Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus

Viorica Bumbea1, Nassim Kamar1, David Ribes1, Laure Esposito1, Anne Modesto2, Joelle Guitard1, Ghassan Nasou1, Dominique Durand1 and Lionel Rostaing1

1 Multiorgan Transplant Unit and 2 Department of Pathology, University Hospital, Toulouse, France

Correspondence and offprint requests to: Lionel Rostaing, CHU, Multiorgan Transplant Unit, University Hospital, 1 av. Jean Pouilhès, TSA 50032, 31059 Toulouse cedex 9, France. Email: rostaing.l{at}chu-toulouse.fr



   Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Switching from calcineurin inhibitors (CNIs) to sirolimus might improve renal function in chronic renal transplant patients.

Methods. In a prospective study, we assessed long-term efficacy and safety parameters in 43 renal transplant recipients who were switched from a CNI (cyclosporin A, 65%; and tacrolimus, 35%) to sirolimus for either chronic allograft dysfunction (n = 38) or recurrent cutaneous cancers (n = 5). A kidney biopsy was done in 79% of patients prior to conversion, and showed either chronic allograft nephropathy (n = 26) or CNI nephrotoxicity (n = 7). Conversion was either abrupt or progressive, with CNI withdrawal over 3 weeks. All patients also received steroids with or without mycophenolate mofetil or azathioprin. Patient data were recorded at baseline (D0), at 1 (D30) and 6 months (D180), and at 1, 1.5 and 2 years post-conversion.

Results. After a mean post-conversion follow-up of 27±1.5 months, 58% of the patients were still on sirolimus. The survival of intent to treat patients and grafts was 95.3 and 93%, respectively. Overall, there was significant improvement in renal function, creatinine clearance increasing from 49.4±14.9 to 53±16.3 ml/min at D30 (P = 0.01), and to 54.7±20 ml/min at D180 (P = 0.01). Thereafter, creatinine clearance was not different from baseline, i.e. 54.7±21.7, 52.8±20 and 51.7±20.3 ml/min at years 1, 1.5 and 2, respectively. We divided the patients into two groups: responders (n = 29), those with an increase in creatinine clearance at 6 months post-conversion compared with D0, and non-responders (n = 14), those with a decrease in creatinine clearance at 6 months post-conversion compared with D0. In univariate analysis, factors predictive of response included proteinuria at D0 and the magnitudes of the differences between D30 and D0 for serum creatinine and lactate dehydrogenase. The conversion was associated with (i) significant decreases in serum calcium, phosphorus and uric acid, and in haemoglobin levels; (ii) significant increases in serum alkaline phosphatase, total cholesterol, parathyroid hormone, and the number of patients on statin and recombinant erythropoietin therapies; and (iii) the appearance of de novo proteinuria of >1 g/day in 28% of patients (P<0.0009), which was >2 g/day in 12% of the entire cohort. Kidney biopsies in 17 patients 2 years after conversion showed the same Banff scores as observed at baseline. We identified three independent predictive factors for a renal response to the switch: absence of proteinuria, presence of antihypertensive therapy at D0 and serum lactate dehydrogenase level at D30.

Conclusion. Conversion from CNIs to sirolimus in renal transplant patients with chronic allograft nephropathy was associated with improved renal function; however, 33% of the patients developed overt proteinuria.

Keywords: anaemia; calcineurin inhibitor; chronic allograft nephropathy; creatinine; renal function; sirolimus



   Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In the last two decades, the long-term results for organ transplantation, particularly those of kidneys, have improved due to the use of calcineurin inhibitors (CNIs) such as cyclosporin A and tacrolimus. These drugs are nephrotoxic, however, and renal insufficiency of the native kidneys is an emerging and important problem in solid-organ transplantation [1]. Following renal transplantation, the leading cause of late graft loss among surviving recipients still is a non-specific process, which is termed ‘chronic allograft nephropathy’ (CAN). Clinically, this process describes the inexorable decline in renal function with time. It is associated with renal biopsy findings such as renal interstitial fibrosis, tubular atrophy, vascular occlusive changes and glomerulosclerosis [2]. Risk factors that are associated with CAN include both immune and non-immune mechanisms [3]. Among the non-immune factors is CNI-related nephrotoxicity. Recently, Nankivell et al. have described in recipients of kidney–pancreas transplants the evolution of CAN over a 10-year period, confirming the ubiquitous scarring of kidney transplants that occurs with the continuous use of CNIs [4]. This was also confirmed in a study that showed that conversion from cyclosporin to azathioprine at 3 months post-transplantation reduced the incidence of CAN [5]. The introduction of target of rapamycin (TOR) inhibitors, e.g. sirolimus and everolimus, a new class of potent immunosuppressants, has made it possible to develop alternative immunosuppressive combinations [6]. The blockade of mammalian TOR (mTOR) results in the inhibition of interleukin (IL)-2-induced lymphocyte proliferation and of intimal proliferation of the vasculature, which is a hallmark of CAN [6]. These properties, associated with the fact that mTOR inhibitors lack nephrotoxicity, have made these drugs a promising alternative to CNI-based immunosuppression in renal transplant patients. It has been demonstrated recently that sirolimus-based therapy started after early cyclosporin withdrawal [7] or sirolimus-based therapy without CNIs [8], given to de novo renal transplant patients, resulted in long-term improved renal function and a diminished prevalence of CAN, compared with renal transplant patients who received a CNI-based regimen or cyclosporin A in combination with sirolimus. Some studies of renal transplants have demonstrated the feasibility, immediate renal benefits and the safety of withdrawing CNIs and introducing sirolimus, for any of various reasons, in chronic renal transplant patients [9,10]. Recently, Diekmann et al. reported on the 1 year results of a prospective study of a cohort of renal transplant patients with CAN who were switched from a CNI to sirolimus with a 1–2 month overlap [11]. They found that the only independent predictor for positive outcome after conversion from CNI to sirolimus in CAN was a proteinuria <800 mg/day. The aims of our study were to (i) assess the long-term results, at up to 2 years, of a cohort of renal transplant patients who, mainly due to CAN, were converted from CNI-based immunosuppression to sirolimus-based immunosuppression; (ii) identify prognostic factors for successful conversion; and (iii) analyse the safety and the efficacy of the conversion.



   Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
All 43 patients in this single-centre study gave informed consent to participate in the study. Their mean age was 45±13 years; 38 (88.4%) were men. All were recipients of a cadaveric renal transplant, with a median time since renal transplantation of 4.5 years (0.5–16). They were on CNI-based immunosuppression; cyclosporin A in 28 cases (65%) and tacrolimus in 15 cases (35%). All of them received steroids (n = 43), with some in addition receiving either azathioprine (n = 4) or mycophenolate mofetil (n = 31). Whenever possible, a kidney biopsy was performed before altering the immunosupressive regimen (n = 34, 79%); and histological lesions suggestive of CAN were graded according to the Banff 97 classification system [2]. CNI toxicity was diagnosed if the biopsy showed tubular vacuolization, segmental arteriolopathy, arteriolar myocyte vacuolization and striped or diffuse interstitial fibrosis [2].

Conversion protocol
Initially, we undertook a progressive conversion of patients’ therapies (n = 21) from CNI-based to sirolimus-based, i.e. sirolimus was given on day 1 at a loading dose of 12–15 mg, then at a dose of 3–5 mg/day. Sirolimus trough levels were obtained weekly. The dose was adjusted to achieve trough levels of 8–12 ng/ml. In parallel, the CNI dose was reduced by 50% on day 1 and another 25% on day 7, before being withdrawn on day 14. As it sometimes took up to 3 weeks in some patients to obtain the targeted sirolimus trough levels, we later decided to perform an abrupt switch. Thus, 22 patients had an abrupt conversion, whereby CNI was withdrawn on day 1 and sirolimus started on day 1 with a loading dose of 15–18 mg, followed by a daily dose of 4–6 mg/day to achieve target trough levels of 8–12 ng/ml. The patients’ other immunosuppressive drugs remained unchanged. Pneumocytis carini prophylaxis, with sulfamethoxazole–trimethoprim (400/80 mg three times weekly), was given for the 6 months following conversion. None of the patients had acute rejection during the 3 months before conversion. During the first post-conversion month, follow-up visits were scheduled weekly; later, the patients were monitored on a monthly basis until 6 months post-conversion, and then at 3 month intervals (or at shorter intervals in cases where there were adverse events or other medical reasons). Each follow-up visit included a physical examination, with blood pressure being measured, laboratory screening for sirolimus trough levels, determination of haematological (haemoglobin, white blood cell and platelet counts) and biochemical parameters [serum creatinine, sodium, potassium, calcium, phosphate, uric acid and lactate dehydrogenase (LDH)], and tests for urinary protein and liver function [i.e. aspartate (AST) and alanine (ALT) aminotransferases, {gamma}-glutamyl transpeptidase ({gamma}GT), alkaline phosphatase, cholesterol and triglycerides]. Parathyroid hormone (PTH) levels were assessed at the time of conversion and then yearly. Creatinine clearance was calculated according to the Cockcroft and Gault formula. Data are given for 1 and 6 months and 1, 1.5 and 2 years post-conversion. The renal response to sirolimus was defined at 6 months post-conversion based on the stability or improvement of creatinine clearance compared with that on the day of conversion. In order to determine the factors predictive of the response to conversion from CNI to sirolimus, we identified responders as those patients in whom the difference between the creatinine clearance (CC) at 6 months post-conversion (D180CC) minus the observed value at the time of conversion (D0CC) was positive, i.e. D180CC – D0CC>0. Conversely, those patients in whom the difference was negative were defined as non-responders.

