Rare combination of two rare diseases: non-amyloid monoclonal gammopathy of renal significance and hypertrophic cardiomyopathy - difficult diagnosis

The spectrum of monocolonal gammopathy of renal significance (MGRS) merges a group of diseases, driven by the deposition of monoclonal immunoglobulins in the patients, who do not meet criteria for diagnostics of multiple myeloma and other blood malignancies. By definition, the diagnosis of MGPS is based on kidney biopsy findings. One of the rare variants of MGRS, defined in 2004, is proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), presenting with nephrotic syndrome with microhematuria, arterial hypertension, impairment of kidney function, and characterized by a proliferative or membranoproliferative pattern of damage with mesangial and subendothelial deposits of monoclonal immunoglobulin G kappa (IgGκ), or, much rarer - monoclonal IgAκ or IgMκ. Even rarer described PGNMID with monoclonal deposits of the light chain kappa, and we found just one case of PGNMID with monoclonal deposits of the light chain lambda in the literature. Detection of paraprotein in the serum or urine in PGNMIG is possible only in 20-32% of cases and identification of secreting clones in the bone marrow is successful in less than 10% of cases. In contrast with immunoglobulin amyloidosis, heart, and other organ involvement were not described in association with PGNMID. Hypertrophic cardiomyopathy (HCM) is a genetic cardiomyopathy, caused by mutations in the genes, encoding sarcomere proteins, with the autosome-dominant type of inheritance. Diagnostic criteria for HCN is the left ventricular (LV) wall thickening >15 mm in the absence of other cardiac or systemic disease, which can cause LV hypertrophy. Phenotypic overlap between HCV and LV hypertrophy/pseudohypertrophy of other etiology, including arterial hypertension and amyloidosis is common, definite confirmation of the true HCM is possible only with genetic testing. Hereby we present a case of a previously not reported combination of PGNMID with monoclonal light chain lambda deposits and genetically confirmed HCM and discuss the difficulties of diagnostics and differential diagnostics.

биопсия почки, пролиферативный гломерулонефрит с депозитами моноклональных иммуноглобулинов, моноклональный белок, легкие цепи лямбда, хроническая болезнь почек, хроническая сердечная недостаточность, kidney biopsy, proliferative glomerulonephritis with monoclonal immunoglobulin deposits, monoclonal protein, lambda light chains, chronic kidney disease, chronic heart failure

1. Leung N., Bridoux F., Hutchison C.A. et al. International Kidney and Monoclonal Gammopathy Research Group. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood. 2012. 120(22):4292-4295. doi: 10.1182/blood-2012-07-445304

2. Leung N., Bridoux F., Batuman V. et al. The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol. 2019. 15(1):45-59. doi: 10.1038/s41581-018-0077-4

3. Gozzetti A., Guarnieri A., Zamagni E. et al. Monoclonal gammopathy of renal significance (MGRS): Real-world data on outcomes and prognostic factors. Am J Hematol. 2022. 97(7):877-884. doi: 10.1002/ajh.26566

4. Смирнов А.В., Добронравов В.А. Храброва М.С. Клинико-морфологическая характеристика и отдаленный прогноз при моноклональной гаммапатии ренального значения: опыт одного центра. Нефрология. 2020. 24(6):19-27. doi: 10.36485/1561-6274-2020-24-6-19-27

5. Резник Е.В., Нгуен Т.Л., Устюжанин Д.В. и соавт. «Красные флаги» диагностики инфильтративных заболеваний сердца. Российский кардиологический журнал. 2023. 28:5259. doi: 10.15829/1560-4071-2023-5259

6. Marian A.J., Braunwald E. Hypertrophic Cardiomyopathy. Circulation Research. 2017. 121:749-770. doi: 10.1161/CIRCRESAHA.117.311059.

7. Bridoux F., Leung N., Hutchison C.A. et al. International Kidney and Monoclonal Gammopathy Research Group. Diagnosis of monoclonal gammopathy of renal significance. Kidney Int. 2015. 87(4):698-711. doi:10.1038/ki.2014.408

8. Смирнов А.В., Афанасьев Б.В., Поддубная И.В. и соавт. Моноклональная гаммапатия ренального значения: консенсус гематологов и нефрологов России по введению нозологии, диагностике и обоснованности клон-ориентированной терапии. Нефрология. 2019. 23(6):9-28. doi: 10.36485/1561-6274-2019-236-9-28

9. Rosner M.H., Edani A., Yanagita M. et al. American Society of Nephrology Onco-Nephrology Forum. Paraprotein-Related Kidney Disease: Diagnosing and Treating Monoclonal Gammopathy of Renal Significance. Clin J Am Soc Nephrol. 2016. 11(12):2280-2287. doi: 10.2215/CJN.02920316

10. Bhutani D., Premkumar V., Shirazayan S. et al. Treatment of Non-Amyloid Monoclonal Gammopathies of Renal Significance (MGRS) with Clone Directed Therapies-Single Center Experience. Blood. 2019. 134 (Suppl 1):5565. doi: 10.1182/blood-2019-128455

11. Zakharova E.V., Makarova T.A., Stolyarevich E.S., Vorobieva O.A. Monoclonal immunoglobulin-mediated kidney disease: What is beyond amyloidosis in real practice? Journal of Onconephrology. 2019. 3(3):105-112.

