Nephrotic syndrome pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Pathophysiology

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.[1] Eventually, hypovolemia and renal hypoperfusion will lead to activation of the renin-angiotensin-aldosteron system (RAAS), vasopressin[2][3][4], atrial natriuretic peptide (ANP)[5][6][7][8] and the sympathetic nervous system[9], causing sodium retention.[1]

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[1]:

  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[1]:

  • Renin-angiotensin-aldosterone system
  • Vasopressin
  • Atrial natriuretic peptide (ANP)
  • Sympathetic nervous system

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.[10][11][12][13][14][15] Volume depletion associated with nephrotic syndrome is only seen in a minority of patients.[1] 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.[16][17][18] These changes were not seen in rats that received moderate continuous plasmapheresis. It is postulated that in some glomerular diseases, such as MCD, 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.[16][17][18]


It is believed that excessive proteinuria, as seen in patients with minimal change disease, and depletion of serum alubmin creates a disequilibrium between plasma and extravascular stores of albumin in attempt to restore the plasma-to-interstitial difference in colloid oncotic pressure.[12] The disequilibrium creates a state of uncompensated hypovolemia when COP becomes < 8 mmHg.[12] The dropping pressure temporarily stimulates aldosterone and other sodium-handling indices to retain sodium.[12][19][20] Following sodium retention, a steady-state is reached and sodium is no longer actively retained.[21][22][15] If a stable steady-state is not reached in cases when COP cannot be maintained above 8 mmHg, massive proteinuria persists and patients have a worse clinical presentation. [12]

Edema formation is not simply due to a sodium retention following a decrease in systemic volume and fall in plasma colloid pressure.[23][24] Recent evidence has shown that edema formation and sodium retention may thus be related to a primary intrinsic dysfunction of the renal handling of sodium followed by superimposing hypovolemia.[10][25][26] Tubular absorption is increased in patients with nephrotic syndrome even in segments beyond the distal convolted tubule due to unknown mechanism.[27][12] Nonetheless, an increase in the sodium/potassium/ATPase activity and amount with increase of aldosterone-dependent expression of epithelial sodium channels (ENaC)[28][29][30] were noted in the cortical collecting duct of nephrotic kidneys.[28][31][32][33] A modest decrease in GFR and filtration fraction due to a decrease in effective circulating volume leads to volume retention.[27]

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.[1] On the contrary, the extent of edema may be very different even with the same degree of proteinuria.[12] Several hypotheses suggest that patient and disease characteristics may account for the varying degree of edema in patients with similar amounts of proteinuria.(0,75,76)

