EPS meetingEPS meeting

Guido GarosiU.O.C. Nefrologia, Dialisi e TrapiantoAzienda Ospedaliera Universitaria SeneseSiena, Italy

Guido GarosiU.O.C. Nefrologia, Dialisi e TrapiantoAzienda Ospedaliera Universitaria SeneseSiena, Italy

Post-transplant EPSPost-transplant EPS

Naarden, The NetherlandsFebruary 4th 2010

Naarden, The NetherlandsFebruary 4th 2010

is post-transplant EPSa remarkable problem?is post-transplant EPSa remarkable problem?

46 EPS casesAt diagnosis:12 on PD13 after switch to HD22 after transplantation

46 EPS casesAt diagnosis:12 on PD13 after switch to HD22 after transplantation

50% of EPS cases after transplantation50% of EPS cases after transplantation

The overall incidence of EPS is stableThe incidence during PD seems to decreaseThe incidence after PD seems to increase

The overall incidence of EPS is stableThe incidence during PD seems to decreaseThe incidence after PD seems to increase

13 EPS cases during 2004-2005in Rotterdam + Utrecht:- 7 post-transplant- 3 after shift to HD- 3 during PD

13 EPS cases during 2004-2005in Rotterdam + Utrecht:- 7 post-transplant- 3 after shift to HD- 3 during PD

>50% of EPS cases after transplantation>50% of EPS cases after transplantation

During last years post-transplant EPS seems to bethe most frequent form of the disease,exceeding the cases of EPS during PD or after shift to HD, at least in the countries with a high transplantation rate

During last years post-transplant EPS seems to bethe most frequent form of the disease,exceeding the cases of EPS during PD or after shift to HD, at least in the countries with a high transplantation rate

The greater incidence of post-transplant EPSwith respect to HD cases seems to suggesta pathogenetic role of transplantation itself,independent from PD withdrawal

The greater incidence of post-transplant EPSwith respect to HD cases seems to suggesta pathogenetic role of transplantation itself,independent from PD withdrawal

This seems to be confirmed if we considerthat usually patients shifting from PD to HDshould be in greater numberwith respect to PD patients undergoing transplantation

This seems to be confirmed if we considerthat usually patients shifting from PD to HDshould be in greater numberwith respect to PD patients undergoing transplantation

is post-transplant EPS a remarkable problem?

is post-transplant EPS a remarkable problem?

Yes !Yes !

is the frequencyof post-transplant EPS

increasing?

is the frequencyof post-transplant EPS

increasing?

the incidence ofpost-transplant EPS

is actually increasingwith respect to

previous epidemiological

studies

prospective

transplant centers

transplant centers

Nomoto Y et al: Sclerosing encapsulating peritonitis in patients undergoing continuous ambulatory peritoneal dialysis: A report of the Japanese Sclerosing Encapsulating Peritonitis Study Group. Am J Kidney Dis 1996;20:420-7Rigby RJ et al: Sclerosing peritonitis: The experience in Australia. Nephrol Dial Transplant 1998;13:154-9Lee HJ et al: Sclerosing encapsulating peritonitis as a complication of long term continuous ambulatory peritoneal dialysis in Korea. Nephrol (Carlton) 2003;8:S33-9Kawanishi H: Long-Term Peritoneal Dialysis Study Group: Encapsulating Peritoneal Sclerosis in Japan: Prospective multicenter controlled study. Perit Dial Int 2001;21:S67-71Kawanishi H et al: Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study. Am J Kidney Dis 2004;44:729-37Summers AM et al: Single-center experience of encapsulating peritoneal sclerosis in patients on peritoneal dialysis for end stage renal failure. Kidney Int 2005;68:2381-8

