Complications of Peritoneal Dialysis Part II: Nonmechanical Complications

Nonmechanical, noninfectious complications of peritoneal dialysis (PD) can be categorized into abnormal-appearing dialysate, encapsulating peritoneal sclerosis (EPS) or metabolic complications. While an abnormal-appearing dialysate alarms patients, it is important to recognize that aside from peritonitis, most etiologies are not related to PD; the PD catheter serves as a window into the peritoneal space. Nonetheless, it is important to rule out significant underlying disease. EPS is a rare but devastating complication, with high morbidity and mortality. As the disease is most treatable when detected early, we review early signs and symptoms as well as treatment options. Finally, PD may cause or exacerbate metabolic derangements such as hyponatremia, hypokalemia, hyperglycemia, and hyperlipidemia. Abnormal-Appearing Dialysate Hemoperitoneum As little as 2 ml of blood per liter of dialysate is sufficient to cause hemoperitoneum, a bloody-appearing dialysate, as shown in Figure 1. The reported incidence varies from 3.8% to as much as 17% in a center with a significant proportion of reproductive age women., PD is not the direct cause of hemoperitoneum aside from catheter-related bleeding or EPS, which will be discussed in its own section. Instead, hemoperitoneum that would be undetected in the general population is more frequently reported in PD patients because blood in the abdomen can be easily visualized in the drained dialysate. Standard medical treatment depends on the cause, but generally includes utilization of rapid exchanges, room temperature dialysate, and heparinized dialysate with 500 units of heparin per liter of dialysate to prevent coagulation of the blood in the lumen of the catheter. Early hemoperitoneum is commonly related to PD catheter insertion, in a population with dysfunctional platelets due to uremia. One case series revealed that 5.9% of patients suffer from bleeding on laparoscopic PD catheter insertion. If surgical revision is not required, it is recommended to provide low-volume flushes until the drained dialysate is clear. Lower volumes can be used for recently implanted catheters to reduce the likelihood of a leak. Blood inside the abdominal cavity can clot the PD catheter or result in abdominal adhesions if the abdomen is kept dry. The most common cause of hemoperitoneum is retrograde menstruation, and it is often recurrent. Other causes among women of child-bearing age include endometriosis, ovulation, ovarian cyst rupture, and ectopic pregnancy., A compatible history, reassuring clinical examination, in conjunction with rapidly self-resolving hemoperitoneum are consistent with retrograde menstruation or ovulation-related hemoperitoneum. However, diagnostic imaging, laparoscopy, or laparotomy may be indicated in cases of persistent bleeding or in the unstable patient. Women of menstrual age should be educated and reassured about the possibility of hemoperitoneum associated with menstruation or ovulation. For patients with recurrent hemoperitoneum due to menstruation or ovulation, an estrogen-containing oral contraceptive may be helpful as a preventive measure, although not necessarily indicated. Bleeding from intra-abdominal solid organs may be also result in hemoperitoneum. Liver and kidney cysts can rupture and cause hemoperitoneum, especially in patients with autosomal dominant polycystic kidney disease. Procedures and treatments, including fine needle aspiration, radiation therapy, and colonoscopy, have been reported to cause hemoperitoneum. Malignancy is an infrequent but significant cause of hemoperitoneum. With respect to solid organ malignancies, both hepatic tumors and gastrointestinal stromal tumors have been implicated. Hematological malignancies affecting the spleen may also result in hemoperitoneum. Diagnostic imaging, with or without contrast, may be required to determine the source of bleeding. While standard medical treatment may be sufficient for minor and self-limited hemoperitoneum, an unstable patient may require interventional radiology or surgical treatment. Chyloperitoneum Chyloperitoneum presents as milky-white dialysate as seen in Figure 2, and the measured triglyceride level exceeds 110 mg/dl (1.24 mM). Chyloperitoneum occurs when there is a disruption to the lymphatic drainage system, whereby lymph contacts the dialysate. Lymph is a vehicle to transport lipids, often from the small bowel to the systemic circulation. The principal component is chylomicrons, formed from dietary long-chain fatty acids, and thus, the chyloperitoneum may wax and wane depending on the fat content of food. Certain medications such as calcium channel blockers can cause reversible chyloperitoneum through unknown mechanisms. The diagnosis is confirmed with resolution of chyloperitoneum after discontinuing the medication. A recent history of trauma, abdominal surgery, or thoracic surgery can also disrupt the lymphatic system. Owing to the anatomy