Conflict of interests: Josette M Eris is on the Transplant Advisory Board of Novartis, Jansen Cilag and has received research grants from Novartis, Roche and Pfizer.
A role for everolimus in post-transplant encapsulating peritoneal sclerosis: First case report
Version of Record online: 14 MAR 2014
© 2014 Asian Pacific Society of Nephrology
Special Issue: Renal Transplant Case Series 2013. Guest Editor: Peter Kerr. Publication of this supplement has been supported through an independent educational grant from Novartis Australia
Volume 19, Issue Supplement S1, pages 27–30, April 2014
How to Cite
Sud, R., Garry, L., Spicer, S. T., Allen, R. D., Eris, J. M., Wyburn, K., Verran, D., Cooper, C. L. and Chadban, S. (2014), A role for everolimus in post-transplant encapsulating peritoneal sclerosis: First case report. Nephrology, 19: 27–30. doi: 10.1111/nep.12196
- Issue online: 14 MAR 2014
- Version of Record online: 14 MAR 2014
- Accepted manuscript online: 27 JAN 2014 05:57AM EST
- Manuscript Accepted: 18 DEC 2013
- encapsulating peritoneal sclerosis;
- renal transplantation;
- total parenteral nutrition
Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis (PD) that carries a high morbidity and mortality. The ‘two hit theory’ suggests that long term deterioration of the peritoneum combined with intraperitoneal inflammation is needed in the pathogenesis of EPS. For unclear reasons, post transplantation EPS is being increasingly reported in patients previously on PD. To date, there is no proven effective therapy with an absence of randomised controlled trials. Individual case reports and small case series have reported on the use of tamoxifen and corticosteroids for medical management of EPS. The use of everolimus has been reported in a single case, and never in the setting of renal transplantation. Here, we present the first case of post-transplant encapsulating peritoneal sclerosis treated successfully with a combination of everolimus, tamoxifen, low dose corticosteroid and surgery.
A 37-year-old man of Vietnamese background presented to our hospital in March 2009 for deceased donor renal transplantation.
End-stage renal failure was secondary to hepatitis C-related mesangioproliferative glomerulonephritis with cryoglobulinaemia. He had been on automated peritoneal dialysis for over 6 years with a combination of dextrose based peritoneal dialysis solutions. There had been no previous episodes of peritoneal dialysis-related peritonitis. A preceding peritoneal equilibration test showed that he was a high average transporter. In the year prior to transplant he had lost all residual renal function, and had signs of peritoneal membrane failure. At the time of being called for transplantation, he was hypertensive to 250/110 mmHg and was fluid overloaded in excess of 5 L, as a consequence of gradual ultrafiltration failure. Biochemically he was under-dialysed with a urea of 28 mmol/L and creatinine 1180 μmol/L. Hypertension had been complicated by severe left ventricular hypertrophy, diastolic dysfunction and moderate pulmonary hypertension. Other comorbidities were renal osteodystrophy and renal anaemia. Previous liver biopsies and his hepatitis C viral loads by polymerase chain reaction suggested that this disease was quiescent with no evidence of cirrhosis.
The donor was a 46-year-old, brain dead man. There was a 5/6 HLA mismatch with a cold ischemic time of 15.5 hours. Serology showed cytomegalovirus donor and recipient positivity. Transplantation was planned with ‘standard’ induction therapy including basiliximab, methylprednisone, tacrolimus and mycophenolate mofetil. Standard prophylactic agents including valganciclovir, trimethoprim/sulfamethoxazole, pantoprazole and nystatin were also commenced. Hypertension was aggressively managed prior to transplant.
The transplant surgery was complicated by donor kidney core biopsy-related haematuria and subscapular bleeding with blood pressure instability. Because of the likelihood of need for dialysis after transplant surgery, the surgeon opted to leave the Tenckoff catheter in situ. Dialysis was not required. However, residual peritoneal fluid became infected with methicillin-resistant Staphylococcus aureus (MRSA). The infected Tenckoff catheter was removed 9 days after transplantation, and a 2 week course of intravenous vancomycin for MRSA peritonitis was completed. Immunosuppression was also switched from Mycophenolate to azathioprine in view of severe diarrhoea, and valganciclovir and bactrim were stopped secondary to leucopenia. Despite the intra- and postoperative complications, there was immediate and good graft function, with a discharge creatinine on day 25 of 75 μmol/L.