Nomoto Y et al: Sclerosing encapsulating peritonitis in patients undergoing continuous ambulatory peritoneal dialysis: A report of the Japanese Sclerosing Encapsulating Peritonitis Study Group. Am J Kidney Dis 1996;20:420-7Rigby RJ et al: Sclerosing peritonitis: The experience in Australia. Nephrol Dial Transplant 1998;13:154-9Lee HJ et al: Sclerosing encapsulating peritonitis as a complication of long term continuous ambulatory peritoneal dialysis in Korea. Nephrol (Carlton) 2003;8:S33-9Kawanishi H: Long-Term Peritoneal Dialysis Study Group: Encapsulating Peritoneal Sclerosis in Japan: Prospective multicenter controlled study. Perit Dial Int 2001;21:S67-71Kawanishi H et al: Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study. Am J Kidney Dis 2004;44:729-37Summers AM et al: Single-center experience of encapsulating peritoneal sclerosis in patients on peritoneal dialysis for end stage renal failure. Kidney Int 2005;68:2381-8

Previous studies were usually retrospective and did not involve only transplant centers,so there is the possibility that they did not considerall post-transplant EPS patients

Previous studies usually did not make a clear distinction between EPS arising during PD, after switch to HD,and post-transplantation

is the frequencyof post-transplant EPS

increasing?

is the frequencyof post-transplant EPS

increasing?

likely !

Hypothesis:acceleration of inflammatory-fibroticprocesses due to increased peritonealconcentration of fibrin, IL1, TGFβ, VEGF(lack of peritoneal lavage)

Hypothesis:acceleration of inflammatory-fibroticprocesses due to increased peritonealconcentration of fibrin, IL1, TGFβ, VEGF(lack of peritoneal lavage)

Kawanishi H et al: Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study. Am J Kidney Dis 2004;44:729-37Margetts PJ et al: Inflammatory cytokines, angiogenesis, and fibrosis in the rat peritoneum. Am J Pathol 2002;160:2285-94Fieren MWJA et al: Endotoxin-stimulated peritoneal macrophages obtained from continuous ambulatory peritoneal dialysis patients show an increased capacity to release interleukin-1β in vitro during infectious peritonitis. Eur J Clin Invest 1990;20:453-7

Kawanishi H et al: Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study. Am J Kidney Dis 2004;44:729-37Margetts PJ et al: Inflammatory cytokines, angiogenesis, and fibrosis in the rat peritoneum. Am J Pathol 2002;160:2285-94Fieren MWJA et al: Endotoxin-stimulated peritoneal macrophages obtained from continuous ambulatory peritoneal dialysis patients show an increased capacity to release interleukin-1β in vitro during infectious peritonitis. Eur J Clin Invest 1990;20:453-7

Pathogenesis of EPSafter PD withdrawal

Pathogenesis of EPSafter PD withdrawal

Proposal:to continue exchanges of fluidsa few times per week after PD withdrawal

Proposal:to continue exchanges of fluidsa few times per week after PD withdrawal

Kawanishi H et al: Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study.Am J Kidney Dis 2004;44:729-37

Kawanishi H et al: Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study.Am J Kidney Dis 2004;44:729-37

Pathogenesis of EPSafter PD withdrawal

Pathogenesis of EPSafter PD withdrawal

Result:so far, no convincing evidenceof a beneficial effecton the development or course of EPS

Result:so far, no convincing evidenceof a beneficial effecton the development or course of EPS

ultrafiltration failure and peritonitisare risk factors for EPS

very often associated to HD shift,never to transplantation

ultrafiltration failure and peritonitisare risk factors for EPS

very often associated to HD shift,never to transplantation

post-transplant EPS usually showsan acute-onset presentation,

at variance withthe more commonly describedinsidious and chronic course

post-transplant EPS usually showsan acute-onset presentation,

at variance withthe more commonly describedinsidious and chronic course

Pathogenetic differences betweenHD and post-transplant EPS

Pathogenetic differences betweenHD and post-transplant EPS

transplantationper se

does playa role in the development

of EPS

transplantationper se

does playa role in the development

of EPS

Transplantation

Japanese studies, at variance with Europe, show much more EPS cases

after shift to PD than post-transplantation

Japanese studies, at variance with Europe, show much more EPS cases

after shift to PD than post-transplantation

Hypothesis:- Lower transplantation rate in Japan- Differences in inflammatory reactivity- Genetic differences

