Pathology of Renal Diseases Associated with Dysfunction of the Alternative Pathway of Complement: C3 Glomerulopathy and Atypical Hemolytic Uremic Syndrome (aHUS)

Abstract

Dysfunction of the alternative pathway of complement in the fluid phase results in deposition of complement factors in the renal glomeruli. This results in glomerular injury and an ensuing proliferative response. The term “C3 glomerulopathy” is used to define such an entity. It includes both C3 glomerulonephritis and dense deposit disease (DDD). Both C3 glomerulonephritis and DDD are characterized by a proliferative glomerulonephritis and bright glomerular C3 mesangial and capillary wall staining with the absence or scant staining for immunoglobulins (Ig). The two conditions are distinguished based on electron microscopy findings: mesangial and capillary wall deposits are noted in C3 glomerulonephritis, while ribbon-shaped dense osmiophilic intramembranous and mesangial deposits are noted in DDD. On the contrary, uncontrolled activation of the alternative pathway of complement on endothelial cell surface results in endothelial injury with an ensuing thrombotic microangiopathy, termed atypical hemolytic uremic syndrome (aHUS). Kidney biopsy in aHUS is often indistinguishable from other forms of thrombotic microangiopathy including enterohemorrhagic Escherichia coli–induced HUS and thrombotic thrombocytopenic purpura and shows thrombi in glomerular capillaries, mesangiolysis, and endothelial injury as evidenced by swelling and double contour formation along the glomerular capillary walls, with negative immunofluorescence studies for Ig and complement factors and no deposits on electron microscopy.

Keywords

glomerulonephritis - classification - membranoproliferative glomerulonephritis - C3 glomerulonephritis - complement

• References

• 1 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis—a new look at an old entity. N Engl J Med 2012; 366 (12) 1119-1131
• 2 Nasr SH, Satoskar A, Markowitz GS , et al. Proliferative glomerulonephritis with monoclonal IgG deposits. J Am Soc Nephrol 2009; 20 (9) 2055-2064
• 3 Sethi S, Zand L, Leung N , et al. Membranoproliferative glomerulonephritis secondary to monoclonal gammopathy. Clin J Am Soc Nephrol 2010; 5 (5) 770-782
• 4 Sethi S, Rajkumar SV. Monoclonal gammopathy-associated proliferative glomerulonephritis. Mayo Clin Proc 2013; 88 (11) 1284-1293
• 5 Rennke HG. Secondary membranoproliferative glomerulonephritis. Kidney Int 1995; 47 (2) 643-656
• 6 Weening JJ, D'Agati VD, Schwartz MM , et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004; 15 (2) 241-250
• 7 Zand L, Fervenza FC, Nasr SH, Sethi S. Membranoproliferative glomerulonephritis associated with autoimmune diseases. J Nephrol 2014; 27 (2) 165-171
• 8 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification. Semin Nephrol 2011; 31 (4) 341-348
• 9 Pickering MC, D'Agati VD, Nester CM , et al. C3 glomerulopathy: consensus report. Kidney Int 2013; 84 (6) 1079-1089
• 10 Servais A, Noël LH, Frémeaux-Bacchi V, Lesavre P. C3 glomerulopathy. Contrib Nephrol 2013; 181: 185-193
• 11 Sethi S, Nester CM, Smith RJH. Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion. Kidney Int 2012; 81 (5) 434-441
• 12 Xiao X, Pickering MC, Smith RJH. C3 glomerulopathy: the genetic and clinical findings in dense deposit disease and C3 glomerulonephritis. Semin Thromb Hemost 2014; 40 (4) 465-471
• 13 Fakhouri F, Frémeaux-Bacchi V, Noël L-H, Cook HT, Pickering MC. C3 glomerulopathy: a new classification. Nat Rev Nephrol 2010; 6 (8) 494-499
• 14 Fervenza FC, Smith RJH, Sethi S. Association of a novel complement factor H mutation with severe crescentic and necrotizing glomerulonephritis. Am J Kidney Dis 2012; 60 (1) 126-132
• 15 Sethi S, Vrana JA, Theis JD, Dogan A. Mass spectrometry based proteomics in the diagnosis of kidney disease. Curr Opin Nephrol Hypertens 2013; 22 (3) 273-280
• 16 Sethi S, Gamez JD, Vrana JA , et al. Glomeruli of dense deposit disease contain components of the alternative and terminal complement pathway. Kidney Int 2009; 75 (9) 952-960
• 17 Sethi S, Fervenza FC, Zhang Y , et al. Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement. Kidney Int 2013; 83 (2) 293-299
• 18 Nasr SH, Valeri AM, Appel GB , et al. Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin J Am Soc Nephrol 2009; 4 (1) 22-32
• 19 Braun MC, Stablein DM, Hamiwka LA, Bell L, Bartosh SM, Strife CF. Recurrence of membranoproliferative glomerulonephritis type II in renal allografts: The North American Pediatric Renal Transplant Cooperative Study experience. J Am Soc Nephrol 2005; 16 (7) 2225-2233
• 20 Lu D-F, Moon M, Lanning LD, McCarthy AM, Smith RJ. Clinical features and outcomes of 98 children and adults with dense deposit disease. Pediatr Nephrol 2012; 27 (5) 773-781
• 21 Andresdottir MB, Assmann KJ, Hoitsma AJ, Koene RA, Wetzels JF. Renal transplantation in patients with dense deposit disease: morphological characteristics of recurrent disease and clinical outcome. Nephrol Dial Transplant 1999; 14 (7) 1723-1731
• 22 Zand L, Lorenz EC, Cosio FG , et al. Clinical findings, pathology and outcomes of c3 glomerulonephritis following kidney transplantation. J Am Soc Nephrol 2013; ; doi: 10.1681/ASN.2013070715
• 23 Lorenz EC, Sethi S, Leung N, Dispenzieri A, Fervenza FC, Cosio FG. Recurrent membranoproliferative glomerulonephritis after kidney transplantation. Kidney Int 2010; 77 (8) 721-728
• 24 Noris M, Mescia F, Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol 2012; 8 (11) 622-633
• 25 Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361 (17) 1676-1687
• 26 Tsai H-M. Untying the knot of thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome. Am J Med 2013; 126 (3) 200-209