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Proteinuria with sirolimus therapy.
Christophe Legendre Hôpital Necker, Université
Paris V Paris, France
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Proteinuria with sirolimus therapy

• 1. Proteinuria and renal transplantation.
• 2. Proteinuria and sirolimus, the data
• - in patients converted from CsA,
• - in de novo patients,
• 3. The mechanisms of increased proteinuria
• - CNI withdrawal,
• - the role of sirolimus itself

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Proteinuria and renal transplantation
n 3365
Fernandez- Fresnedo G et al, Nephrol Dial
Transplant 2004
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Fernandez- Fresnedo G et al, Nephrol Dial
Transplant 2004
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Proteinuria and renal transplantation
484 patients, mean follow-up 7.2 years
Halimi JM et al, Am J Transplant 2005 (in
press)
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Proteinuria and renal TR
Proteinuria No proteinuria
Proteinuria 0.5 Halimi JM et al, Am J Transplant 2005 (in
press)
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Proteinuria and sirolimus, the data

• . Proteinuria was first reported in 2003 after
  renal allograft recipients were converted from a
  CNI-based regimen to a SRL-based regimen.
• . 32 cases of proteinuria with a nephrotic
  syndrome in 18 cases out of 50 converted
  patients.
• . Presence of focal segmental glomerular
  sclerosis in 4 cases.

Morelon E et al, Transplant Proc 2003
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Proteinuria and sirolimusconversion
Csa-sirolimus.
Butani L, Transplantation 2004
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Proteinuria and sirolimusconversion
Csa-sirolimus.

• . Report of 4 cases of heavy proteinuria, edema
  and decline of graft function after conversion.
• . Withdrawal of SRL and reintroduction of CNI
  resulted in remission in 4 patients.

Dittrich E et al, Transplant Int 2004
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Proteinuria and sirolimusconversion
Csa-sirolimus.
1.6
1.6
1.4
1.4
0.4
Letavernier E et al, Transplantation (In press)
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Proteinuria and sirolimusconversion
Csa-sirolimus.
Letavernier E et al, Transplantation (In press)
12
Proteinuria and sirolimusconversion
Csa-sirolimus.
1.9
0.9
0.3
Letavernier E et al, Transplantation (In press)
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Proteinuria and sirolimus of albumin (agarose
gel with SDS).
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Proteinuria and sirolimusconversion
Csa-sirolimus.

• . Monocentric retrospective study (n23).
• . Conversion to SRL after a mean of 667 days.
• . 16/23 patients discontinued SRL 7 because of a
  nephrotic range proteinuria.
• . Occurred 9 days after conversion.
• . Association with history of acute rejection
• 5/9 versus 1/13, p0.02.

Hadaya K et al, ATC 2004
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Proteinuria and sirolimusconversion
Csa-sirolimus.

• . Observational retrospective analysis in 30
  liver and 29 kidney transplant recipients.
• . Liver (n30)
• - 2 cases of proteinuria,
• . Kidney (n29)
• - 14 patients with increasing proteinuria.

Dervaux T et al, ICTS 2004
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Proteinuria and sirolimusconversion
Csa-sirolimus.

• . Increase in proteinuria in 40 kidney and heart
  transplant recipients (n41). Lacha J et al, ATC
  2005
• . Increase in proteinuria in 61 of kidney
  transplant recipients ( 100 in 30 of cases).
  More prominent when Pu is low before switch
  (n94). Ruiz C et al, ATC 2005
• . Few data with Tac 16 without Pu (Tac-SRL-Ste)
  versus 35 without Pu (SRL-Ste) (n87). Morales
  JM et al, ATC 2005

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Proteinuria and sirolimusconversion
Csa-sirolimus.

• . De novo proteinuria in 20 and increase in
  proteinuria in 28 of kidney transplant
  recipients (n86). Birne R et al, ERA-EDTA 2005
• . De novo proteinuria ( 0.5g/d) in 37 of kidney
  transplant recipients ( 2g/d in 12). Bumbea V
  et al, ERA-EDTA 2005

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Proteinuria and sirolimusconversion
Csa-sirolimus.

• . What are the predictors of a successful
  conversion from CNI to sirolimus?
• - 59 patients studied,
• - proteinuria below 0.8g/d is the only
  independent predictor for positive outcome in
  a multivariate analysis.

