Conversion from calcineurin inhibitors to sirolimus in chronic allograft dysfunction: changes in glomerular haemodynamics and proteinuria

Saurina, Anna; Campistol, Josep M.; Piera, Carlos; Diekmann, Fritz; Campos, Begoña; Campos, N Gonzalo; Cuevas, X; Oppenheimer, Federico

doi:10.1093/ndt/gfi266

Cited by 83 publications

(54 citation statements)

References 15 publications

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“…The mechanism by which the Tac/SRL combination is potentially more nephrotoxic is unclear. The mechanism implicated includes a complex cascade of events leading to perturbation of glomerular hemodynamics in the setting of Tac/SRL combination therapy (29).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Kidney Allograft Function and Survival in Prednisone-Free Regimens

Chhabra

Skaro

Leventhal

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives The optimal maintenance immunosuppressive regimen to improve long-term renal allograft function and graft survival is yet to be determined.Design, setting, participants, & measurements This observational study prospectively compared tacrolimus/ sirolimus with tacrolimus/mycophenolate mofetil in renal transplant recipients using a prednisone-free regimen with over 8.5 years of follow-up. Patients received methylprednisonlone and anti-IL2 receptor antagonist (Basiliximab) induction and were blindly randomized to either the tacrolimus/mycophenolate mofetil (n=45) or tacrolimus/sirolimus (n=37) groups. Outcome measures included patient and renal allograft survival, incidence of acute rejection, and estimated GFR.Results The tacrolimus/mycophenolate mofetil group compared with the tacrolimus/sirolimus group had overall better renal allograft survival (91% versus 70%, P=0.02); 13 patients (35.1%) in the tacrolimus/sirolimus group and 8 patients (17.8%) in the tacrolimus/mycophenolate mofetil group experienced biopsy-proven acute cellular rejection (P=0.07). By 3 months post-transplant, estimated GFR was significantly lower in the tacrolimus/ sirolimus group compared with the tacrolimus/mycophenolate mofetil group (47.7 versus 59.6 ml/min per 1.73 m 2 , P=0.0002), and this trend persisted throughout the follow-up period. Also, the slope of decline in the tacrolimus/ sirolimus group was significantly steeper than in the tacrolimus/mycophenolate mofetil group.Conclusions This study shows that, in a prednisone-free immunosuppressive regimen, long-term renal graft survival and function are significantly worse in the tacrolimus/sirolimus group than the tacrolimus/ mycophenolate mofetil group. The synergistic nephrotoxic effect and higher acute rejection rates in the tacrolimus/sirolimus compared with the tacrolimus/mycophenolate mofetil group adversely affect graft survival.

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Section: Discussionmentioning

confidence: 99%

Long-Term Kidney Allograft Function and Survival in Prednisone-Free Regimens

Chhabra

Skaro

Leventhal

et al. 2012

Clinical Journal of the American Society of Nephrology

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“…Proteinuria was reported to increase in renal transplant recipients with chronic allograft dysfunction who had been shifted to sirolimus treatment after withdrawal of a calcineurin inhibitor (27). Proteinuria was typically of glomerular origin (28) and could not be explained just by an increase in GFR associated with cyclosporin withdrawal (29). Finding that sirolimus exacerbated both proteinuria and different markers of podocyte damage in a model of severe puromycin-induced glomerular injury (30) can be taken to suggest that sirolimus may have a direct nephrotoxic effect, particularly in patients with advanced renal disease, such as our patients with ADPKD.…”

Section: Safetymentioning

confidence: 99%

Effect of Sirolimus on Disease Progression in Patients with Autosomal Dominant Polycystic Kidney Disease and CKD Stages 3b-4

