V.G. SHAKIROVA¹, E.V. MARTYNOVA², A.R. SAUBANOVA³, I.M. KHAERTYNOVA¹, S.F. KHAYBULLINA^2,4, E.E. GARANINA²

¹Kazan State Medical Academy — Branch Campus of RMACPE MH Russia, Kazan²Kazan (Volga Region) Federal University, Kazan³Republican Clinical Infectious Diseases Hospital named after Professor A.F. Agafonova of the Ministry of Health of the Republic of Tatarstan, Kazan⁴University of Nevada, Reno, the USA

Contact:

Shakirova V.G. ― PhD (medicine), Associate Professor of the Department of Infectious Diseases, Address: 83 Pobedy Ave., Kazan, Russian Federation, 420110, tel. +7-987-224-10-80, e-mail: vene-hakirova@yandex.ru Objective ― to study the dynamics of renal injury biomarkers in patients with hemorrhagic fever with renal syndrome HFRS.

Material and methods. Urine samples of 64 patients with HFRS (56 men and 8 women) collected at admission and before discharge were examined. Changes in kidney function were investigated by multiplex analysis using a panel of nephrotoxicity 1 and 2 (Bio-Rad, Hercules, CA).

Results. Analysis of 12 urinal biomarkers of nephrotoxicity in patients with HFRS during the oliguric period helped to reveal a high level of clusterin, KIM-1 MCP-1, IL-18 and NGAL, and during the period of polyuria ― an increase in the activity of clusterin, KIM-1, IL-18 and MCP-1, GST-π and cystatin C.

Conclusion. Determination of clusterin in urine can serve as a marker for acute renal damage in HFRS. An increase in the activity of clusterin and KIM-1, NGAL, IL-18 in the urine of patients with HFRS during oliguria indicates damage to the proximal tubules of the nephron, while high levels of clusterin, KIM-1, IL-18 and NGAL cystatitis C, as well as GST-π during the period of polyuria indicate a lesion of the proximal and distal tubules.

Key words: hantaan hemorrhagic fever, markers of nephrotoxicity, clusterin, proximal tubules.

(For citation: Shakirova V.G., Martynova E.V., Saubanova A.R., Khaertynova I.M., Khaybullina S.F., Garanina E.E. Analysis of markers of renal damage in patients with hantaan hemorrhagic fever. Practical Medicine. 2019. Vol. 17, № 8, P. 97-102)

