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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 1  |  Page : 37-42
Management of chronic allograft dysfunction by switch over to rapamycin


1 Department of Nephrology, Pondicherry Institute of Medical Sciences, Pondicherry;Department of Nephrology, Madras Medical Mission Hospital, Chennai, India
2 Department of Nephrology, Madras Medical Mission Hospital, Chennai, India

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Date of Web Publication8-Jan-2010
 

   Abstract 

The aim of this study was to evaluate the efficacy of conversion from Calcineurin Inhibitors (CNI)-based to a rapamycin-based immunosuppressive regimen in renal transplant reci­pients who had allograft dysfunction, in a South Indian population. We analyzed the results of 75 (19.5%) of the 398 renal transplants performed over a five-year period from 2002 to 2007, who were converted from a CNI-based immunosuppression to rapamycin including patients with chronic allograft dysfunction, chronic allograft injury and malignancy. The data analyzed included serial rapamycin levels, serum creatinine, eGFR by nankivel formula, lipid profile, hemoglobin and serum potassium levels. Statistical analysis was performed using student's t test and the Kaplan Meir survival curve was used to predict probability of survival among patients on rapamycin. The mean age of the study patients was 39.6 ± 12.2 yrs and there was a male predominance (74.6%). Diabetic nephropathy was the predominant cause (36%) of end-stage renal disease (ESRD). Statistical analysis revealed a significant improvement in GFR of 14.6 mL/min and decrease in potassium by 0.7 mmol/L after initiation of rapamycin. There were no significant differences in terms of lipid profile, platelet count, hemoglobin and urine albumin levels. Rapamycin was discontinued in one patient due to hypokalemic nephropathy and in another patient due to delayed wound healing. To our knowledge, this is the first study to provide information on the conversion from a CNI to rapamycin-based immunosuppression in a cohort of Indian renal transplant recipients. In conclusion, the findings of our study confirm that rapamycin-based immunosuppressive regimen improves renal function and graft survival with mini­mal side effects, in comparison to CNI-based immunosuppression.

How to cite this article:
Sundaram V, Abraham G, Fathima N, Sundaram V, Reddy YN, Mathew M, Sathiah V. Management of chronic allograft dysfunction by switch over to rapamycin. Saudi J Kidney Dis Transpl 2010;21:37-42

How to cite this URL:
Sundaram V, Abraham G, Fathima N, Sundaram V, Reddy YN, Mathew M, Sathiah V. Management of chronic allograft dysfunction by switch over to rapamycin. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2020 Jan 28];21:37-42. Available from: http://www.sjkdt.org/text.asp?2010/21/1/37/58705

   Introduction Top


Rapamycin (sirolimus), a newer potent immu­nosuppressive agent, has invoked great interest in the field of transplantation as evidenced by the exponential increase in its clinical applica­tion. It inhibits mammalian target of rapa­mycin (MTOR), a kinase that acts during both co-stimulatory and cytokine driven pathways, thereby inhibiting cellular proliferation and cell signal transduction. [1],[2] It has shown a favo­rable impact on rejection rates and a toxicity profile that differs from calcineurin inhibitors (CNI). The efficacy of rapamycin has been validated in recent times. It has been used in combination therapies with CNI, as de novo therapy, and also as replacements for CNI especially for CNI-induced chronic allograft dysfunction.

Many of these early trials involving conver­sion from CNI to rapamycin were not ade­quately powered and there is no literature in­volving the South Asian population. Thus, this study was undertaken to evaluate the efficacy of rapamycin in patients who were randomly switched over from a CNI-based regimen in a tertiary care centre in South India. In India, re­nal transplants are performed in both private and government hospitals; regrafting is seldom done, and CNI-based regimens along with pred­nisolone and azathioprine are the cornerstone for maintenance immunosuppression. Introduc­tion of rapamycin into the immunosuppressive regimen have benefited not only in reducing CNI toxicity and malignancies, but also as an alternative agent to prolong graft and patient survival.


   Material and Methods Top


The study design was a retrospective analysis of renal transplant patients who were conver­ted from CNI to rapamycin in a single centre in South India. The records of all 378 renal transplant patients transplanted from January 2002 to March 2007 were reviewed for poten­tial inclusion into the study, under the super­vision of a nephrologist. Three of the patients who were switched over were deceased donor transplants and the remaining were live do­nors. Overall, 75 patients who had been con­verted to rapamycin, either randomly or secon­dary to CNI toxicity, chronic allograft injury (CAI) or malignancy, were included into this study. Information from the patient records in­cluding demographic data, biochemical para­meters such as serum creatinine, lipid profile, serum electrolytes, hemoglobin and serial ra­pamycin levels were analyzed. The glomerular filtration rate (GFR) was calculated using the Nankivel formula. Statistical analyses consisted primarily of descriptive statistics, which were comparative in nature, between data at the time of initiation of rapamycin to most recently recovered parameters. Nominal data were eva­luated using the student's t test and survival curves were generated using the Kaplan-Meyer method.