On week 7 after transplantation, a computed tomography (CT) scan with contrast was performed to investigate new onset abdominal cramps and diarrhoea. This showed a large perigraft collection with large volume ascites, peritoneal enhancement, and thickened small bowel loops. Percutaneous drainage of the collection and ascites revealed frank pus that cultured positive for MRSA. Abdominal drains were left on free drainage and antibiotics recommenced for MRSA peritonitis, but as a result of ongoing abdominal cramps and diarrhoea the patient returned to theatres for a laparotomy and abdominal washout. This showed that the intra-abdominal space and small bowel were covered with pus and loculations. There were organising fibrin bands throughout the small bowel. An extensive division of adhesions was performed, and a peritoneal biopsy obtained. Histopathology revealed an extensively denuded surface mesothelium, with submesothelial interstitial fibrosis and vascular sclerosis consistent with chronic damage to the peritoneum (Fig. 1).
The acute peritoneal infection was treated with a prolonged treatment course of intraperitoneal and intravenous daptomycin. Despite successful treatment, ongoing abdominal pain and postprandial fullness and bloating persisted. For this, recurrent hospital admissions were arranged during the first nine months post transplant. The patient's appetite was significantly reduced with frequent episodes of vomiting following meals. Malnutrition was a major problem, with the weight declining from 50 to 39 kg. Serum albumin dropped to 30 g/L. Total parenteral nutrition was started on multiple occasions during hospital admissions. Large volumes of a sterile dark blood stained ascitic effluent were repeatedly drained. CT imaging showed pronounced thickening and enhancement of the peritoneal lining with loculated fluid collections (Fig. 4). The proximal small bowel and duodenum were dilated. A provisional diagnosis of encapsulating peritoneal sclerosis was made. Tamoxifen 20 mg BD was commenced as treatment. One month later, due to a lack of response, Tacrolimus and Azathioprine were switched to everolimus.
Endoscopy had also been arranged to investigate ongoing symptoms. It showed a florid gastritis with mucosal oedema narrowing the pylorus. Histopathology of a gastric biopsy confirmed cytomegalovirus (CMV) inclusions. This was treated with a course of intravenous ganciclovir. A small bowel series was performed as symptoms of postprandial fullness and vomiting had continued despite treatment of CMV. This showed almost complete intestinal obstruction at the duodenojejunal flexure, thought to be secondary to encapsulating sclerosing peritonitis. Despite multiple attempts, a nasojejunal feeding tube was unable to be advanced to the jejunum to allow oral feeding.
A laparotomy was performed. This showed that the small bowel was cocooned in the centre of the abdominal cavity by a thick fibrous layer (Fig. 2). This layer extended over the parietal and visceral peritoneum, which was chronically thickened and discoloured, causing obstruction of the duodenojejunal flexure. An extensive division and removal of the sclerotic tissue was performed. A peritoneal biopsy once again showed an extensively denuded surface mesothelium. This was now associated with fibrin deposition, and a mononuclear cell infiltrate (Fig. 3).
Following surgery there was a rapid improvement in the patients' condition. He was able to tolerate an oral intake 3 days after the surgery. Over the next 24 months, medical therapy continued. The patient continued to improve with gradual weight gain to 55 kg, and improving nutritional status. Appetite improved, with complete resolution of postprandial vomiting, abdominal fullness and bloating. Abdominal pain subsided and diarrhoea resolved. Serum albumin returned to normal values, 40 g/L. He had three episodes of subacute small bowel obstruction that responded to conservative measures. He has not required further surgery for intestinal obstruction and CT imaging has shows that peritoneal thickness remains stable with no fluid collections (Fig. 4). We postulate, that the lack of further peritoneal thickening and encapsulation over the last 24 months reflects a positive therapeutic response to ongoing medical therapy with everolimus, tamoxifen and low dose corticosteroids. Graft function remains stable with a creatinine of 90 μmol/L. He has developed moderate proteinuria, 700 mg/day, since commencing everolimus, though this has remained stable with time.