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Siddall EC, Radhakrishnan J (2012). "The pathophysiology of edema formation in the nephrotic syndrome". Kidney Int. 82 (6): 635–42. doi:10.1038/ki.2012.180. PMID 22718186.
  2. ↑ Usberti M, Federico S, Meccariello S, Cianciaruso B, Balletta M, Pecoraro C; et al. (1984). "Role of plasma vasopressin in the impairment of water excretion in nephrotic syndrome". Kidney Int. 25 (2): 422–9. PMID 6727137.
  3. ↑ Rascher W, Tulassay T (1987). "Hormonal regulation of water metabolism in children with nephrotic syndrome". Kidney Int Suppl. 21: S83–9. PMID 3306110.
  4. ↑ Tulassay T, Rascher W, Lang RE, Seyberth HW, Schärer K (1987). "Atrial natriuretic peptide and other vasoactive hormones in nephrotic syndrome". Kidney Int. 31 (6): 1391–5. PMID 2956451.
  5. ↑ Perico N, Delaini F, Lupini C, Benigni A, Galbusera M, Boccardo P; et al. (1989). "Blunted excretory response to atrial natriuretic peptide in experimental nephrosis". Kidney Int. 36 (1): 57–64. PMID 2554049.
  6. ↑ Hildebrandt DA, Banks RO (1988). "Effect of atrial natriuretic factor on renal function in rats with nephrotic syndrome". Am J Physiol. 254 (2 Pt 2): F210–6. PMID 2964203.
  7. ↑ Radin MJ, McCune SA (1993). "The effect of atrial natriuretic peptide infusion on renal haemodynamics and plasma lipoproteins in puromycin aminonucleoside nephrosis in rats". Clin Exp Pharmacol Physiol. 20 (4): 245–51. PMID 8485924.
  8. ↑ Keeler R, Feuchuk D, Wilson N (1987). "Atrial peptides and the renal response to hypervolemia in nephrotic rats". Can J Physiol Pharmacol. 65 (10): 2071–5. PMID 2962709.
  9. ↑ DiBona GF (1990). "Role of the renal nerves in renal sodium retention and edema formation". Trans Am Clin Climatol Assoc. 101: 38–44, discussion 44-5. PMC 2376505. PMID 2486445.
  10. ↑ 10.0 10.1 Meltzer JI, Keim HJ, Laragh JH, Sealey JE, Jan KM, Chien S (1979). "Nephrotic syndrome: vasoconstriction and hypervolemic types indicated by renin-sodium profiling". Ann Intern Med. 91 (5): 688–96. PMID 496101.
  11. ↑ Vande Walle J, Donckerwolcke R, Boer P, van Isselt HW, Koomans HA, Joles JA (1996). "Blood volume, colloid osmotic pressure and F-cell ratio in children with the nephrotic syndrome". Kidney Int. 49 (5): 1471–7. PMID 8731116.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 Vande Walle JG, Donckerwolcke RA, Koomans HA (1999). "Pathophysiology of edema formation in children with nephrotic syndrome not due to minimal change disease". J Am Soc Nephrol. 10 (2): 323–31. PMID 10215332.
  13. ↑ Hammond TG, Whitworth JA, Saines D, Thatcher R, Andrews J, Kincaid-Smith P (1984). "Renin-angiotensin-aldosterone system in nephrotic syndrome". Am J Kidney Dis. 4 (1): 18–23. PMID 6377881.
  14. ↑ Shapiro MD, Hasbargen J, Hensen J, Schrier RW (1990). "Role of aldosterone in the sodium retention of patients with nephrotic syndrome". Am J Nephrol. 10 (1): 44–8. PMID 2188506.
  15. ↑ 15.0 15.1 Bohlin AB, Berg U (1984). "Renal sodium handling in minimal change nephrotic syndrome". Arch Dis Child. 59 (9): 825–30. PMC 1628730. PMID 6486860.
  16. ↑ 16.0 16.1 Manning RD, Guyton AC (1983). "Effects of hypoproteinemia on fluid volumes and arterial pressure". Am J Physiol. 245 (2): H284–93. PMID 6881362.
  17. ↑ 17.0 17.1 Manning RD (1987). "Effects of hypoproteinemia on renal hemodynamics, arterial pressure, and fluid volume". Am J Physiol. 252 (1 Pt 2): F91–8. PMID 3544869.
  18. ↑ 18.0 18.1 Joles JA, Koomans HA, Kortlandt W, Boer P, Dorhout Mees EJ (1988). "Hypoproteinemia and recovery from edema in dogs". Am J Physiol. 254 (6 Pt 2): F887–94. PMID 3132859.
