Morphological and immunohistochemical predictors of renal response to therapy patients with myeloma cast nephropathy and dialysis-dependent acute kidney injury

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Aim. Reveal morphological and immunohistochemical predictors of reversibility of dialysis-dependent acute kidney injury (AKI) in patients with myeloma cast nephropathy (MCN) based on the study of kidney biopsy.

Materials and methods. Renal pathological findings were studied in 36 patients with MCN and dialysis-dependent stage 3 AKI (AKIN, 2012). The study of biopsy samples was performed by a semi-quantitative and quantitative analysis using computer morphometry. The expression of E-cadherin, vimentin and á-smooth muscle actin was determined immunohistochemically in the tubular cells and interstitium. Induction therapy for 26 patients was carried out to bortezomib-based programs; in 10 patients other schemes were used. A comparative analysis of morphological changes in nephrobiopathy depending on the renal response was performed in patients with achieved hematologic remission.

Results. Improved renal function was observed only in patients with hematologic response to therapy. There were no differences in the number of sclerotic glomeruli, protein casts, the area of inflammatory interstitial infiltration, and the degree of acute tubular damage in patients with and without renal response. In patients with renal response compared with patients without improving renal function, the area of interstitial fibrosis was less (24.9% and 45.9%, respectively; p=0.001), and the area of E-cadherin expression was larger (15.9% and 7.1%, respectively; p=0.006). Interstitial fibrosis of 40% or more and/or the area of expression of E-cadherin less than 10% of the area of tubulo-interstitium have an unfavorable prognostic value in achieving a renal response in MCN.

Conclusion. If the interstitial fibrosis area is 40% or more and the expression area of E-cadherin is less than 10%, the probability of the absence of a renal response is 93.3% (OR=24.5) even when a hematological response to induction therapy is achieved. The number of protein casts, the prevalence of acute tubular damage and inflammatory interstitial infiltration have not prognostic value.

About the authors

I. G. Rekhtina

National Research Center for Hematology

Email: kazarina.ev@yandex.ru
ORCID iD: 0000-0001-5440-4340

д.м.н., зав. отд-нием химиотерапии плазмоклеточных дискразий ФГБУ «НМИЦ гематологии»

Russian Federation, Moscow

E. V. Kazarina

National Research Center for Hematology

Author for correspondence.
Email: kazarina.ev@yandex.ru
ORCID iD: 0000-0002-9854-9354

врач-нефролог группы гемодиализа отд-ния реанимации и интенсивной терапии ФГБУ «НМИЦ гематологии»

Russian Federation, Moscow

E. S. Stolyarevich

Moscow City Nephrology Center, Moscow City Hospital 52; Yevdokimov Moscow State University of Medicine and Dentistry

Email: kazarina.ev@yandex.ru
ORCID iD: 0000-0002-0402-8348

д.м.н., проф., патологоанатомическое отд-ние ГБУЗ «ГКБ №52»; каф. нефрологии ФГБОУ ВО «МГМСУ им. А.И. Евдокимова»

Russian Federation, Moscow

A. M. Kovrigina

National Research Center for Hematology; Federal Research Clinical Center of Specialized Types of Medical Care and Medical Technologies

Email: kazarina.ev@yandex.ru
ORCID iD: 0000-0002-1082-8659

д.б.н., проф. каф. клинической лабораторной диагностики и патологической анатомии Академии последипломного образования ФГБУ ФНКЦ, зав. патологоанатомическим отд-нием ФГБУ «НМИЦ гематологии»

Russian Federation, Moscow

V. N. Dvirnyk

National Research Center for Hematology

Email: kazarina.ev@yandex.ru
ORCID iD: 0000-0002-9877-0796

к.м.н., зав. центральной клинико-диагностической лаб. ФГБУ «НМИЦ гематологии»

Russian Federation, Moscow

S. M. Kulikov

National Research Center for Hematology

Email: kazarina.ev@yandex.ru
ORCID iD: 0000-0001-8188-5557

к.т.н., зав. информационно-аналитическим отд. ФГБУ «НМИЦ гематологии»

Russian Federation, Moscow

L. P. Mendeleeva

National Research Center for Hematology

Email: kazarina.ev@yandex.ru
ORCID iD: 0000-0002-4966-8146

д.м.н., проф., зам. ген. дир. по научной работе и инновациям ФГБУ «НМИЦ гематологии»