EPS is a rare, but devastating complication of PD therapy. It is characterised by marked sclerotic thickening of the peritoneal membrane that causes bowel loops to become adherent and encapsulated resulting in intermittent bowel obstruction. The clinical presentation is with ultrafiltration failure and altered gastrointestinal transit in a patient who has been on peritoneal dialysis for many years. Symptoms of altered gastrointestinal transit include abdominal fullness, bloating, anorexia, nausea and vomiting initially, and complete intestinal obstruction in the most severe stage. It is commonly associated with malnutrition as a result of reduced oral intake, and a recurrent bloody effluent that collects in pockets created within the peritoneal cavity.
The aetiology of EPS is unclear. Traditional risk factors include increased risk proportional to duration of PD, recent cessation of PD, use of dialysis solutions with lower biocompatibility and peritonitis episodes. The ‘two hit theory’ suggests that long term deterioration of the peritoneum combined with intraperitoneal inflammation is needed in the pathogenesis of EPS. This case is consistent with that theory.
Long term PD induced peritoneal damage is an inevitable consequence of the use of dialysis solutions that are inherently bio-incompatible. This damage to the membrane is histologically seen as mesothelial denudation, submesothelial interstitial fibrosis and vascular sclerosis. The vascular changes result in chronic plasma exudation from the peritoneal vasculature to the peritoneal surface and eventual fibrin deposition. The deposition and organisation of fibrin results in formation of a peritoneal capsule, and combined with peritoneal fibroblast activation and proliferation, they are major features in the pathogenesis of EPS. Honda et al. have proposed that the presence of fibrin deposition, fibroblast swelling, capillary angiogenesis and a mononuclear cell infiltrate on peritoneal biopsy be required for a histological diagnosis of EPS.
Recent studies have reported an increase in the incidence of EPS following renal transplantation. One proposed factor is that following transplantation, fibrin can accumulate on a reactive peritoneum as PD fluid-related peritoneal lavage has stopped. The universal use of calcineurin inhibitors (CNI) in immunosuppression protocols is another proposed explanation, as CNI may propagate pro-fibrotic processes that are important in the pathogenesis of EPS.
To our knowledge, this is the first case report of post-transplantation EPS that has been treated with everolimus. One previous case report suggested favourable use of everolimus for a non transplant, peritoneal dialysis patient who developed EPS. Everolimus, in addition to its immunosuppressive effects through mammalian target of rapamycin (mTOR) inhibition, has well known antiproliferative properties for which it has been used therapeutically. In rat models, it has been shown to have beneficial effects on reducing peritoneal fibrosis.
In this case a combination of treatment modalities, including everolimus, tamoxifen, corticosteroids, stopping CNI, intermittent total parenteral nutrition and surgery, were utilised to result in a successful outcome for the patient. Surgery was essential in gaining immediate control over life threatening symptoms. However, it is not possible to determine which of these treatments has had the greatest benefit, as no uniformly successful therapy for EPS exists at present. Tamoxifen is the most studied medical treatment, but to our knowledge, its use has only been reported in small case series of non-transplant patients, and only in case studies of EPS post renal transplantation. Surgical treatments for EPS are reported in larger case series, but recurrence rates are high. The immunosuppressive and antiproliferative properties of everolimus give it a theoretical role for use in the disease. With no effective management for EPS, prospective randomised controlled trials of this rare disease are required. To further investigate the role for everolimus in EPS, one approach would be to randomise patients at high risk of EPS post renal transplantation to standard CNI based immunosuppression versus switch to an everolimus based maintenance immunosuppression.
- 2Pathology of encapsulating peritoneal sclerosis. Perit. Dial. Int. 2005; 25 (Suppl 4): S19–S29., .