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NDT Advance Access published online on April 23, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm181
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Influence of sirolimus on proteinuria in de novo kidney transplantation with expanded criteria donors: comparison of two CNI-free protocols

Fritz Diekmann1,2, Alex Gutiérrez-Dalmau1, Sonia López1, Federico Cofán1, Núria Esforzado1, María José Ricart1, Esther Rossich1, Núria Saval1, José Vicente Torregrosa1, Federico Oppenheimer1 and Josep M. Campistol1

1Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain and 2Department of Nephrology Charité Campus Mitte Berlin, Germany

Correspondence and offprint requests to: Fritz Diekmann, MD, Department of Nephrology and Renal Transplantation, Hospital Clínic, Villarroel, 170, E-08036 Barcelona, Spain. Email: fdiekman{at}clinic.ub.es



   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background. The contribution of mammalian target of rapamycin (mTOR) inhibitors to proteinuria is controversial. The aim was to analyse proteinuria in suboptimal kidney calcineurin inhibitor-(CNI) free de novo immunosuppression.

Methods. All patients from our centre with donors >60 years and CNI-free treatment were included (n = 108). Patients were divided into two groups: (i) SRL group: sirolimus (SRL) + prednisone + mycophenolate mofetil (MMF) + antiCD25; (ii) MMF group: prednisone + MMF w/ or w/o antiCD25 (n = 75). Follow-up was 12 months.

Results. Donors were slightly younger in the SRL group (68 vs 71 years; P < 0.05), receptor age (67 vs 65 years) was not significantly different. Patient survival in the MMF group was 88 vs 94% in the SRL group, however, these differences did not reach statistical significance. One-year graft survival censored for death was 83% in the MMF group and 94% in the SRL group. Acute rejection rate was 45% in the MMF and 15% in the SRL group (P < 0.01). The incidence of CNI introduction was higher in the MMF-group (35 vs 5; P < 0.05). The intention-to-treat analysis revealed significant differences of proteinuria [SRL vs MMF at 12 months: 461 (163–6988) vs 270 (53–3029) mg/day], which did not exist in the on-therapy (OT) analysis [SRL vs MMF at 12 months: 357 (199–1428) vs 279 (53–3029) mg/day]. New onset nephrotic range proteinuria seemed to occur slightly more frequently in SRL patients (3/33 vs 1/75; P = 0.049), however, all four cases occurred in a context of recurrent disease, or previous drug-independent damage or non-adherence. All of these patients were converted to CNI.

Conclusion. SRL-based compared with MMF-based treatment in kidney transplantation with advanced age donors is associated with an acceptable outcome, however, with increased proteinuria in the intention-to-treat analysis. A large subgroup of the patients in the MMF group experienced acute rejection and required conversion to CNI.

Keywords: calcineurin inhibitor; expanded criteria donors; IL-2 receptor antagonist; mTOR inhibitor; mycophenolate mofetil; proteinuria



   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
A considerable number of patients converted from calcineurin inhibitors (CNIs) to sirolimus (SRL) due to chronic allograft dysfunction have developed an increase of proteinuria after the conversion [1–5]. Whether mammalian target of rapamycin (mTOR) inhibitors might whether mammalian forget of rapamyein (m TOR) inhibitors might be a contributor factor, as well as the role of possible pathomechanisms, remains controversial, especially because this increase has only been observed in some patients and is not a universal phenomenon. Nevertheless, among those patients who developed an increase of proteinuria after conversion from CNI to SRL treatment, this seemed to be more prominent in patients who already had some degree of proteinuria or already experienced a severe decline of renal function before the conversion. There seems to be a haemodynamic component leading to an increase of intraglomerular pressure and subsequent hyperfiltration in some conversion patients after withdrawal of the CNI [6]. Moreover, some conversion patients experienced de novo proteinuria and glomerulopathy after withdrawal of the CNI and introduction of SRL. Most interestingly, this was reversible after re-conversion from SRL to CNI [7]. In all of these studies SRL therapy is compared with protocols that contain CNI therapy, which itself is known to be antiproteinuric, and it is difficult to distinguish between effects of CNI withdrawal and genuine SRL-associated effects.

