KIDNEY DISEASE ASSOCIATED WITH MONOCLONAL GAMMOPATHIES: SINGLE-CENTER STUDY

INTRODUCTION: Renal injury associated with monoclonal gammopathies (MG) is an area of interest of practical onconephrology. Prevalence, spectrum and renal outcome as far as approaches to treatment in this pathological entity, particularly in Russian population, still remain unclear and need refinement. AIM: Analysis of the prevalence, spectrum, treatment approaches and renal outcome in kidney injury associated with monoclonal gammopathies (MG).

PATIENTS AND METHODS: Patients with MG and renal injury proven by kidney biopsies from 01.01.2011 till 01.05.2018 were enrolled into this one-center prospective study (n=119). Cases of MG of undetermined significance and non-amyloid kidney lesions were estimated as MG of renal significance (MGRS). Treatment approaches, haematological and renal responses were analysed. Worsening of kidney function was estimated as eGFR decrease >25 % from initial value or initiation of renal replacement treatment (RRT), improving – as eGFR increase >25 % from the initial value or the discontinuation of RRT. Other cases were determined as stable kidney function. Kidney outcome was determined in RRT initiation or eGFR<15 ml/min/1,73m2 at the end of follow-up. Long-term kidney outcome was estimated by Kaplan-Meier survival analysis. The median follow-up period was 12 (2; 27) months.

RESULTS. Prevalence of kidney injury associated with MG among all performed kidney biopsies was 7,5 %, MGRS – 0,94 %. Multiple myeloma (MM), AL-amyloidosis and lymphoproliferative disorder (LPD) were diagnosed in 39, 55 and 10 patients, respectively. Prevalence of kidney injury types was the following: Al-amyloidosis (53 %); cast nephropathy (12 %); light chain deposition disease (12 %); C3-glomerulopathy (3 %); proliferative glomerulonephritis (GN) with monoclonal immunoglobulin deposits (3 %); cryoglobulinemic GN (2 %); thrombotic microangiopathy (2 %); podocytopathy (2 %); acute tubular necrosis – 2 %; immunotactoid GN (1 %); fibrillary GN (1 %); proximal tubulopathy (1 %), combination of different types (6 %). Patients mostly were treated with bortezomib and dexamethasone. Autologous stem cell transplantation was performed in 13 patients. Haematological response was achieved in 48,8 %, 45,4 % and 46,7 % of patients with MM, AL-amyloidosis and MGRS, respectively. Worsening of kidney function was registered in 11,1 % of MM and in 37,2 % of AL-amyloidosis; improving or stable kidney function was in 88,9 % and 62,7 % MM and AL-amyloidosis patients, respectively. In MGRS improving (20 %) and stable kidney function (80 %) were detected. Four-years cumulative renal survival in MM, AL-amyloidosis, MGRS and LPD groups was 63 %, 54 %, 80 % and 39 %, respectively, and does not differ between 4 groups.

CONCLUSION: MG-associated kidney disease represented by diverse clinical and morphological patterns is standard problem in routine clinical practice. It is associated with inferior renal outcome and requires a practical implementation of highly-specialized interdisciplinary approach to diagnostics and treatment.

1. Merlini G, Stone MJ. Dangerous small B-cell clones. Blood 2006; 108 (8): 2520–2530. doi: 10.1182/blood-2006-03-001164

2. International Myeloma Working Group (IMWG) criteria for the diagnosis of multiple myeloma. 2015. Режим доступа (available at): https://imwg.myeloma.org/international-myeloma-working-group-imwg-criteria-for-the-diagnosis-of-multiple-myeloma

3. Gertz MA. Waldenström macroglobulinemia: 2018 update on diagnosis, risk stratification, and management. Am J Hematol 2018; 1–11. doi: 10.1002/ajh.25292

4. NCCN Clinical Practice Guidelines in Oncology version 4.2014. Non-Hodgkin’s lymphomas. Режим доступа (available at): https://www.nccn.org/about/nhl.pdf

