Painful Crural Ulcerations and Proteinuria as Complications After Several Years of Therapy With mTOR Inhibitors in the Renal Allograft Recipient: A Case Report

doi:10.1016/j.transproceed.2013.06.002

Transplantation Proceedings

Volume 45, Issue 9, November 2013, Pages 3418-3420

https://doi.org/10.1016/j.transproceed.2013.06.002 Get rights and content

Abstract

Background

Proliferation signal inhibitors (mammalian target of rapamycin [mTOR]) are a class of immunosuppressive drugs with a new mechanism of action and safety profile, different form calcineurin inhibitors. However, their use is limited because of an high incidence of adverse reactions, the majority of which occur within the first 6 months after commencing treatment. In this paper, we report a patient with substantial proteinuria and painful crural ulcerations that appeared after a few years of mTOR inhibitor therapy and necessitated their withdrawal.

Case Report

A 43-year-old man who received a cadaveric kidney was converted to sirolimus from cyclosporine after being diagnosed with adenocarcinoma and carcinoma clarocellulare of his own removed cystic kidney. After 5.5 years of fairly good tolerance of the treatment, proteinuria and painful crural ulcerations appeared. Because of the progressive character of the adverse reactions and no satisfactory results of the applied treatment, mTOR therapy was discontinued. Proteinuria was reduced, pain improved, and the ulcerations healed.

Conclusions

This case report indicates that adverse reactions may develop as a result of mTOR inhibitor use even after many years of good tolerance of the drug and they may necessitate its withdrawal.

Section snippets

Case Report

A 43-year-old man with end-stage renal disease underwent deceased donor kidney transplantation in 2003 and was ordered three-drug immunosuppressive regimen consisting of cyclosporine, mycophenolate mofetil, and steroids. In January 2004, right nephrectomy was performed because of rupture; in April 2005, a planned nephrectomy of the patient's left polycystic kidney was performed owing to recurrent, severe infections of the urinary system. The removed kidney was 30 × 17 × 15 cm. Macroscopically,

Discussion

The discovery of a new immunosuppressive drug, rapamycin, in the early 1970s gave hope for modern immunosuppression without nephrotoxicity typical of the CNI. Moreover, this drug was designed to prevent arteriolar hyalinization and glomerulosclerosis, as well as tubular and parenchymal damage. Owing to its ability to inhibit angiogenesis, it was also believed to have an antineoplastic effect. The pharmacologic profile of everolimus, a rapamycin analog, was described in 1997.¹⁶ Free of

Conclusion

The presented case report points out that adverse reactions may develop as a result of the mTORi use even after many years of good tolerance of the drug and they may necessitate its withdrawal from the therapy.

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Futhermore, sirolimus also reduces the endothelial cell response to vascular endothelial growth factor (VEGF), an effect that contributes to its antiangiogenic activity [7,8]. However, treatment with sirolimus has been associated with side effects such as anemia, skin lesions, impaired wound healing, proteinuria, dyslipidemia, insulin resistance and diabetes [9,10]. In order to improve the pharmacokinetic profile of the sirolimus and enhance medication efficacy, some sirolimus delivery systems have been developed [11–15].
Sirolimus is an immunosuppressive drug with activity in rheumatoid arthritis through inhibition of mTOR and T-lymphocytes activation and proliferation. However, its side effects limit usefulness. In this study, we developed sirolimus-loaded biodegradable implants, evaluated in vivo release of the drug and anti-inflammatory and antiangiogenic activities. Implants containing sirolimus were inserted into the subcutaneous tissue of mice and drug released was determined during 42 days. Histology of the skin and subcutaneous tissue close to the implanted site was performed after 7 and 42 days. The antiangiogenic activity of sirolimus implants was evaluated in the chorioalantoic membrane (CAM) from chicken eggs. The mice model of fibrovascular tissue growth induced by implantation of a subcutaneous cotton pellet was used to evaluate anti-inflammatory activity. Sirolimus implant promoted a slow release of the drug during 42 days. Histology did not show signs of intense local inflammatory response at the site of implantation. Sirolimus implants reduced vessels formation in the CAM and proliferation of fibrovascular tissue. Concluding, sirolimus-loaded implants reduced angiogenesis and chronic inflammatory response in the models evaluated. This preliminary study indicates that the implants are safe to the experimental animals and that they may represent a promising alternative for the treatment of chronic inflammation.
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Kidney/musculoskeletal: In a case report, a 43-year-old renal transplant patient on sirolimus developed proteinuria and painful crural ulcerations. After sirolimus was discontinued, proteinuria was reduced, pain improved and the ulcerations healed [50A]. For safety reasons the UK regulatory authority has recommended that oral TAC products be described and dispensed by brand name only, in order to ensure maintenance of therapeutic response when a patient is stabilised on a particular brand, and to minimise the risk of inadvertent switching between products from different suppliers [51S].
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Progress in transplantationCase reportPainful Crural Ulcerations and Proteinuria as Complications After Several Years of Therapy With mTOR Inhibitors in the Renal Allograft Recipient: A Case Report

Abstract

Background

Case Report

Conclusions

Section snippets

Case Report

Discussion

Conclusion

Clin Biochem

Am J Transplant

Am J Transplant

Kidney Int

Transplant Proc

Management of side effects of sirolimus therapy

Transplantation

Sirolimus is associated with new-onset diabetes in kidney transplant recipients

J Am Soc Nephrol

Incidence of anemia in sirolimus-treated renal transplant recipients: the importance of preserving renal function

Transpl Int

The impact of sirolimus, mycophenolate mofetil, cyclosporine, azathioprine and steroids on wound healing in 513 kidney transplant recipients

Transplantation

Sirolimus-associated pulmonary toxicity

Transplantation

Progress in transplantation
Case report
Painful Crural Ulcerations and Proteinuria as Complications After Several Years of Therapy With mTOR Inhibitors in the Renal Allograft Recipient: A Case Report