Proteinuria does not seem to be a problem in SRL-based de novo therapy in optimal donor kidney transplantation, again compared with CNI-based treatment [8]. However, little is known about the risk of developing SRL-associated proteinuria in de novo kidney transplantation in patients with a high risk of proteinuria due to suboptimal organ quality, i.e. recipients of organs from expanded criteria donors. Therefore, the aim of our study was to analyse the development of proteinuria in patients who received a kidney from an expanded criteria donor with de novo treatment based on SRL in comparison with a control group that also received a CNI-free treatment, however, based on mycophenolate mofetil (MMF).



   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All kidney transplant patients from our centre who received a kidney from a donor over 60 years of age and who had a de novo immunosuppressive therapy free of CNI with a minimum follow-up of 6 months were included (n = 108). All patients received MMF 2 g pre-operatively and then 2 g/day, methylprednisolone 500 mg intraoperatively, then prednisolone 0.5 mg/kg/day tapered to 5 mg at day 90. The patients were divided into two sequential groups according to baseline immunosuppressive therapy:

  1. SRL-based treatment group: SRL + prednisone + MMF with antiCD25 antibody induction treatment (n = 33). SRL was introduced at day 5 starting with three consecutive daily doses of 6 mg/day, continuing with 3 mg/day. SRL target levels were 10–15 ng/ml. These patients were transplanted between December 2002 and November 2004.
  2. MMF-based treatment group: prednisone + MMF with or without antiCD25 antibody induction treatment (n = 75). These patients were transplanted between December 1996 and November 2002.

Patient and graft survival, acute rejection rates and adverse events were recorded during the follow-up period. Serum creatinine and 24 h urinary protein excretion were recorded after 12 months. The follow-up period was 12 months. At the end of follow-up, safety parameters such as blood pressure, lipid concentrations and haemoglobin were recorded.

Statistical analysis was performed with the SPSS 11.0 statistics package and R version 2.2.1 of the R Foundation for Statistical Computing. Values are given as mean ± SD, except for non-normal distribution due to proteinuria. Proteinuria values are provided as median and range. The non-parametric Mann–Whitney U or the Chi-square tests—where appropriate—were used for comparison between the two groups.



   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The demographics of the study patients are provided in Tables 1 and 2. Except for slight differences in donor age and the incidence of hypertensive nephropathy, the groups were comparable.


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  		Table 1. Demographic patient data and outcome 1 year after transplantation

 

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  		Table 2. Cause of end-stage renal disease

 
Patient and graft survival are depicted in Figures 1–3GoGo. Patient survival in the MMF group was 88 vs 94% in the SRL group. However, these differences did not reach statistical significance.


Figure 1
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  		Fig. 1. This figure shows patient survival during the first year after transplantation in the patient group with MMF-based therapy (n = 75) compared with the patients who received sirolimus-based therapy (n = 33). The difference is not statistically significant.

 

Figure 2
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  		Fig. 2. This figure shows unadjusted graft survival during the first year after transplantation in the patient group with MMF-based therapy (n = 75) compared with the patients who received sirolimus-based therapy (n = 33). The difference is not statistically significant.

 

Figure 3
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  		Fig. 3. This figure shows graft survival adjusted for death with a functioning graft during the first year after transplantation in the patient group with MMF-based therapy (n = 75) compared with the patients who received sirolimus-based therapy (n = 33). The difference is not statistically significant.

 
One-year unadjusted graft survival was 77% in the MMF group and 88% in the SRL group and censored for death, 83 and 94%, respectively.

The rates of acute rejection were significantly different with 15% in the SRL group and 45% in the MMF group (P < 0.01). Two patients were lost to follow-up in the MMF group. The number of patients who required the introduction of CNI treatment was higher in the MMF group [35 patients (45%)] vs the SRL group [5 patients (15%)] (P < 0.05). In the MMF-based patient group, the introduction of CNI treatment was performed due to acute rejection in all of the 35 aforementioned patients, whereas CNIs were introduced in two of the SRL-treated patients due to acute rejection and in three for nephrotic range proteinuria.

