Presentation is loading. Please wait.

Presentation is loading. Please wait.

CORSO INTERATTIVO: LA PERITONITE SCLEROSANTE DIAGNOSI E TERAPIA Roberto Corciulo Divisione di Nefrologia e Dialisi Azienda Ospedaliero Policlinico Università.

Similar presentations


Presentation on theme: "CORSO INTERATTIVO: LA PERITONITE SCLEROSANTE DIAGNOSI E TERAPIA Roberto Corciulo Divisione di Nefrologia e Dialisi Azienda Ospedaliero Policlinico Università."— Presentation transcript:

1 CORSO INTERATTIVO: LA PERITONITE SCLEROSANTE DIAGNOSI E TERAPIA Roberto Corciulo Divisione di Nefrologia e Dialisi Azienda Ospedaliero Policlinico Università di Bari Bari, 19 marzo 2010

2 Diagnosis of EPS Clinical signs and symptoms Laboratory tests Effluent markers Peritoneal permeability Radiological findings Biopsy Laparoscopy The diagnosis of EPS is made on the basis of abdominal symptoms related to encapsulation of bowel by a fibrous cocoon. Anorexia, nausea, vomiting, and weight loss are common but nonspecific. Tests for anemia, albumin and high C-reactive protein levels have been suggested as adjunct tests. AR-Ca125 and AR- IL 6.

3 Time Course of Effluent Markers in PD Patients Who Develop Peritoneal Sclerosis Krediet R et al., Contributions to Nephrology, 2009; 163:54-59

4 The combination of AR-CA pg/min had a sensitivity of 70% and a specificity of 89% for the development of EPS. Krediet R et al., Contributions to Nephrology, 2009; 163:54-59 The sensitivity and specificity of the combination of dialysate CA125 and IL-6 in patients with UFF suggest that it is possible to identify patients at risk for clinically established EPS. DE Sampimon et al., Perit Dial Int, 2010 Vol. 30 in press Effluent Markers and EPS An international multicenter study was initiated to evaluate the peritoneal function and peritoneal and systemic inflammatory markers (IL1 ,TNF, IL6,IFN  ). Preliminary results indicate high levels of cytokines in the peritoneal effluent correlating with alterations of peritoneal membrane transport. Global Fluid Study, Topley N et al,

5 Diagnosis of EPS Clinical signs and symptoms Laboratory tests Effluent markers Peritoneal permeability Radiological findings Biopsy Laparoscopy The diagnosis of EPS is made on the basis of abdominal symptoms related to encapsulation of bowel by a fibrous cocoon. Anorexia, nausea, vomiting, and weight loss are common but nonspecific. Tests for anemia, albumin and high C-reactive protein levels have been suggested as adjunct tests. AR-Ca125 and AR- IL 6. Changes in peritoneal membrane transport characteristics with an increase in peritoneal membrane small solute transport and a fall in ultrafiltration characteristic are frequently associated with a subsequent diagnosis of EPS, but not in all cases

6 In study of EPS, 78% of patients had high or high-average transport as demonstrated on a standard PET and 22% had low- average transport. It has been suggested that the differences in peritoneal transport characteristics reflect the stage of disease, with early disease being reflected in hyperpermeability and late disease in loss of both small solute transport and ultrafiltration. Campbell S et al., Am J Kidney Dis 1994; 24:819–25. Peritoneal Transport Parameters in EPS

7 DE Sampimon et al., Adv Perit Dial, 2007; Vol. 23:107 Time Course of Peritoneal Transport Parameters in PD Patients Who Develop Peritoneal Sclerosis

8 A smaller peritoneal vascular surface area leads to less-rapid dissipation of glucose as the osmotic agent, which was indeed shown by decreased glucose absorption 1 year before the PS diagnosis. That situation would result in higher FWT and net UF. The opposite case suggests a specific impairment of peritoneal water transport. Whether that impairment is attributable to aquaporin-1 dysfunction or to more diffuse alterations in the peritoneal interstitial tissues. Time Course of Peritoneal Transport Parameters in PD Patients Who Develop Peritoneal Sclerosis DE Sampimon et al., Adv Perit Dial, 2007; Vol. 23:107 Two recently developed tests (Mini-PET, Double Mini-PET) are promising tools for evaluating the FWT and the osmotic conductance to glucose in patients with peritoneal sclerosis. La Milia V, G Ital Nefrol Nov-Dec;24(6):510-25

