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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT Table of Contents   
Year : 2007  |  Volume : 18  |  Issue : 4  |  Page : 609-612
Post-Renal Transplant Hemolytic Uremic Syndrome following Combination Therapy with Tacrolimus and Everolimus


1 Sri Ramachandra Medical College and Research Institute, Chennai, India
2 Madras Medical Mission Hospital, Chennai, India

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   Abstract 

A 34-year old male renal transplant recipient developed thrombotic microangiopathy (Hemolytic Uremic Syndrome) in the early post-transplant period following combined immuno­suppressive therapy with tacrolimus and everolimus. The management consisted of discontinuation of tacrolimus and substitution with mycophenolate mofetil. His renal functions improved, the hematological abnormalities reversed and he continues to have good graft function one year later.

Keywords: Thrombotic microangiopathy, tacrolimus, everolimus, renal transplantation

How to cite this article:
Pratap B, Abraham G, Srinivas C N, Bhaskar S. Post-Renal Transplant Hemolytic Uremic Syndrome following Combination Therapy with Tacrolimus and Everolimus. Saudi J Kidney Dis Transpl 2007;18:609-12

How to cite this URL:
Pratap B, Abraham G, Srinivas C N, Bhaskar S. Post-Renal Transplant Hemolytic Uremic Syndrome following Combination Therapy with Tacrolimus and Everolimus. Saudi J Kidney Dis Transpl [serial online] 2007 [cited 2019 Oct 14];18:609-12. Available from: http://www.sjkdt.org/text.asp?2007/18/4/609/36521

   Introduction Top


Immunosuppressive medications are the mainstay of renal transplant recipients. Over the past two decades, there have been dramatic decline in the rates of acute rejection and allo­graft failure that occur in the first 3-6 months after kidney transplantation. [1] mTOR inhibitors play a major role in preventing allograft reject­tion. Combination of immunosuppressive me­dications such as calcineurin inhibitors (CNI) and mTOR inhibitors have shown superior efficacy in preventing rejection episodes. However, their combined use, both early and late following transplantation, may give rise to thrombotic microangiopathy.

Here, we describe a patient who developed allograft dysfunction and thrombotic micro­angiopathy while using everolimus, tacrolimus and a microemulsion form of cyclosporin.


   Case Report Top


A 34-year-old male with chronic kidney di­sease and hypertension on maintenance hemo­dialysis underwent a live related transplant on August 24, 2005. He weighed 53 kgs. He had been on hemodialysis twice a week for the past one year for the past one year.

Baseline investigations showed hemoglobin (Hb) of 8.5 g/dl, random blood glucose of 78 mg/dl, blood urea of 57 mg/dl, serum creatinine of 5.2 mg/dl, serum sodium of 137 mEq/L, potassium of 4.1 mEq/L, chloride of 96 mEq/L, bicarbonate of 26.1 mEq/L, aPTT of 72/32sec, total count of 8200 cells/ mm 3 , differential count of P59 L33 M2 E5 B1, platelet count of 279,000 cells/mm 3 and prothrombin time of 14.20/12sec with an INR of 1.24. Urine analysis showed albumin +++, pus cells 1­2/hpf, RBC 4-6/hpf, epithelial cells 1-2/hpf, occasional granular casts but no crystals. Blood, sputum and urine cultures had no growth. Homocysteine level was 12.21 umol/L, PTH 64.3pg/ml, calcium 9.1 mg/dl, lipo­protein A 18.9 mg/dl and hsCRP 37.6 mg/L. He tested negative for HBsAg, HCV, HIV and VDRL.

He was immunosuppressed with predniso­lone 25 mg, sodium salt of mycophenolic acid 720 mg and cyclosporin 225mg twice a day. He developed a biopsy proven acute rejection on the fifth post-operative day which was trea­ted with methylprednisolone pulses. Cyclos­porine was discontinued and tacrolimus was substituted at 3 mg twice a day. His serum creatinine stabilized at 1.8 mg/dl. The serum trough tacrolimus level was 7.72 ng/ml and hence the dosage was increased to 5 mg twice a day. As the serum creatinine remained at that level, the sodium salt of mycophenolic acid was discontinued and everolimus 1.25 mg twice a day was initiated on the 16 th post­operative day. Seven days after that, the serum level of everolimus was 7.70 ng/ml and the tacrolimus trough level was 17.1 ng/ml. The tacrolimus levels were reduced to 4 mg twice a day. The everolimus level was further reduced to 0.75 mg twice a day and a week later, the serum levels were 7.73 ng/ml and 30 ng/ml of everolimus and tacrolimus, respectively.

The serum creatinine increased to 2.2 mg/dl thirty-four days after initiating everolimus. An allograft biopsy was done which showed thrombus in the arteriole [Figure - 1] and the serum LDH was 591I IU/L. The platelet count progressively dropped to 95,000 cells/mm 3 . The peripheral smear showed helmet cells schistocytes, suggestive of the Hemolytic Ure­mic Syndrome (HUS). The LDH level re­mained high. The C4D staining also showed positivity. Tacrolimus was discontinued and patient was initiated on mycophenolate mofetil 750 mg twice a day. The serum creatinine came down to 1.2 mg/dl 14 days after discon­tinuing tacrolimus. The LDH level came down to 450 IU/L, platelet count increased to 246,000 cells/mm 3 and hemoglobin rose to 11.1 gm/dl. He developed post-transplant dia­betes and was started on regular insulin.


