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病史

7 岁女性患者，既往体健，新发高血压、血尿和蛋白尿。血清肌酐 0.41mg/dl，尿常规蛋白 4+，尿红细胞>400/ HPF。

肾活检病理

 

图1 肾小球系膜及毛细血管内细胞增多（HE染色， 40×）。

 

图2  肾小球基底膜重塑（®）以及活动性的细胞性新月体（D）（六胺银染色，40×）。

图3 C3沿肾小球毛细血管袢弥漫性及线状沉积（C3 免疫荧光，20×）

图4 电镜下显示强嗜锇性的电子致密物沉积沿肾小球毛细血管袢基底膜沉积。

图5 电镜显示强嗜锇性电子致密物沉积沿肾小管基底膜沉积（®）。

最终诊断

致密物沉积病

 

讨论

致密沉积病（DDD）是一种罕见与 C3 相关的肾小球疾病，具有典型的超微结构特点。以往DDD被称为膜增生性肾小球肾炎（MPGN）II型，但形态学上并不总表现为膜增生性病变。DDD的病理形态学改变包括以下5种病变：膜增生型、系膜增生型、新月体型、急性增殖和渗出型、以及未分类型。因此DDD的特征性病理改变是电镜下见强嗜锇性电子致密物沿肾小球基底膜内沉积¹，类似沉积物亦见于鲍曼囊壁和肾小管基底膜。DDD常见局灶性新月体如本例所示，而弥漫性新月体形成则不常见²。DDD免疫荧光染色C3阳性，但仍不清楚其沉积物的组成。质谱分析结果提示沉积物中存在补体旁路途径成分³。

DDD常见于15岁以下儿童，男女发病相似^4-6。DDD亦见于成人，多数与单克隆副球蛋白相关。患者临床表现包括血尿和蛋白尿。成人和儿童DDD的确切病因尚不清楚，可能与遗传或获得性的补体旁路途径异常导致其过度激活有关⁷。单克隆副球蛋白相关的病例中存在针对补体成分的自身抗体导致液相期补体旁路途径获得性抑制，是发病的可能病因^8-10。在无单克隆副球蛋白的病例中，其机制与补体旁路途径中的多种缺陷有关，包括针对补体成分的自身抗体，如C3肾炎因子（C3NeF）和/或补体成分的基因变异，最常见的是H因子缺乏^4，11。此外也有证据表明DDD与C3肾小球病一样，可能由既往感染诱发^2，6，12。80% 的 DDD 患者存在C3NeF，但C3NeF并不特异性，亦见于健康个体^5，13。有文献报道了一种罕见形式的C4型DDD¹⁴。

约 50% DDD 患者在确诊后10年内进展为终末期肾病 (ESRD)。DDD患者预后较差的因素包括诊断时年龄较小、组织学表现为新月体肾小球肾炎、诊断时血清肌酐和蛋白尿升高、活检时慢性病变>20%、上皮下驼峰状沉积物以及存在肾病综合征^1,2,4,6,16。DDD移植后复发较常见^4-6,19,20。

DDD治疗具有挑战性，取决于是否存在单克隆副球蛋白或特定的遗传变异。 免疫抑制治疗如类固醇激素效果不佳，也缺乏随机临床试验来为治疗决策提供依据^{2，5，7，21，22}。依库珠单抗成功治疗DDD已有报道，但在治疗移植患者DDD时结果则不尽相同^19，23-28。补体终末产物抑制剂的疗效仍在研究中，其效果可能取决于终末补体激活的程度²⁴。对DDD患者要常规筛查是否存在基因异常、副球蛋白和补体血清学的检查。

 

References

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