9 Diagnosis of EPS Clinical signs and symptoms Laboratory tests Effluent markers Peritoneal permeability Radiological findings Biopsy Laparoscopy The diagnosis of EPS is made on the basis of abdominal symptoms related to encapsulation of bowel by a fibrous cocoon. Anorexia, nausea, vomiting, and weight loss are common but nonspecific. Tests for anemia, albumin and high C-reactive protein levels have been suggested as adjunct tests. AR-Ca125 and AR- IL 6. Changes in peritoneal membrane transport characteristics with an increase in peritoneal membrane small solute transport and a fall in ultrafiltration characteristic are frequently associated with a subsequent diagnosis of EPS, but not in all cases Plain abdominal film, Contrast studies, Ultrasound, CTscan, 18 F- fluorodeoxyglucose PET

10 Test Findings Plain abdominal film Dilated small bowel loops Air fluid levels Peritoneal calcifications Contrast studies Bowel motility disturbances Separated rigid dilated bowel loops Varying degrees of obstruction accompanied by hypermotility Ultrasound Dilated fixed loops matted together and tethered posteriorly Intraperitoneal echogenic strands Echogenic bowel membrane with a trilaminar “sandwich appearance” around the bowel Computed tomography Radiologic Findings in EPS

11 CT scan scoring parameters Tarzi RM et al., Clin J Am Soc Nephrol, 2008; 3: 1702–1710

12 CT scan scores for EPS pts, HD and PD controls **P 0.01, ***P , Fisher’s exact test Tarzi RM et al., Clin J Am Soc Nephrol, 2008; 3: 1702–1710 The median total score for the EPS patients was 9 (range 2 – 16); for PD controls it was 1 (0 – 3) and for hemodialysis controls

13 Total CT scan scores at diagnosis in EPS patients Tarzi RM et al., Clin J Am Soc Nephrol, 2008; 3: 1702–1710 CT scan scores and prognostic indices The total CT scan score at the time of diagnosis of EPS did not correlate with the clinical outcome (death, peritoneolysis surgery, or prolonged TPN). outcome

14 Peritoneal calcification Peritoneal thickening Bowel wall thickening Bowel tethering Loculation Bowel dilatation Peritoneal calcification Peritoneal thickening Bowel wall thickening ( large and small ) Bowel tethering Loculation Bowel dilatation Peritoneal enhancement CT Scan parameters “Vlijm” study “Tarzi” study Tarzi RM et al., Clin J Am Soc Nephrol, 2008; 3: 1702–1710Vlijm A et al., Perit Dial Int 2009; 29:517–22

15 EPS pts (n.15) Controls (n.16) CT findings in EPS pts and controls *p <0.05, **p <0.01, ***p < CT scans were blindly and independently reviewed by 3 radiologists

16 CT scans can be used to reliably make the diagnosis of EPS. Peritoneal enhancement is very specific to EPS; therefore, CT with contrast enhancement should be preferred. Finding a single EPS-diagnostic feature on a CT scan, therefore, does not make a diagnosis of EPS and clinical features need to be considered. In patients with a confirmed diagnosis of EPS, there is no relationship between severity of changes on the CT scan and subsequent outcome. There is also no relationship between changes in subsequent CT scan and clinical status. This would suggest that there is little benefit in regularly repeating the scan once the diagnosis is made. CT Scan and EPS

17 CT scan in EPS Peritoneal thickeningLoculation Bowel tethering Bowel tethering and dilatation

18 CT scan in EPS “cocoon” and peritoneal enhancement “cocoon” Bowel wall thickening Peritoneal calcification

19 Diagnosis of EPS Clinical signs and symptoms Laboratory tests Effluent markers Peritoneal permeability Radiological findings Biopsy Laparoscopy The diagnosis of EPS is made on the basis of abdominal symptoms related to encapsulation of bowel by a fibrous cocoon. Anorexia, nausea, vomiting, and weight loss are common but nonspecific. Tests for anemia, albumin and high C-reactive protein levels have been suggested as adjunct tests. AR-Ca125 and AR- IL 6. Changes in peritoneal membrane transport characteristics with an increase in peritoneal membrane small solute transport and a fall in ultrafiltration characteristic are frequently associated with a subsequent diagnosis of EPS, but not in all cases Removing the catheter or conditions not PD related (kidney transplant or abdominal surgery) Plain abdominal film, Contrast studies, Ultrasound, CTscan, 18 F- fluorodeoxyglucose PET To exclude acute pathological states or obtain a biopsy specimen of the peritoneum.

