Minimal change disease 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 ; Vamsikrishna Gunnam M.B.B.S [2]
Overview
Minimal change disease (MCD) is one of the major cause of idiopathic nephrotic syndrome (NS).Minimal-change disease (MCD), also known as lipoid nephrosis or nil disease.The exact pathogenesis of minimal change disease is not well-understood. T-cell dysfunction may mediate the pathogenesis of minimal change disease.Due to the remarkable observation of disease recurrence after transplantation and the resolution of renal disease in recipients of kidneys from donors with MCD, it has been suggested that the presence of circulatory compounds may be attributable to the disease. Factors associated with the pathophysiology of minimal change disease include glomerular permeability factor (GPF) from T cells, hemopexin, interleukin (IL)13, cardiotrophin-like cytokine (CLC)-1, and vascular endothelial growth factor (VEGF).
Pathophysiology
- The exact pathogenesis of minimal change disease is not well-understood.[1] [2][3][4]
- T-cell dysfunction plays an important role in the pathogenesis of minimal change disease.[5]
- Increased levels of several cytokines are also implemented in the pathogenesis of minimal change disease.[6]
- It is understood that minimal change disease is the result caused by either "two-hit" theory which include the induction of CD80 (B7-1) and regulatory T-cell (Treg) dysfunction.[7][8]
- T cells release pro-inflammatory cytokines that ultimately damage the polyanion barrier of the renal glomerulus and subsequently heavy proteinuria.[9]
- When measured, CD8 lymphocytes increased and CD4 lymphocytes decreased in relapses of disease, emphasizing the role of an abnormal T cell response in MCD.[10]
- Due to the remarkable observation of disease recurrence after transplantation and the resolution of renal disease in recipients of kidneys from donors with MCD, it has been suggested that the presence of circulatory compounds may be attributable to the disease.[1][3][4]
- In guinea pigs , glomerular permeability factor (GPF), a possible lymphokine that has an activity similar to tumor necrosis factor (TNF), is produced by T cells.[11]
- Products secreted from T cell hybridomas from patients with MCD were contributory to the induction of significant proteinuria in rats.[12]
- Hemopexin, a plasma glycoprotein and an acute phase reactant in humans, seems to enhance the role of GPF and further promote proteinuria through the glomerular basement membrane.[13]
- The following is a list that shows factors that have been shown to be associated with the pathogenesis of MCD
- GPF from T cells[12][11]
- Hemopexin[13][14]
- Interleukin-(IL)13[15]
- IL-12[16][17]
- Tumor necrosis factor-alpha (TNF-α)
- Cardiotrophin-like cytokine (CLC)-1[18]
- Angiopoietin-like 4 (Angpl4)[18]
- Soluble urokinase plasminogen activator receptor (suPAR)[19]
- Vascular endothelial growth factor (VEGF)[20]
- Heparinase[20]
- Sialidase[20]
- C-mip intracellular protein[20]
- CD80[20]
- Beta-3 integrin 1[20]
- In MCD, albumin excretion is significantly elevated with consequential hypoalbuminemia, increased protein catabolism, and hyperlipidemia that may be so extensive that cannot be compensated.[21][22]
- However, Carrie and colleagues showed that the fractional excretion of dextran was decreased in MCD patients, suggesting a probable decrease in the size of the glomerular pores.[21]
- A decrease in nephrin and dystroglycan, two important podocyte proteins, and consequential slit-pore membrane obliteration between podocyte foot processes occur with effacement or fusion of the foot processes.[23]
- However, recent data in 2004 showed that the degree of podocyte effacement does not seem to correlate with the degree of proteinuria.[24][25]
- The loss of important proteins also includes immunoglobulin and complement proteins, such as factor B. Concomitantly, serum concentrations of IgA and IgG were found to be low in patients with MCD.[26][27]
- In contrast, an elevation in serum concentration of IgM and occasional glomerular IgM deposition further underscore the hypothesis.[26][28]
- This finding suggested that patients with MCD may have abnormal immunological capacity of immunoglobulin switching.
- The most likely etiology for switching defect may be a deficiency of thymic cell function.[26][9]
- In conclusion, patients with MCD are more susceptible to infections. Other significant components lost in urine include and thyroid-binding globulin,and iron and copper-binding transferrin.[29][30][31][32][33]
- Loss of protein S and antithrombin III lead to excessive production of factors V and VIII, making minimal change disease a hypercoagulable state.[9]
Genetics
- The development of Minimal change disease (MCD) is the result of genetic mutations in protein tyrosine phosphatase receptor type O also known as glomerular epithelial protein 1 (GLEPP1).[34][35]
References
- ↑ 1.0 1.1 Hoyer JR, Vernier RL, Najarian JS, Raij L, Simmons RL, Michael AF (2001). "Recurrence of idiopathic nephrotic syndrome after renal transplantation. 1972". J Am Soc Nephrol. 12 (9): 1994–2002. PMID 11518795.
