EPS meeting. Post-transplant EPS. Naarden, The Netherlands February 4 th 2010

Transcription

1 Naarden, The Netherlands February 4 th 2010 EPS meeting Post-transplant EPS Guido Garosi U.O.C. Nefrologia, Dialisi e Trapianto Azienda Ospedaliera Universitaria Senese Siena, Italy

2 is post-transplant EPS a remarkable problem?

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4 46 EPS cases At diagnosis: 12 on PD 13 after switch to HD 22 after transplantation The overall incidence of EPS is stable The incidence during PD seems to decrease The incidence after PD seems to increase 50% of EPS cases after transplantation

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6 13 EPS cases during in Rotterdam + Utrecht: - 7 post-transplant - 3 after shift to HD - 3 during PD >50% of EPS cases after transplantation

7 During last years post-transplant EPS seems to be the 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 EPS with respect to HD cases seems to suggest a pathogenetic role of transplantation itself, independent from PD withdrawal This seems to be confirmed if we consider that usually patients shifting from PD to HD should be in greater number with respect to PD patients undergoing transplantation

8 is post-transplant EPS a remarkable problem? Yes!

9 is the frequency of post-transplant EPS increasing?

10 prospective transplant centers the incidence of post-transplant EPS is actually increasing with respect to previous epidemiological studies transplant centers

11 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;20:420-7 Rigby RJ et al: Sclerosing peritonitis: The experience in Australia. Nephrol Dial Transplant 1998;13:154-9 Lee HJ et al: Sclerosing encapsulating peritonitis as a complication of long term continuous ambulatory peritoneal dialysis in Korea. Nephrol (Carlton) 2003;8:S33-9 Kawanishi H: Long-Term Peritoneal Dialysis Study Group: Encapsulating Peritoneal Sclerosis in Japan: Prospective multicenter controlled study. Perit Dial Int 2001;21:S67-71 Kawanishi H et al: Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study. Am J Kidney Dis 2004;44: Summers AM et al: Single-center experience of encapsulating peritoneal sclerosis in patients on peritoneal dialysis for end stage renal failure. Kidney Int 2005;68: Previous studies were usually retrospective and did not involve only transplant centers, so there is the possibility that they did not consider all 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

12 is the frequency of post-transplant EPS increasing? likely!

13 Pathogenesis of EPS after PD withdrawal Hypothesis: acceleration of inflammatory-fibrotic processes due to increased peritoneal concentration 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: Margetts PJ et al: Inflammatory cytokines, angiogenesis, and fibrosis in the rat peritoneum. Am J Pathol 2002;160: Fieren 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

14 Pathogenesis of EPS after PD withdrawal Proposal: to continue exchanges of fluids a few times per week after PD withdrawal Result: so far, no convincing evidence of a beneficial effect on the development or course of EPS Kawanishi H et al: Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study. Am J Kidney Dis 2004;44:729-37

15 Pathogenetic differences between HD and post-transplant EPS ultrafiltration failure and peritonitis are risk factors for EPS very often associated to HD shift, never to transplantation post-transplant EPS usually shows an acute-onset presentation, at variance with the more commonly described insidious and chronic course

16 transplantation per se does play a role in the development of EPS Transplantation

17 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

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19 Japanese studies no significant inflammation, calcification, and vasculopathy in EPS inflammation could be different between populations

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23 Pathogenetic role of transplantation per se in post-transplant EPS Pivotal role of the modality of immunosuppressive therapy Reliable scheme of the pro-fibrotic and anti-fibrotic properties of each immunosuppressive drug

24 EPS cases recovering after kidney transplantation 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 continuous ambulatory peritoneal dialysis. Am J Kidney Dis 1995;26: immunosuppressive protocols with high-dose steroids

25 kidney transplantation: tacrolimus, mycophenolate mofetil, low-dose steroid post-transplant EPS high-dose steroid success steroid tapering relapse of EPS increase in steroid dose success