20 “Tanned’’ and thickened parietal peritoneum with adhesions and area of calcification (see arrows). When you have a high index of suspicion of ESP with a low threshold for diagnostic, laparoscopy can be an effective strategy for establishing an early diagnosis and the treatment schedule. Furthermore, laparoscopy can be repeated to manage the duration of therapy and limit the extensive exposure to immunosuppressive therapy Laparoscopy and ESP

21 Adapted from AI Chin et al., Am J of Kidney Dis, 2006; Vol 47, No 4 (April): Simple Peritoneal Sclerosis Preserve Observe PATHOGENESIS AND MANAGEMENT OF PERITONEAL SCLEROSIS AND EPS Inflammation/Fibrosis (Pre-emptive Tx) Corticosteroids Tamoxifen +/-

22 In a prospective cohort, 15 of 42 cases (35.7%) treated with prednisolone alone, experienced clinical improvement. Therapeutic Methods and Outcomes: corticosteroids Kawanishi H et al., Am J Kidney Dis 2004; 44:729–37. Corticosteroids appears effective only in the early disease stage after EPS onset

23 Tamoxifen is a SERM, a selective estrogen receptor modulator, and as such is a nonsteroidal estrogen antagonist in many tissues. Tamoxifen has also been used for fibrosing syndromes such as retroperitoneal fibrosis, fibrosing mediastinitis, idiopathic sclerosing cervicitis and rapidly growing desmoid tumors. Tamoxifen and EPS

24 TGF  1 production Metalloproteinase Degrade type IV collagen Tamoxifene Mechanism of action of Tamoxifen 1 2 The accumulation of AGEs is known to enhance the surface expression of RAGE. The ligand engagement of RAGE induces up-regulation of TGF-  and myofibroblast transdifferentiation of mesothelial cells (epithelial-to- mesenchymal transition, EMT) A more likely explanation of tamoxifen’s effect on EPS is down- regulation of TGF-  with subsequent inhibition of fibroblast TGF-  1 production.*, **, *** **A De Vriese et al., NDT 2006; 21: *** WG Payne et al., Ann Plast Surg 2006; 56:301-5 *S Guest, Perit Dial Inter, 2009 Vol. 29, pp. 252–255 However, significant recent work in animal models repeatedly demonstrated that overexpressed TGF-b1 production leads to peritoneal thickening and fibrosis.

25 Del Peso G et al., Adv Perit Dial, 2003; Vol. 19:32-35 Tamoxifen and EPS: mortality Mortality rate % p<0,03 Follow-up 47.4±58 29±20 months 71% 22% 23/450 pts (5,1%) with sclerosing peritonitis P=0,03 74,4% 45,8% 63 pts with severe EPS Survival in tamoxifen treated patients, correcting for calendar time, age, use of corticosteroids, was higher in comparison to not treated patients (HR 0.39) Betjes MGH et al., J Am Soc Nephrol 2009; (Nov) 20: 457A

26 Treatment regimes used in Pan-Thames EPS Study G Balasubramaniam et al., NDT, 2009; 24(10): Transplanted 111 cases of EPS identified from 11 units

27 G Balasubramaniam et al., NDT, 2009; 24(10): Kaplan–Maier survival curve in Pan-Thames EPS Study Overall outcome Survival with various treatments No Rx Imm Tam Imm and Tam (include steroids) Overall, 53% patients died and the median survival was 14 months. 111 cases of EPS identified from 11 units

28 Tamoxifen treated patients had a significantly lower mortality. The results support the use of tamoxifen to treat patients with severe EPS. Betjes MGH et al., J Am Soc Nephrol 2009; (Nov) 20:457A The efficacy of tamoxifen in acutely ill patients with EPS complements its possible prophylactic use in patients with the earlier and milder disease, sclerosing peritonitis. Eltoum MA et al., Perit Dial Int 2006; 26:203–206 Del Peso G et al., Adv Perit Dial, 2003; Vol. 19:32-35 Tamoxifen should be administered at a daily dose of 10 mg-40 mg for 6-12 months. Tamoxifen can be safely given to HIV patients with peritoneal dialysis-related EPS. Nevertheless, caution is required as tamoxifen could interact with certain antiretroviral agents. Mesquita M et al., Clin Drug Investig. 2007;27(10):727-9 Tamoxifen: home message Tamoxifen reduces antithrombin III, protein C and S levels, and therefore it may actually be detrimental—leading to the formation of small vessel thrombi, and ultimately to calciphylaxis.Treatment should be withheld in any patient with deficiency of protein C or in patients with another known hypercoaguable state, such as activated protein C resistance due to factor V Leiden—a common genetic defect in many white European families. Korzets A et al., NDT, 2006; 21: 2975–2978

