Advertisement

Journal of Nephrology

, Volume 32, Issue 1, pp 65–73 | Cite as

Infusion of autologous bone marrow derived mononuclear stem cells potentially reduces urinary markers in diabetic nephropathy

  • Abduzhappar GaipovEmail author
  • Zhannat Taubaldiyeva
  • Manarbek Askarov
  • Zaiyrkhan Turebekov
  • Larisa Kozina
  • Askhat Myngbay
  • Olga Ulyanova
  • Saltanat Tuganbekova
Original Article
  • 18 Downloads

Abstract

Background

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Previous studies demonstrated safety and efficacy of autologous bone marrow-derived mononuclear cells (ABM-MNCs) in induced type-1 diabetes mellitus (T1DM) rats. However, the effect of ABM-MNCs on urinary markers of DN in humans is not well studied. We evaluated the therapeutic effect of ABM-MNCs on the urinary markers microalbuminuria (MAU), urinary type-IV collagen and urinary neutrophil gelatinase-associated lipocalin (uNGAL) in T1DM patients with and without nephropathy.

Methods

This prospective open-label pilot study included 15 patients with T1DM, who had completed 2 visits within 6 months. Patients were divided into two groups according to the presence (DN, n = 7) and absence of nephropathy (T1DM, n = 8). ABM-MNCs were injected at each visit as per study protocol. Routine laboratory data, diabetes tests (fasting serum C-peptide and insulin, glycated hemoglobin, fasting and postprandial glucose), 24-h MAU and urinary type-IV collagen were measured at each visit. uNGAL levels were studied before and after 3 days of ABM-MNCs infusion at each visit.

Results

Mean age of patients was 29.2 ± 10.4 years, 33% were male, and 27% of the overall group had hypertension. MAU was significantly reduced in the overall group (− 26.0%, p = 0.037), including in DN (− 83.2%, p = 0.021). A short-term significant reduction of uNGAL levels was observed 3 days after ABM-MNCs administration during the both the 1st visit (median 13.4 vs. 9.5 ng/ml, p = 0.027) and 2nd visit (median 8.8 vs. 6.4 ng/ml, p = 0.042) in both groups. However this reduction did not remain significant at the 6-month follow-up. Urinary type-IV collagen did not respond significantly to ABM-MNCs infusion.

Conclusion

Infusion of autologous bone marrow-derived mononuclear cells significantly reduced levels of MAU in DN patients. Further studies with larger sample size are needed to confirm these observations.

Keywords

Type-1 diabetes mellitus, nephropathy Autologous bone-marrow derived stem cells Microalbuminuria Urinary neutrophil gelatinase-associated lipocalin 

Notes

Acknowledgements

Preliminary results of this study were presented at 53rd ERA-EDTA Congress, May 21–24, 2016, Vienna, Austria and at 52nd ERA-EDTA Congress, May 28– June 1, 2015, London, United Kingdom.

Author Contributions

AG, ZT, ST study concept and design. ZT, MA, LK, ZT, OU acquisition of data. AG, AM, MA Analysis and interpretation of data. AG, AM, ZT Drafting of the manuscript. Critical revision of the manuscript for important intellectual content and approval of the final version all authors.

Funding

This study is supported by grant N 0104 RK 00133, C03.01 (Title and code of scientific and technical project: Innovative cell technology in regenerative medicine, 0.0634) from the Ministry of Healthcare of Republic of Kazakhstan to JSC National Scientific Medical Research Center (Project timeframe 2013–2015 years).

Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest in this work.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The protocol of this study (protocol No 004/СТ-14; 24th April 2014) was approved by the Ethical Committee of the National Scientific Medical Research Centre.

Informed consent

Informed consent was obtained from all patients. Research involving human participants.