Diekmann F et al, Am J Transplant 2004
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Proteinuria and sirolimusconversion
Csa-sirolimus.
Diekmann F et al, Am J Transplant 2004
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Proteinuria and sirolimusconversion
Csa-sirolimus.
The CONVERT Trial (n 830)
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Proteinuria and sirolimusconversion
Csa-sirolimus.
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Proteinuria and sirolimusde novo patients.
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Proteinuria and sirolimusde novo patients.
Flechner S et al, Am J Transplant 2004
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Proteinuria and sirolimusde novo patients.
Randomization n150
Transplantation
Group A n71
Group B n74
ATG 5 days MMF 2g/day STEROIDS WITHDRAWN AT
MONTH 6
Sirolimus (SRL) Load 15mg x 2 days 10mg /
day T0 10-15ng/ml (HPLC)
Neoral (CsA) 6-8 mg/kg/d T0 150-250ng/ml
W1-M3 75-150 ng/ml M3-M6
Lebranchu Y et al, ATC 2005
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Proteinuria at 12 months.
Mean 0.64 vs 0.18 g/d for SRL vs CsA
p
Lebranchu Y et al, ATC 2005
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Proteinuria over 12 months.
g/24 hours
Lebranchu Y et al, ATC 2005
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Proteinuria and sirolimusconversion
Csa-sirolimus.
Skhiri H et al, Transplant Int 2005
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Mechanism of proteinuriaCNI withdrawal.
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Mechanism of proteinuriaCNI withdrawal.
Lamas S, Kidney Int 2005
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Mechanism of proteinuriaCNI withdrawal.

• . In heart transplant recipients, progressive
  withdrawal of CsA leads to an increase of
  proteinuria
• - 162 70µg/min (0.23g/d) at baseline
• - 546 300µg/min (0.79g/d) at 48 months.

Myers B et al, Kidney Int 1988
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Mechanism of proteinuriaconversion CNI-MMF.

• . Very few data on proteinuria after conversion
  from CsA to MMF in kidney transplant recipients!

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Mechanism of proteinuriaconversion CNI-MMF.

• . In unstable patients
• - Weir M et al, Kidney Int 2001 No data
• - Dudley C et al, Transplantation 2005 . No
  data
• - Ducloux D et al, Transplant Int 2002
• - 31 patients with chronic allograft
  dysfunction,
• - Pu 0.70 0.6 g/d before switch,
• - Pu 1.79 1.1g/d at end of follow-up
  (p0.04).

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Mechanism of proteinuriaconversion CNI-MMF.
Houdé I et al, Transplantation 2000
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Mechanism of proteinuriaconversion CNI-MMF.

• . In stable patients
• - Abramowicz D et al, Transplantation 2002
  No data
• - Pascual M et al, Transplantation 2003 ..
  No data
• - Thervet E et al, Clin Transplantation 2000
• - 28 patients on CsA-Aza-ste,
• - 40 weeks of follow-up,
• - Pu at baseline 0.1 g/d,
• - Pu at end of follow-up 0.2 g/d.

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Mechanism of proteinuriaconversion CNI-MMF.

• . In stable patients
• - Smak Gregoor PJ et al, JASN 2002
• - patients on CsA-MMF-Ste,
• - at 6 months post-RT, withdrawal of CsA or
  ste,
• - proteinuria 0.5 g/d
• - at baseline18 (CsA-), 16 (ste-), 15
  (control),
• - at end of FU 18, 20, 12 (ns).

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Mechanism of proteinuriathe role of sirolimus.

• . Acute nephrotoxicity in non-transplant patients
  with a chronic glomerulopathy. Fervenza PM et al,
  NDT 2004
• . Proinflammatory effects of RAD in an
  experimental model of mesangial proliferative
  glomerulonephritis. Daniel C et al, Exp Nephrol
  2000
• . Rapamycin ameliorates proteinuria-associated
  tubulo-interstitial inflammation and fibrosis in
  experimental membranous nephropathy. Bonegio RGB
  et al, JASN 2005

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Mechanism of proteinuriano specific
pathological aspect!
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Summary

• Proteinuria is a prognostic marker in renal
  transplantation.
• 2. Proteinuria appears or increases in
  transplant patients converted from CNI to SRL but
  we do not know yet precisely
• - in which patients,
• - what are the prognostic consequences,
• - the response to (which!) therapy.
• 3. The exact mechanism is unknown but the
  hemodynamic effect of CNI withdrawal is likely to
  be essential.

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Thanks for your attention!