of the lymphatics, increased venous pressure secondary to constrictive pericarditis, congestive heart failure, and superior vena cava syndrome can also result in chyloperitoneum. Lymphoma or other solid organ tumors that disrupt the lymphatic system should be ruled out in cases of chyloperitoneum. Tuberculous peritonitis has been reported to present as chyloperitoneum, although in combination with other peritonitis symptoms., The preferred treatment is to treat the underlying etiology, if possible. Temporary PD cessation can lead to spontaneous cure in some cases, especially with recent trauma or procedures. However, if a primary etiology is unknown or untreatable, dietary changes should be implemented to limit formation and loss of chylomicrons in the dialysate. A high protein, low fat diet is preferred. An exception is medium-chain triglycerides because they are directly absorbed by the small bowel, bypassing the lymphatic system. In refractory cases despite PD rest and dietary changes, total parental nutrition is an effective alternative. Somatostatin analogs have been successfully used in conjunction with dietary changes and temporary PD cessation. Noninfectious Causes of a Cloudy Dialysate The most common cause of cloudy dialysate is PD peritonitis. However, there are instances where a noninfectious etiology is responsible for cloudy dialysate, especially in the absence of abdominal pain. We present an approach on the basis of the distribution of differential cell types in the dialysate specimen. In cases where lymphocyte and eosinophil counts are elevated, especially if concurrently neutrophil comprise <50% of all cells, noninfectious causes must be considered; when neutrophils make up more than 50% of cell counts, noninfectious causes are considered when an infectious etiology is not found, or the clinical course is atypical for bacterial peritonitis. Eosinophilic Dialysate The definition of an eosinophilic dialysate can be variable; however, several sources have used >10% eosinophilic predominance or >100 eosinophils/mm3 as a threshold., As a result, the dialysate may be also neutrophil predominant, and infectious peritonitis must first be ruled out. Eosinophilic dialysate can be classified as early or late. Early presentations that occur within weeks after PD initiation are believed to be related to an allergic response to either air introduced at the time of catheter insertion or chemicals found in the dialysate, dialysate bag, or tubing. A prospective study in 2007 showed that 6.3% of patients starting continuous ambulatory PD demonstrated eosinophilic dialysate within the first 30 days of dialysis initiation. All cases spontaneously resolved within the same study period without any treatment. Noninfectious causes of late-presenting eosinophilic dialysate have been reported as an allergic reaction to intraperitoneal antibiotics, such as vancomycin or cephalosporins., Successful treatment options include withdrawal of the inciting drug or in combination with a brief course of corticosteroids administered systemically or locally in the peritoneum. Lymphocyte-Predominant Dialysate A lymphocyte-predominant dialysate is not well defined in the literature because it is a rare phenomenon. The most common etiology of lymphocytic-predominant dialysate is various types of lymphoma, where lymphocytes make up 79%–99% of all cells analyzed. Indeed, cytologic analysis performed on cloudy dialysate has been used to diagnose lymphoma. Drug reaction was found to be responsible for a dialysate specimen with 91% lymphocytes because the patient responded to hydralazine withdrawal after failed antibiotic treatment. Contrary to expectations, mycobacterium peritonitis is usually neutrophil-predominant, although the ratio of neutrophils to lymphocytes tends to be lower than the ratio with typical bacterial peritonitis. Neutrophil-Predominant Dialysate The default diagnosis for a patient with a neutrophil-predominant dialysate with abdominal pain is PD peritonitis. However, if the etiology is noninfectious, it will be treated as culture-negative peritonitis unless there is heightened vigilance. Noninfectious etiologies respond poorly to antibiotics, and PD catheters have been removed for “refractory peritonitis.” In addition to an abrupt and avoidable modality change, there may be resultant treatment delay for the underlying intraabdominal pathology. Inflammation of intraperitoneal organs may result in a neutrophil-predominant dialysate. Abdominal pain may also be present, although pain may be localized to the inflamed organ or a specific region, unlike diffuse abdominal pain encountered in PD peritonitis. In the literature, cholecystitis, appendicitis, and bowel ischemia have all been reported. With a cloudy neutrophil-predominant dialysate, these processes are typically transmural because cloudy dialysate suggest visceral peritoneum involvement. Feculent dialysate suggests viscus perforation. Inflammation from retroperitoneal organs may also result in a