5. Leung N, Bridoux F, Hutchison CA et al. 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

6. Nasr SH, Valeri AM, Sethi S et al. Clinicopathologic correlations in multiple myeloma: a case series of 190 patients with kidney biopsies. Am J Kidney Dis 2012; 59 (6):786–794. doi: 10.1053/j.ajkd.2011.12.028

7. Decourt A, Gondouin B, Delaroziere JC et al. Trends in survival and renal recovery in patients with multiple myeloma or light-chain amyloidosis on chronic dialysis. Clin J Am Soc Nephrol 2016; 11(3): 431–441. doi: 10.2215/CJN.06290615

8. Bridoux F, Leung N, Hutchison CA et al. Diagnosis of monoclonal gammopathy of renal significance. Kidney Int 2015;87(4): 698–711. doi: 10.1038/ki.2014.408

9. Al-Hussain T, Hussein MH, Al Mana H, Akhtar M. Renal involvement in monoclonal gammopathy. Adv Anat Pathol 2015; 22 (2):121–134. doi: 10.1097/PAP.0000000000000056

10. Steiner N, Göbel G, Suchecki P et al. Monoclonal gammopathy of renal significance (MGRS) increases the risk for progression to multiple myeloma: an observational study of 2935 MGUS patients. Oncotarget 2017; 9 (2): 2344–2356. doi: 10.18632/oncotarget.23412

11. Rosner MH, Edeani A, Yanagita M et al. 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

12. Paueksakon P, Revelo MP, Horn RG et al. Monoclonal gammopathy: significance and possible causality in renal disease. Am J Kidney Dis 2003; 42 (1): 87–95. doi: -

13. Zand L, Nasr SH, Gertz MA et al. Clinical and prognostic differences among patients with light chain deposition disease, myeloma cast nephropathy and both. Leuk Lymphoma 2015; 56 (12): 3357–3364. doi: 10.3109/10428194.2015

14. Fish R, Pinney J, Jain P et al. The Incidence of major hemorrhagic complications after renal biopsies in patients with monoclonal gammopathies. Clin J Am Soc Nephrol 2010; 5 (11): 1977–1980. doi: 10.2215/CJN.00650110

15. Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150 (9): 604–612. doi: -

16. Greipp PR, San Miguel J, Durie BG et al. International staging system for multiple myeloma. J Clin Oncol 2005; 23 (15): 3412–3420. doi: 10.1200/JCO.2005.04.242

17. Palumbo A, Avet-Loiseau H, Oliva S et al. Revised international staging system for multiple myeloma: a report from international myeloma working group. J Clin Oncol 2015; 33 (26): 2863–2869. doi: 10.1200/JCO.2015.61.2267

18. Gertz MA, Comenzo R, Falk RH et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th international symposium on amyloid and amyloidosis. Am J Hematol 2005; 79 (4): 319–328. doi: 10.1002/ajh.20381

19. Sipovskyi VG, Dobronravov VA, Karunnaya AV, Smirnov AV. Clinical and morphological analysis of changes of peritubular microcirculation vessels of kidney interstitial tissue in patients with IgA-nephropathy (IgAN) with estimation of lectin pathway of complement activation. Nephrology (Saint-Petersburg) 2013; 17(4): 89–94. (In Russ.) doi: 10.24884/1561-6274-2013-17-4-89-94

20. Kumar S, Paiva B, Anderson KC et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 2016;17 (8): e328–e346. doi: 10.1016/S1470-2045(16)30206-6

21. Palladini G, Dispenzieri A, Gertz MA et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on freelight chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol 2012; 30 (36): 4541–4549. doi: 10.1200/JCO.2011.37.7614

22. Fermand JP, Bridoux F, Kyle RA 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. Owen RG, Kyle RA, Stone MJ et al. Response assessment in Waldenström macroglobulinaemia: update from the VIth International Workshop. Br J Haematol 2013;160 (2): 171–176. doi: 10.1111/bjh.12102

