Introduction

Hemoperitoneum is one of the non infective complication of peritoneal dialysis (PD) and is a benign complication in most cases. The most common cause of bloody peritoneal effluent is related to the menstrual cycle, but hemoperitoneum was the main presenting clinical findings of a sclerosing peritonitis. [1] (full text) [2]. We report a case of hemoperitoneum occurring in a patient after the dropout from PD to hemodialysis.

Case report

The patient was a 55 years old woman with end-stage renal disease due to IgA nephropathy ( kidney biopsy in 1987). In January 2003 she begins continuous ambulatory peritoneal dialysis after self-positioning catheter implantation. The treatment was 4 exchanges of 2 liters 1.36% glucose-containing solutions. At the beginning of the PD, peritoneal equilibration test (PET) resulted in a medium-high peritoneal transport with a D/P creatinine at 4 hours of 0.68. In January 2007 the patient show a reduction of urine output (450 ml/24h) with uncontrolled hypertension and edema as well as hyperglycemia. Therefore she begins automated PD with 10 liters of 2,27% glucose-containing solution and 5 liters at 1.36%, with filling volume of 2000 ml for 13 cycles of 24 minutes. At the same time she had two episodes of exit-site infection by Pseudomonas Aeruginosa. Given the persistence of the edematous state, and a further diuresis contraction, in December 2007 the patient change the dialysis schedule, starting CCPD-1 with 15 liters of 2.27% glucose-containing solution for 8 cycles of 37 minutes length and filling volume of 1800 ml, using wet-day technique with 1500 ml icodextrin. The following PET shows that the peritoneal membrane (PM) transport characteristics remained medium-high with a D/P creatinine at 4 hours of 0.73. In July 2008 the patient was hospitalized for an acute pancreatitis, PD was continued. Up to January 2010 she continued CCPD-1 using dialysis solutions by 2.27% and 3.86% glucose and icodextrin during daytime. In June 2010 a new PET evidenced ultrafiltration (UF) failure and characterized by a high transport. In September 2010 arteriovenous fistula was prepared. C-reactive protein (CRP) levels was very high (182 mg/l). In October 2010 she was hospitalized for a culture-negative peritonitis, so in February 2011 began regular hemodialysis treatment (Figura 2). In March 2011 the peritoneal catheter was removed since there is no fibrin in the peritoneal lavage nor there being ascites. Simultaneously biopsy of the PM was performed with evidence of wide fibro-jalyn foci. In July 2011 the patient was hospitalized for abdominal pain, fatigue, nausea and vomiting. Abdominal ultrasound (US) detects a loculated ascitis and tickening of the PM layer confirmed by a computed tomography (CT) scan which also showed posterior dislocation of intestinal loops without signs of occlusion. (Figura 1) Evacuative paracentesis was performed by a gravity drainage for about 5 liters of bloody ascitis: fluid culture and citology was negative, CA 125 levels was decreased. In 2011 September a new CT scan shows the reappearance of ascitis thus therapy with prednisone 25 mg daily and tamoxifen 20 mg daily was started; azathioprine 50 mg daily is added in October. In March 2012 she was hospitalized for a new episode of abdominal pain, evacuative paracentesis showed a dark-bloody ascitis. Currently the patient has moderate abdominal distension with moderate residual ascitis; CRP values was 1.8 mg/l in december 2011 and 1.6 mg/l in july 2012. No more gastrointestinal signs and fatigue are present actually.