29 Adapted from AI Chin et al., Am J of Kidney Dis, 2006; Vol 47, No 4 (April): Preserve Observe Corticosteroids Tamoxifen +/- Azathioprine or Cyclophosphamide +/- Cessation of PD PATHOGENESIS AND MANAGEMENT OF PERITONEAL SCLEROSIS AND EPS Inflammation/Fibrosis + CT scan Dx Simple Peritoneal Sclerosis

30 Each patient needs to be considered individually, taking into account the following factors: 1. Age and prognosis of patient; 2. Length of time on PD, especially total glucose load and history of peritoneal infections; 3. Access to and suitability for transplantation; 4. Potential risk of HD in this particular patient (hemodynamic stability, vascular access); and 5. Quality of life of the patient. All these items should be discussed and any decision should be agreed to by the patient. Recommendation for ISPD Brown EA et al., Perit Dial Int 2009; 29:595–600

31 Withdrawal permits regression of peritoneal fibrosis only in its early stages. If the peritoneal catheter is removed, the situation of a “dry” peritoneum may lead to new fibrin deposition and accelerate the sclerosing process. Because of majority of patients (58%-68%) developed EPS after discontinuation of PD, preservation of the peritoneal catheter and periodic irrigation of the peritoneal cavity for 6 – 12 months after cessation of PD therapy has been advocated to prevent intestinal adhesions. It is hypothesized that the constant flushing away by PD of the proinflammatory cytokines and coagulation and fibrinolysis factors actually retards the development of EPS. Preservation of the peritoneal catheter and periodic irrigation of cavity

32 It has been suggested that immunosuppression is more likely to be beneficial if administered early in the ‘‘inflammatory’’ stage of the disease. The basis for this observation remains unknown, but it is postulated that cytokines implicated in the genesis of peritoneal sclerosis may be down-regulated by immunosuppression. Specific treatment regimens may include steroids plus an additional agent such as cyclophosphamide or azathioprine. Immunosuppression

33 Therapeutic strategies of EPS Prednisolone 0.5 mg/kg per day Cyclophosphamide 1 mg/kg per day +/- 1 month 4-6 months Prednisolone 5-10 mg per day +/- Azathioprine 1 mg/kg per day Tamoxifen mg per day +/- Tamoxifen mg per day +/- Prednisolone 1 mg/kg per day* Everolimus 1.5 mg per day Tamoxifen 10 mg per day month 4-6 months Everolimus 1.5 mg per day Tamoxifen 10 mg per day + Prednisolone 0.3 mg/kg per day + *Frascà GM et al., Abstracts Book XIV Convegno DP, 2008

34 Corticosteroids +/- Tamoxifen +/- Cessation of PD Adapted from AI Chin et al., Am J of Kidney Dis, 2006; Vol 47, No 4 (April): Simple Peritoneal Sclerosis Irrigation Azathioprine or Cyclophosphamide Ileus Bowel obstruction TPN Surgery +/- PATHOGENESIS AND MANAGEMENT OF PERITONEAL SCLEROSIS AND EPS

35 Treatment of EPS and Its Outcome Adapted from AI Chin et al., Am J of Kidney Dis, 2006; Vol 47, No 4 (April): When intestinal obstruction sets in, total parenteral nutrition should be considered early. If obstructive symptoms persist, total intestinal enterolysis may be necessary. This should be performed by a surgeon with expertise in this procedure, as it carries a high mortality rate, justified only by the high mortality rate of progressive EPS, unresponsive to more conservative treatment.

36 Surgery of EPS

37 Corticosteroids +/- Tamoxifen +/- Cessation of PD Adapted from AI Chin et al., Am J of Kidney Dis, 2006; Vol 47, No 4 (April): Simple Peritoneal Sclerosis Irrigation Azathioprine or Cyclophosphamide Ileus Bowel obstruction TPN Surgery +/- Tx Immunosuppression PATHOGENESIS AND MANAGEMENT OF PERITONEAL SCLEROSIS AND EPS