neutrophil-predominant dialysate. Examples include pancreatitis as well as splenic abscess and infarction., Solid organ malignancies including renal cell carcinoma and endometrial cancer have been reported to present initially with a neutrophil predominant dialysate. In these cases, imaging is recommended if clinical assessment including the physical examination suggests an intra-abdominal pathology. Table 1 summarizes common and rare etiologies of abnormal-appearing dialysate with respect to the clinical presentation. Table 1 Summary of abnormal-appearing dialysate | Dialysate Appearance | Common | Rare | |---|---|---| | Hemoperitoneum | PD catheter insertion Retrograde menstruation or peritoneal endometriosis Ovulation After intra-abdominal procedures | Ectopic pregnancy Malignancy Cyst rupture from autosomal dominant polycystic kidney disease | | Chyloperitoneum | Medication related Postoperative lymphatic disruption • Thoracic surgery • Abdominal surgery | Lymphoma Impaired lymphatic drainage • Constrictive pericarditis • Congestive heart failure • SVC syndrome | | Noninfectious cloudy dialysate | Intra-abdominal process • Inflammation • Infection • Bowel ischemia Local allergic reaction • Initial contact with air, dialysate, or PD catheter • Intra-abdominal medications | Solid organ malignancy Lymphoma Systemic medication allergy | Encapsulating Peritoneal Sclerosis (EPS) EPS is a rare but devastating complication of PD. Its prevalence ranges from 0.7 to 13.6 per 1000 patient-years. Frequently, the diagnosis is not made until later stages of the disease, where a fibrous membrane, described as a cocoon, encases the small bowel and results in bowel obstruction. As a result, early diagnosis and treatment is paramount. Pathophysiology and Presentation The precise pathophysiology remains unknown. Review of histopathology suggests two concurrent processes of fibrosis and inflammation, leading to its variable clinical presentation. Time on PD is the major risk factor. Other suggested risk factors include use of hypertonic dialysate, peritonitis episodes, bioincompatible dialysate, and calcineurin inhibitors. The early phase of EPS is termed the inflammatory phase. At this stage, the symptoms are nonspecific and may include nausea and abdominal discomfort. Subtle signs include unexplained hemoperitoneum or recurrent culture-negative peritonitis, often without typical pain of peritonitis. For patients who are no longer on PD, EPS may present as unexplained ascites. The second phase of the disease is termed the sclerosing phase, although both likely occur concurrently. As a fibrotic membrane forms around the bowel, normal peristalsis is impaired, and constipation or frank recurrent bowel obstruction may occur. When these symptoms are present, computed tomography (CT) imaging often shows widespread peritoneal calcification, bowel tethering, loculation, and bowel obstruction, as seen in Figures 3 and 4. While individual findings are not diagnostic, a scoring system has been proposed to use CT as an adjunct in confirming the diagnosis. However, EPS remains a clinical diagnosis, and CT imaging is not definitive. An atypical form of EPS has been reported, where fibrosis and sclerosis occur at single or multiple points along the small bowel, with transition points on CT. Treatment and Prevention The limited treatment options in EPS are often on the basis of the observational and retrospective studies. Immunosuppressive agents have had variable success in EPS treatment because they may attenuate the underlying inflammatory process. While corticosteroids are first line, azathioprine and mycophenolate have also had limited success., A recent review of corticosteroid dosing and duration in EPS showed considerable heterogeneity, although most studies reported benefit compared with placebo. At our center, we use low-dose prednisone at 20–30 mg daily. We evaluate symptoms at the 1-month mark to determine whether ongoing treatment is warranted. If so, we undertake a very slow taper on the basis of clinical response. In parallel, tamoxifen and mammalian target of rapamycin inhibitors have been proposed as effective agents to target the fibrotic and sclerosing pathway., In a retrospective review, tamoxifen dosed at 10–20 mg/d for at least 4 weeks was associated with improved survival. With respect to sirolimus use, they are most frequently used in post-transplant patients who present with EPS and replace the calcineurin inhibitor; Frascà et al. describe a case where everolimus was used with effect in EPS with a target level of <4 ng/L. Nutritional support is highly recommended as adjunctive therapy, as oral intake is often reduced. A last resort is surgical enterolysis or surgical removal of the fibrotic membrane encasing the small bowel. In an experienced center in Japan, the median survival after enterolysis for EPS was 85 months; however, surgical expertise is scarce given the rarity of the disease. Many centers elect to stop PD in cases of EPS, although there are