Concurrent development of encapsulating peritoneal sclerosis and calciphylaxis in a patient with peritoneal dialysis for end-stage renal disease

Abstract

Both encapsulating peritoneal sclerosis (EPS) and calciphylaxis are rare but severe complications involving patients with end-stage renal disease. In this report, we discuss a unique case of a 73-year-old female patient who had undergone 8 years of peritoneal dialysis for IgA nephropathy and concurrently developed these two synchronous complications within 3 months of each other. Diagnosis and management of both conditions were discussed in detail as well as the possible association between the two. With surgical treatment for EPS and measures to minimise bone mineral disorder abnormalities, both complications have been successfully managed to date.

Background

Encapsulating peritoneal sclerosis (EPS) is a rare but unfortunately devastating complication of renal replacement therapy, and in some cases non-dialysis-requiring chronic kidney disease.¹ The overall prevalence of EPS varies from 0.4% to 8.9% in peritoneal dialysis (PD) patients, and a longer duration on PD increases the risk of this complication.² The risk factors for EPS include female gender, diabetes mellitus, repeated peritonitis and dependence on dialysis for more than 2 years.³ EPS is characterised by progressive and excessive fibrotic thickening of the peritoneum, leading to encapsulation or cocooning of the bowels, which can lead to intestinal obstruction.⁴ EPS may occur and progress even after the discontinuation of PD and is associated with high mortality rate of around 50% usually within 12 months from the time of diagnosis.^{5 6} Management includes cessation of PD, tamoxifen and surgical intervention in later stages.¹

Calciphylaxis is also a rare but severe vascular complication in patients with end-stage renal disease (ESRD).⁷ Its exact epidemiology remains unknown, but the annual incidence rate in haemodialysis patients is reported to be 0.04% in Germany and 0.35% in the USA.^8–10 However, specific calciphylaxis incidence in other renal replacement therapies including PD is not reported.¹¹ Also known as calcific uraemic arteriopathy, calciphylaxis is characterised by painful skin lesions caused by cutaneous arteriolar calcification, leading to tissue ischaemia and infarction.¹² Pain from local tissue necrosis and sepsis as a consequence of secondary infection are causes of increased morbidity and mortality in patients developing this complication.¹³ Once calciphylaxis has been diagnosed, the prognosis is generally poor (survival <1 year).³

With both EPS and calciphylaxis being uncommon conditions, there are few reports in the literature about synchronous development of these complications. In this report, we will discuss a unique case of concurrent EPS and calciphylaxis in a patient who had recently changed modality from peritoneal dialysis of.

Case presentation

A 73-year-old woman with underlying IgA nephropathy diagnosed in 1996 commenced PD in 2009 after gradual progression. In terms of her medical history, she had suffered a pulmonary embolism in 2009, with a history of hypertension since 1996. Five years after commencing PD, the patient underwent a coronary artery bypass graft in 2014 following a non-ST elevation myocardial infarction, and the year after revascularisation she suffered a posterior circulation transient ischaemic attack with a concurrent diagnosis of new-onset atrial fibrillation for which she commenced warfarin in 2015. The patient had undergone counselling regarding the risks of EPS in March 2015 and electively changed modality to haemodialysis in March 2016. In March 2017, she was admitted with progressive weight loss, chronic diarrhoea, nausea and failing nutrition. CT imaging of her abdomen revealed changes consistent with EPS described elsewhere in this report. The patient was referred for further assessment for consideration of a peritonectomy with adhesiolysis. At the same admission, prior to consideration for peritoneal surgery, the patient experienced bilateral indurated skin lesions on both lower limbs and was referred to dermatology for further assessment. A skin biopsy had to be delayed initially due to an elevated international normalised ratio (INR) and was subsequently undertaken in the recovery phase after her peritoneal surgery, and this confirmed calciphylaxis. The patient made an uneventful surgical recovery.,

Investigations

In March 2017, at initial assessment for weight loss and failing nutrition, despite erythropoietin supplementation, the patient was found to be progressively anaemic with a haemoglobin of 74 g/L, with raised inflammatory markers (C reactive protein 238 mg/L, leucocytosis 15.2×10⁹/L). Erythrocyte sedimentation rate was noted to be in excess of 100 mm/hour.

CT imaging of the chest, abdomen and pelvis during the above assessment showed progressive small bowel wall calcification throughout the peritoneum with an increase in peritoneal fluid and peritoneal enhancement (figures 1–3). This allowed the diagnosis of EPS to be made. In retrospect, CT colonography conducted 4 months prior to this presentation was felt to have evidence of possible early small bowel calcification (figure 4).