Hypothesis:- Lower transplantation rate in Japan- Differences in inflammatory reactivity- Genetic differences

no significant inflammation, calcification, and vasculopathy in EPS

no significant inflammation, calcification, and vasculopathy in EPS

Japanese studiesJapanese studies

inflammation could be differentbetween populations

inflammation could be differentbetween populations

Pathogenetic role of transplantation“per se” in post-transplant EPS

Pathogenetic role of transplantation“per se” in post-transplant EPS

Pivotal role of the modality of immunosuppressive therapyPivotal role of the modality of immunosuppressive therapy

Reliable scheme of the pro-fibrotic and anti-fibrotic properties of eachimmunosuppressive drug

Reliable scheme of the pro-fibrotic and anti-fibrotic properties of eachimmunosuppressive drug

EPS cases recovering after kidneytransplantation

EPS cases recovering after kidneytransplantation

Junor BJ, McMillan MA:Immunosuppression in sclerosing peritonitis.Adv Perit Dial 1993;9:187-9

Junor BJ, McMillan MA:Immunosuppression in sclerosing peritonitis.Adv Perit Dial 1993;9:187-9

Hawley CM, Wall DR, Johnson DW, Campbell SB, Griffin AD, Rigby RJ, Petrie JJB:Recovery of gastrointestinal function after renal transplantation in a patients with sclerosing peritonitis secondary to continuousambulatory peritoneal dialysis.Am J Kidney Dis 1995;26:658-61

Hawley CM, Wall DR, Johnson DW, Campbell SB, Griffin AD, Rigby RJ, Petrie JJB:Recovery of gastrointestinal function after renal transplantation in a patients with sclerosing peritonitis secondary to continuousambulatory peritoneal dialysis.Am J Kidney Dis 1995;26:658-61

immunosuppressive protocolswith high-dose steroids

immunosuppressive protocolswith high-dose steroids

kidney transplantation:tacrolimus, mycophenolate mofetil, low-dose steroidkidney transplantation:tacrolimus, mycophenolate mofetil, low-dose steroid

post-transplant EPSpost-transplant EPS

high-dose steroidhigh-dose steroid

successsuccess steroid taperingsteroid tapering

relapse of EPSrelapse of EPS

increase in steroid doseincrease in steroid dose

successsuccess

Several reports from Japan confirm thatsteroids alone may be efficacious in EPSSeveral reports from Japan confirm thatsteroids alone may be efficacious in EPS

Kawanishi H, Kawagushi Y, Fukui H, Hara S, Imada A, Kubo H, Kin M, Nakamoto M, Ohira S, Shoji T:Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study.Am J Kidney Dis 2004;44:729-37

Kawanishi H, Kawagushi Y, Fukui H, Hara S, Imada A, Kubo H, Kin M, Nakamoto M, Ohira S, Shoji T:Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study.Am J Kidney Dis 2004;44:729-37

Kuriyama S, Tomonari H:Corticosteroid theraphy in encapsulating peritoneal sclerosis.Nephrol Dial Transplant 2001;16:1304-5

Kuriyama S, Tomonari H:Corticosteroid theraphy in encapsulating peritoneal sclerosis.Nephrol Dial Transplant 2001;16:1304-5

Mori Y, Matsuo S, Sutoh H, Toriyama T, Kawahara H, Hotta N:A case of a dialysis patient with sclerosing peritonitis successfullytreated with corticosteroid therapy alone.Am J Kidney Dis 1997;30:275-8

Mori Y, Matsuo S, Sutoh H, Toriyama T, Kawahara H, Hotta N:A case of a dialysis patient with sclerosing peritonitis successfullytreated with corticosteroid therapy alone.Am J Kidney Dis 1997;30:275-8

Steroid theraphy is useful in EPSSteroid theraphy is useful in EPS

the present trend to reduce or abolish steroids after transplantation

could be associated to a growingtendency in post-transplant EPS

the present trend to reduce or abolish steroids after transplantation

could be associated to a growingtendency in post-transplant EPS

Whenever the immunosuppressiveregimen at diagnosis isreported,it is always basedon CNI (cyclosporinor tacrolimus)in all patients, without exception

Whenever the immunosuppressiveregimen at diagnosis isreported,it is always basedon CNI (cyclosporinor tacrolimus)in all patients, without exception

