Since proteins cannot be synthesized at the required rate, hyperlipidemia is triggered — cholesterol, triglyceride, and phospholipid levels in the blood rise sharply.

This happens due to:

• mobilization of fat from stores;
• stimulation of cholesterol synthesis;
• decreased activity of serum enzymes (lipoprotein lipase);
• enhanced lipid production directly in the kidneys.

Excess lipids are filtered into the primary urine (lipiduria occurs). Tubular epithelium attempts to reabsorb these fats, resulting in their accumulation in the cytoplasm of nephrocytes. Fatty degeneration of the kidneys develops, which is often combined with hyaline-droplet degeneration due to the reabsorption of filtered protein.

Clinical variants and complications

Nephrotic syndrome can be an independent leading manifestation (pure nephrotic variant) or can be combined with arterial hypertension (mixed form). It is also a typical stage in secondary renal damage, such as in amyloidosis.

Prolonged loss of specific proteins leads to serious complications:

• Thrombosis (including renal vein thrombosis and pulmonary embolism) due to urinary loss of antithrombin III and hypercoagulation.
• Infections (up to peritonitis) due to the loss of immunoglobulins (hypogammaglobulinemia).
• Nephrotic crisis (hypovolemic shock) — a critical drop in plasma volume.

Class and exam questions

What else to study on this topic

• Etiology of primary and secondary nephrotic syndrome
• Stages of development of renal amyloidosis
• Types of tubular epithelial dystrophies (hyaline-droplet, hydropic)
• Pathogenesis of complications: mechanisms of thrombosis and immune suppression
• Clinical and morphological forms of chronic glomerulonephritis

Other topics in the "Additional Topics" section

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