Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

Rapamycin-induced proteinuria following allogeneic hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 44, pages 63–65 (2009)Cite this article

Retrospectively, rapamycin was started when proteinuria was already evident without clinical signs of a nephrotic syndrome. As no kidney biopsy was performed we can only speculate on the cause of initial proteinuria. The laboratory investigations (Table 2) revealed the differential diagnosis of a membranous nephropathy or a focal segmental glomerular sclerosis in combination with a calcineurin inhibitor nephropathy, because of selective glomerular-tubular proteinuria in the nephrotic range. Membranous glomerulonephritis (GN) and minimal change GN have been reported to develop in a few patients, because of chronic GVHD of the kidney.1

Table 2 Evaluation of the cause of proteinuria
Full size table

Nevertheless, it is possible that chronic GVHD was not the cause of proteinuria in our patient because proteinuria already existed before HSCT. Rapamycin is well known to aggravate proteinuria and in some cases induces nephrotic syndrome in patients after renal transplantation.2, 3, 4 A recent ongoing prospective trial in renal transplant patients revealed that patients with a proteinuria of more than 500 mg switched to rapamycin are prone to an increase in proteinuria and a decline in renal function.5 The histologic changes induced by rapamycin vary between the different reports. Unspecific changes, but also the induction of various forms of GN such as IgA nephritis, membranous GN, membranoproliferative GN and focal segmental glomerulosclerosis have been described.2, 3 The causes of rapamycin-induced proteinuria are so far unknown. In experimental studies it was proposed that a decrease of vascular endothelial growth factor and/or an increase in proinflammatory cytokines such as interleukin-6 might be responsible for the pathologies observed.6, 7, 8 Rapamycin-induced proteinuria is not only observed in renal transplant patients, but was recently shown also in long-term cardiac transplant patients.9 In patients after SCT data on the clinical efficacy of rapamycin is scarce. Jurado et al.10 provide evidence that rapamycin is beneficial in the treatment of refractory chronic GVHD, whereas others found rapamycin in combination with a calcineurin inhibitor to be detrimental in patients after SCT.11 Interestingly, they observed—in line with our report—renal toxicity of rapamycin as three patients developed acute renal failure.11 Therapeutically, it has been proven that concomitant application of an ACE-inhibitor or an angiotensin receptor blocker is beneficial in the setting of rapamycin-induced proteinuria not only in kidney transplant,12 but also in heart transplant patients.9 Therefore, we immediately started ACE-inhibitor treatment, which was found to be beneficial, even though it led to transient increase of serum creatinine (Figure 1). Nevertheless, we cannot exclude that ACE-inhibitor treatment without discontinuing rapamycin would have led to a comparable decrease in proteinuria.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Brukamp K, Doyle AM, Bloom RD, Bunin N, Tomaszewski JE, Cizman B . Nephrotic syndrome after hematopoietic cell transplantation: do glomerular lesions represent renal graft-versus-host disease? Clin J Am Soc Nephrol 2006; 1: 685–694.

    Article  Google Scholar 

  2. Franco AF, Martini D, Abensur H, Noronha IL . Proteinuria in transplant patients associated with sirolimus. Transplant Proc 2007; 39: 449–452.

    Article  CAS  Google Scholar 

  3. Dittrich E, Schmaldienst S, Soleiman A, Horl WH, Pohanka E . Rapamycin-associated post-transplantation glomerulonephritis and its remission after reintroduction of calcineurin-inhibitor therapy. Transpl Int 2004; 17: 215–220.

    Article  CAS  Google Scholar 

  4. Augustine JJ, Bodziak KA, Hricik DE . Use of sirolimus in solid organ transplantation. Drugs 2007; 67: 369–391.

    Article  CAS  Google Scholar 

  5. Oberbauer R, Schena FP, Wali R, Pascoe M, Alberu J, del Carmen Rial M et al. Conversion from Calcineurin Inhibitors to Sirolimus Compared with Continued Use of Calcineurin Inhibitors in Renal Allograft Recipients: 24-Month Safety and Efficacy Results from the CONVERT Trial. Congress of the American Society of Nephrology: San Diego, 2006.

    Google Scholar 

  6. Daniel C, Renders L, Amann K, Schulze-Lohoff E, Hauser IA, Hugo C . Mechanisms of everolimus-induced glomerulosclerosis after glomerular injury in the rat. Am J Transplant 2005; 5: 2849–2861.

    Article  CAS  Google Scholar 

  7. Hochegger K, Jansky GL, Soleiman A, Wolf AM, Tagwerker A, Seger C et al. Differential effects of rapamycin in anti-GBM glomerulonephritis. J Am Soc Nephrol 2008; 19: 1520–1529.

    Article  CAS  Google Scholar 

  8. Weichhart T, Costantino G, Poglitsch M, Rosner M, Zeyda M, Stuhlmeier KM et al. The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 2008; 29: 565–577.

    Article  CAS  Google Scholar 

  9. Aliabadi AZ, Pohanka E, Seebacher G, Dunkler D, Kammerstatter D, Wolner E et al. Development of proteinuria after switch to sirolimus-based immunosuppression in long-term cardiac transplant patients. Am J Transplant 2008; 8: 854–861.

    Article  CAS  Google Scholar 

  10. Jurado M, Vallejo C, Perez-Simon JA, Brunet S, Ferra C, Balsalobre P et al. Sirolimus as part of immunosuppressive therapy for refractory chronic graft-versus-host disease. Biol Blood Marrow Transplant 2007; 13: 701–706.

    Article  CAS  Google Scholar 

  11. Furlong T, Kiem HP, Appelbaum FR, Carpenter PA, Deeg HJ, Doney K et al. Sirolimus in combination with cyclosporine or tacrolimus plus methotrexate for prevention of graft-versus-host disease following hematopoietic cell transplantation from unrelated donors. Biol Blood Marrow Transplant 2008; 14: 531–537.

    Article  CAS  Google Scholar 

  12. Barama AA . Mechanisms and management of proteinuria in kidney transplant patients. Drugs 2008; 68 (Suppl 1): 33–39.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine IV, Innsbruck Medical University, Innsbruck, Austria

    K Hochegger & A R Rosenkranz

  2. Department of Internal Medicine, LKH Natters, Natters, Austria

    E Wurz

  3. Department of Internal Medicine V, Innsbruck Medical University, Innsbruck, Austria

    D Nachbaur & J Clausen

Authors
  1. K Hochegger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Wurz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Nachbaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A R Rosenkranz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Clausen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Hochegger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hochegger, K., Wurz, E., Nachbaur, D. et al. Rapamycin-induced proteinuria following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 44, 63–65 (2009). https://doi.org/10.1038/bmt.2008.433

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2008.433

This article is cited by

Search

Advanced search

Quick links