In our transplant program, the initial immuno­suppressive regimen consisted of prednisolone, 0.5 mg/kg body wt, microemulsion form of cyclosporine (Neoral), 8 mg/kg body wt and azathioprine, 2.5 mg/kg body wt. In the last three years, azathioprine was replaced by myco­phenolate mofetil (MMF) or sodium salt of mycophenylic acid, 720 mg BD after induction with a single dose of either basuliximab 20 mg or dacluzimab, 1 mg/kg body wt. Early biopsy proven acute rejections were treated with inj solumedrol 500 mg-1000 mg, administered for three days. All the 75 study patients were initiated on CNI post-transplantation. Allograft biopsy was performed for allograft dysfunction as evidenced by rise in creatinine of 0.3 mg above baseline after three months. Among the 75 patients, two patients on oral anticoagu­lation and three others with malignancy were switched over without evaluation by an allo­graft biopsy. The biopsy showed evidence of glomerulosclerosis, interstitial fibrosis, tubular atrophy, and/or arteriolar hyalinosis of varying severity in the switch-over group. In two pa­tients, C4D staining was strongly positive; both were treated with plasmapheresis, immunoglo­bulin and rituximab. Initially, the whole blood trough levels of CSA were estimated. Rapa­mycin was then initiated at 2 mg/day for two days followed by a maintenance dose of 1 mg/day. A 25% reduction in CSA dosage was made in one week followed by a further 25% reduction over the next two weeks. Subsequent reduction of CSA was made with monitoring of rapamycin levels, which was maintained between 4-8 ng/mL. The time of switch-over was as early as three months to two years post­transplantation. CSA was discontinued at six weeks if the serum creatinine was declining. Other immunosuppressive agents including prednisolone and MMF were continued with rapamycin. Dyslipidemic patients with an LDL level of 100 mg/dL were routinely initiated on HMG COA reductase inhibitors (lovostatin, simvostatin, atorvastatin or rosuvastatin). Dosage varied from 10 mg-50 mg for lipid control. Patients with anemia were evaluated for defi­ciency of iron, folic acid and B12 and appro­priate therapeutic interventions including ery­thropoietin therapy. Hypokalemic patients (< 3.5 mmol/L) were counselled regarding dietary supplementation and maintenance potassium therapy. Patients who received multiple organ transplants were excluded from the study.


   Results Top


Of the 75 patients included in the study, males (76.4%) formed the majority of the study sam­ple and the mean age of patients was 39.6 yrs (range 13-65). Diabetic Nephropathy (DN) (36%) was the predominant cause of end-stage renal disease (ESRD). The mortality among the patients studied in the sample was 8% (n = 6). The probability of graft survival was 97%, 93% and 88% respectively in the first three years post-transplantation as shown in the Kaplan Meir survival curve [Figure 1]. The mean va­lues of serial rapamycin levels are depicted in [Figure 2]. There was significant improvement in serum creatinine and GFR after initiation of rapamycin P< 0.001, [Figure 3]. Serum pota­ssium levels were lower after treatment with rapamycin P< 0.001, [Figure 3]. Other adverse effects after switch to rapamycin are shown in [Table 2]. There were no significant differences in hemoglobin and lipid profile after treatment with rapamycin. Rapamycin was withdrawn in two patients due to hypokalemic nephropathy in one and delayed wound healing in the other.


   Discussion Top


Rapamycin is a potent antiproliferative drug that reduces early rejection rates following kidney transplantation even in high-risk pa­tients. [3],[4] Several studies have previously shown that patients who receive a kidney transplant benefit from CNI withdrawal and treatment with rapamycin. [5],[6] It has also been demonstrated that early CNI withdrawal prevents progression of CAI in patients who received a kidney transplant. [7] Safety of switching over from CNI to rapamycin is confirmed by the absence of acute rejection. 8 Potential side effects related to simultaneous administration of CNI and ra­pamycin can be avoided by this regimen. [8]

To our knowledge, this is the first study, which analyzed the benefits of switching from CNI to rapamycin in a South Asian population. The findings of our study show that rapa­mycin-based immunosuppressive regimens are more effective than those that are CNI-based, in improving serum creatinine and GFR espe­cially in the setting of chronic allograft dys­function, CAI and malignancy. These findings were similar to those reported in earlier studies in patients with CAI. [9] However, unlike other studies we did not find any significant change in lipid profile after initiation of treatment with rapamycin. The decreased incidence of dysli­pidemia in our patients is probably because majority of the high-risk patients were already initiated on statins and life style modification.