Discussion

As described in this case-report, in patients undergoing PD, the occurrence of hemoperitoneum with clinical and radiological signs above mentioned, without other demonstrated abdominal pathology, may be very suggestive of encapsulating peritoneal sclerosis (EPS). EPS is a rare but serious complication of PD that can leads high mortality, and could represent the most advanced stage of PM sclerosis and a series of inflammatory changes of the PM. The annual incidence of EPS increases with lenght of PD: it is rare in patients on PD for less than 2 years. In the australian experience Rigby reported an increased prevalence from 1.9% for patients on PD > 2 years to 10.8 and 19.4 % in patients on PD for greater than 6 and 8 years respectively [3] (full text). Whereas in the japanese multicenter study [4] the incidence (and mortality rate) of EPS was 0% in patients who had undergone PD for 3 years up to 5.9% (28.6%) for 10 years and 17.2% (100%) more than 15 years. But lower incidence was found in an, more recent, Australian and New Zealand survey: 0.3 %, 0.8 % and 3.9 % at 3,5 and 8 years [5]. Though EPS may occur on PD, most patients became symptomatic after cessation of PD [3] (full text) [4] [5]. The time on PD might be only a risk factor in the development of EPS so a “second hit” must occur e.g. an inflammatory stimulus, discontinuation of PD or genetic predisposition [6] [7]. Recurrent episodes of peritonitis, with special reference to Staphylococcus aureus and Pseudomonas aeruginosa, combined with the length of PD, are considered the most common causes of EPS [3] (full text) [9] (full text). Other important factors for PM sclerosis are the bioincompatibility of dialysis solutions, the prolonged contact of the PM with the glucose degradation products of and advanced glycation end products (GDPs, AGEs), and the dialysis bags plasticizers [9] (full text) [12] (full text). The diagnosis is mainly based on clinical suspicion and radiologic findings as described below [3] (full text). There are several aspects in our case that are suggestive for EPS. First, the PD duration (8 years) with PM exposure to glucose solutions. Bioincompatibility of this solutions induce a chronic sterile inflammation of the peritoneal cavity as reported by Cnossen [8] (full text). Rigby reported that dextrose itself is toxic due to passive glycosylation of the submesothelial tissue when the mesothelium is breached due to injury. [3] (full text) Moreover, glucose per se induces mesothelial cells to secrete Fibroblast Growth Factor and may have a role in PM fibrosis [15], [16] (full text). The dialysate bio-incompatibility is also characterized by PM exposure to GDPs and AGEs (formed through heat sterilization products, their level rise with ageing of the dialysate and is accelerated by storage at high temperature) [3] (full text). Furthermore hypertonicity and acidity of the PD solutions as well as plasticisers in the dialysate [3] (full text) are the main stimulating factors promoting UF loss, PM fibrosis and sclerosis. This is confirmed by Cnossen who found that long-term contact of the peritoneal cavity to non-physiological dialysis fluids promotes AGE accumulation in the peritoneum [8] (full text). This may favor the expression of growth factors such as TGF-β1, macrophage colony stimulating factor, interleukin-1β and VEGF stimulating transformation of mesothelial cells to myofibroblasts and initiating peritoneal fibrosis. [8] (full text) [9] (full text)