Russian Federation, Moscow

References

  1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15 (12):e538-e548. doi: 10.1016/S1470-2045 (14)70442-5
  2. 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):1544-57. doi: 10.1200/JCO.2015.65.0044
  3. Bladé J, Fernández-Llama P, Bosch F, et al. Renal failure in multiple myeloma: Presenting features and predictors of outcome in 94 patients from a single institution. Arch Int Med. 1998;158(17):1889-93. doi: 10.1001/archinte.158.17.1889
  4. Yadav P, Cook M, Cockwell P. Current Trends of Renal Impairment in Multiple Myeloma. Kidney Dis. 2016;1(4):241-57. doi: 10.1159/000442511
  5. Mendeleeva LP, Solovev MV, Alexeeva A, et al. Multiple Myeloma in Russia (First Results of the Registration Trial). Blood. 2017;130(Suppl. 1):5408.
  6. Рехтина И.Г., Менделеева Л.П., Бирюкова Л.С. Диализзависимая почечная недостаточность у больных множественной миеломой: факторы обратимости. Терапевтический архив. 2015;87(7):72 [Rekhtina IG, Mendeleeva LP, Biryukova LS. Dialysis-dependent renal failure in patients with multiple myeloma: Reversibility factors. Terapevticheskij Arhiv. 2015;87(7):72 (In Russ.)]. doi: 10.17116/terarkh201587772-76
  7. Ying WZ, Wang PX, Sanders PW. Pivotal role of apoptosis signal-regulating kinase 1 in monoclonal free light chain-mediated apoptosis. Am J Pathol. 2012;180(1):41-7. doi: 10.1016/j.ajpath.2011.09.017
  8. Hertig A, Bonnard G, Ulinski T, et al. Tubular nuclear accumulation of Snail and epithelial phenotypic changes in human myeloma cast nephropathy. Human Pathol. 2011;42(8):1142-8. doi: 10.1016/j.humpath.2010.11.006
  9. Рехтина И.Г., Менделеева Л.П., Варламова Е.Ю., Бирюкова Л.С. Сравнение эффективности бортезомибсодержащих программ в достижении раннего гематологического и почечного ответа у больных миеломной нефропатией с диализзависимой почечной недостаточностью. Гематология и трансфузиология. 2015;60(4):4-7 [Rekhtina IG, Mendeleeva LP, Varlamova EYu, Biryukova LS. Comparison of the efficiency of bortezomib-based protocols in induction of an early hematological and renal response in myeloma nephropathy patients with hemodialysis-dependent renal failure. Gematologiya i transfuziologiya. 2015;60(4):4-7 (In Russ.)].
  10. Ludwig H, Adam Z, Hajek R, et al. Light chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple myeloma: results of a phase II study. J Clin Oncol. 2010;28(30):4635-41. doi: 10.1200/JCO.2010.28.1238
  11. Ludwig H, Rauch E, Kuehr T, et al. Lenalidomide and dexamethasone for acute light chain-induced renal failure: a phase II study. Haematologica. 2015;100(3):385-91. doi: 10.3324/haematol.2014.115204
  12. Dimopoulos MA, Roussou M, Gkotzamanidou M, et al. The role of novel agents on the reversibility of renal impairment in newly diagnosed symptomatic patients with multiple myeloma. Leukemia. 2013;27(2):423-9. doi: 10.1038/leu.2012.182
  13. Рехтина И.Г., Казарина Е.В., Столяревич Е.С. и др. Прогностическое значение фиброза интерстиция в нефробиоптате в обратимости острого почечного повреждения при цилиндровой нефропатии у пациентов с множественной миеломой. Нефрология и диализ. 2019;21(3):312-9 [Rekhtina IG, Kazarina EV, Stolyarevich ES, et al. Interstitial fibrosis and outcomes of acute kidney injury in myeloma cast nephropathy. Nefrologiya i dializ. 2019;21(3):312-9 (In Russ.)]. doi: 10.28996/2618-9801-2019-3-312-319
  14. Hutchison CA, Bladé J, Cockwell P, et al.; International Kidney and Monoclonal Gammopathy Research Group. Novel approaches for reducing free light chains in patients with myeloma kidney. Nat RevNephrol. 2012;8(4):234-43. doi: 10.1038/nrneph.2012.14
  15. Bridoux F, Carron PL, Pegourie B, et al.; MYRE Study Group. Effect of High-Cutoff Hemodialysis vs Conventional Hemodialysis on Hemodialysis Independence among Patients with Myeloma Cast Nephropathy: A Randomized Clinical Trial. JAMA. 2017;318(21):2099-110. doi: 10.1001/jama.2017.17924