References

  1. 1.
    Atkinson MA, Eisenbarth GS, Michels AW (2014) Type 1 diabetes. Lancet 383(9911):69–82.  https://doi.org/10.1016/S0140-6736(13)60591-7 CrossRefGoogle Scholar
  2. 2.
    Katsarou A, Gudbjornsdottir S, Rawshani A, Dabelea D, Bonifacio E, Anderson BJ, Jacobsen LM, Schatz DA, Lernmark A (2017) Type 1 diabetes mellitus. Nat Rev Dis Primers 3:17016.  https://doi.org/10.1038/nrdp.2017.16 CrossRefGoogle Scholar
  3. 3.
    Hadjadj S, Cariou B, Fumeron F, Gand E, Charpentier G, Roussel R, Kasmi AA, Gautier JF, Mohammedi K, Gourdy P, Saulnier PJ, Feigerlova E, Marre M, French JDNCRI, Group Ss, Group Ds (2016) Death, end-stage renal disease and renal function decline in patients with diabetic nephropathy in French cohorts of type 1 and type 2 diabetes. Diabetologia 59(1):208–216.  https://doi.org/10.1007/s00125-015-3785-3 CrossRefGoogle Scholar
  4. 4.
    Perkins BA, Krolewski AS (2009) Early nephropathy in type 1 diabetes: the importance of early renal function decline. Curr Opin Nephrol Hypertens 18(3):233–240.  https://doi.org/10.1097/MNH.0b013e3283293db1 CrossRefGoogle Scholar
  5. 5.
    Araki S-i, Haneda M, Koya D, Isshiki K, Kume S, Sugimoto T, Kawai H, Nishio Y, Kashiwagi A, Uzu T (2010) Association between urinary type IV collagen level and deterioration of renal function in type 2 diabetic patients without overt proteinuria. Diabetes care 33(8):1805–1810CrossRefGoogle Scholar
  6. 6.
    Okonogi H, Nishimura M, Utsunomiya Y, Hamaguchi K, Tsuchida H, Miura Y, Suzuki S, Kawamura T, Hosoya T, Yamada K (2001) Urinary type IV collagen excretion reflects renal morphological alterations and type IV collagen expression in patients with type 2 diabetes mellitus. Clin Nephrol 55(5):357–364Google Scholar
  7. 7.
    Schmidt-Ott KM, Mori K, Li JY, Kalandadze A, Cohen DJ, Devarajan P, Barasch J (2007) Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 18(2):407–413.  https://doi.org/10.1681/ASN.2006080882 CrossRefGoogle Scholar
  8. 8.
    Yang YH, He XJ, Chen SR, Wang L, Li EM, Xu LY (2009) Changes of serum and urine neutrophil gelatinase-associated lipocalin in type-2 diabetic patients with nephropathy: one year observational follow-up study. Endocrine 36(1):45–51.  https://doi.org/10.1007/s12020-009-9187-x CrossRefGoogle Scholar
  9. 9.
    Nielsen SE, Schjoedt KJ, Astrup AS, Tarnow L, Lajer M, Hansen PR, Parving HH, Rossing P (2010) Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule 1 (KIM1) in patients with diabetic nephropathy: a cross-sectional study and the effects of lisinopril. Diabet Med 27(10):1144–1150.  https://doi.org/10.1111/j.1464-5491.2010.03083.x CrossRefGoogle Scholar
  10. 10.
    Taghizadeh-Ghehi M, Sarayani A, Ashouri A, Ataei S, Moslehi A, Hadjibabaie M (2015) Urine neutrophil gelatinase associated lipocalin as an early marker of acute kidney injury in hematopoietic stem cell transplantation patients. Renal failure 37(6):994–998CrossRefGoogle Scholar
  11. 11.
    Carey I, Byrne R, Childs K, Horner M, Bruce M, Wang B, Dusheiko G, Agarwal K (2018) Serum NGAL can act as an early renal safety biomarker during long-term nucleos(t)ide analogue antiviral therapy in chronic hepatitis B. J Viral Hepat 25(10):1139–1150.  https://doi.org/10.1111/jvh.12916 CrossRefGoogle Scholar
  12. 12.