12. Nasr S.H., Markowitz G.S., Stokes M.B. et al. Proliferative glomerulonephritis with monoclonal IgG deposits: a distinct entity mimicking immune-complex glomerulonephritis. Kidney Int. 2004. 65(1):85-96. doi: 10.1111/j.1523-1755.2004.00365.x

13. Nasr S.H., Satoskar A., Markowitz G.S. et al. Proliferative glomerulonephritis with monoclonal IgG deposits. J Am Soc Nephrol. 2009. 20(9):2055-2064.

14. Soares S.M., Lager D.J., Leung N. et al. A proliferative glomerulonephritis secondary to a monoclonal IgA. Am J Kidney Dis. 2006. 47(2):342-349. doi: 10.1053/j.ajkd.2005.10.023

15. Bhutani G., Nasr S.H., Said S.M., et al. Hematologic characteristics of proliferative glomerulonephritides with nonorganized monoclonal immunoglobulin deposits. Mayo Clin. Proc. 2015. 90(5):587-596. doi: 10.1016/j.mayocp.2015.01.024

16. Vignon M., Cohen C., Faguer S. et al. The clinicopathologic characteristics of kidney diseases related to monotypic IgA deposits. Kidney Int. 2017. 91(3):720-728. doi: 10.1016/j.kint.2016.10.026

17. Bridoux F., Javaugue V., Nasr SH., Leung N. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits: a nephrologist perspective. Nephrol Dial Transplant. 2021. 36(2):208-215. doi: 10.1093/ndt/gfz17620

18. Lin L., Chen N. A Review on the Diagnosis and Treatment of Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits. Int J Gen Med. 2022. 15:8577-8582. doi: 10.2147/IJGM.S386733

19. Li M., Xu G. An update of proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Clin. Kidney J. 2021. 15(6):1041-1048. doi: 10.1093/ckj/sfab269

20. Grogan M., Dispenzieri A., Gertz M.A. Light-chain cardiac amyloidosis: strategies to promote early diagnosis and cardiac response. Heart. 2017. 103(14):1065-1072. doi: 10.1136/heartjnl-2016-310704

21. Buxbaum J.N., Genega E.M., Lazowski P. et al. Infiltrative nonamyloidotic monoclonal immunoglobulin light chain cardiomyopathy: an underappreciated manifestation of plasma cell dyscrasias. Cardiology. 2000. 93(4):220-228. doi: 10.1159/000007030

22. Fermand J-P., Bridoux F., Kyle R.A. et al. How I treat monoclonal gammopathy of renal significance (MGRS). Blood. 2013. 122(22):3583-3590. doi: 10.1182/blood-2013-05-495929

23. Alpers C.E., Tu W.H., Hopper J., Biava C.G. Single light chain subclass (kappa chain) immunoglobulin deposition in glomerulonephritis. Hum Pathol. 1985. 16(3):294-304. doi: 10.1016/s0046-8177(85)80017-43

24. Nasr S.H., Larsen C.P., Sirac C. et al. Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone. Kidney Int. 2020. 97(3):589-601. doi: 10.1016/j.kint.2019.10.025

25. De La Flor J.C., Apaza J., Díaz F. et al. An Exceptional Case of Light Chain Only Variant of Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits Secondary to Chronic Lymphocytic Leukemia: A Case Report and Review of the Literature. Case Rep Nephrol. 2022. 2022:9207282. Published 2022 Oct 19. doi: 10.1155/2022/9207282

26. Gumber R., Cohen J.B., Palmer M.B. et al. A clone-directed approach may improve diagnosis and treatment of proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Kidney Int. 2018. 94(1):199-205. doi: 10.1016/j.kint.2018.02.020

27. Zand L., Rajkumar S.V., Leung N. et al. Safety and Efficacy of Daratumumab in Patients with Proliferative GN with Monoclonal Immunoglobulin Deposits. J Am Soc Nephrol. 2021. 32(5):1163-1173. doi: 10.1681/ASN.2020101541

28. Insights QD. New Content Release: HGMD Professional 2022.1. QIAGEN Digital Insights. 2022. https://digitalinsights.qiagen.com/news/blog/clinical/new-content-release-hgmd-professional-2022-1/ (accessed 27 Mar 2023).

29. Рыжкова О.П., Кардымон О.Л., Прохорчук Е.Б. и соавт. Руководство по интерпретации данных последовательности ДНК человека, полученных методами массового параллельного секвенирования (MPS) (редакция 2018, версия 2). Медицинская генетика. 2019. 18:3-23. doi: 10.25557/2073-7998.2019.02.3-23