Dysproteinemias Related Renal Disorders, Monoclonal Gammopathy (Paraproteinemia), Nephrology Perspective - Dr. Gawad

1. Dysproteinemias Related Renal Disorders Monoclonal Gammopathy (Paraproteinemia) Nephrology Perspective Mohammed Abdel Gawad Lecturer of Nephrology, School of Medicine, NewGiza University Nephrology Consultant, Alexandria MD Nephrology, Mansoura University European Specialty Examination in Nephrology (ESENeph) – UK Founder of NephroTube.com Annual Conference of Assiut – Nephrology Chapter – 28 October 2021

2. To download the lecture contact me drgawad@gmail.com For more Nephrology lectures visit www.NephroTube.com

4. Talk Outline • Back to basics • Kidney deposits: Hypothesized mechanism / Clinical presentation • Dysproteinemia diagnosis: Lab • Dysproteinemia diagnosis: Renal biopsy • Dysproteinemia diagnosis: Bone marrow biopsy • Monoclonal Gammopathy of Renal Significance (MGRS) • High cutoff dialyzers • Final message

6. Monoclonal Abs (Ig, Gama Globulin) • Antibodies that are identical because they were produced by one type of B cell. • Detect only one epitope on the antigen. • Antibodies that are non-identical because they were produced by different B cell resources. • Detect multiple epitopes on any one antigen. Polyclonal Abs (Ig, Gama Globulin) Semin Immunol. 2008;20:49

7. Monoclonal gammopathy (paraproteinemia) signifies the production of monoclonal immunoglobulin or immunoglobulin fragments (i.e., light or heavy chains) by a clonal proliferation of plasma cells or B cells Am J Kidney Dis (2019), 74(6):822-836

9. Monoclonal gammopathy - associated renal lesions Kidney International (2015) 87, 698–711

10. Kidney International (2015) 87, 698–711

11. Dysproteinemia-Associated Kidney Diseases: Hypothesized mechanism of injury Am J Kidney Dis (2019), 74(6):822-836

12. Dysproteinemia-Associated Kidney Diseases: Hypothesized mechanism of injury Am J Kidney Dis (2019), 74(6):822-836

14. Serum protein electrophoresis (SPE) Paraprotein is a monoclonal Ig (gamma globulin) that is produced in excess by the clonal proliferation of plasma cells Electrophoresis. 1997;18:1775-1780

15. Serum protein electrophoresis (SPE) Serum immunofixation electrophoresis (sIFE) Can detect the whole immunoglobulin (cannot reliably differentiate monoclonal from polyclonal light chain expansion) 10 times more sensitive for immunoglobulins Only detects increased LC in patients who have very high levels of LC-only myeloma 10 times more sensitive for LC Semi-quantitative Not quantitative Laboratory Diagnostic Tests Clin Chem. 2002;48(9):1437-1444

16. Urine PEP, immunofixation electrophoresis (uIFS) (to detect Bence Jones Proteinuria) Serum PEP, immunofixation electrophoresis (sIFE) • Can detect low levels of LC • Yet remains less sensitive than sFLC measurement because sFLC are elevated before urine overflow may occur. More sensitive Dr. Henry Bence-Jones 31 December 1813 / / April 20, 1873 Laboratory Diagnostic Tests

17. Serum Free Light Chains (к and λ) Measurement Normal к/λ CKD к/λ Abnormal к/λ ratio 0.26–1.65 0.37–3.17 Significant accumulation of sFLC occurs (approximately five-fold) Occurs as a result of overproduction of a single к or λ clone Am J Kidney Dis (2019), 74(6):822-836

18. Am J Kidney Dis (2019), 74(6):822-836

19. Dysproteinemia-Associated Kidney Diseases: Paraprotein detection rate Am J Kidney Dis (2019), 74(6):822-836

20. Diagnosis of dysproteinemia Urine Analysis Discrepancy between PCR in urine and dipstick results suggests LC deposition disease Light chain proteins are not detected by dipstick but are counted through PCR Light chain proteins are counted through PCR but will not affect ACR Discrepancy between PCR and ACR in urine suggests LC deposition disease

22. Comprehensive Clinical Nephrology. 4th edition, chapter 26

23. J Am Soc Nephrol 19: 34–37, 2008

24. J Am Soc Nephrol 19: 34–37, 2008

25. J Am Soc Nephrol 19: 34–37, 2008 DNAJB9 is novel proteomic tissue biomarker specific for fibrillary glomerulonephritis on immunohistochemistry Kidney Int Rep. 2017 Aug 8;3(1):56-64

26. Immunotactoid glomerulopathy Am J Kidney Dis (2019), 74(6):822-836

27. κ light chain monoclonal immunoglobulin deposition disease Am J Kidney Dis (2019), 74(6):822-836

28. Proliferative glomerulonephritis with monoclonal immunoglobulin G3 (IgG3) κ deposits Am J Kidney Dis (2019), 74(6):822-836

29. Am J Kidney Dis (2019), 74(6):822-836 Light chain cast nephropathy

31. Kidney International (2011) 79, 1289–1301 Dysproteinemia-Associated Kidney Diseases: Clone detection

32. Am J Kidney Dis (2019), 74(6):822-836 Dysproteinemia-Associated Kidney Diseases: Clone detection

34. MGUS MGRS Smoldering (asymptomatic) myeloma Active (symptomatic) myeloma Serum M-protein <3 g/100ml <3 g/100ml 3 g/100ml 3 g/100ml Bone marrow clonal plasma cells <10% <10% 10% 10% or Plasmacytoma Related organ or tissue impairment Absent and No evidence of other B-cell proliferative disorders Renal injury Absent/ Asymptomatic Requires 1 or more of the following: • Calcium elevation • Renal insufficiency • Anaemia • Bone osteolytic lesion Monoclonal Gammopathy of Renal Significance (MGRS) Am J Kidney Dis (2019), 74(6):822-836

36. JAMA. 2017;318(21):2099-2110 94 patients MYRE Trial

37. JAMA. 2017;318(21):2099-2110

38. 90 patients Lancet Haematol. 2019 Apr;6(4):e217-e228

40. Suspected dysproteinemia in a kidney disease SPEP, Serum immunofixation, SFLC +ve for dysproteinemia Bone marrow biopsy Target treatment for the type of clonal proliferation -ve for dysproteinemia High suspicion for dysproteinemia in a kidney disease Renal biopsy +ve for dysproteinemia -ve for dysproteinemia Follow up and treatment according to presentation

41. Thank You drgawad@gmail.com www.NephroTube.com

Dysproteinemias Related Renal Disorders, Monoclonal Gammopathy (Paraproteinemia), Nephrology Perspective - Dr. Gawad

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Dysproteinemias Related Renal Disorders, Monoclonal Gammopathy (Paraproteinemia), Nephrology Perspective - Dr. Gawad