Nephrotic syndrome pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, Serge Korjian


The pathophysiology of hypoalbuminemia in nephrotic syndrome is multifactorial. Proteinuria plays an important role in the pathogenesis of hyperlipidemia in nephrotic syndrome. Neurohormonal changes in the renin-angiotensin-aldosterone system, vasopressin, atrial natriuretic peptide (ANP), and sympathetic nervous system are is implicated in edema formation in nephrotic syndrome.



The pathophysiology of hypoalbuminemia in nephrotic syndrome is multifactorial. The glomerular basement membrane (GBM) is normally formed of heparan sulfate and proteoglycans that contain anion sites.[1] These sites occupy the lamina rara externa of the GBM. Quantitative loss of the anion sites and neutralization of the GBM charge-selective barrier are directly related to albuminuria.[2] In nephrotic syndrome, the kidneys lose the size and charge perm-selectivity of the glomerular capillary wall and protein leakage will occur.[3][4] As such, the glomerulus will lose the ability to prevent the passage of macromolecules, such as albumin through the barrier, and albumin excretion will ensue.[4][5][6][7] In addition to the increased renal loss of albumin, increased renal catabolism always contributed to hypoalbuminemia.[7][8] Although initially believed that increased albumin intake would increase serum levels of albumin, results showed that following ingestion of albumin, albuminuria was exacerbated due to protein trafficking along the renal tubules.[8] It is thus common practice to restrict protein intake in nephrotic syndrome.[8][9] The use of ACE-inhibitors to reduce the degree of proteinuria suggested that neurohormonal changes related to angiotensin II must have a significant role in hypoalbuminemia as well.[1]

In addition, circulating factors, such as vascular permeability factor (VPF) and other lymphokines produced by T cells, are believed to play a role in binding to polyanions in the GBM and neutralizing the barrier.[10][11][12] Inflammatory changes have been related to proteinuria and related ultrastructural abnormalities may also be part of the multifactorial process behind hypoalbuminemia.[1] Hemodynamic factors, such as a reduction in glomerular plasma flow, were also shown to play a role in the urinary loss of proteins. Consequently, an increase in the clearance of proteins along the glomerular capillary is observed due to removal of water and the creation of a diffusion gradient along the Bowman's space. When the intravascular pool of albumin is lost, interstitial stores are shifted into the intravascular compartment and are similarly lost to eventually deplete all albumin stores.[1]


Proteinuria plays an important role in the pathogenesis of hyperlipidemia in nephrotic syndrome.[8] When hypoalbuminemia is present, the liver increases lipoprotein synthesis due to the decreased low plasma oncotic pressure. The process by which the liver increases the production of its products is believed to be regulated by a substance that is not yet identified. Animal studies have shown that in nephrotic syndrome, enzymes like hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase - the enzyme responsible for the rate limiting step in lipid synthesis, and acyl-coenzyme-A-cholesterol acyltransferase are both increased.[13][14][15] In parallel, activities cholesterol-7-alpha-hydroxylase and lipoprotein lipase are decreased.[13][14][15] Both processes validate that lipid synthesis is increased in nephrotic syndrome. Hyperlipidemia due to increase apo-B containing lipoproteins occurs secondary to the decrease in oncotic pressure, not to hypoalbuminemia per se.[1] The severity of lipid abnormalities directly correlates with the severity of proteinuria, but is not associated with the identity of glomerular lesions or primary etiology of nephrotic syndrome.[16][17] Increased triglycerides, LDL, and VLDL are increased and also contribute to the glomerular damage in mechanisms that remain unclear.[18] It is perhaps that abnormalities in the metabolism of triglycerides, rather than increased synthesis, are responsible for hypertriglyceridemia. It is believed that lipoprotein-mediated conversion of VLDL to LDL (via IDL) may be slowed down in nephrotic syndrome.[19][20] In contrast, HDL2 is generally reduced whereas HDL3 is elevated due to a reduction in the lecithin-cholesterol acyltransferase activity.[16]