CNI in post-transplant EPSCNI in post-transplant EPS

CNI:- Induce nephrotoxicity with interstitial fibrosis- Increase TGF-β transcription in human T lymphocytes- Modulate expression of TGF-β and other growth factors- Upregulate expression of VEGF (mRNA and protein)- Upregulate expression of VEGF receptors

CNI:- Induce nephrotoxicity with interstitial fibrosis- Increase TGF-β transcription in human T lymphocytes- Modulate expression of TGF-β and other growth factors- Upregulate expression of VEGF (mRNA and protein)- Upregulate expression of VEGF receptors

Profibrotic effects of CNIProfibrotic effects of CNI

Van Nieuwenhoven FA et al: Imbalance of growth factors signalling in diabetic kidneydisease: is connective tissue growth factor (CTGF, CCN2) the perfect intervention point? Nephrol Dial Transplant 2005;20:6-10Myers BD et al: Cyclosporine-associated chronic nephropathy. N Eng J Med 1984;31:699-705Shibab FS et al: Role of transforming growth factor-β1 in experimental chronic cyclosporinnephropathy. Kidney Int 1996;49:1141-51Shin GT et al: In vivo expression of transforming growth factor-β in humans. Transplantation1998;65:3313-18Shibab FS et al: Expression of vascular endothelial growth factor and its receptors Flt-1 and KDR/FLK-1 in chronic cyclosporin nephrotoxicity. Transplantation 2001;72:164-168

Van Nieuwenhoven FA et al: Imbalance of growth factors signalling in diabetic kidneydisease: is connective tissue growth factor (CTGF, CCN2) the perfect intervention point? Nephrol Dial Transplant 2005;20:6-10Myers BD et al: Cyclosporine-associated chronic nephropathy. N Eng J Med 1984;31:699-705Shibab FS et al: Role of transforming growth factor-β1 in experimental chronic cyclosporinnephropathy. Kidney Int 1996;49:1141-51Shin GT et al: In vivo expression of transforming growth factor-β in humans. Transplantation1998;65:3313-18Shibab FS et al: Expression of vascular endothelial growth factor and its receptors Flt-1 and KDR/FLK-1 in chronic cyclosporin nephrotoxicity. Transplantation 2001;72:164-168

CNI as a trigger for post-transplant EPS: a quite obvious role

CNI as a trigger for post-transplant EPS: a quite obvious role

in rats treatedwith PD,

peritonealfibrosis is

significantlyincreased by

CNI and prevented by

steroids

in rats treatedwith PD,

peritonealfibrosis is

significantlyincreased by

CNI and prevented by

steroids

inefficacy of azathioprineinefficacy of azathioprine

MMF as a way to reduce CNIMMF as a way to reduce CNI

- Block of T-cell cycle at late G1 phase by inhibiting IL2- Inhibition of growth-factor stimulated proliferation in

vascular smooth muscle cells, liver and lung fibrosis- Inhibition of mesenchimal cell proliferation- Down-regulation of lipopolysaccharide- and

interferon-γ-induced inflammatory gene transcription

- Block of T-cell cycle at late G1 phase by inhibiting IL2- Inhibition of growth-factor stimulated proliferation in

vascular smooth muscle cells, liver and lung fibrosis- Inhibition of mesenchimal cell proliferation- Down-regulation of lipopolysaccharide- and

interferon-γ-induced inflammatory gene transcription

Effects of mTOR-I (sirolimus, everolimus):inhibition of fibrosis, angiogenesis, inflammation

Effects of mTOR-I (sirolimus, everolimus):inhibition of fibrosis, angiogenesis, inflammation

Schuller W et al: SDZ RAD, a new rapamycin derivative. Pharmacological properties in vitro and in vivo. Transplantation 1997;64:36-42Cao W et al: Effects of rapamycin on growth-factor stimulated vascular smooth muscle cellsDNA synthesis. Transplantation 1995;59:390-5Neef M et al: Low-dose oral rapamycin treatment reduces fibrogenesis, improves liverfunction, and prolongs survival in rats with established liver cirrhosis. J Hepatol2006;45:786-96Simler NR et al: The rapamycin analgue SDZ RAD attenuates bleomycin-induced pulmonaryfibrosis in rats. Eur Respir J 2002;19:1124-7Kristof AS: Stimulation of signal transducer and activator of transcription-1 (STAT-1)-dependent gene transcription by lipopolysaccharide and interferon-γ is regulated bymammalian target of rapamycin. J Biol Chem 2003;278:33637-44

