Year : 2010 | Volume
: 21 | Issue : 1 | Page : 37--42
Management of chronic allograft dysfunction by switch over to rapamycin
Varun Sundaram1, Georgi Abraham1, Nusrath Fathima2, Vivek Sundaram2, Yogesh N.V Reddy2, Milly Mathew2, Vijaiaboobbathi Sathiah2,
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
Internal Medicine, Madras Medical Mission Hospital, J Jayalalitha Nagar, Chennai - 600037, Tamilnadu
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«SQ»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 Oct 21 ];21:37-42
Available from: https://www.sjkdt.org/text.asp?2010/21/1/37/58705
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. , 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
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 ( , Several studies have previously shown that patients who receive a kidney transplant benefit from CNI withdrawal and treatment with rapamycin. , It has also been demonstrated that early CNI withdrawal prevents progression of CAI in patients who received a kidney transplant.  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. 
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.  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. 
However, in some patients with post-transplant glomerulonephritis, rapamycin can have a detrimental effect on renal function as observed by Morellon and colleagues.  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. 
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]
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