Ruggenenti

Gentile

Perico

et al. 2016

CJASN

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Background and objectives The effect of mammalian target of rapamycin (mTOR) inhibitors has never been tested in patients with autosomal dominant polycystic kidney disease (ADPKD) and severe renal insufficiency.Design, setting, participants, & measurements In this academic, prospective, randomized, open label, blinded end point, parallel group trial (ClinicalTrials.gov no. NCT01223755), 41 adults with ADPKD, CKD stage 3b or 4, and proteinuria #0.5 g/24 h were randomized between September of 2010 and March of 2012 to sirolimus (3 mg/d; serum target levels of 5-10 ng/ml) added on to conventional therapy (n=21) or conventional treatment alone (n=20). Primary outcome was GFR (iohexol plasma clearance) change at 1 and 3 years versus baseline.Results At the 1-year preplanned interim analysis, GFR fell from 26.765.8 to 21.366.3 ml/min per 1.73 m 2 (P,0.001) and from 29.665.6 to 24.966.2 ml/min per 1.73 m 2 (P,0.001) in the sirolimus and conventional treatment groups, respectively. Albuminuria (73.8681.8 versus 154.96152.9 mg/min; P=0.02) and proteinuria (0.360.2 versus 0660.4 g/24 h; P,0.01) increased with sirolimus. Seven patients on sirolimus versus one control had de novo proteinuria (P=0.04), ten versus three patients doubled proteinuria (P=0.02), 18 versus 11 patients had peripheral edema (P=0.04), and 14 versus six patients had upper respiratory tract infections (P=0.03). Three patients on sirolimus had angioedema, 14 patients had aphthous stomatitis, and seven patients had acne (P,0.01 for both versus controls). Two patients progressed to ESRD, and two patients withdrew because of worsening of proteinuria. These events were not observed in controls. Thus, the independent data and safety monitoring board recommend early trial termination for safety reasons. At 1 year, total kidney volume (assessed by contrastenhanced computed tomography imaging) increased by 9.0% from 2857.761447.3 to 3094.661519.5 ml on sirolimus and 4.3% from 3123.461695.3 to 3222.661651.4 ml on conventional therapy (P=0.12). On follow-up, 37% and 7% of serum sirolimus levels fell below or exceeded the therapeutic range, respectively.Conclusions Finding that sirolimus was unsafe and ineffective in patients with ADPKD and renal insufficiency suggests that mTOR inhibitor therapy may be contraindicated in this context.

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“…Ducloux et al (17) reported that in 31 renal transplant recipients whose cyclosporine (CsA) was withdrawn because of cyclosporine toxicity or CAN, baseline proteinuria was 0.79 Ϯ 0.6 g/d and increased to 1.79 Ϯ 0.8 g/d 24 mo after CsA withdrawal. Because CNI reduce renal blood flow, CNI withdrawal may reveal existing CAN lesions that result in proteinuria, and an increase in intraglomerular pressure has been described after the switch (3,5,18).…”

Section: Sirolimus-induced Proteinuria and Glomerular Lesionsmentioning

confidence: 99%

High Sirolimus Levels May Induce Focal Segmental Glomerulosclerosis De Novo

Letavernier¹,

Bruneval²,

Mandet³

et al. 2007

Clinical Journal of the American Society of Nephrology

182

112

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Sirolimus has been associated with high-range proteinuria when used in replacement of calcineurin inhibitors in renal transplant recipients with chronic allograft nephropathy (CAN). Primary FSGS was demonstrated previously in some such patients, but the coexistence of CAN lesions made the interpretation uneasy. However, nephrotic syndrome and FSGS were observed recently in three patients who received sirolimus de novo, without medical history of primary FSGS or CAN. Markers of podocyte differentiation were studied in kidney biopsies of the three patients who received sirolimus de novo and of five patients who switched to sirolimus. All patients developed FSGS lesions of classic type (not otherwise specified), but only switched patients exhibited advanced sclerotic lesions. Immunohistochemistry showed that some podocytes in FSGS lesions had absent or diminished expression of the podocyte-specific epitopes synaptopodin and p57, reflecting dedifferentiation, and had acquired expression of cytokeratin and PAX2, reflecting a immature fetal phenotype. Such a pattern of epitope expression provides evidence for podocyte dysregulation. Moreover, a decrease in vascular endothelial growth factor expression was observed in some glomeruli. In conclusion, sirolimus induces FSGS that is responsible for proteinuria in some transplant patients.

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Conversion from calcineurin inhibitors to sirolimus in chronic allograft dysfunction: changes in glomerular haemodynamics and proteinuria

Cited by 83 publications

References 15 publications

Long-Term Kidney Allograft Function and Survival in Prednisone-Free Regimens

Long-Term Kidney Allograft Function and Survival in Prednisone-Free Regimens

Effect of Sirolimus on Disease Progression in Patients with Autosomal Dominant Polycystic Kidney Disease and CKD Stages 3b-4

High Sirolimus Levels May Induce Focal Segmental Glomerulosclerosis De Novo

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