   Discussion Top


Everolimus is one of the new mTOR inhibit­tors used as an immunosuppressant to prevent acute and chronic rejection and it has a better oral bioavailability than sirolimus. [1] It acts by blocking growth-driven transduction signals in the T-cell response to alloantigen and thus, acts at a later stage than the calcineurin inhi­bitors cyclosporin and tacrolimus. Typically, mTOR inhibitors and CNIs are used in combination post-renal transplant as they show syner­gism in immunosuppression. [2] The advantage of everolimus seems to be its lower nephro­toxicity in comparison with cyclosporine and tacrolimus.

In order to improve efficacy and to reduce adverse effects, everolimus drug monitoring is essential, as was done in our patient. The recommended therapeutic range for evero­limus is a trough concentration of 3 to 8 ng/mL, as concentrations above 3 ng/mL have been associated with a decreased incidence of rejection and concentrations over 8 ng/mL with increased toxicity. [3] Patients on evero­limus who have problems with absorption, who take concurrent cytochrome P450 inhibitors or inducers or are noncompliant, will attain the greatest benefit from drug monitoring. [3]

Although there is a paucity of reports on the combined use of tacrolimus and evero­limus, one recent team of researchers has suggested that the data for the use of sirolimus doses, ranging from 0.5 to 2 mg/ day with conventional doses of tacrolimus, are associated with reduced renal function, higher blood pre­ssure and an increase in serum lipids compared with MMF/ tacrolimus therapy. [4] The relation between everolimus and HUS is relatively new and still under study. In a three-year study comparing everolimus to mycophenolate mo­fetil, researchers had to discontinue everolimus due to development of HUS. [5] Despite using pharmacologically acceptable doses of evero­limus and tacrolimus in our patient, he deve­loped HUS with allograft dysfunction. A reduction in the dosage of everolimus and discontinuation of tacrolimus facilitated the reversal of HUS, LDH and platelet abnor­malities and normalization of renal function. Once HUS develops, withdrawal of either mTOR or CNI inhibitors has been suggested. [6] As everolimus had more advantages and fewer side effects, we discontinued tacrolimus. The control of blood pressure with antihypertensives is essential in cases of HUS, [7] especially in severe hypertensives already under treatment. CNIs have been identified as risk factors for HUS in transplantation especially with higher blood levels. [7] As we are in the learning curve of using different combinations of old and new immunosuppressive medications, the dose of each drug should be adjusted according to each individual. [8] HUS is a common occurrence in solid organ transplant recipients. [9] Post­transplant HUS is characterized by micro­angiopathic hemolysis, thrombocytopenia and renal failure. In half of renal transplant reci­pients and in all non-renal solid-organ trans­plant recipients, HUS was attributed to cyclos­porin or tacrolimus therapy. [9] Notably, infec­tions were not a significant precipitating factor for post-transplant HUS. Physicians caring for transplant recipients need to be aware of this potentially severe graft and life-threatening disorder since prompt recognition and removal of identifiable risk factors is critical in the management of post-transplant HUS as exem­plified in our patient.

This case report identifies the problems of combined immunosuppressive therapy with CNIs and mTOR inhibitors including HUS and thrombotic microangiopathy. It can be concluded that a careful selection and usage of drugs with meticulous monitoring of drug levels should be done to prevent post­transplant HUS.

 
   References Top

1.United States Renal Data System. USRDS 2003 Annual Data Report: Atlas of End Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive Kidney Diseases, Bethesda, MD; 2003.  Back to cited text no. 1    
2.Kirchner GI, Meier-Wiedenbach I, Manns MP. Clinical pharmacokinetics of everolimus. Clin Pharmacokinet 2004;43:83-95.  Back to cited text no. 2  [PUBMED]  
3.Mabasa VH, Ensom MH. The role of therapeutic monitoring of everolimus in solid organ transplantation. Ther Drug Monit 2005;27:666-76.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Ribes D, Kamar N, Esposito L, Rostaing L. Combined use of tacrolimus and sirolimus in de novo renal transplant patients: Current data. Transplant Proc 2005;37:2813-6.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Lorber MI, Mulgaonkar S, Butt KM, et al. Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: A 3-year randomized, multicenter, phase III study. Transplantation 2005;80:244-52.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004; 351:2715-29.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Rerolle JP, Akposso K, Lerolle N, et al. Tacrolimus-induced hemolytic uremic syndrome and end-stage renal failure after liver transplantation. Clin Transplant 2000; 14:262-5.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Iraivan KT, Mathew M, et al. Hemolytic Uremic Syndrome in an elderly post­transplant patient following combination therapy with rapamycin and cyclosporine. J Renal Sci 2003;6:22-4.  Back to cited text no. 8    
9.Singh N, Gayowski T, Marino IR. Hemolytic uremic syndrome in solid-organ transplant recipients. Transplant Int 1996;9:68-75.  Back to cited text no. 9    

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Correspondence Address:
Georgi Abraham
Department of Medicine, Sri Ramachandra Medical College and Research Institute, Chennai – 600116
India
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PMID: 17951952

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