  16. Chanan-Khan AA, Kaufman JL, Mehta J, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood. 2007;109(6):2604-6. doi: 10.1182/blood-2006-09-046409
  17. Семочкин С.В., Желнова Е.И., Мисюрина Е.Н. и др. Клиническое значение восстановления функции почек у больных впервые диагностированной множественной миеломой, осложненной тяжелой и диализ-зависимой почечной недостаточностью. Гематология и трансфузиология. 2019;64(3):283-96 [Semochkin SV, Zhelnova EI, Misyurina EN, et al. Сlinical importance of renal recover on outcomes of newly diagnosed multiple myeloma patients with severe and dialysis-dependent kidney failure. Gematologiya i transfuziologiya. 2019;64(3):283-96 (In Russ.)]. doi: 10.35754/0234-5730-2019-64-3-283-296
  18. KDIGO. Kidney Disease: Improving Global Outcomes. CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3(1):339. doi: 10.1038/kisup.2012.48
  19. 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 Dialys Transplant. 2016;31(1):64-72. doi: 10.1093/ndt/gfv283
  20. Levey AS, Stevens LA, Schmid CH, et al.; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Int Med. 2009;150(9):604-12. doi: 10.7326/0003-4819-150-9-200905050-00006
  21. Solez K, Colvin RB, Racusen LC, et al. Banff 07 Classification of Renal Allograft Pathology: Updates and Future Directions. Am J Transplant. 2008;8(4):753-60. doi: 10.1111/j.1600-6143.2008.02159.x
  22. Cattran DC, Coppo R, Cook HT, et al. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Intl. 2009;76(5):534-45. doi: 10.1038/ki.2009.243
  23. Ryan MT. Supplemental Digital Content. Health Phys. 2013;104(5):453. doi: 10.1097/HP.0b013e318287c86c
  24. Казарина Е.В., Рехтина И.Г., Столяревич Е.С. и др. Способ определения выраженности интерстициального фиброза почек при миеломной нефропатии. Патент РФ на изобретение №2686846/06.05.19 Бюл. №13 [Kazarina EV, Rekhtina IG, Stolyarevich ES, et al. Method for determining intensity of interstitial renal fibrosis in myelome nephropathy Patent RF na izobretenie №2686846/06.05.19 Byul. №13 (In Russ.)]. https://elibrary.ru/item.asp?id=37476505
  25. Vongwiwatana A, Tasanarong A, Rayner DC, et al. Epithelial to mesenchymal transition during late deterioration of human kidney transplants: The role of tubular cells in fibrogenesis. Am J Transplant. 2005;5(6):1367-74. doi: 10.1111/j.1600-6143.2005.00843.x
  26. Galichon P, Hertig A. Epithelial to mesenchymal transition as a biomarker in renal fibrosis: are we ready for the bedside? Fibrogen Tis Rep 2011;4 (1):11. doi: 10.1186/1755-1536-4-11
  27. Basnayake K, Cheung CK, Sheaff M, et al. Differential progression of renal scarring and determinants of late renal recovery in sustained dialysis dependent acute kidney injury secondary to myeloma kidney. J Clin Pathol. 2010;63(10):884-7. doi: 10.1136/jcp.2010.079236
  28. Vansthertem D, Gossiaux A, Declèves AE, et al. Expression of nestin, vimentin, and NCAM by renal interstitial cells after ischemic tubular injury. J Biomed Biotechnol. 2010;2010:193259. doi: 10.1155/2010/193259
  29. Чеботерева Н.В., Бобкова И.H., Варшавский В.А. и др. Роль гладкомышечного α-актина в развитии фиброза почек у больных хроническим гломерулонефритом. Терапевтический архив. 2006;78(5):17-21 [Chebotereva NV, Bobkova IH, Varshavskij VA, et al. The role of smooth muscle al-phaactin in development of renal fibrosis in patients with chronic glomerulonephritis. Terapevticheskij Arhiv. 2006;78(5):17-21 (In Russ.)].
  30. Burns WC, Thomas MC. The molecular mediators of type 2 epithelial to mesenchymal transition (EMT) and their role in renal pathophysiology. Exp Rev Mol Med 2010;12:e17. doi: 10.1017/S1462399410001481
  31. Hertig A, Verine J, Mougenot B, et al. Risk factors for early epithelial to mesenchymal transition in renal grafts. Am J Transplant. 2006;6(12):2937-46. doi: 10.1111/j.1600-6143.2006.01559.x

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