RPS Case of the Month
A pediatric nephritic syndrome
Lame Balikani, MD, MPH11
Laura Biederman2, MD2
1. Department of Pathology, Robert J. Tomsich-Pathology & Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio2. Nationwide Children’s Hospital, Columbus, Ohio, USA Ohio State Wexner Medical Center, Columbus, Ohio, USA
A 7-year-old previously healthy female now presenting with new-onset hypertension, hematuria, and proteinuria. Serum creatinine is 0.41 and urinalysis shows 4+ protein and >400 RBC/HPF.
KIDNEY BIOPSY FINDINGS
Figure 1: Glomerulus with mesangial and endocapillary hypercellularity (H&E 40x).
Figure 2: Glomerular basement membrane remodeling (arrow) and an active cellular crescent (arrowhead). (silver stain, 40x).
Figure 3: Diffuse, linear glomerular capillary loop staining for C3 (C3 immunofluorescence, 20x).
Figure 4: Electron microscopy shows intensely osmophilic deposits along the glomerular capillary loop.
Figure 5: Electron microscopy shows intensely osmophilic deposits along the tubular basement membranes (arrow).
Dense Deposit Disease
Dense deposit disease (DDD) is a rare C3-related glomerulopathy with classic ultrastructural findings. Although historically called membranoproliferative glomerulonephritis type II, this disease does not always have a membranoproliferative pattern. There are 5 patterns associated with DDD including membranoproliferative, mesangial proliferative, crescentic, acute proliferative and exudative, and unclassified. Therefore, the pathognomonic feature is the presence of densely osmophilic deposition along/transformation of the glomerular basement membranes.1 These characteristic depositions can also be seen along Bowman’s capsule and tubular basement membranes. Focal crescents are commonly seen, as in this case, though a diffuse crescentic process is uncommon.2 Although they stain for C3 on immunofluorescence, the composition of the deposits in DDD is unknown. On mass spectrometry analysis, they have been shown to contain alternative complement pathway components.3
DDD classically occurs in children, usually before age 15 with both genders equally affected.4-6However, it is also seen in the adult population, most commonly in association with a monoclonal paraprotein. Patients classically present with hematuria and proteinuria. In both adults and children, the exact etiology is unknown but is related to either genetic or acquired dysregulation of the alternative complement pathway with resultant over-activation.7 In cases related to a monoclonal paraprotein, autoantibodies to complement components have been described, and acquired inhibition of the alternative complement pathway in the fluid phase has been proposed as a possible etiology.8-10 In the cases without a monoclonal paraprotein, it is associated with various defects in the alternative complement pathway including autoantibodies to complement components including C3 nephritic factor (C3NeF) and/or genetic predispositions in complement genes, most notably factor H deficiency.4,11 Additionally, there is some evidence that, like C3 glomerulopathy, it may be triggered by an antecedent infection in some patients.2,6,12 Although C3NeF activity is seen in approximately 80% of patients with DDD, it should be noted that C3NeF is non-specific and can be seen in healthy individuals.5,13 A rare form of C4 DDD has also been reported in the literature.14
Approximately 50% of patients diagnosed with DDD progress to end-stage renal disease (ESRD) within 10 years of diagnosis.4,15 Younger age a diagnosis, crescentic glomerulonephritis on histologic evaluation, elevated serum creatinine and proteinuria at the time of diagnosis, >20% chronic changes on biopsy, subepithelial humps, and possibly the presence of nephrotic syndrome predict a poor prognosis in patients with DDD.1,2,4,6,16-18 Those who progress to ESRD often require dialysis and/or renal transplant. Unfortunately, DDD recurs frequently in the transplant.4-6,19,20Treatment is challenging and depends on the presence of a monoclonal paraprotein or certain genetic abnormalities. Immunosuppression including steroids is not consistently effective, and there are no randomized trials to inform therapeutic decisions.2,5,7,21,22 Some studies report, success in treating DDD with eculizumab with variable outcomes in the allograft setting.19,23-28 However, some of the utility of terminal complement inhibitors remains under investigation, and their utility may depend on the degree of terminal complement activation.24 Additional workup for genetic abnormalities, paraproteins, and complement serologies is generally performed in these patients.
1. Walker PD, Ferrario F, Joh K, Bonsib SM. Dense deposit disease is not a membranoproliferative glomerulonephritis. Mod Pathol. Jun 2007;20(6):605-16. doi:10.1038/modpathol.3800773
2. Nasr SH, Valeri AM, Appel GB, et al. Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin J Am Soc Nephrol. Jan 2009;4(1):22-32. doi:10.2215/cjn.03480708
3. Sethi S, Gamez JD, Vrana JA, et al. Glomeruli of Dense Deposit Disease contain components of the alternative and terminal complement pathway. Kidney Int. May 2009;75(9):952-60. doi:10.1038/ki.2008.657
4. Servais A, Noël LH, Roumenina LT, et al. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. Aug 2012;82(4):454-64. doi:10.1038/ki.2012.63
5. Lu DF, Moon M, Lanning LD, McCarthy AM, Smith RJ. Clinical features and outcomes of 98 children and adults with dense deposit disease. Pediatr Nephrol. May 2012;27(5):773-81. doi:10.1007/s00467-011-2059-7
6. Medjeral-Thomas NR, O'Shaughnessy MM, O'Regan JA, et al. C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol. Jan 2014;9(1):46-53. doi:10.2215/cjn.04700513
7. Pickering MC, D'Agati VD, Nester CM, et al. C3 glomerulopathy: consensus report. Kidney Int. Dec 2013;84(6):1079-89. doi:10.1038/ki.2013.377
8. Sethi S, Sukov WR, Zhang Y, et al. Dense deposit disease associated with monoclonal gammopathy of undetermined significance. Am J Kidney Dis. Nov 2010;56(5):977-82. doi:10.1053/j.ajkd.2010.06.021
9. Meri S, Koistinen V, Miettinen A, Törnroth T, Seppälä IJ. Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis. J Exp Med. Apr 1 1992;175(4):939-50. doi:10.1084/jem.175.4.939
10. Jokiranta TS, Solomon A, Pangburn MK, Zipfel PF, Meri S. Nephritogenic lambda light chain dimer: a unique human miniautoantibody against complement factor H. J Immunol. Oct 15 1999;163(8):4590-6.