Figure 1.

Portal venous phase CT scan (axial image of the abdomen) shows small bowel wall calcification (arrowheads).

Figure 2.

Portal venous phase CT scan (sagittal image of the chest, abdomen and pelvis) shows small bowel wall calcification (arrowheads), peritoneal enhancement (arrow), and intraperitoneal free fluid (F) and urinary bladder (b).

Figure 3.

Portal venous phase CT scan (coronal image of the chest, abdomen and pelvis) shows small bowel wall calcification (arrowheads), peritoneal enhancement (arrow) and intraperitoneal free fluid (F).

Figure 4.

CT colonography showing very early small bowel wall calcification (arrowheads).

Secondary hyperparathyroidism has been managed since the early phases of chronic kidney disease (CKD), but acceleration in markers of bone mineral disease was noted during her time on dialysis (figure 5).

Figure 5.

Graph showing moderate hyperphosphataemia and secondary hyperparathyroidism.

Skin biopsies identified small vessel proliferation and foci of calcification in the subcutis, and the calcification was associated with the wall of intermediate-sized vessels in the venous plexus, consistent with calciphylaxis (figures 6–7).

Figure 6.

H&E section shows the skin with subcutaneous fatty tissue. In the subcutis there is calcium deposition on the walls of small and intermediate-sized blood vessels. These blood vessels show fibrosis of the intima and complete occlusion of the lumina. The features are in keeping with calciphylaxis.

Figure 7.

H&E section shows fibrosis of the intima and complete occlusion of the lumina of the blood vessels (arrows).

Differential diagnosis

EPS is diagnosed as a combination of clinical symptoms and imaging findings.¹⁴ The symptoms may manifest as nausea, vomiting, weight loss, anorexia, changes in bowel habit and abdominal pain. None of these symptoms is specific to EPS. Therefore, CT is the method of choice in diagnosing EPS by demonstrating peritoneal and bowel wall thickening and calcification.¹⁴ Previous studies demonstrated that there are significant abnormalities detectable on CT scans at the time of the diagnosis of EPS, such as peritoneal calcification and thickening, bowel wall thickening, bowel tethering, dilation, and fluid loculation.^{14 15} These characteristics can be reliably scored; however, the total CT scan score does not show a correlation with the clinical outcomes, making the score unsuited for predicting clinical course.^{14 15}

Indurated rashes appeared on both lower limbs during the admission. Calciphylaxis is typically found in patients with ESRD who have severe hyperparathyroidism and is consistent with the clinical history.^{12 16} The cardinal features of calciphylaxis include cutaneous purplish lesions, such as plaques and patches, which progress to extensive tissue damage and necrosis.^{12 16} However, such presentation can simulate polyarteritis nodosa, systemic lupus erythematosus and coumadin necrosis, also known as warfarin skin necrosis (WSN). WSN and calciphylaxis share common clinical features and warfarin treatment is a risk factor for calciphylaxis.¹⁷ The patient has been medicated with warfarin due to atrial fibrillation since 2015. Biopsy is a very helpful investigation method in understanding the histological features of the underlying disorder. WSN is usually associated with fibrinoid necrosis of the entire epidermal and dermal vessels,¹⁷ while calciphylaxis is associated with the presence of calcium deposits within small-sized and medium-sized vessels, as well as extravascular and subcutaneous calcifications, and is an important discriminator for this patient’s diagnosis.^{16 17} Our patient’s biopsy identified small vessel proliferation and foci of calcification in the subcutis; the calcification was associated with the wall of medium-sized vessels in the venous plexus, which is consistent with calciphylaxis.

Treatment

For ESRD secondary to IgA nephropathy, the patient was undergoing continuous ambulatory PD before a change in modality to haemodialysis. She was initially listed for deceased donor transplantation, but this was suspended in view of poor nutritional status and development of ascites. After 7 years of PD, haemodialysis was commenced due to membrane failure and counselling on the future risks of EPS. She developed evidence of EPS on CT (abdomen and pelvis) after cessation of PD and underwent peritonectomy. Incidentally, she again underwent laparotomy with adhesiolysis and defunctioning loop colostomy a year later for large bowel obstruction secondary to a non-malignant diverticular stricture.