little data to support this practice. After transitioning to hemodialysis, several centers have reported leaving the PD catheter in situ and performing intermittent PD flushes. It is postulated that inflammatory debris and fibrin are cleared from the abdomen with intermittent flushes., While time on PD is a consistent risk factor for PD, it must be emphasized that it is a rare phenomenon, even among patients who have been on PD for more than 5 years. Furthermore, some cases of EPS are reported to occur after switching to hemodialysis or after kidney transplantation., As such, a personalized decision should be made with regard to switching to hemodialysis to prevent EPS, given the paucity of definitive evidence. Metabolic Complications of PD Hyponatremia The incidence of hyponatremia in PD ranges from 6% to 29%. Hyponatremia has been associated with worse cognitive function, malnutrition, and higher rates of peritonitis and all-cause mortality among PD patients in retrospective observational studies. Similar to evaluating patients with normal kidney function, hyperosmotic and isoosmotic hyponatremia need to be ruled out. Poor diabetes control can lead to hyperglycemia and consequent hypertonic hyponatremia. Icodextrin is metabolized to maltose-based polysaccharides that are absorbed from the peritoneum and can be measured in the serum. With once daily use, the fall in serum sodium from icodextrin is not expected to exceed 3 mM; however, when used twice daily, more significant hyponatremia has been reported., For PD patients with significant urine output and residual kidney function, etiologies such as medication-related and syndrome of inappropriate antidiuretic hormone should be considered; for PD patients presenting with hypo-osmotic hyponatremia without residual kidney function, it is helpful to assess the patient's weight. In patients who have weight gain, hyponatremia may be due to excessive free water intake or failure to remove free water through PD. In patients who have apparent weight loss, hyponatremia may be a result of net loss of total body sodium or potassium., This is especially true for PD patients admitted to the hospital, where decreased oral intake, ongoing sodium and potassium losses, and potential hypotonic fluid administration all exacerbate hyponatremia. We have adapted an algorithm by Musso and Bargman in Figure 5 as an algorithmic approach to PD patients with hyponatremia. Treatment is focused on reversing the underlying cause of hyponatremia. For patients with increased total body water and acute hyponatremia, rapid exchanges with high-concentration dextrose solutions may achieve greater free water removal because of sodium sieving. We recommend free water restriction in this specific context because liberal free water intake may maintain hyponatremia despite sodium sieving. It must be emphasized that the negative outcomes of hyponatremia in PD patients are likely a result of the same comorbidities that lead to the hyponatremia, not the hyponatremia itself. Hypokalemia Hypokalemia was found to be associated with higher peritonitis rates and higher mortality rates from the most recent PD Outcomes and Practice Patterns Study. Risk factors for hypokalemia include poor nutrition, coexisting comorbidities, and use of proton pump inhibitors., Patients starting PD with residual renal function have the highest risk of hypokalemia and may warrant more frequent monitoring. Oral supplementation, in conjunction with potassium sparing diuretics, has proven to be an effective therapy. A randomized controlled trial demonstrated lower peritonitis risk among patients treated with preemptive oral supplementation to target potassium of 4–5 mM, when compared with a reactive approach when potassium drops below 3.5 mM. Cardiovascular mortality and all-cause mortality were not significantly different, although the intervention period was only 52 weeks. Hyperglycemia The absorption of glucose from dextrose-based PD solutions is estimated to be 50–150 g/d, depending on the regimen of PD solutions used and membrane transport characteristics. Glucose absorption has clinical implications on both the diagnosis of new-onset diabetes and the management of pre-existing diabetes. The diagnosis of new-onset diabetes is challenging in PD patients. Fasting glucose levels in PD patients can be unreliable because of the near-constant and unpredictable glucose uptake from the dialysate. Serum hemoglobin A1c levels may also be unreliable in PD patients because of reduced hemoglobin, insufficient clearance, and reduced red blood cell lifespan., Within the confines of these limitations, the prevalence of new-onset diabetes among patients who initiate PD is reported to be 4%–8%. In hemodialysis patients who do not have the same glucose load, the prevalence of new-onset diabetes is reported to be similar, although one study from Taiwan showed an adjusted hazard ratio of 1.61 for PD patients.,, As a result, glucose loading from PD may not independently explain the