The price of 1 mg of rapamycin in India va­ries from US$2 to US$7.5 depending upon the manufacturer and hence, can be used as a via­ble and effective alternative to prolong graft survival in patients with graft dysfunction as regrafting is rarely performed in our country due to logistic reasons. 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. This study also su­ggests that for maintenance therapy, low dose rapamycin is effective in improving graft func­tion in Indian patients. We propose that the low prevalence of adverse effects observed in our South Indian patients is probably dose related.

The limitations of our study is that it was a retrospective analysis and from a single center. Serial rapamycin levels were not checked for all recipients due to logistic reasons. Rapamy­cin was not used de novo immediately after transplant in our patients and hence, its effi­cacy in preventing acute rejections in the immediate post-transplant period could not be ascertained from our study.

In contrast to the ongoing multicentric CON­VERT study, where patients were switched to rapamycin when the GFR was 40 mL/min or more, we included patients whose GFR was as low as 27 mL/min and found significant im­provement in their renal function. We found the use of rapamycin beneficial in patients with post-transplant malignancy as a rescue the­rapy, especially in Kaposi's sarcoma. Giovanni Stallone et al have demonstrated the efficacy of rapamycin in patients with Kaposi's sarco­ma by serially monitoring the levels of vas­cular endothelial growth factor (VEGF), Flk­1/KDR protein, and phosphorylated Akt and p70S6. [10]

However, in some patients with post-trans­plant glomerulonephritis, rapamycin can have a detrimental effect on renal function as ob­served by Morellon and colleagues. [11] Therefore, the switch to rapamycin in this small subgroup of patients should be done with utmost caution. Although the best time of conversion to ra­pamycin is still the topic of debate in various protocol studies, clinical experience suggests that the benefit will be greater in early con­version. [11]

In conclusion, the findings of our study con­firm that rapamycin-based immunosuppressive regimen improves renal function and graft sur­vival with minimal side effects, in comparison to CNI-based immunosuppression.[Table 1]

 
   References Top

1.Chueh SJ, Kahan BD. Clinical application of sirolimus in renal transplantation: An update. Transplant Int 2005;18:261-77  Back to cited text no. 1      
2.Valente JF, Hricik D, Weigel K, et al. Compa­rison of Sirolimus vs Mycophenolate mofetil on surgical complications and wound healing in adult kidney transplantation. Am J Transplant 2003;33:1128-34.  Back to cited text no. 2      
3.Hriah DE, Anton HA, Knaurs TC, et al. Out­comes of African American Kidney transplant recipients treated with sirolimus, tacrolimus and corticosteroids. Transplantation 2002;74:189-93.  Back to cited text no. 3      
4.Hricek DE. Safety and efficacy of mTOR inhibitors and other immunosuppressive regimen in African-American renal transplant recipients. Am J Kidney Dis 2001;38:511-5.  Back to cited text no. 4      
5.Johnson RW, Kreis H, Ober Bauer R, et al. Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in renal function and lower blood pressure. Transplantation 2001; 72:777-86.  Back to cited text no. 5      
6.Kreis H, Ober Bauer R, Camoistol JM, et al Rapamycin immune maintenance regimen trial: Long term benefits with sirolimus based the-rapy after early cyclosporine withdrawal. J Am Soc Nephrol 2004;15.809-17.  Back to cited text no. 6      
7.Ruiz JC, Campistol JM, Crinyo JM, et al. Early cyclosporine withdrawal in kidney transplant recipients receiving sirolimus prevents prog­ression of chronic pathologic allograft lesions. Transplantation 2004;78:1312-8.  Back to cited text no. 7      
8.Stallone G, Infante B, Schere A. Rapamycin for treatment of Chronic allograft nephropathy in renal transplant recipients. J Am Soc Nephrol 2005;6:3755-62.  Back to cited text no. 8      
9.Wzgal J, Paczek L, Senatorship G, et al. Siro­limus rescue treatment in CNI Nephrotoxicity after kidney transplantation. Transplant Proc 2002;34:3785.  Back to cited text no. 9      
10.Stallone G, Schena A, Infante B. Sirolimus for Kaposi Sarcoma in renal transplant recipients. N Engl J Med 2005;352:1317-23.  Back to cited text no. 10      
11.Diekmann F, Campistol JM. Conversion from calcineurin inhibitors to sirolimus in chronic allograft nephropathy: Benefits and risk. Nephrol Dial Transplant 2006;21:562-8.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]  

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Correspondence Address:
Georgi Abraham
Internal Medicine, Madras Medical Mission Hospital, J Jayalalitha Nagar, Chennai - 600037, Tamilnadu
India
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PMID: 20061690

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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]

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