Statistical analysis
The data are presented as means, SDs, medians, and minimum and maximum for quantitative variables, and the numbers of observations and frequencies for qualitative variables. Normality was tested by the Kolmogorov–Smirnov test.

The follow-up data were assessed by one-way analysis of variance (ANOVA) with time-repeated measures for quantitative variables: time D0 to year 2 (within-subject factor), and for the factor response (between-subject factor). If there were significant effects over time, i.e. if a P-value of <0.05 was obtained in ANOVA analysis, then paired tests were used to analyse differences between each time point. The paired Student t-test was applied to compare the differences in means between each time point. For cases where the difference was not normally distributed, the Wilcoxon signed rank paired test was applied.

The McNemar test was used to evaluate changes in qualitative variables between each time point, i.e. day 0 after conversion, day 30, day 180, year 1, year 1.5 and year 2. Sidak's adjustment for multiple comparisons was used to determine the effects of time on qualitative variables.

Predictive factors for response groups were assessed using the {chi}2 test for categorical data or Fisher's exact test when the values were <5. Odds ratios (ORs) are reported along with 95% confidence intervals. All tests were two sided, and P<0.05 was considered statistically significant. Statistical analysis was performed using the SAS software, version 8.2.



   Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
After a mean post-conversion follow-up of 27±1.5 months, 58% of patients were still on sirolimus-based therapy (Figure 1). The survival of the intent to treat patients and of grafts was 95.3 and 93%, respectively. Two patients died with a functioning graft. One had hepatitis C virus-related cirrhosis at the time of conversion, and at 18 months post-conversion he developed hepato-renal syndrome, which led to his death. The other patient died of myocardial infarction at 18 months post-conversion, with stable renal function. Another patient lost his graft at 2 years post-conversion due to the progression of CAN.



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Fig. 1. Survival rates of patients after conversion from calcineurin inhibitor-based therapy to sirolimus-based therapy for chronic allograft dysfunction.

 
As far as mean daily doses of sirolimus are concerned, there was a trend towards lower amounts over time: 3.77±1.7, 3.8±1.6, 3.68±1.8, 3.26±1.7 and 3.28±1.4 mg/day at 1 and 6 months and at 1, 1.5 and 2 years, respectively (P = 0.066). This corresponds to statistically significant changes in the trough levels, i.e. 11.6±5.7, 9.9±3.3, 8.3±3.5, 8±3.1 and 9.8±3.9 ng/ml at 1 and 6 months, and at 1, 1.5 and 2 years, respectively (P = 0.018).

Renal function
Overall, at 1 and 6 months after conversion, there were significant decreases in serum creatinine from 164.5±44 to 152.8±39 and 153.7±45 µmol/l, respectively (P = 0.02); thereafter, serum creatinine remained stable without any significant differences from pre-conversion values: 154.2±55 µmol/l at 1 year, 160±59 µmol/l at 1.5 years and 146.7±43 µmol/l at 2 years. Creatinine clearance improved significantly at 1 and 6 months post-conversion compared with baseline: 53±16.3 and 54.7±20 vs 49.4±14.9 ml/min, respectively (P = 0.01). Thereafter, it showed no statistically significant difference from baseline: 54.7±21.7 (P = 0.09), 52.8±20 and 51.7±20.3 ml/min at 1, 1.5 and 2 years post-conversion, respectively.