At 1 year post-transplant, 13 patients in the MMF group received either treatment with angiotensin receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACE-I) compared with six patients in the SRL group; P = NS

Three patients in the SRL group (9%) developed nephrotic range proteinuria compared with one patient in the MMF group (P = 0.049). The intention-to-treat analysis revealed significant differences of proteinuria. These differences did not exist in the on-therapy(OT) analysis.

One patient developed nephrotic range proteinuria in the MMF group 2 months after transplantation. She had rapidly progressive glomerulonephritis as cause of end-stage renal disease and developed nephrotic range proteinuria 1 month after transplantation. The transplant biopsy at that time showed acute rejection, Banff II, and a recurrence of rapidly progressive glomerulonephritis shortly after transplantation. The rejection was treated successfully with methylprednisolone bolus therapy and tacrolimus was introduced as additional therapy. However, nephrotic range proteinuria persisted. The patient lost the graft due to recurrent disease 7 months after transplantation.

Two of the nephrotic range proteinuria patients in the SRL group had end-stage renal disease due to unknown cause and had not been biopsied before the transplantation. The first of these patients developed nephrotic range proteinuria in association with a biopsy-proven borderline rejection 4 months after transplantation. At that time, the serum creatinine was 1.6 mg/dl. The nadir creatinine had been 1.2 mg/dl 6 weeks after transplantation. He was treated with steroid bolus therapy and returned to his baseline creatinine. However, nephrotic range proteinuria persisted after anti-rejection therapy. The biopsy showed no signs of de novo glomerulopathy. Antiproteinuric treatment with an angiotensin receptor blocker (ARB) was only partially successful. SRL therapy was withdrawn without knowledge of the transplant centre physician and without introduction of a CNI. Subsequently, the patient developed a late acute humoral rejection, which was treated with plasmapheresis, intravenous immunoglobulin and rituximab. Moreover, tacrolimus was added. The serum creatinine returned to 2.0 mg/dl, however, proteinuria persisted at values of 3 g/day. The second patient showed nephrotic range proteinuria 5 months after transplantation with a maximum value of 5.8 g/day. At that time, her serum creatinine was 1.9 mg/dl with a nadir of 1.6 mg/dl 1 month after transplantation. She was not biopsied due to anticoagulation treatment for a mechanical aortic valve. A conversion from SRL to cyclosporine A (CsA) was performed 7 months after transplantation. Subsequently, the creatinine oscillated between values of 1.9 and 2.6 mg/dl and proteinuria decreased to 2.4 g/day 1 week after the conversion and eventually decreased to 0.4 g/day. However, she lost her graft 11 months after transplantation due to non-adherence and withdrawal of immunosuppressive medication on her own free will, without consulting her physician.

The third patient with nephrotic range proteinuria in the SRL-group had hypertensive nephropathy as underlying disease leading to end-stage renal failure. She developed nephrotic range proteinuria 4 months after transplantation. At that time, the serum creatinine had reached its nadir of 1.6 mg/dl. No biopsy was performed. However, the patient was converted to CsA. After introduction of CsA creatinine increased slightly and stabilized at 2.0 mg/dl and proteinuria decreased from 4.1 g/day to 1.4 g/day 4 weeks after the conversion. A biopsy that was performed 16 months after transplantation contained only three glomeruli, two of them completely sclerosed and one with mesangial fibrous thickening. Moreover, it showed signs of chronic allograft nephropathy (CAN) Banff II.

We could not observe any significant differences between the two groups in terms of blood pressure, lipids or haemoglobin (Table 3).


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  		Table 3. Blood pressure, lipid concentrations and haemoglobin 1 year after transplantation

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This is, to our knowledge, the first study describing proteinuria in advanced age donor kidneys in association with SRL de novo treatment compared with a CNI-free MMF-based treatment. Since both treatment arms are free of de novo CNI therapy, a potential confounding effect of the antiproteinuric action of CNI can be excluded.

The SRL treatment arm yielded good 1-year patient and graft survival, however, the MMF-based treatment group showed an unacceptably high incidence of acute rejection, patient and graft loss, which led to stopping the MMF-based de novo protocol after the year 2002.

