Interstitial fibrosis and outcomes of acute kidney injury in myeloma cast nephropathy

The aim of the study: to assess the prognostic value of interstitial fibrosis (FI) extension in kidney biopsy for achieving a renal response to therapy in myeloma cast nephropathy (MCN) patients with dialysis-dependent acute kidney injury (AKI). Materials and methods: kidney biopsy samples were retrospectively studied in 30 patients with MCN and dialysis-dependent AKI. Interstitial fibrosis and tubular atrophy (IFTA) were evaluated using semi-quantitative (standard) method. In addition, a quantitative morphometric computer-aided analysis was performed for FI. The results were compared with clinical data. Results: FI was found in kidney biopsy samples of all patients, median of its severity was 28.3% [14.5; 59]. In 12 (40%) cases the FI was graded as the 1st (mild) degree [median 21.5%; 14.5; 24.1], in 16 (53%) patients - the 2nd (moderate) degree FI was found [median 40%; 25.1; 48.2], in 2 (7%) patients 3rd (severe) degree FI was found [54.1% and 59%]. All 30 patients who were dependent on hemodialysis at the beginning of anti-myeloma treatment, 17 (57%) of them achieved myeloma response, among them 10 patients demonstrated renal response. In the absence of myeloma response, the improvement of renal function was not observed in any case. The median quantifed FI in patients with renal response was 22.9% [14.5; 39.3]; in those without improvement renal function it was 47.1% [40.8; 59], p<0.001. The FI value of 40% or higher of the total renal cortex surface makes it possible to predict a lack of improvement kidney function with a probability of 85% (95% CI), even in whose patients in whom a hematological response to anti-myeloma treatment was achieved. Conclusion: renal response in patients with MCN and dialysis-dependent acute kidney injury was observed only when the hematological response was achieved at the first anti-myeloma treatment's line. In most patients by the beginning of treatment, FI was graded as moderate. Quantifying FI in a kidney biopsy of 40% or higher before starting therapy is an unfavorable prognostic factor in the reversibility of dialysis-dependent acute kidney injury.

цилиндровая нефропатия, острое почечное повреждение, интерстициальный фиброз, множественная миелома, myeloma cast nephropathy, acute kidney injury, interstitial fibrosis

1. Yadav P, Cook M, Cockwell P. Current trends of renal impairment in multiple myeloma. Kidney Dis (Basel, Switzerland). 2016;1(4):241-257. doi:10.1159/000442511.

2. Dimopoulos MA, Delimpasi S, Katodritou E, et al. Significant improvement in the survival of patients with multiple myeloma presenting with severe renal impairment after the introduction of novel agents. Ann Oncol. 2014;25(1):195-200. doi:10.1093/annonc/mdt483.

3. Mendeleeva LP, Solovev MV., Alexeeva A, et al. Multiple Myeloma in Russia (First Results of the Registration Trial). Blood. 2017;130 (Suppl 1).

4. Li J, Zhou D Bin, Jiao L, et al. Bortezomib and dexamethasone therapy for newly diagnosed patients with multiple myeloma complicated by renal impairment. Clin Lymphoma Myeloma. 2009. doi:10.3816/CLM.2009.n.077.

5. 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):385-391. doi:10.3324/haematol.2014.115204.

6. 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. Гематол. и трансфузиол. 2015; 60 (4): 4-7.

7. Dimopoulos MA, Roussou M, Gavriatopoulou M, et al. Bortezomib-based triplets are associated with a high probability of dialysis independence and rapid renal recovery in newly diagnosed myeloma patients with severe renal failure or those requiring dialysis. Am J Hematol. 2016;91(5):499-502. doi:10.1002/ajh.24335.

8. Рехтина И.Г., Менделеева Л.П., Бирюкова Л.С. Диализзависимая почечная недостаточность у больных множественной миеломой: факторы обратимости. Тер. архив. 2015;7:72-76.

9. 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):2604-2606. doi:10.1182/blood-2006-09-046409.

10. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney inter., Suppl. 2013; 3: 1-150.

11. 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. doi:10.1038/leu.2012.182.

12. 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):4635-4641. doi:10.1200/JCO.2010.28.1238.

13. 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.

14. 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.

15. Heptinstall’s pathology of the kidney - 2 volume set, 6th edition. J.C. Jennette, J.L. Olson, M.M. Schwartz, F.G. Silva. Lippincott Williams & Wilkins, 2007. ISBN: 978/0/7817/4750/9, NLM: WJ 300, LC: RC903.9, 1531 p.

16. Sengul S, Zwizinski C, Simon EE, Kapasi A, Singhal PC, Batuman V. Endocytosis of light chains induces cytokines through activation of NF-КB in human proximal tubule cells. Kidney Int. 2002;62(6):1977-1988. doi:10.1046/j.1523-1755.2002.00660.x

17. Basnayake K, Stringer SJ, Hutchison CA, Cockwell P. The biology of immunoglobulin free light chains and kidney injury. Kidney Int. 2011;79(12):1289-1301. doi:10.1038/ki.2011.94.

18. Lovisa S, LeBleu VS, Tampe B, et al. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med. 2015. doi:10.1038/nm.3902.

19. Leung N, Nasr SH. Myeloma-related kidney disease. Adv Chronic Kidney Dis. 2014. doi:10.1053/j.ackd.2013.08.009.

20. Bohle A, Mackensen-Haen S, von Gise H, et al. The consequences of tubulo-interstitial changes for renal function in glomerulopathies. Pathol - Res Pract. 1990;186(1):135-144. doi:10.1016/S0344-0338(11)81021-6

21. Berchtold L, Friedli I, Vallée JP, Moll S, Martin PY, Seigneux S. Diagnosis and assessment of renal fibrosis: The state of the art. Swiss Med Wkly. 2017. doi:10.4414/smw.2017.14442.

22. 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):884-887. doi:10.1136/jcp.2010.079236.

23. Рехтина И.Г., Голицина Е.П., Варшавский В.А., Горчакова С.В., Бирюкова Л.С., Обратимость тяжелой почечной недостаточности при миеломной болезни. http://journal.nephro.ru/index.php?r=journal/articleView& articleId=630. Published 2009. Accessed February 4, 2019.

24. 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.

25. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Inter., Suppl. 2012; 2: 1-138.

26. 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:10.7326/0003-4819-150-9-200905050-00006.

27. 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.

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

29. 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. doi:10.1016/S1470-2045(16)30206-6.

30. Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: Updates and future directions. In: American Journal of Transplantation. 2008. doi:10.1111/j.1600-6143.2008.02159.x.

31. Tervaert TWC, Mooyaart AL, Amann K, et al. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 2010;21(4):556-563. doi:10.1681/ASN.2010010010.

32. Cattran DC, Coppo R, Cook HT, et al. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int. 2009;76(5):534-545. doi:10.1038/ki.2009.243.

33. Farris AB, Adams CD, Brousaides N, et al. Morphometric and visual evaluation of fibrosis in renal biopsies. J Am Soc Nephrol. 2011. doi:10.1681/ASN.2009091005.