REFERENCES

1. Mustonen J., Mäkelä S., Outinen T. et al. The pathogenesis of nephropathia epidemica: new knowledge and unanswered questions. Antiviral Research, 2013, vol. 100, no. 3, rr. 589-604.
2. Davidyuk Y.N., Kabwe E., Khaiboullina S.F. et.al. Genetic diversity of Puumala virus isolates in the Republic of Tatarstan and the Republic of Mordovia. BioNanoSci, 2017, vol. 7, no. 2, rr. 309-312.
3. Garanina S.B., Platonov V.A., Zhuravlev E.I., et al. Genetic diversity and geographic distribution of hantaviruses in Russia. Zoonoses and Public Health, 2009, vol. 56, no. 6-7, rr. 297-309.
4. Yanagihara R., Amyx H.L., Gajdusek D.C. Experimental infection with Puumala virus, the etiologic agent of nephropathia epidemica, in bank voles (Clethrionomys glareolus). Journal of Virology, 1985, vol. 55, no. 1, rr. 34-38.
5. Diglisic G., Rossi C.A., Doti A., Walshe D.K. Seroprevalence study of Hantavirus infection in the community based population. Maryland Medical Journal, 1999, vol. 48, no. 6, rr. 303-6.
6. Shakirova V.G., Khaertynova I.M., Khaertynov K.S., Gayfullina E.G. Clinical and epidemiological characteristics of HFRS with various forms of severity in the territory of the Republic of Tatarstan. Prakticheskaya meditsina, 2011, no. 3, pp. 181-184 (in Russ.).
7. Mustonen J., Helin H., Pietilä K., et al. Renal biopsy findings and clinicopathologic correlations in nephropathia epidemica. Clinical Nephrology, 1994, vol. 41, no. 3, rr. 121-126.
8. Groen J., Bruijn J.A., Gerding M.N., et al. Hantavirus antigen detection in kidney biopsies from patients with nephropathia epidemica. Clinical Nephrology, 1996, vol. 46, no. 6, rr. 379-383.
9. Ferluga D., Vizjak A. Hantavirus nephropathy. Journal of the American Society of Nephrology, 2008, vol. 19, no. 9, rr. 1653-1658.
10. Temonen M., Mustonen J., Helin H., et al. Cytokines, adhesion molecules, and cellular infiltration in nephropathia epidemica kidneys: an immunohistochemical study. Clinical Immunology and Immunopathology, 1996, vol. 78, no. 1, rr. 47-55.
11. Coca S.G., Parikh C.R. Urinary biomarkers for acute kidney injury: perspectives on translation. Journal of the American Society of Nephrology, 2008, vol. 3, no. 2, rr. 481-90.
12. Martensson J., Martling C.R., Bell M. Novel biomarkers of acute kidney injury and failure: clinical applicability. Brit. J. Anestesia, 2012, vol. 109, no. 6, rr. 843-50.
13. Chiusolo A., Defazio R., Zanetti E., et.al. Kidney injury molecule 1 expression in rat proximal tubule after treatment with segment-specific nephrotoxicants: A tool for early screening of potential kidney toxicity. Toxicol Pathology, 2010, vol. 38, no. 3, rr. 338-45.
14. Infektsionnye bolezni: natsional’noe rukovodstvo, pod red. N.D. Yushchuka, Yu.Ya. Vengerova [Infectious Diseases: National Guide, ed. N.D. Yushchuk, Yu.Ya. Vengerova]. Moscow: GOETAR-Media, 2009. 1056 p.
15. Mishra J., Ma Q., Prada A., et al. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. Journal of the American Society of Nephrology, 2003, vol. 14, no. 10, rr. 2534-2543.
16. Han W.K., Bailly V., Abichandani R. et al. Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney International, 2002, vol. 62, no. 1, rr. 237-244.
17. Carson W.E., Dierksheide J.E., Jabbour S. et al. Coadministration of interleukin-18 and interleukin-12 induces a fatal inflammatory response in mice: critical role of natural killer cell interferon-gamma production and STAT-mediated signal transduction. Blood, 2000, vol. 96, no. 4, rr. 1465-1473.
18. Dvergsten J., Manivel J.C., Correa-Rotter R., Rosenberg M.E. Expression of clusterin in human renal diseases. Kidney International, 1994, vol. 45, no. 3, rr. 828-835.
19. Rosenberg M.E., Paller M.S. Differential gene expression in the recovery from ischemic renal injury. Kidney International, 1991, vol. 39, no. 6, rr. 1156-1161.
20. Harding M.A., Chadwick L.J., Gattone II V.H., Calvet J.P. The SGP-2 gene is developmentally regulated in the mouse kidney and abnormally expressed in collecting duct cysts in polycystic kidney disease. Developmental Biology, 1991, vol. 146, no. 2, rr. 483-490.
21. Correa-Rotter R., Ibarra-Rubio M.E., Schwochau G., et al. Induction of clusterin in tubules of nephrotic rats. Journal of the American Society of Nephrology, 1998, vol. 9, no. 1, rr. 33-37.
22. Jung G.S., Kim M.K., Jung Y.A. et al. Clusterin attenuates the development of renal fibrosis. Journal of the American Society of Nephrology, 2012, vol. 23, no. 1, rr. 73-85.
23. Kim N., Yoo J.C., Han J.Y. et al. Human nuclear clusterin mediates apoptosis by interacting with Bcl-XL through Cterminal coiled coil domain. Journal of Cellular Physiology, 2012, vol. 227, no. 3, rr. 1157-1167.
24. Wilson M.R., Easterbrook-Smith S.B. Clusterin binds by a multivalent mechanism to the Fc and Fab regions of IgG. Biochimica et Biophysica Acta (BBA) – Protein Structure and Molecular Enzymology, 1992, vol. 1159, no. 3, rr. 319-326.
25. French L.E., Tschopp J., Schifferli J.A. Clusterin in renal tissue: preferential localization with the terminal complement complex and immunoglobulin deposits in glomeruli. Clinical and Experimental Immunology, 1992, vol. 88, no. 3, rr. 389-393.
26. Choi N.H., Mazda T., Tomita M. A serum protein SP40, 40 modulates the formation of membrane attack complex of complement on erythrocytes. Molecular Immunology, 1989, vol. 26, no. 9, rr. 835-840.
27. Choi N.H., Nakano Y., Tobe T. et al. Incorporation of SP-40,40 into the soluble membrane attack complex (SMAC, SC5b-9) of complement. International Immunology, 1990, vol. 2, no. 5, rr. 413-417.
28. Saunders J.R., Aminian A., McRae J.L. et al. Clusterin depletion enhances immune glomerular injury in the isolated perfused kidney. Kidney International, 1994, vol. 45, no. 3, rr. 817-827.
29. Ichimura T., Bonventre J.V., Bailly V. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is upregulated in renal cells after injury. The Journal of Biological Chemistry, 1998, vol. 273, no. 7, rr. 4135-4142.
30. Vaidya V.S., Waikar S.S., Ferguson M.A. et al. Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans. Clinical and Translational Science, 2008, vol. 1, no. 3, rr. 200-208.
31. Liangos O., Perianayagam M.C., Vaidya V.S., et al. Urinary N-acetyl-beta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. Journal of the American Society of Nephrology, 2007, vol. 18, no. 3, rr. 904-912.
32. Bernier G.M., Conrad M.E. Catabolism of human beta-2-microglobulin by the rat kidney. American Journal of Physiology-Legacy Content, 1969, vol. 217, no. 5, rr. 1359-1362.
33. Sundberg A., Appelkvist E.L., Dallner G., Nilsson R. Glutathione transferases in the urine: sensitive methods for detection of kidney damage induced by nephrotoxic agents in humans. Environmental Health Perspectives, 1994, vol. 102, supplement 3, rr. 293-296.
34. Harrison D.J., Kharbanda R., Cunningham D.S. et al. Distribution of glutathione S-transferase isoenzymes in human kidney: basis for possible markers of renal injury. Journal of Clinical Pathology, 1989, vol. 42, no. 6, rr. 624-628.