higher rate of new-onset diabetes compared with the general population. Risk factors for new-onset diabetes include older age, higher body mass index, and higher C-reactive protein values. New-onset diabetes is associated with worse cardiovascular and overall mortality outcomes in retrospective studies. In 2020, the prevalence of diabetes among all incident dialysis patients was 60% in the United States. However, there is limited literature on hyperglycemia treatment in PD patients. The use of dextrose-based solutions may cause serum glucose to rise apart from meals, necessitating a change in the diabetes treatment regimen. However, insulin requirements are reduced in some patients because insulin resistance is ameliorated with PD initiation., We note that continuous glucose measurement devices are presently not approved for dialysis patients. In addition, the use of icodextrin may interfere with certain incompatible glucose measurement or continuous glucose monitoring devices where the metabolites will be misread as glucose. Treatment of a falsely elevated glucose reading can lead to hypoglycemia. Hyperlipidemia Hyperlipidemia has been associated with increased risk of cardiovascular disease, the leading cause of death among PD patients. Similar to patients with CKD, PD patients have abnormal lipid metabolism. Apo-B–associated lipoproteins levels are elevated secondary to reduced metabolism while Apo-A–associated lipoprotein levels fall compared with the general population. These changes result in elevated LDL, triglycerides, and reduced HDL. The degree of hyperlipidemia in PD patients exceeds that in hemodialysis patients. One proposed explanation is that the continuous glucose loading provides a substrate for increased endogenous lipid synthesis. A prospective trial demonstrated that a PD regimen with icodextrin and amino acid–based dialysate in place of a dextrose-only regimen improved lipid profile at 3 and 6 months. Another suggested cause is the loss of albumin in dialysate stimulating abnormal lipid synthesis in a mechanism similar to nephrotic syndrome. Clinical trials with amino acid–based dialysate have shown mixed results with respect to plasma lipid levels. The Improved Metabolic Control of Physioneal, Extraneal and Nutrineal (IMPENDA) and Evaluation of Dianeal, Extraneal and Nutrineal in diabetic PD patients (EDEN) studies demonstrated that PD prescriptions containing amino acid–based dialysate and icodextrin achieved lower serum lipid levels when compared with dextrose-only PD prescriptions. However, the amino acids and icodextrin group also demonstrated higher mortality from congestive heart failure. Aside from lifestyle changes and reducing glucose exposure through alternative dialysate, pharmacotherapy is also available to reduce plasma LDL. Statins and ezetimibe have proven efficacy in hyperlipidemia in PD patients., Sevelamer, an oral phosphate binder, is also proven to improve lipid profiles. Despite numerous studies demonstrating increased cardiovascular-related mortality associated with hyperlipidemia in PD patients, there is little evidence to support pharmacological treatment. The German Diabetes and Dialysis Study (4D) study, which was a randomized controlled trial with diabetic hemodialysis patients with a median follow-up period of 4 years, did not demonstrate any benefit on cardiovascular death, nonfatal myocardial infarction, and stroke.

Nonmechanical PD complications can arise as a result of the interactions between the patient and the infused dialysate. Transmembrane diffusion of dextrose can result in unwanted metabolic derangements of hyperglycemia, hyponatremia, and hyperlipidemia. In addition, drained dialysate provides a window into the abdominal cavity and allows non–kidney-related diseases to be diagnosed from hemoperitoneum or chyloperitoneum. Similarly, it is important to be mindful of noninfectious causes of cloudy dialysate, especially when the clinical course is atypical for culture-negative peritonitis. EPS is postulated to be a result of long-term dialysate exposure and must be recognized early to avoid devastating outcomes. Disclosures J. Bargman reports consultancy for Bayer, DaVita Healthcare Partners, GlaxoSmithKline, and Otsuka; honoraria from Baxter Healthcare, DaVita Healthcare Partners, and GlaxoSmithKline; advisory or leadership role as an Associate Editor for JASN; role on the Editorial Boards of CJASN and Nephrology, Peritoneal Dialysis International; and speakers bureau for Baxter Canada, Baxter Global, DaVita Healthcare Partners, and GlaxoSmithKline. The remaining author has nothing to disclose. Funding None. Acknowledgments This article is part of the Home Dialysis – Fundamentals and Beyond series led by Yeoungjee Cho and Matthew B. Rivara. Author Contributions Conceptualization: Joanne Bargman. Supervision: Joanne Bargman. Writing – original draft: Xin Bo Justin Cheng. Writing – review & editing: Joanne Bargman, Xin Bo Justin Cheng.

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