Second, the increased permeability of the PM, with the UF loss and PM thickening are typical signs of EPS [4]. Initially, the UF decrease seems to be linked both to the raising permeability to small molecules (which leads the osmotic gradient dissipation - type I UF deficit) and increased peritoneal lymphatic reabsorption due to expanded vascular surface area as a consequence of increased neoangiogenesis. Later, severe PM fibrosis, especially in EPS, subverts the peritoneal hydrodynamic and leads to Type II UF deficiency (low permeability) [8] (full text). Moreover we found a decreased CA 125 levels in dyalisate. This may be due to loss of mesothelial cells and may be an alarming sign for the development of EPS when suddenly decrease. At last, elevated plasma levels of CRP, although not specific for EPS, have been suggested as indicative sign [21]. However there is not yet a good marker able to allow an early diagnosis [8] (full text). Third, the history of exit-site infection by Pseudomonas Aeruginosa and a culture-negative peritonitis before PD discontinuation may represent additional aspects promoting the EPS. Rigby show that the peritonitis appears critical in the development of EPS because there is a loss of the mesothelium with subserosal stroma exposure to high concentrations of glucose and consequent thickening and reduplication of basement membranes and changes in the collagen and matrix secondary to passive glycosylation. These changes are also compatible with chronic exposure to bacterial toxins derived from catheter biofilm [3] (full text) [9] (full text). Staphilococcus Aureus, Pseudomonas Aeruginosa and Fungi may be more likely to lead an early onset of EPS [3] (full text). Finally in our case the evidence of wide fibrojalyn foci at the biopsy of the peritoneum is in agreement with literature regarding the peritoneum signs of the EPS patients. In effect with damage of the PM there is decreased fibrinolysis; a fibrin mantle forms that is progressively organized, resulting in a sheath of new fibrous tissue. PD acts to remove the fibrin and inflammatory mediators, so cessation of dialysis may promote fibrin accretion and has been implicated in the progression of EPS [3] (full text), [4]. Fibrin deposition and fibroblast swelling are the parameters that exhibited statistically significant differences [22]. However histological findings are only one diagnostic pillar of EPS [6]. The clinical manifestations are various, often non specific, related to gastrointestinal disturbance and include abdominal pain, nausea, vomiting, anorexia, weight loss, malnutrition, abdominal fulness, impaired UF, bloody dialysate (or ascitis when PD was discontinued) [1] (full text) [3] (full text). In this case report the initial clinical manifestations are: diffuse abdominal pain, vomiting and bloody ascitis just after the peritoneal catheter removal. The latter is the most frequently reported [2] but is not a rule. In the australian’s experience haemoperitoneum was 7% only, over 90 % had small-bowel obstruction [3] (full text), nevertheless absent in our case were there was a sub-ileus and so it was not necessary to start parenteral nutrition for bowel rest (historically part of EPS treatment). Radiological evaluation that include US and CT scan was compatible with EPS: US detect abnormalities of the small intestine peristalsis, clustered bowel loops with adhesions to the posterior abdominal wall, echogenic areas between bowel loops, membrane formation in front of the small intestine, loculated ascitis, and thickening of the PM as well as the intestinal wall as reported in the literature [23] [24]. CT scan confirm the PM thickening and loculated ascites without signs of occlusion (Figura 1). More broadly, as reported in the literature, peritoneal calcifications are most evident in patients on PD for the longest time and and that have the small intestine distension related to adhesions of bowel loops with “cocoon”; that are particularly involved in patients with advanced stages of EPS. Signs of obstruction and PM enhancement with contrast-enhanced CT may be present. PM enhancement might be due to an increased vascular peritoneal surface area. [23] [25]. Although frequently unsuccessful the EPS treatment includes steroid therapy, immunosuppression and surgery through peritonectomy and enterolysis. Latus reports that the time of first clinical symptoms consistent with EPS to requirement of surgery is very short [6]. In contrast Nakamoto reserve surgery if conservative therapy does not improve the symptoms of EPS [1] (full text) [2]. Elevated CRP levels could be correlated with requirement for surgery in patients whit EPS [6]. The earlier stages of disease respond better to conservative treatment because early stage of inflammation [2]. In literature better results are reported with tamoxifen and some immunosuppressive drugs, including steroids [27] (full text) [28] (full text), but mostly are case reports. Improvement or resolution of EPS symptoms was observed with addition of azathioprine or cyclosporin, after renal transplantation [1] (full text) [29]. In contrast Fieren recently suggested that kidney transplantation as another possible risk factor for development of EPS [30] (full text). Despite the disappointing results reported in the literature our patient responded well to conservative treatment with tamoxifen, corticosteroids and azathioprine. The effectiveness of therapy is based on clinical examination, CRP dosing and ultrasound monitoring of ascitis, as described. Surgery has not been considered.

Conclusions

This case describes one of the most important complication of PD: the EPS. Clinical aspects suggestive for EPS are: long-term PD, increased permeability of the PM, bloody ascitis, history of exit-site infection by Pseudomanas Aeruginosa and culture-negative peritonitis preceding the PD discontinuation. Other signs are loculated ascitis and bundling of bowel loops with adhesions to the posterior abdominal wall with thickening of PM layers detected by US and CT scan. The patient responded well to conservative treatment with tamoxifen, corticosteroids and azathioprine as instead described in the earlier stages of the disease. Surgery has not been considered. Because of the current progress in diagnostic technology and therapeutic methodology of EPS, it appears that PD can be continued successfully, with an acceptable low risk for EPS,  for about 6 - 8 years. Stricter caution is required for patients receiving PD for longer periods.