26 Several reports from Japan confirm that steroids 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: Kuriyama S, Tomonari H: Corticosteroid theraphy in encapsulating peritoneal sclerosis. Nephrol Dial Transplant 2001;16: Mori Y, Matsuo S, Sutoh H, Toriyama T, Kawahara H, Hotta N: A case of a dialysis patient with sclerosing peritonitis successfully treated with corticosteroid therapy alone. Am J Kidney Dis 1997;30:275-8

27 Steroid theraphy is useful in EPS the present trend to reduce or abolish steroids after transplantation could be associated to a growing tendency in post-transplant EPS

28 CNI in post-transplant EPS Whenever the immunosuppressive regimen at diagnosis is reported, it is always based on CNI (cyclosporin or tacrolimus) in all patients, without exception

29 Profibrotic effects of CNI 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 Van Nieuwenhoven FA et al: Imbalance of growth factors signalling in diabetic kidney disease: is connective tissue growth factor (CTGF, CCN2) the perfect intervention point? Nephrol Dial Transplant 2005;20:6-10 Myers BD et al: Cyclosporine-associated chronic nephropathy. N Eng J Med 1984;31: Shibab FS et al: Role of transforming growth factor-β1 in experimental chronic cyclosporin nephropathy. Kidney Int 1996;49: Shin GT et al: In vivo expression of transforming growth factor-β in humans. Transplantation 1998;65: Shibab 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: CNI as a trigger for post-transplant EPS: a quite obvious role

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39 in rats treated with PD, peritoneal fibrosis is significantly increased by CNI and prevented by steroids inefficacy of azathioprine

40 MMF as a way to reduce CNI

41 Effects of mtor-i (sirolimus, everolimus): inhibition of fibrosis, angiogenesis, inflammation - 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 Schuller W et al: SDZ RAD, a new rapamycin derivative. Pharmacological properties in vitro and in vivo. Transplantation 1997;64:36-42 Cao W et al: Effects of rapamycin on growth-factor stimulated vascular smooth muscle cells DNA synthesis. Transplantation 1995;59:390-5 Neef M et al: Low-dose oral rapamycin treatment reduces fibrogenesis, improves liver function, and prolongs survival in rats with established liver cirrhosis. J Hepatol 2006;45: Simler NR et al: The rapamycin analgue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats. Eur Respir J 2002;19: Kristof AS: Stimulation of signal transducer and activator of transcription-1 (STAT-1)- dependent gene transcription by lipopolysaccharide and interferon-γ is regulated by mammalian target of rapamycin. J Biol Chem 2003;278:

42 Clinical use of mtor-i - 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 EPS has ever been reported in mtor-i based immunosuppressive therapy, devoid of CNI mtor-i as the most rational basis for immunosuppressive therapy in ex-pd transplant patients

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46 How to prevent EPS?

47 (2009) 41: Stopping PD at 5 years in order to avoid EPS: is it rational? The precautionary principle suggesting to anticipate harm before it occurs when the absence of scientific certainty makes it difficult to predict the likelihood of harm occurring seems reasonable with etiological factors, not with risk factors Epidemiology shows that EPS cases during PD are just ¼ EPS cases after PD stopping are ¾ Which is the risk of shifting patients to HD without definite indications? Negative impact on quality of life We do not think so It may actually increase the incidence of EPS

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49 (2009) 41: What to do to prevent EPS? Use of new biocompatible PD solutions Inhibition of renin-angiotensin system as 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 failure or increased peritoneal transport

50 (2009) 41: What to do to prevent post-transplant EPS? To treat ex-pd patients at transplantation with mtor-i, mycophenolate mofetil and steroids, with avoidance or minimization of CNI Many immunosuppressive protocols based on mtor-i and mycophenolate mofetil have already been successfully developed to prevent or to minimize the nephrotoxic effect of CNI, without any significant increase in rejection rate The trend to decrease or avoid steroids could not be pursued rigorously in ex-pd patients Aim: such a specific immunosuppressive protocol for PD patients receiving kidney transplantation

51 in collaboration with transplantation centers, survey in all post-transplant ex-pd patients in order to clarify the 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

52 mtor-i CNI it seems extremely important to have as much data as possible from any center throughout the world it should be wonderful to collect data from many countries!

53 mtor-i CNI it seems extremely important to have as much data as possible from any center throughout the world Join in!