J Nephropathol. 2017;6(2): 90-96.
doi: 10.15171/jnp.2017.15
PMID: 28491859
PMCID: PMC5418076
Scopus ID: 85008477661
  Abstract View: 3892
  PDF Download: 2412

Original Article

Autophagy in kidney transplants of sirolimus treated recipients

Sagar Bhayana 1, Arpita Baisantry 1,2, Thomas D. Kraemer 1, Christoph Wrede 3,4, Jan Hegermann 3,4, Jan-Hinrich Bräsen 5, Clemens Bockmeyer 5, Jan Ulrich Becker 5, Matthias Ochs 3,4, Wilfried Gwinner 1, Hermann Haller 1, Anette Melk 2, Roland Schmitt 1 *

1 Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
2 Department of Paediatric Nephrology and Gastroenterology, Hannover Medical School, Hannover, Germany
3 Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
4 REBIRTH Cluster of Excellence, Hannover, Germany
5 Institute of Pathology, Medical School Hannover, Hannover, Germany
*Corresponding author: Roland Schmitt, schmitt.roland@mh-hannover.de


Background: Mammalian target of rapamycin (mTOR) inhibitors are increasingly used as immunosuppressive agents in kidney transplantation. In the experimental setting it has been shown that mTOR inhibitors promote autophagy, but the concept that this might also occur in transplant patients has not been addressed.

Objectives: This study was designed to investigate the association between mTOR inhibition and autophagy in renal transplants under routine clinical conditions.

Materials and Methods: Protocol transplant biopsies of patients receiving sirolimus were compared to biopsies of patients treated without mTOR inhibitor. Electron microscopy was used for quantitative stereological analysis of autophagosomal volume fractions. Ultrastructural analysis was focused on podocytes to avoid cell type bias. Autophagy-related gene products were profiled by QPCR from laser assisted microdissected glomeruli and by immunohistochemistry for semiquantitative evaluation.

Results: By electron microscopy, we observed a significant > 50% increase in podocytic autophagosomal volume fractions in patients treated with sirolimus. Evaluation of biopsy material from the same patients using transcriptional profiling of laser capture microdissected glomeruli revealed no differences in autophagy-related gene expressions. Immunohistochemical evaluation of autophagic degradation product p62 was also unaltered whereas a significant increase was observed in podocytic LC3 positivity in biopsies of sirolimus treated patients.

Conclusions: These results indicate an association of sirolimus treatment and autophagosome formation in transplant patients. However, they might reflect autophagosomal buildup rather than increased autophagic flux. Further research is needed to investigate the potential functional consequences in short- and long-term outcome of patients treated with mTOR inhibitors.

Keywords: Autophagy, mTOR inhibitors, Sirolimus, Kidney transplant biopsy, Electron microscopy

Implication for health policy/practice/research/medical education:

In this proof-of-principle study we found that routine immunosuppressive treatment of kidney allograft recipients with sirolimus was associated with an increased autophagosomal volume fraction in podocytes as shown by electron microscopy. At the same time we found only minor changes in biochemical parameters of autophagy. While it is not possible to conclude from these findings whether mTOR inhibition increased autophagic flux or rather induced autophagosomal buildup, these data provide the first formal evidence for a significant impact of sirolimus on the autophagic pathway in the clinical transplant setting.  This link is of practical relevance and should be further investigated given the increasingly recognized role of dysregulated autophagy in kidney disease.

Please cite this paper as: Bhayana S, Baisantry A, Kraemer TD, Wrede C, Hegermann J, Bräsen JH, et al. Autophagy in kidney transplants of sirolimus treated recipients. J Nephropathol. 2017;6(2):90-96. DOI: 10.15171/jnp.2017.15.

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