- ↑ Kim SH, Park SJ, Han KH, Kronbichler A, Saleem MA, Oh J, Lim BJ, Shin JI (May 2016). "Pathogenesis of minimal change nephrotic syndrome: an immunological concept". Korean J Pediatr. 59 (5): 205–11. doi:10.3345/kjp.2016.59.5.205. PMC 4897155. PMID 27279884.
- ↑ 3.0 3.1 Mauer SM, Hellerstein S, Cohn RA, Sibley RK, Vernier RL (1979). "Recurrence of steroid-responsive nephrotic syndrome after renal transplantation". J Pediatr. 95 (2): 261–4. PMID 376811.
- ↑ 4.0 4.1 Ali AA, Wilson E, Moorhead JF, Amlot P, Abdulla A, Fernando ON; et al. (1994). "Minimal-change glomerular nephritis. Normal kidneys in an abnormal environment?". Transplantation. 58 (7): 849–52. PMID 7940721.
- ↑ Shalhoub RJ (1974). "Pathogenesis of lipoid nephrosis: a disorder of T-cell function". Lancet. 2 (7880): 556–60. PMID 4140273.
- ↑ Eddy AA, Symons JM (August 2003). "Nephrotic syndrome in childhood". Lancet. 362 (9384): 629–39. doi:10.1016/S0140-6736(03)14184-0. PMID 12944064.
- ↑ Shimada M, Araya C, Rivard C, Ishimoto T, Johnson RJ, Garin EH (April 2011). "Minimal change disease: a "two-hit" podocyte immune disorder?". Pediatr. Nephrol. 26 (4): 645–9. doi:10.1007/s00467-010-1676-x. PMID 21052729.
- ↑ Shalhoub RJ (September 1974). "Pathogenesis of lipoid nephrosis: a disorder of T-cell function". Lancet. 2 (7880): 556–60. PMID 4140273.
- ↑ 9.0 9.1 9.2 Saha TC, Singh H (2006). "Minimal change disease: a review". South Med J. 99 (11): 1264–70. PMID 17195422.
- ↑ Fiser RT, Arnold WC, Charlton RK, Steele RW, Childress SH, Shirkey B (1991). "T-lymphocyte subsets in nephrotic syndrome". Kidney Int. 40 (5): 913–6. PMID 1762295.
- ↑ 11.0 11.1 Lagrue G, Xheneumont S, Branellec A, Hirbec G, Weil B (1975). "A vascular permeability factor elaborated from lymphocytes. I. Demonstration in patients with nephrotic syndrome". Biomedicine. 23 (1): 37–40. PMID 1174637.
- ↑ 12.0 12.1 Koyama A, Fujisaki M, Kobayashi M, Igarashi M, Narita M (1991). "A glomerular permeability factor produced by human T cell hybridomas". Kidney Int. 40 (3): 453–60. PMID 1787645.
- ↑ 13.0 13.1 Cheung PK, Stulp B, Immenschuh S, Borghuis T, Baller JF, Bakker WW (1999). "Is 100KF an isoform of hemopexin? Immunochemical characterization of the vasoactive plasma factor 100KF". J Am Soc Nephrol. 10 (8): 1700–8. PMID 10446937.
- ↑ Lennon R, Singh A, Welsh GI, Coward RJ, Satchell S, Ni L; et al. (2008). "Hemopexin induces nephrin-dependent reorganization of the actin cytoskeleton in podocytes". J Am Soc Nephrol. 19 (11): 2140–9. doi:10.1681/ASN.2007080940. PMC 2573012. PMID 18753258.
- ↑ Lai KW, Wei CL, Tan LK, Tan PH, Chiang GS, Lee CG; et al. (2007). "Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats". J Am Soc Nephrol. 18 (5): 1476–85. doi:10.1681/ASN.2006070710. PMID 17429054.
- ↑ Le Berre L, Bruneau S, Renaudin K, Naulet J, Usal C, Smit H, Soulillou JP, Dantal J (May 2011). "Development of initial idiopathic nephrotic syndrome and post-transplantation recurrence: evidence of the same biological entity". Nephrol. Dial. Transplant. 26 (5): 1523–32. doi:10.1093/ndt/gfq597. PMID 20935016.
- ↑ Saxena S, Mittal A, Andal A (1993). "Pattern of interleukins in minimal-change nephrotic syndrome of childhood". Nephron. 65 (1): 56–61. doi:10.1159/000187441. PMID 8413792.
- ↑ 18.0 18.1 McCarthy ET, Sharma M, Savin VJ (2010). "Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis". Clin J Am Soc Nephrol. 5 (11): 2115–21. doi:10.2215/CJN.03800609. PMID 20966123.
- ↑ Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J; et al. (2011). "Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis". Nat Med. 17 (8): 952–60. doi:10.1038/nm.2411. PMID 21804539.