Edema Formation

The pathophysiology of edema formation in nephrotic syndrome is still controversial. Researchers hypothesize that the "underfill" mechanism is responsible for edema formation due to loss of plasma albumin and colloid oncotic pressure, followed by increased filtration from the intravascular space to the interstitial space.[21] Eventually, hypovolemia and renal hypoperfusion will lead to activation of the renin-angiotensin-aldosterone system (RAAS), vasopressin,[22][23][24] atrial natriuretic peptide (ANP),[25][26][27][28] and the sympathetic nervous system[29], causing sodium retention.[21]

The Starling equation adequately explains the net fluid movement between the intravascular and the interstitial compartments:

Jv is the net fluid movement between compartments; Pc is the capillary hydrostatic pressure; Pi is the interstitial hydrostatic pressure; σ is the reflection coefficient to proteins. It is a measure of vascular permeability; πc is the capillary oncotic pressure; πi is the interstitial oncotic pressure; Kf is the overall filtration permeability constant to volume flow; it is a product of the hydraulic conductance and capillary surface area. It is a measure of vascular permeability.

Protective mechanisms against the formation of edema in hypoalbuminemia are[21]:

  1. "Washdown" of interstitial protein concentration; Increase in fluid filtration from the intravascular space into the interstitial space.
  2. "Washout" of interstitial proteins; Increase in fluid delivery to interstitial space to increase lymphatic flow.

In summary, the role of the following neurohormonal changes is implicated in edema formation in nephrotic syndrome:[21]

Although the mechanism seemed straightforward, newer studies showed that the pathophysiology is not as simple as once thought. Even the inhibition of the RAAS pathway using ACE-inhibitors did not seem to inhibit sodium retention as expected.[30][31][32][33][34][35] Volume depletion associated with nephrotic syndrome is only seen in a minority of patients.[21] In fact, the rate at which protein loss occurs is equally important. When plasmapheresis was conducted in rats to control the rate of plasma protein reduction, rapid loss of proteins was associated with increase in RAAS and positive sodium balance with decrease in plasma and blood volumes.[36][37][38] These changes were not seen in rats that received moderate continuous plasmapheresis. It is postulated that in some glomerular diseases, such as minimal change disease, where proteinuria occurs very rapidly, the rate of protein loss might mimic rat studies and edema formation occurs due to changes unseen in moderate protein loss.[36][37][38]

It is believed that excessive proteinuria, as seen in patients with minimal change disease, and depletion of serum albumin creates a disequilibrium between plasma and extravascular stores of albumin in attempt to restore the plasma-to-interstitial difference in colloid oncotic pressure (COP).[32] The disequilibrium creates a state of uncompensated hypovolemia when COP becomes < 8 mmHg.[32] The dropping pressure temporarily stimulates aldosterone and other sodium-handling indices to retain sodium.[32][39][40] Following sodium retention, a steady-state is reached and sodium is no longer actively retained.[41][42][35] If a stable steady-state is not reached in cases when COP cannot be maintained above 8 mmHg, massive proteinuria persists.[32]

Edema formation is not simply due to a sodium retention following a decrease in systemic volume and fall in plasma colloid pressure.[43][44] Recent evidence has shown that edema formation and sodium retention may thus be less related to hypovolemia itself, but rather to a primary intrinsic dysfunction of the renal handling of sodium followed by superimposing hypovolemia.[30][45][46] Tubular absorption is increased in patients with nephrotic syndrome, even in segments beyond the distal convoluted tubule, due to mechanisms that remain obscured.[47][32] Nonetheless, an increase in the sodium/potassium/ATPase activity and amount associated with an increase of aldosterone-dependent expression of epithelial sodium channels (ENaC)[48][49][50] were noted distally in the cortical collecting duct of nephrotic kidneys, emphasizing the role of the kidneys themselves in the pathogenesis of edema formation.[48][51][52][53]

Finally, it is important to recognize that the pathology of edema formation is not homogeneous and that sodium retention alone cannot explain edema formation in nephrotic syndrome.[21] On the contrary, the extent of edema may be very different even with the same degree of proteinuria.[32] Several hypotheses suggest that patient and disease characteristics may account for the varying degree of edema in patients with similar amounts of proteinuria.


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