Specialist dermatology input was sought for diagnosis and management of skin complications, which were proven to be due to calciphylaxis lesions on her lower legs and left breast. Warfarin for atrial fibrillation was switched to low molecular weight heparin in view of calciphylaxis. Calciphylaxis lesions may regress with supportive management, including pain control and wound care, management of bone mineral disease with consideration of parathyroidectomy or calcimimetics to control severe hyperparathyroidism, and ensuring optimal dialysis dosing. In this patient bone mineral indices were optimised, and her secondary hyperparathyroidism remained under control with the help of calcimimetics and non-calcium-based binders. Non-randomised evidence suggests that there may be a role for sodium thiosulfate, although the precise mechanism for this is unknown and recent randomised studies have not demonstrated benefit.

Outcome and follow-up

Following the institution of the above management measures, calciphylaxis lesions have regressed with no recurrence and there has been no clinical progression in EPS. She has a functioning colostomy following surgery for diverticular stricture. She remains on maintenance hospital haemodialysis in terms of modality for ongoing renal replacement therapy. Six months prior to this clinical report, she was switched from daily therapeutic subcutaneous low molecular weight heparin therapy to treatment with a novel oral anticoagulant, apixaban, with dose modification and therapeutic monitoring according to local anticoagulation protocols.

Discussion

A review of the literature reveals two reports of concurrent occurrence of EPS and calciphylaxis. In both these reports, the use of tamoxifen is thought to play a possible role due to the fact that tamoxifen used in EPS to inhibit fibroblast-transforming growth factor beta (TGF-β) may play a role in initiating calciphylaxis due to oestrogen-like effects on tissues and by virtue of increasing serum levels of factors VIII, IX and vWF (von Willebrand factor), predisposing to a prothrombotic state.¹⁸

EPS, on the whole, is a rare disease, and with factors such as increased awareness and early diagnosis, better surveillance, and earlier discontinuation of PD with increasing access to transplantation, projections in England are showing that case numbers will decrease in future years. There is a paucity of evidence with relation to medical or surgical treatments for EPS. Surgical expertise is usually centralised for this rare disease due to case load and centre experience. An example of this is the designation of national referral centres at Manchester and Cambridge for patients in England.¹⁹

Despite calciphylaxis not being overwhelmingly rare, there are no published guidelines on this condition. Global guidelines such as those published by Kidney Disease Improving Global Outcomes (KDIGO) and national guidelines such as those issued by the Renal Association do not refer to this extreme complication of renal bone mineral disease—possibly primarily due to a paucity of specific evidence with relation to effective interventions.²⁰ Small trials showing contrasting effects on coronary and aortic calcification and with no proven effect on mortality outcomes provide inconclusive evidence on the use of this agent.²¹

Calciphylaxis, typified by vascular calcification with the microvasculature, is thought to reflect disturbances between tissue factors, mitigating (eg, matrix Gla protein, fetuin and pyrophosphate, among others) and promoting (eg, elevated calcium phosphate product, osteocalcin, osteonectin) tissue calcification. EPS is said to occur in the context of peritoneal fibrosis complicated by additional inflammatory stimuli resulting in exposure to further proinflammatory (TGF-β1, interleukin 6, Cellular Communication Network Factor 2 (CCN2)) and proangiogenic (vascular endothelial growth factor) cytokines. Factors regulating tissue calcification such as matrix Gla protein are produced by macrophages as well as from other sources—this is one example of the potential overlap between pathways mediating tissue inflammation and calcification. Based on this, we speculate that overlap and cross talk between pathways and sites affected by uraemia, inflammation, calcification, fibrosis, coagulation pathways and the concurrent occurrence of EPS and calciphylaxis are not entirely unexpected.

The lack of similar reports in the literature suggests that there may be unique factors operative in our patient and the temporal relationship with warfarin may be the significant factor relevant here. Our report is therefore the first report of a concurrent diagnosis of EPS and calciphylaxis in a patient without exposure to tamoxifen. Due to these concerns and her cardiovascular history, we chose not to use tamoxifen or steroids in our patient following the diagnosis of EPS.

Learning points.

• Bowel obstruction in a patient with a history of peritoneal dialysis should prompt consideration of encapsulating peritoneal sclerosis in the differential, although this is a rare occurrence.

• Painful cutaneous nodules, indurated plaques and progression to ulceration in patients with end-stage renal failure may be due to calcific uraemic arteriopathy, otherwise known as calciphylaxis.

• Warfarin is a recognised risk factor for calciphylaxis.

• Both diagnoses are individually rare.

• This case report described concurrent occurrence of both in an individual patient, and both diagnoses may share common mediators and pathways that need further research.

Ethics statements

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