- ↑ 20.0 20.1 20.2 20.3 20.4 20.5 Parikh SM (2012). "Circulating mediators of focal segmental glomerulosclerosis: soluble urokinase plasminogen activator receptor in context". Am J Kidney Dis. 59 (3): 336–9. doi:10.1053/j.ajkd.2011.09.011. PMID 22033283.
- ↑ 21.0 21.1 Carrie BJ, Salyer WR, Myers BD (1981). "Minimal change nephropathy: an electrochemical disorder of the glomerular membrane". Am J Med. 70 (2): 262–8. PMID 6162382.
- ↑ GITLIN D, CORNWELL DG, NAKASATO D, ONCLEY JL, HUGHES WL, JANEWAY CA (1958). "Studies on the metabolism of plasma proteins in the nephrotic syndrome. II. The lipoproteins". J Clin Invest. 37 (2): 172–84. doi:10.1172/JCI103596. PMC 293074. PMID 13513748.
- ↑ Wernerson A, Dunér F, Pettersson E, Widholm SM, Berg U, Ruotsalainen V; et al. (2003). "Altered ultrastructural distribution of nephrin in minimal change nephrotic syndrome". Nephrol Dial Transplant. 18 (1): 70–6. PMID 12480962.
- ↑ van den Berg JG, van den Bergh Weerman MA, Assmann KJ, Weening JJ, Florquin S (2004). "Podocyte foot process effacement is not correlated with the level of proteinuria in human glomerulopathies". Kidney Int. 66 (5): 1901–6. doi:10.1111/j.1523-1755.2004.00964.x. PMID 15496161.
- ↑ Regele HM, Fillipovic E, Langer B, Poczewki H, Kraxberger I, Bittner RE; et al. (2000). "Glomerular expression of dystroglycans is reduced in minimal change nephrosis but not in focal segmental glomerulosclerosis". J Am Soc Nephrol. 11 (3): 403–12. PMID 10703664.
- ↑ 26.0 26.1 26.2 Giangiacomo J, Cleary TG, Cole BR, Hoffsten P, Robson AM (1975). "Serum immunoglobulins in the nephrotic syndrome. A possible cause of minimal-change nephrotic syndrome". N Engl J Med. 293 (1): 8–12. doi:10.1056/NEJM197507032930103. PMID 1079322.
- ↑ Spika JS, Halsey NA, Fish AJ, Lum GM, Lauer BA, Schiffman G; et al. (1982). "Serum antibody response to pneumococcal vaccine in children with nephrotic syndrome". Pediatrics. 69 (2): 219–23. PMID 7058096.
- ↑ Waldherr R, Gubler MC, Levy M, Broyer M, Habib R (1978). "The significance of pure diffuse mesangial proliferation in idiopathic nephrotic syndrome". Clin Nephrol. 10 (5): 171–9. PMID 365403.
- ↑ CARTWRIGHT GE, GUBLER CJ, WINTROBE MM (1954). "Studies on copper metabolism. XI. Copper and iron metabolism in the nephrotic syndrome". J Clin Invest. 33 (4): 685–98. doi:10.1172/JCI102939. PMC 1087284. PMID 13152208.
- ↑ RIFKIND D, KRAVETZ HM, KNIGHT V, SCHADE AL (1961). "Urinary excretion of iron-binding protein in the nephrotic syndrome". N Engl J Med. 265: 115–8. doi:10.1056/NEJM196107202650303. PMID 13741582.
- ↑ Ellis D (1977). "Anemia in the course of the nephrotic syndrome secondary to transferrin depletion". J Pediatr. 90 (6): 953–5. PMID 859066.
- ↑ Stec J, Podracká L, Pavkovceková O, Kollár J (1990). "Zinc and copper metabolism in nephrotic syndrome". Nephron. 56 (2): 186–7. PMID 2243574.
- ↑ Afrasiabi MA, Vaziri ND, Gwinup G, Mays DM, Barton CH, Ness RL; et al. (1979). "Thyroid function studies in the nephrotic syndrome". Ann Intern Med. 90 (3): 335–8. PMID 106751.
- ↑ Ozaltin F, Ibsirlioglu T, Taskiran EZ, Baydar DE, Kaymaz F, Buyukcelik M, Kilic BD, Balat A, Iatropoulos P, Asan E, Akarsu NA, Schaefer F, Yilmaz E, Bakkaloglu A (July 2011). "Disruption of PTPRO causes childhood-onset nephrotic syndrome". Am. J. Hum. Genet. 89 (1): 139–47. doi:10.1016/j.ajhg.2011.05.026. PMC 3135805. PMID 21722858.
- ↑ Kang MM, Shan SL, Wen XY, Shan HS, Wang ZJ (2015). "Tumor-Suppression Mechanisms of Protein Tyrosine Phosphatase O and Clinical Applications". Asian Pac. J. Cancer Prev. 16 (15): 6215–23. PMID 26434819.