Schuller W et al: SDZ RAD, a new rapamycin derivative. Pharmacological properties in vitro and in vivo. Transplantation 1997;64:36-42Cao W et al: Effects of rapamycin on growth-factor stimulated vascular smooth muscle cellsDNA synthesis. Transplantation 1995;59:390-5Neef M et al: Low-dose oral rapamycin treatment reduces fibrogenesis, improves liverfunction, and prolongs survival in rats with established liver cirrhosis. J Hepatol2006;45:786-96Simler NR et al: The rapamycin analgue SDZ RAD attenuates bleomycin-induced pulmonaryfibrosis in rats. Eur Respir J 2002;19:1124-7Kristof AS: Stimulation of signal transducer and activator of transcription-1 (STAT-1)-dependent gene transcription by lipopolysaccharide and interferon-γ is regulated bymammalian target of rapamycin. J Biol Chem 2003;278:33637-44

Clinical use of mTOR-IClinical use of mTOR-I

mTOR-I as the most rational basisfor immunosuppressive therapy

in ex-PD transplant patients

mTOR-I as the most rational basisfor immunosuppressive therapy

in ex-PD transplant patients

- Endovascular medicine: drug-eluting stents- Oncology: antiproliferative agents- Transplantation: alternative agents for CNI toxicity,

namely to prevent CNI-associated fibrosis;association with delayed healing of surgical wounds

- Endovascular medicine: drug-eluting stents- Oncology: antiproliferative agents- Transplantation: alternative agents for CNI toxicity,

namely to prevent CNI-associated fibrosis;association with delayed healing of surgical wounds

No case of post-transplant EPShas ever been reported in mTOR-I based

immunosuppressive therapy, devoid of CNI

No case of post-transplant EPShas ever been reported in mTOR-I based

immunosuppressive therapy, devoid of CNI

How to prevent EPS?

Stopping PD at 5 years in order to avoid EPS:is it rational?

We do not think soIt may actually increase the incidence of EPS

The “precautionary principle” suggesting “to anticipate harm before itoccurs when the absence of scientific certainty makes it difficult to predictthe likelihood of harm occurring” seems reasonable with etiological factors, not with risk factors

Epidemiology shows thatEPS cases during PD are just ¼EPS cases after PD stopping are ¾

Which is the risk of shifting patients to HD without definite indications?Negative impact on quality of life

(2009) 41:903-907

(2009) 41:903-907

What to do to prevent EPS?

Use of new biocompatible PD solutions

Inhibition of renin-angiotensin systemas the elective therapy of hypertension in PD

Prophylaxis with tamoxifen 10 mg/die in:- patients in PD after 5 years- patients in PD with ultrafiltration failureor increased peritoneal transport

What to do to prevent post-transplant EPS?To treat ex-PD patients at transplantationwith mTOR-I, mycophenolate mofetil and steroids,with avoidance or minimization of CNI

(2009) 41:903-907

Aim: such a specific immunosuppressive protocolfor PD patients receiving kidney transplantation

Many immunosuppressive protocols based on mTOR-I and mycophenolatemofetil have already been successfully developed to prevent or to minimize the nephrotoxic effect of CNI, without any significant increase in rejection rateThe trend to decrease or avoid steroidscould not be pursued rigorously in ex-PD patients

in collaboration with transplantation centers, surveyin all post-transplant ex-PD patients in order to clarifythe development of post-transplant EPS with respect

to the detailed modalities of immunosuppression

mTOR-I

CNI

specific immunosuppressive protocol for PD patients receiving kidney transplantation:

large doses of mTOR-I, possible use of mycophenolate mofetil, judicious dosage of steroids,

avoidance or minimization of CNI

it seems extremely important to haveas much data as possible

from any center throughout the world

mTOR-I

CNI

it should be wonderfulto collect data

from many countries!

it seems extremely important to haveas much data as possible

from any center throughout the world

mTOR-I

CNI

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