At the day of conversion, 82% of patients had physiological proteinuria, <150 mg/day; 13% of patients had mild proteinuria (between 150 and 500 mg/day), but the proteinuria of 5% of patients was between 500 and 1000 mg/day. There was no significant change in the pattern of proteinuria at 1 and 6 months post-conversion. This was not the case afterwards. Overall, 12 patients (28%) develop proteinuria >1 g/day. Thus, at 1 year post-conversion, the proteinuria of 19.4% of patients (seven out of 36) was >1000 mg/day (P = 0.01), and 20.6% of patients (six out of 29) had >1000 mg/day proteinuria at 2 years (P = 0.01). In addition to these, during the study period, five patients developed nephrotic-range proteinuria with impairment of renal function. Of these, at the time of conversion to sirolimus, only one patient had no proteinuria. These five patients underwent a transplant biopsy at the time of developing this proteinuria. In all cases, we found de novo lesions of focal and segmental hyalinosis, in addition to glomerular double contours—with the latter already present in the pre-conversion biopsy specimens. We did not perform follow-up transplant biopsies in these five patients. These patients were then switched from sirolimus to tacrolimus. With a median follow-up of 9 months since withdrawal of sirolimus and conversion to tacrolimus, all but one recovered from the nephrotic-range proteinuria, though they had some degree of proteinuria persisting. In addition, renal function stabilized in all patients except the one who had persisting nephrotic syndrome.

With respect to the five patients converted to sirolimus because of recurrent cutaneous cancers, renal function improved in three of them and remained stable in two. None of these patients developed de novo proteinuria.

Renal transplant histological findings
Prior to their conversion to sirolimus, 34 patients (79%) had renal biopsies, which showed CNI-related nephrotoxicity in seven cases, CAN in six and features of both CAN and CNI-related nephrotoxicity in 21. The median chronic Banff score for these 34 renal biopsies was c.g 0; c.i 1; c.t 1; m.m 1. Repeat graft biopsies were done in 17 patients (50%) at an average of 2 years after conversion. Their median chronic Banff scores remained absolutely unchanged at c.g 0; c.i 1; c.t 1; c.v 1, m.m 1, being stable in 11 cases, improved in three and deteriorated in three. To identify the factors that might be associated with the response to the conversion to sirolimus at D180, we used univariate analysis and took into account all of the variables from D0, D30 and D180, and, for each variable, the differences between D30 and D0, and between D180 and D0, i.e. D30 – D0 and D180 – D0. Table 1 shows the variables for which P is <0.1. When comparing these results between non-responders and responders, the responders (67.4% of patients) had a significant improvement in serum creatinine over D0 (P = 0.038) as well as an improvement in creatinine clearance, although the difference did reach a level of significance (P = 0.08) (Table 1). In addition, the rate of proteinuria at day 0 (P = 0.018), as well as LDH levels at 1 month post-conversion (P = 0.008) were significantly lower in the responders compared with the non-responders (Table 1). In the multivariate analysis, we identified three independent factors that predicted a positive response to the conversion from CNI to sirolimus: the absence of proteinuria at day 0, the concomitant use of antihypertensive drugs at day 0 and the level of LDH at 1 month post-conversion (Table 2). The association of predicted probabilities and observed responses was 87.2%.


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Table 1. Significant variables of the univariate analysis associated with an improvement in creatinine clearance at 6 months after conversion from CNIs to sirolimus

 

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Table 2. Significant variables in the multivariate analysis associated with an improvement in creatinine clearance 6 months after conversion from CNIs to sirolimus

 
Blood pressure
At the time of conversion, the mean systolic blood pressure was 141.9±18 mmHg and the diastolic blood pressure was 80.8±9 mmHg; 35 patients (81.4%) were taking antihypertensive drugs. After conversion, there was no significant change in the number of patients taking antihypertensive drugs, nor in the number of antihypertensive drugs taken per patient. Hence, at 1 month, 1 year and 2 years post-conversion, 79, 92.5 and 96.5%, respectively, were on antihypertensive drugs (P = NS). However, with respect to the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), the pattern changed significantly after conversion to sirolimus. Thus, at day 0, 16 patients were taking ACEIs and four were taking ARBs, and one had both medications, i.e. 49% of patients were taking ACEIs, ARBs or both. At 1 month post-conversion, this percentage was unchanged. Subsequently, however, the percentage increased to 63% at 6 months (P = 0.058), 71% at 1 year (P = 0.0027), 76% at 1.5 years (P = 0.0016) and 72.4% at 2 years (P = 0.002). There was no significant change in diastolic blood pressure after conversion; on the other hand, systolic blood pressure decreased to 141.4±18 mmHg (NS), 136.4±18 mmHg (P = 0.02) and 139.5±13 mmHg (NS) at 1 month, 1 year and 2 years, respectively.