Although on-treatment proteinuria does not differ significantly between the two groups, the incidence of nephrotic range proteinuria was slightly higher in the SRL-based group. However, there was no difference in the OT analysis after 1 year. All nephrotic range proteinuria patients received CNI treatment later on. In the four patients who developed nephrotic range proteinuria, it was difficult to attribute the finding to a genuine drug effect, because they had an underlying diagnosis justifying a certain amount of proteinuria (recurrent glomerular disease in the patient of the MMF group, borderline rejection in one, non-adherence in the second and subsequent diagnosis of CAN in the third of the SRL patients). Thus, the study only allows to conclude that proteinuria in these patients was associated with a certain treatment, without necessarily being caused by the treatment, in a situation of previous and ongoing acute damage in the setting of suboptimal organ quality.

These cases demonstrate that especially in these patients a close follow-up is extremely important in order to handle the medically difficult situation and to ensure patient compliance and communication between centre physicians and local nephrologists.

A study by Flechner et al. [8] comparing SRL de novo therapy with CNI-based therapy in patients with optimal donor kidneys and good post-transplant kidney function showed no increased proteinuria in the SRL-treated patients. In contrast to that, Lebranchu et al. [9] and Stephany and co-workers [10] observed higher proteinuria values or a higher incidence of proteinuria in the SRL group comparing an SRL-based with a CNI-based regimen. However, all of these studies compare the influence of SRL with antiproteinuric CNI treatment. Therefore, the comparison of SRL with a regimen that lacks a direct antiproteinuric effect might be helpful to elucidate the question of the proteinuric effect of SRL beyond the haemodynamic differences in comparison with CNIs.

Proteinuria seems to increase in many patients whose immunosuppression was converted to an mTOR inhibitor for declining renal function [2,3,5]. Haemodynamic changes secondary to CNI withdrawal might be one possible pathomechanism [6]. However, some of the conversion patients developed nephrotic range proteinuria after conversion without showing prior proteinuria [2,11]. It might be speculated that haemodynamic changes are not sufficient to explain the increase of urinary protein excretion in this small group of patients. This hypothesis was confirmed by a recent publication by van den Akker et al. [12] who observed an increase of proteinuria after conversion from a CNI-free immunosuppressive protocol based on azathioprin to SRL—a change of treatment that should not influence glomerular haemodynamics.

The OT analysis of our study patients compares the rejection-free non-nephrotic patients in the MMF-based group with the patients without nephrotic range proteinuria in the SRL group and shows no difference of proteinuria. This suggests that SRL might contribute indirectly to a mechanism leading to glomerular damage with subsequent nephrotic proteinuria in a few patients and not have any genuine influence in terms of inducing moderate proteinuria in the majority of patients. A study by Daniel and colleagues supports this hypothesis. In this study, the authors show that everolimus application can exert a detrimental effect on glomerular recovery in an animal model of glomerulonephritis [13]. The authors of this study suggest that mTOR inhibitors negatively influence endothelial glomerular repair mechanisms by blocking the vascular endothelial growth factor (VEGF) system. A similar effect might play a role in the development of nephrotic range proteinuria in patients with already impaired renal function or who received an organ of suboptimal quality.

A limitation of our study is the fact that the control group is a historical one. We did not intend to use kidney function in terms of creatinine or creatinine clearance as a primary endpoint, mostly because of the fact that a treatment in 1996 might not be comparable with the treatment almost 10 years later in terms of kidney function. However, due to the unfavourable results in terms of unacceptably high rejection rates, a similar CNI-free treatment, based exclusively on MMF, does not seem to be justifiable, and therefore, is not available as a routine treatment today. Moreover, although advances in antiproteinuric treatments might have been available for the patients in the SRL group, these did not prevent the higher incidence of nephrotic range proteinuria in this group. Since both regimens were free of CNIs, but a slightly higher incidence of nephrotic range proteinuria occurred in the SRL group, a genuine contributory role of SRL to the pathomechanism cannot be excluded.