    Bolignano D, Lacquaniti A, Coppolino G, Donato V, Campo S, Fazio MR, Nicocia G, Buemi M (2009) Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol 4(2):337–344.  https://doi.org/10.2215/CJN.03530708 CrossRefGoogle Scholar
  13. 13.
    Finne P, Reunanen A, Stenman S, Groop PH, Gronhagen-Riska C (2005) Incidence of end-stage renal disease in patients with type 1 diabetes. JAMA 294(14):1782–1787.  https://doi.org/10.1001/jama.294.14.1782 CrossRefGoogle Scholar
  14. 14.
    Davies LC, Alm JJ, Heldring N, Moll G, Gavin C, Batsis I, Qian H, Sigvardsson M, Nilsson B, Kyllonen LE, Salmela KT, Carlsson PO, Korsgren O, Le Blanc K (2016) Type 1 Diabetes Mellitus Donor Mesenchymal Stromal Cells Exhibit Comparable Potency to Healthy Controls In Vitro. Stem Cells Transl Med 5(11):1485–1495.  https://doi.org/10.5966/sctm.2015-0272 CrossRefGoogle Scholar
  15. 15.
    Couri CE, Oliveira MC, Stracieri AB, Moraes DA, Pieroni F, Barros GM, Madeira MI, Malmegrim KC, Foss-Freitas MC, Simoes BP, Martinez EZ, Foss MC, Burt RK, Voltarelli JC (2009) C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 301(15):1573–1579.  https://doi.org/10.1001/jama.2009.470 CrossRefGoogle Scholar
  16. 16.
    Carlsson PO, Schwarcz E, Korsgren O, Le Blanc K (2015) Preserved beta-cell function in type 1 diabetes by mesenchymal stromal cells. Diabetes 64(2):587–592.  https://doi.org/10.2337/db14-0656 CrossRefGoogle Scholar
  17. 17.
    Voltarelli JC, Couri CE, Stracieri AB, Oliveira MC, Moraes DA, Pieroni F, Coutinho M, Malmegrim KC, Foss-Freitas MC, Simoes BP, Foss MC, Squiers E, Burt RK (2007) Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 297(14):1568–1576.  https://doi.org/10.1001/jama.297.14.1568 CrossRefGoogle Scholar
  18. 18.
    Ezquer F, Ezquer M, Simon V, Pardo F, Yanez A, Carpio D, Conget P (2009) Endovenous administration of bone-marrow-derived multipotent mesenchymal stromal cells prevents renal failure in diabetic mice. Biol Blood Marrow Transpl 15(11):1354–1365.  https://doi.org/10.1016/j.bbmt.2009.07.022 CrossRefGoogle Scholar
  19. 19.
    Park JH, Hwang I, Hwang SH, Han H, Ha H (2012) Human umbilical cord blood-derived mesenchymal stem cells prevent diabetic renal injury through paracrine action. Diabetes Res Clin Pract 98(3):465–473.  https://doi.org/10.1016/j.diabres.2012.09.034 CrossRefGoogle Scholar
  20. 20.
    Wang S, Li Y, Zhao J, Zhang J, Huang Y (2013) Mesenchymal stem cells ameliorate podocyte injury and proteinuria in a type 1 diabetic nephropathy rat model. Biol Blood Marrow Transpl 19(4):538–546.  https://doi.org/10.1016/j.bbmt.2013.01.001 CrossRefGoogle Scholar
  21. 21.
    Penaforte-Saboia JG, Montenegro RM Jr, Couri CE, Batista LA, Montenegro A, Fernandes VO, Akhtar H, Negrato CA, Malmegrim KCR, Moraes DA, Dias JBE, Simoes BP, Gomes MB, Oliveira MC (2017) Microvascular complications in type 1 diabetes: a comparative analysis of patients treated with autologous nonmyeloablative hematopoietic stem-cell transplantation and conventional medical therapy. Front Endocrinol (Lausanne) 8:331.  https://doi.org/10.3389/fendo.2017.00331 CrossRefGoogle Scholar
  22. 22.
    Packham DK, Fraser IR, Kerr PG, Segal KR (2016) Allogeneic mesenchymal precursor cells (MPC) in diabetic nephropathy: a randomized, placebo-controlled, dose escalation study. EBioMedicine 12:263–269.  https://doi.org/10.1016/j.ebiom.2016.09.011 CrossRefGoogle Scholar
  23. 23.
    Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J, Ckd EPI (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604–612CrossRefGoogle Scholar
  24. 24.
    American Diabetes A (2013) Diagnosis and classification of diabetes mellitus. Diabetes Care 36(Suppl 1):S67–S74.  https://doi.org/10.2337/dc13-S067 CrossRefGoogle Scholar
  25. 25.
    KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease (2007) Am J Kidney Dis 49(2 Suppl 2):S12–S154.  https://doi.org/10.1053/j.ajkd.2006.12.005 Google Scholar
  26. 26.
    Dzholdasbekova A, Fedotovskikh G, Askarov M, Komsabakova B, Baigenzhina A, Kairatova A, Abylkassymova G (2015) Systemic administration of autologous mononuclear precultured bone marrow stem cells in heart failure. J Clin Med Kaz 3(37):14–18Google Scholar
  27. 27.
    Rakhimbekova GA, Tuganbekova SK, Askarov MB, Zhusupova AS, Krivoruchko NA, Akshalova GA, Rahimberlina HA, Gaipov AE, Ponomarenko YN, Temirgalieva AM, Tokbergenova AB (2013) Autologous hematopoietic stem cell transplantation in systemic sclerosis. J Clin Med Kaz 3(29):7–10Google Scholar
  28. 28.
    Hamza AH, Al-Bishri WM, Damiati LA, Ahmed HH (2017) Mesenchymal stem cells: a future experimental exploration for recession of diabetic nephropathy. Ren Fail 39(1):67–76.  https://doi.org/10.1080/0886022X.2016.1244080 CrossRefGoogle Scholar
  29. 29.
    Ezquer FE, Ezquer ME, Parrau DB, Carpio D, Yanez AJ, Conget PA (2008) Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol Blood Marrow Transpl 14(6):631–640.  https://doi.org/10.1016/j.bbmt.2008.01.006 CrossRefGoogle Scholar
  30. 30.
    Bhansali S, Dutta P, Yadav MK, Jain A, Mudaliar S, Hawkins M, Kurpad AV, Pahwa D, Yadav AK, Sharma RR, Jha V, Marwaha N, Bhansali S, Bhansali A (2017) Autologous bone marrow-derived mononuclear cells transplantation in type 2 diabetes mellitus: effect on beta-cell function and insulin sensitivity. Diabetol Metab Syndr 9:50.  https://doi.org/10.1186/s13098-017-0248-7 CrossRefGoogle Scholar
  31. 31.
    Ezquer M, Arango-Rodriguez M, Giraud-Billoud M, Ezquer F (2014) Mesenchymal stem cell therapy in type 1 diabetes mellitus and its main complications: from experimental findings to clinical practice. J Stem Cell Res Ther 4(227):2Google Scholar
  32. 32.
    Xu Y-X, Chen L, Wang R, Hou W-K, Lin P, Sun L, Sun Y, Dong Q-Y (2008) Mesenchymal stem cell therapy for diabetes through paracrine mechanisms. Med Hypotheses 71(3):390–393CrossRefGoogle Scholar
  33. 33.
    Remuzzi G, Benigni A, Remuzzi A (2006) Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 116(2):288–296.  https://doi.org/10.1172/JCI27699 CrossRefGoogle Scholar

Copyright information

© Italian Society of Nephrology 2018

Authors and Affiliations

  1. 1.Department of Extracorporeal HemocorrectionJSC National Scientific Medical Research CenterAstanaKazakhstan
  2. 2.Department of EndocrinologyJSC National Scientific Medical Research CenterAstanaKazakhstan
  3. 3.Department of Stem Cell TechnologyJSC National Scientific Medical Research CenterAstanaKazakhstan
  4. 4.Department of Internal MedicineJSC National Scientific Medical Research CenterAstanaKazakhstan
  5. 5.Department of BiochemistryJSC National Scientific Medical Research CenterAstanaKazakhstan
  6. 6.Private Institution “National Laboratory Astana”Nazarbayev UniversityAstanaKazakhstan

Personalised recommendations