38 Mechanism of actionEffects References Corticosteroids Inhibitor of cell mediated immunity (IL2), humoral immunity and leucocyte inflammatory events Anti-inflammatory and immunosuppressive effectKuriyama S et al., Nephrol Dial Transplant 2001; 16: 1304–1305 Azathioprine DNA synthesis inhibitorImmunosuppression suppresses the uncontrolled fibroneogenesis and the inflammatory infiltrate of the peritoneal membrane Wong CF et al., Perit Dial Int 2005; 25: 285–94. Cyclosporin calcineurin inhibitors (CNI)profibrotic effects on peritoneumBozkurt D et al., Perit Dial Int 2009; 29(S2):S206–S210 Cyclosporin calcineurin inhibitors (CNI)induces peritoneal fibrosis and angiogenesis during chronic peritoneal exposure to a glucose-based, lactate- buffered dialysis solution in the rat van Westrhenen R et al., Blood Purif 2007; 25:466–72. Tacrolimus calcineurin inhibitors (CNI)profibrotic propertiesKhanna A et al., Kidney Int 2002; 62:2257–63. Rapamycin or sirolimus mTOR inhibitorregulate the epithelial-to-mesenchymal transition of mesothelial cells.(EMT) Aguilera A et al., Int J Artif Organs 2005; 28: Rapamycin or sirolimus mTOR inhibitorineffective as a treatment for acute ESPRajani R et al., NDT, 2002; 17: 2280 Everolimus mTOR inhibitorinhibit growth factor–stimulated proliferation in vascular smooth muscle cells, in liver fibrosis,and in pulmonary fibrosis by inhibiting mesenchymal cell proliferation Duman S et al., Adv Perit Dial; 2008; Vol. 24:105 Immunosuppression and EPS

39 G Balasubramaniam et al., NDT, 2009; 24(10): HD (n.33) Transplant (n.22) PD (n.7) EPS and Kidney Trasplant in Pan-Thames EPS Study Patients who are transplanted, both before and after the diagnosis of EPS, have the best survival. A strong positive selection bias would favour better survival in this group, but it is useful to highlight that EPS should not preclude patients from transplantation, and all patients should be optimized to receive a transplant as this provides the best survival outcome. Mean survival Pts transplanted (n.14) prior to a diagnosis of EPS 14 months (range 2–101) Pts transplanted (n.8) after diagnosis of EPS 34.5months (range 9–108)

40

41

42 High-risk patients, reported in literature, include patients on PD for more than 8 years, with high peritoneal transport, and a history of multiple peritonitis episodes. For such patients, elective transfer to HD can be considered, but the pros and cons of conversion to HD, including the possibility of accelerated EPS development, should be discussed with the patients. Pre-Emptive Cessation of PD Korte MR et al., Nephrol Dial Transplant 2007; 22:2412–14. Lo WK and Kawanishi H, Perit Dial Int 2009; 29(S2):S211–S214

43 Tamoxifen reduces antithrombin III, protein C and S levels, physiological anticoagulants, and stimulates the release of von Willebrand factor. More recently, tamoxifen has been shown to directly increase calcium entry into platelets, leading to platelet activation. This may suggest that EPS patients treated with tamoxifen may benefit from concurrent antiplatelet therapy to reduce the risk of clot formation. The limited side-effect profile of tamoxifen, with no inherent immunosuppression activity, suggests that this agent can be used in immunocompromised patients and in those with chronic or acute infections such as HIV, hepatitis C, and recent peritonitis Tamoxifen and EPS

44 Clinical Experience with Tamoxifen Therapy for EPS S Guest, Perit Dial Int, 2009; Vol. 29, pp. 252–255

45 Tamoxifen is a SERM, a selective estrogen receptor modulator, and as such is a nonsteroidal estrogen antagonist in many tissues. Tamoxifen has also been used for fibrosing syndromes such as retroperitoneal fibrosis, fibrosing mediastinitis, idiopathic sclerosing cervicitis and rapidly growing desmoid tumors. Mechanism of action was to enhance TGF-  1 production, which stimulates metalloproteinase 2-9, to degrade type IV collagen. However, significant recent work in animal models repeatedly demonstrated that overexpressed TGF-  1 production leads to peritoneal thickening and fibrosis. Tamoxifen and EPS

46 Therapeutic Interventions in Animal Models of EPS Sun-Hee Park et al., Perit Dial Int 2008; 28(S5):S21–S28


Download ppt "CORSO INTERATTIVO: LA PERITONITE SCLEROSANTE DIAGNOSI E TERAPIA Roberto Corciulo Divisione di Nefrologia e Dialisi Azienda Ospedaliero Policlinico Università."

Similar presentations


Ads by Google