In conclusion, this study demonstrates that SRL-based treatment, compared with MMF-based and CNI-free treatment, in kidney transplantation with advanced age donors is associated with an acceptable outcome, however with increased proteinuria in the intention-to-treat analysis. Nevertheless, it shows a lower acute rejection rate and lower incidence of introduction of CNI treatment and no increased proteinuria in the on-treatment analysis.

Conflict of interest statement. The following authors have received speaker fees within the last 3 years from the respective companies: J.M.C.: Astellas, Novartis, Roche, Wyeth; F.D.: Wyeth; F.O.: Astellas, Novartis, Roche, Wyeth.



   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Morelon E and Kreis H. (2003) Sirolimus therapy without calcineurin inhibitors: Necker Hospital 8-year experience. Transpl Proc 35:[Suppl 3A], 52S–57S.[CrossRef][ISI][Medline]
  2. Bumbea V, Kamar N, Ribes D, et al. (2005) Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus. Nephrol Dial Transplant 20:2517–2523.[Abstract/Free Full Text]
  3. Letavernier E, Peraldi MN, Pariente A, Morelon E, Legendre C. (2005) Proteinuria following a switch from calcineurin inhibitors to sirolimus. Transplantation 80:1198–1203.[CrossRef][ISI][Medline]
  4. Butani L. (2004) Investigation of pediatric renal transplant recipients with heavy proteinuria after sirolimus rescue. Transplantation 78:1362–1366.[CrossRef][ISI][Medline]
  5. Diekmann F, Budde K, Oppenheimer F, Fritsche L, Neumayer HH, Campistol JM. (2004) Predictors of success in conversion from calcineurin inhibitor to sirolimus in chronic allograft dysfunction. Am J Transplant 4:1869–1875.[CrossRef][ISI][Medline]
  6. Saurina A, Campistol JM, Piera C, et al. (2006) Conversion from calcineurin inhibitors to sirolimus in chronic allograft dysfunction: changes in glomerular haemodynamics and proteinuria. Nephrol Dial Transpl 21:488–493.[Abstract/Free Full Text]
  7. Dittrich E, Schmaldienst S, Soleiman A, Hörl WH, Pohanka E. (2004) Rapamycin-associated post-transplantation glomerulonephritis and its remission after reintroduction of calcineurin-inhibitor therapy. Transpl Int 17:215–220.[CrossRef][ISI][Medline]
  8. Flechner SM, Kurian SM, Solez K, et al. (2004) De novo kidney transplantation without use of calcineurin inhibitors preserves renal structure and function at two years. Am J Transplant 4:1776–1785.[CrossRef][ISI][Medline]
  9. Lebranchu Y, Etienne I, Topance O, et al. (2004) Preliminary results of a randomized trial comparing sirolimus (SRL) vs cyclosporine (CSA) in 150 transplant patients receiving a cadaveric renal graft. Transplantation 78:Suppl 1, 463.
  10. Stephany BR, Augustine JJ, Krishnamurthi V, et al. (2006) Differences in proteinuria and graft function in de novo sirolimus-based vs calcineurin inhibitor-based immunosuppression in live donor kidney transplantation. Transplantation 82:368–374.[ISI][Medline]
  11. Ruiz JC, Campistol JM, Sánchez-Fructuoso A, et al. (2006) Increase of proteinuria after conversion from calcineurin inhibitor to sirolimus-based treatment in kidney transplant patients with chronic allograft dysfunction. Nephrol Dial Transplant 21:3252–3257.[Abstract/Free Full Text]
  12. van den Akker, Wetzels JFM, Hoitsma AJ. (2006) Proteinuria following conversion from azathioprine to sirolimus in renal transplant recipients. Kidney Int 70:1355–1357.[CrossRef][ISI][Medline]
  13. Daniel C, Renders L, Amann K, Schulze-Lohoff E, Hauser IA, Hugo C. (2005) Mechanisms of everolimus-induced glomerulosclerosis after glomerular injury in the rat. Am J Transplant 5:2849–2861.[CrossRef][ISI][Medline]
Received for publication: 9.10.06
Accepted in revised form: 8. 3.07


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