24. Milani P, Merlini G, Palladini G. Light chain amyloido sis. Mediterr J Hematol Infect Dis 2018; 10(1): e2018022. doi: 10.4084/MJHID.2018.022

25. Dispenzieri A, Katzmann JA, Kyle RA et al. Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study. Lancet 2010; 375 (9727): 1721–1728. doi: 10.1016/S0140-6736(10)60482-5

26. Ecotière L, Thierry A, Debiais-Delpech C et al. Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients. Nephrol Dial Transplant 2016; 31(1): 64–72. doi: 10.1093/ndt/gfv283

27. Kourelis TV, Nasr SH, Dispenzieri A et al. Outcomes of patients with renal monoclonal immunoglobulin deposition disease. Am J Hematol 2016; 91(11): 1123–1128. doi: 10.1002/ajh.24528

28. Uttervall K, Duru AD, Lund J et al. The use of novel drugs can effectively improve response, delay relapse and enhance overall survival in multiple myeloma patients with renal impairment. PLoS One 2014; 9(7): e101819. doi: 10.1371/journal.pone.0101819

29. Gonsalves WI, Leung N, Rajkumar SV et al. Improvement in renal function and its impact on survival in patients with newly diagnosed multiple myeloma. Blood Cancer J 2015; 5: e296. doi: 10.1038/bcj.2015.20

30. Leung N. To biopsy or not to biopsy, that is the question in myeloma cast nephropathy. Nephrol Dial Transplant 2016; 31(1): 1–3. doi: 10.1093/ndt/gfv294

31. Dimopoulos MA, Sonneveld P, Leung N et al. International Myeloma Working Group recommendations for the diagnosis and management of myeloma-related renal impairment. J Clin Oncol 2016; 34 (13): 1544–1557. doi: 10.1200/JCO.2015.65.0044

32. Oweis AO, Al Shelleh SA, Aldaoud N et al. Multiple myeloma in a patient with focal segmental glomerulosclerosis: A Case Report. Am J Case Rep 2018;19: 946–950. doi: 10.12659/AJCR.909696

33. Jeon YL, Lee WI, Choi Y et al. Crystalloid podocytopathy with focal segmental glomerulosclerosis in PCM: a case report. Diagn Pathol 2015; 10: 213. doi: 10.1186/s13000-015-0448-0

34. Dingli D, Larson DR, Plevak MF et al. Focal and segmental glomerulosclerosis and plasma cell proliferative disorders. Am J Kidney Dis 2005; 46(2): 278–282. doi: 10.1053/j.ajkd.2005.05.004

35. Salviani C, Guido G, Serriello I et al. Renal involvement in Waldenström's macroglobulinemia: case report and review of literature. Ren Fail 2014; 36(1): 114–118. doi: 10.3109/0886022X.2013.832859

36. Sethi S, Rajkumar SV. Monoclonal gammopathy-associated proliferative glomerulonephritis. Mayo Clin Proc 2013; 88(11): 1284–1293. doi: 10.1016/j.mayocp.2013.08.002

37. Goodship TH, Cook HT, Fakhouri F et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a «Kidney Disease: Improving Global Outcomes» (KDIGO) Controversies Conference. Kidney Int 2017; 91(3): 539–551. doi: 10.1016/j.kint.2016.10.005

38. Kumar SK, Callander NS, Alsina M et al. Multiple Myeloma, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2017; 15 (2): 230–269. doi: 10.6004/jnccn.2017.0023

39. Cohen C, Royer B, Javaugue V et al. Bortezomib produces high hematological response rates with prolonged renal survival in monoclonal immunoglobulin deposition disease. Kidney Int 2015; 88 (5): 1135–1143. doi: 10.1038/ki.2015.201

40. Kastritis E, Terpos E, Roussou M et al. Evaluation of the Revised International Staging System in an independent cohort of unselected patients with multiple myeloma. Haematologica 2017 Mar;102(3):593–599. doi: 10.3324/haematol.2016.145078