  19. ↑ Koomans HA, Kortlandt W, Geers AB, Dorhout Mees EJ (1985). "Lowered protein content of tissue fluid in patients with the nephrotic syndrome: observations during disease and recovery". Nephron. 40 (4): 391–5. PMID 4022206.
  20. ↑ Koomans HA, Braam B, Geers AB, Roos JC, Dorhout Mees EJ (1986). "The importance of plasma protein for blood volume and blood pressure homeostasis". Kidney Int. 30 (5): 730–5. PMID 3784303.
  21. ↑ Vande Walle JG, Donckerwolcke RA, van Isselt JW, Derkx FH, Joles JA, Koomans HA (1995). "Volume regulation in children with early relapse of minimal-change nephrosis with or without hypovolaemic symptoms". Lancet. 346 (8968): 148–52. PMID 7603230.
  22. ↑ Van de Walle JG, Donckerwolcke RA, Greidanus TB, Joles JA, Koomans HA (1996). "Renal sodium handling in children with nephrotic relapse: relation to hypovolaemic symptoms". Nephrol Dial Transplant. 11 (11): 2202–8. PMID 8941579.
  23. ↑ BROWN E, HOPPER J, WENNESLAND R (1957). "Blood volume and its regulation". Annu Rev Physiol. 19: 231–54. doi:10.1146/annurev.ph.19.030157.001311. PMID 13412057.
  24. ↑ YAMAUCHI H, HOPPER J (1964). "HYPOVOLEMIC SHOCK AND HYPOTENSION AS A COMPLICATION IN THE NEPHROTIC SYNDROME. REPORT OF TEN CASES". Ann Intern Med. 60: 242–54. PMID 14114444.
  25. ↑ Dorhout EJ, Roos JC, Boer P, Yoe OH, Simatupang TA (1979). "Observations on edema formation in the nephrotic syndrome in adults with minimal lesions". Am J Med. 67 (3): 378–84. PMID 474584.
  26. ↑ Brown EA, Markandu ND, Sagnella GA, Squires M, Jones BE, MacGregor GA (1982). "Evidence that some mechanism other than the renin system causes sodium retention in nephrotic syndrome". Lancet. 2 (8310): 1237–40. PMID 6128546.
  27. ↑ 27.0 27.1 Ichikawa I, Rennke HG, Hoyer JR, Badr KF, Schor N, Troy JL; et al. (1983). "Role for intrarenal mechanisms in the impaired salt excretion of experimental nephrotic syndrome". J Clin Invest. 71 (1): 91–103. PMC 436841. PMID 6848563.
  28. ↑ 28.0 28.1 Lourdel S, Loffing J, Favre G, Paulais M, Nissant A, Fakitsas P; et al. (2005). "Hyperaldosteronemia and activation of the epithelial sodium channel are not required for sodium retention in puromycin-induced nephrosis". J Am Soc Nephrol. 16 (12): 3642–50. doi:10.1681/ASN.2005040363. PMID 16267158.
  29. ↑ de Seigneux S, Kim SW, Hemmingsen SC, Frøkiaer J, Nielsen S (2006). "Increased expression but not targeting of ENaC in adrenalectomized rats with PAN-induced nephrotic syndrome". Am J Physiol Renal Physiol. 291 (1): F208–17. doi:10.1152/ajprenal.00399.2005. PMID 16403831.
  30. ↑ Kim SW, Wang W, Nielsen J, Praetorius J, Kwon TH, Knepper MA; et al. (2004). "Increased expression and apical targeting of renal ENaC subunits in puromycin aminonucleoside-induced nephrotic syndrome in rats". Am J Physiol Renal Physiol. 286 (5): F922–35. doi:10.1152/ajprenal.00277.2003. PMID 15075188.
  31. ↑ Vogt B, Favre H (1991). "Na+,K(+)-ATPase activity and hormones in single nephron segments from nephrotic rats". Clin Sci (Lond). 80 (6): 599–604. PMID 1647923.
  32. ↑ Deschênes G, Doucet A (2000). "Collecting duct (Na+/K+)-ATPase activity is correlated with urinary sodium excretion in rat nephrotic syndromes". J Am Soc Nephrol. 11 (4): 604–15. PMID 10752519.
  33. ↑ Deschênes G, Gonin S, Zolty E, Cheval L, Rousselot M, Martin PY; et al. (2001). "Increased synthesis and avp unresponsiveness of Na,K-ATPase in collecting duct from nephrotic rats". J Am Soc Nephrol. 12 (11): 2241–52. PMID 11675400.

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