11. Xiao X, Pickering MC, Smith RJ. C3 glomerulopathy: the genetic and clinical findings in dense deposit disease and C3 glomerulonephritis. Semin Thromb Hemost. Jun 2014;40(4):465-71. doi:10.1055/s-0034-1376334
12. Suga K, Kondo S, Matsuura S, et al. A case of dense deposit disease associated with a group A streptococcal infection without the involvement of C3NeF or complement factor H deficiency. Pediatr Nephrol. Aug 2010;25(8):1547-50. doi:10.1007/s00467-010-1479-0
13. Servais A, Noël LH, Frémeaux-Bacchi V, Lesavre P. C3 glomerulopathy. Contrib Nephrol. 2013;181:185-93. doi:10.1159/000348654
14. Sethi S, Quint PS, O'Seaghdha CM, et al. C4 Glomerulopathy: A Disease Entity Associated With C4d Deposition. Am J Kidney Dis. Jun 2016;67(6):949-53. doi:10.1053/j.ajkd.2016.01.012
15. Smith RJ, Harris CL, Pickering MC. Dense deposit disease. Mol Immunol. Aug 2011;48(14):1604-10. doi:10.1016/j.molimm.2011.04.005
16. Cameron JS, Turner DR, Heaton J, et al. Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis. Am J Med. Feb 1983;74(2):175-92. doi:10.1016/0002-9343(83)90606-x
17. Liu JC, Yang JY, Xiao HJ, et al. [Clinical and pathological characteristics of children with dense deposit disease]. Zhonghua Er Ke Za Zhi. Aug 2009;47(8):593-7.
18. Cansick JC, Lennon R, Cummins CL, et al. Prognosis, treatment, and outcome of childhood mesangiocapillary (membranoproliferative) glomerulonephritis. Nephrol Dial Transplant. Nov 2004;19(11):2769-77. doi:10.1093/ndt/gfh484
19. Regunathan-Shenk R, Avasare RS, Ahn W, et al. Kidney Transplantation in C3 Glomerulopathy: A Case Series. Am J Kidney Dis. Mar 2019;73(3):316-323. doi:10.1053/j.ajkd.2018.09.002
20. 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. Jul 1999;14(7):1723-31. doi:10.1093/ndt/14.7.1723
21. Nester CM, Smith RJ. Treatment options for C3 glomerulopathy. Curr Opin Nephrol Hypertens. Mar 2013;22(2):231-7. doi:10.1097/MNH.0b013e32835da24c
22. Alchi B, Jayne D. Membranoproliferative glomerulonephritis. Pediatr Nephrol. Aug 2010;25(8):1409-18. doi:10.1007/s00467-009-1322-7
23. Bomback AS, Smith RJ, Barile GR, et al. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin J Am Soc Nephrol. May 2012;7(5):748-56. doi:10.2215/cjn.12901211
24. Kasahara K, Gotoh Y, Majima H, Takeda A, Mizuno M. Eculizumab for pediatric dense deposit disease: A case report and literature review. Clin Nephrol Case Stud. 2020;8:96-102. doi:10.5414/cncs110309
25. Rousset-Rouvière C, Cailliez M, Garaix F, Bruno D, Laurent D, Tsimaratos M. Rituximab fails where eculizumab restores renal function in C3nef-related DDD. Pediatr Nephrol. Jun 2014;29(6):1107-11. doi:10.1007/s00467-013-2711-5
26. Holle J, Berenberg-Goßler L, Wu K, et al. Outcome of membranoproliferative glomerulonephritis and C3-glomerulopathy in children and adolescents. Pediatr Nephrol. Dec 2018;33(12):2289-2298. doi:10.1007/s00467-018-4034-z
27. Oosterveld MJ, Garrelfs MR, Hoppe B, et al. Eculizumab in Pediatric Dense Deposit Disease. Clin J Am Soc Nephrol. Oct 7, 2015;10(10):1773-82. doi:10.2215/cjn.01360215
28. Ozkaya O, Nalcacioglu H, Tekcan D, et al. Eculizumab therapy in a patient with dense-deposit disease associated with partial lipodystrophy. Pediatr Nephrol. Jul 2014;29(7):1283-7. doi:10.1007/s00467-013-2748-5