Biochemical parameters
There was no significant change in serum sodium and potassium, but there were significant decreases in serum calcium, phosphate and uric acid, and significant increases in alkaline phosphatase and PTH (Table 3). With respect to haematological parameters, by 1 month after conversion there was a significant decrease in haemoglobin, which remained stable afterwards, but at the expense of a significant increase in the numbers of patients requiring de novo recombinant erythropoietin (rEpo) therapy (Table 3). At D0, only four patients (9.3%) were on rEpo therapy; by 1 and 2 years post-conversion, 39.5 and 32.1% of patients, respectively, required rEpo therapy to maintain their haemoglobin levels within the normal range (P = 0.0003). Also, after conversion, there was a statistically, but not clinically, significant decrease in white blood cell count.


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Table 3. Biochemical and haematological parameters at and after sirolimus conversion

 
Table 4 depicts liver enzymes and lipid profiles after conversion. AST, ALT and {gamma}GT levels did not change significantly throughout the study. Conversion to sirolimus was associated with a significant increase in total cholesterol, which peaked at 1 month post-conversion and decreased thereafter, but at the expense of an increased number of patients treated with statins (P = 0.002). Thus, at D0, 48% of patients (n = 21) were taking statins; 55.8% were taking statins at month 1, 71% at year 1 and 80% at year 2.


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Table 4. Liver enzymes and lipid profiles at and after conversion to sirolimus

 
Tolerance
No acute rejection occurred throughout the study, despite the fact that the mean steroid dose was significantly decreased in that interval [patients received 0.102±0.04, 0.1±0.04, 0.08±0.04 and 0.08±0.04 mg/kg/day at D0, 1 month, 1 year and 2 years post-conversion, respectively (P = 0.0001)]. One hepatitis B virus-positive patient had viral reactivation 9 months after conversion, which was successfully treated with adefovir dipivoxil, without interfering with sirolimus. Otherwise, there were no opportunistic or serious infections. Among 13 patients, i.e. the 30.2% who dropped out, one had persistent and significant thrombopenia (30 000/mm3), and sirolimus was discontinued at 3 months. One patient had severe hypercholesterolaemia, despite statin therapy, and facial oedema: he discontinued sirolimus therapy at month 9. One patient presented with de novo benign intracranial hypertension at 9 months post-conversion, which improved after sirolimus withdrawal and iterative lumbar punctures; two patients stopped sirolimus because of non-nephrotic-range proteinuria (n = 1) or because of deteriorating renal function (n = 1); five patients stopped sirolimus due to the onset of nephrotic-range proteinuria (see above) that occurred at 8–26 (median: 17) months post-conversion.



   Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
To the best of our knowledge, this is the first study to evaluate long-term results in a large cohort of patients with CAN who were switched from CNIs to sirolimus. In this consecutive cohort of 43 long-term renal transplant patients, switching from a CNI to sirolimus was associated with a stabilization or an improvement of renal function in two-thirds of the patients, i.e. in 29 out of 43. However, this was not associated with an improvement in renal histology 2 years later. To date, there have only been a few studies that have evaluated the short-term impact of CNI withdrawal on renal function, and its replacement with sirolimus in renal transplant patients on maintenance immunosuppression. A recent study investigated 59 renal transplant patients with CAN who were switched from CNI to sirolimus [11]. After 1 year, serum creatinine had improved in 54% of patients (from 27.5±7.5 to 22.2±6.4 mg/l). The only factor independently predictive of a positive response to sirolimus conversion was low proteinuria at conversion, <800 mg/day. The major side effects observed in that study were anaemia, which required the use of recombinant erythropoietin in 64% of the patients, and dyslipidaemia.

There have been other reports of conversion from CNI-based immunosuppression to sirolimus in chronic renal transplant patients. Dominguez et al. [9] studied 20 patients, including 12 with CNI toxicity, over a short follow-up of 6 months. They found a significant improvement in renal function. Citterio et al. studied 19 renal transplant patients with progressive allograft dysfunction; their conversion was abrupt, and renal function stabilized or improved in 57% of them [10]. Finally, Amm et al. reported on 57 patients; after conversion from a CNI to sirolimus, a number of patients had further renal function deterioration [12].

An increase in already present proteinuria or emergence of proteinuria are a major side effect of conversion from a CNI to sirolimus. Diekmann et al. found that, after 1 year of conversion to sirolimus, proteinuria was stable in responders, whereas it almost doubled in non-responders [11]. In our study, at conversion, nearly all patients had no proteinuria, practically speaking (<150 mg/day), with only a few percent having proteinuria ranging between 0.5 and 1 g/day. At 1 and 2 years after conversion, 19.4 and 20.6% of patients had proteinuria at >1 g/day. In addition to these, five patients developed nephrotic-range proteinuria. In all these cases, the biopsy performed at the time significant proteinuria appeared showed de novo lesions of focal and segmental hyalinosis superimposed onto pre-existing double-contour glomerular lesions. These observations have already been published in a paper describing a large series of patients treated with high doses of sirolimus initiated at the time of transplantation [13]. In long-term renal transplants, it is possible that the withdrawal of CNIs leads to hyperfiltration because these drugs have constrictive effects on the renal vasculature [14]. This might explain why those who pre-conversion had no proteinuria, despite double-contour glomerular lesions, had developed nephrotic-range proteinuria after CNI withdrawal. Thus, when renal transplant patients are converted from CNIs to sirolimus, the addition of either ACEIs or ARBs might be of interest because of their vasoconstrictive properties on glomerular efferent arterioles [15]. Because we observed de novo proteinuria after converting patients from CNIs to sirolimus, we tended, in the long-term, to substitute some antihypertensive drugs for ACEIs, ARBs or both. This explains why, at 6 months post-conversion, the number of patients on either medication was statistically greater than that at D0 or D30, despite the fact that the number of patients taking antihypertensive drugs or the number of antihypertensive drugs taken per patient remained unchanged.

We found that, after switching from CNI to sirolimus, the patients developed biochemical disorders that suggested chronic tubular toxicity. It is known that sirolimus therapy is sometimes associated with hypokalaemia [16] and it might also alter the handling of other electrolytes by renal tubules. It has been shown that impaired phosphate handling by renal allografts is aggravated under sirolimus-based immunosuppression [17]. We recently have compared the glomerular and the tubular profiles of sirolimus and everolimus in de novo renal transplant patients who were also receiving cyclosporin A. We found that, in those taking sirolimus, the renal tubular handling of phosphorus and uric acid was impaired, because the renal phosphate threshold and uric acid clearance were significantly lower than those in the everolimus group, despite similar levels of PTH (personal data). In the present study, we observed that, in the long-term, i.e. 2 years after conversion from CNIs to sirolimus, there was evidence of chronic tubular lesions, which resulted in hypocalcaemia, hypophosphataemia and hypouricaemia. The incidence of hypocalcaemia might explain the secondary increase in PTH and alkaline phosphatases.

We also found that, after conversion to sirolimus, there was a significant decrease in haemoglobin by as early as 1 month post-conversion. Thereafter, haemoglobin levels stabilized, but at the expense of significantly more frequent use of rEpo therapy in almost 50% of patients. We have shown recently that amongst the most powerful independent factors predicting anaemia within the first year post-transplantation are sirolimus therapy and renal function [18]. Recently, Augustine et al. reported a prevalence of anaemia of 31% in patients on mycophenolate mofetil-based compared with 57% on sirolimus-based therapy in de novo renal transplant patients at 1 year post-transplantation. In a multivariate analysis, the factors predictive of anaemia at 1 year post-transplantation were higher recipient age, female gender, older donor age, chronic infection, decreased renal function at 12 months, and sirolimus therapy [19]. Sirolimus has been shown to block, through mTOR inhibition, S6 kinase activity, and consequently to impair cell replication in erythroid cell lines, because S6 kinase plays a role in mRNA translation in the cell. The net effect is altered erythroid cell development and the resulting anaemia [20].

In summary, conversion from CNIs to sirolimus in renal transplant patients with CAN was associated with improvement in renal function in 29 patients (67.4%); however, 28% of patients developed overt proteinuria. Sirolimus therapy is moderately tolerable; 30.2% of patients withdrew and one-third of patients developed anaemia, which required supportive therapy with darbopoetin. Finally, we were able to identify three independent factors predictive of the renal response to the switch. These were the absence of proteinuria, the presence of antihypertensive therapy at the time of conversion and serum lactate dehydrogenase level at 1 month. A prospective randomized study with kidney biopsies prior to and after the coversion is warranted in order to identify those patients with CAN who might benefit most from this conversion.



   Acknowledgments
 
We thank Ms Delphine Laurenceau for the statistical analysis and Ms Danièle Mencia for secretarial assistance.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Received for publication: 31. 1.05
Accepted in revised form: 15. 4.05