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Selection Committee Member for the Peritoneal Dialysis Region:

Thomas A. Golper MD

Dr. Golper is a Professor of Medicine at Vanderbilt where he directs the Home Dialysis Program. He serves on the KDOQI Peritoneal Adequacy Work Group, and the ISPD North American Chapter Research Consortium. Dr. Golper is Course Director for Home Dialysis University, and he established the ISPD Ad Hoc Advisory Committee on Peritonitis Management.

Competitors for the Peritoneal Dialysis Region

Volume Issues in PD vs Solute Issues in PD

Culture-Negative Peritonitis vs Catheter Dysfunction in PD

Volume Issues in PD

Volume assessment is difficult in peritoneal dialysis patients, and the clinical exam is insensitive. A number of newer techniques are available to help assess volume status. These include bioimpedance, extracellular water to total body water ratio (ECW/TBW ratio), and inferior vena cava (IVC) diameter.

Fluid overload in patients on peritoneal dialysis (PD) is associated with cardiovascular mortality, as well as uncontrolled hypertension, sleep apnea, increased duration of hospitalization, poor quality of life, technique failure, and peritonitis. Hypervolemia may also be an inflammatory stimulus, leading to hypoalbuminemia, wasting, and cardiovascular disease via malnutrition-inflammation-atherosclerosis (MIA) syndrome. Clearly, euvolemia is an important adequacy parameter in PD.

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Measuring volume status can be difficult, and the prevalence of fluid overload depends on the method used for volume assessment. The prevalence of volume overload in PD patients increased from 25% to over 66% when measured using bio-impedance spectroscopy as opposed to clinical judgment alone. In another study, nearly 36% of patients were volume overloaded in the absence of clinical signs or hypertension, and nearly half of asymptomatic PD patients had moderate to severe lung congestion by lung ultrasound.

Many factors contribute to volume overload in PD patients. In a small study, PD patients had higher mean thirst scores and higher fluid intake compared to their hemodialysis (HD) counterparts. Hyperglycemia may stimulate thirst and hypertonic peritoneal dialysis solutions can worsen this. Additionally, fast transporters quickly absorb glucose from the peritoneal cavity, thus diminishing the osmotic gradient needed for adequate ultrafiltration.

PD patients see their healthcare providers less frequently than HD patients, which may contribute to volume overload, although they certainly can be taught self-exam. The contribution of residual kidney function is unclear. Urine output was not associated with fluid status in a European cohort, but did have effects on fluid status in another US cohort.

Fig 1 summarizes the patient-related and PD-related factors influencing fluid status. Kim and Van Biesen, Semin Nephrol.

The type of dialysate, as well as the technique used, may influence volume status. A recent Cochrane review reported increased urine output and higher residual kidney function with use of neutral pH – low glucose degradation products (GDP) PD solution for more than 12 months. However, some studies found volume overload and lower ultrafiltration with low GDP solutions. For patients with reduced residual kidney function, a long day dwell with icodextrin solution can improve fluid status by increasing ultrafiltration. An observational study showed no difference between automated peritoneal dialysis (APD) and continuous ambulatory peritoneal dialysis (CAPD) for volume control and sodium removal. Some studies clearly show that shorter dwells and more frequent cycles on APD are associated with decreased sodium removal in patients with slower transport characteristics.

An essential step to achieve euvolemia in PD patients is to increase awareness of the risks of hypervolemia and acknowledge that clinical assessment may be insufficient to detect volume overload. Incorporating technology in the patient assessment may or may not facilitate volume control. Restriction of salt and fluid intake and use of diuretics can help avoid volume overload. It is important to ensure that the PD prescription reflects the peritoneal membrane characteristics of the patient. Use of short dwell nocturnal APD in fast transporters will aid volume control, while CAPD will work most effectively in slow transporters. Management of volume status is a critical aspect of PD therapy.

Solute Issues in PD

The peritoneal capillary membrane is the primary determinant of solute transport in the peritoneal cavity. Transport across the peritoneal membrane is explained by a three pore model:

1. Large pores: Few in number, they transport macromolecules.
2. Small pores: Numerous, they allow small solute and water transport.
3. Ultrasmall pores: They only allow water transport leading to sodium sieving.

Based on peritoneal membrane characteristics, PD patients are classified into different transporter status as below:

Twardowski ZJ, Blood Purif

Those patients with high transporter status benefit from shorter, more frequent dwells (ie APD) that maximize ultrafiltration. Low transporters do better with longer dwell times (ie CAPD) to maximize clearance.

The total solute clearance on PD includes the peritoneal clearance and renal clearance. Residual kidney function is predictive of survival. In patients with minimal residual renal function, a Kt/V urea of <1.6-1.7 is predictive of mortality. While residual kidney function has a powerful and consistent effect on patient survival, the survival effects of peritoneal clearance are less compelling. Because of these differing effects on survival, it is unscientific to add the peritoneal and renal clearance into a combined total clearance. However, this is often done, and the ISPD guidelines recommend a total Kt/V urea of ≥ 1.7.

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Various factors influence solute diffusion in PD. Reduced peritoneal surface area from prior episodes of peritonitis or adhesions from abdominal surgery reduce solute clearance. Peritoneal permeability increases during peritonitis due to greater perfusion of the peritoneal capillaries, leading to a transient high transporter state. Solute size influences diffusion. Middle molecule (between 0.5 and 60 kDaltons) removal is enhanced by extending the time of dialysis. Techniques with longer dwell time (ie CAPD) can achieve more adequate middle molecule clearance, while the frequent dwells associated with APD will not allow for increased middle molecule clearance. Transporter status also affects solute clearance, as does declining residual kidney function and increasing dwell volume. Use of Icodextrin in long day dwells increases both clearance and ultrafiltration.

In the early days of chronic dialysis therapy, it was noted that PD had a lower rate of small molecule clearance than hemodialysis, though patients fared equally well with either modality. PD was thought to compensate for less low molecular weight clearance with superior removal of middle molecules. However, the NCDS study showed that “hours of treatment time had no significant effects” (P =0.06 for shorter versus longer time on HD) and dismissed time on dialysis and associated middle molecule clearance as insignificant. It also declared urea clearance as an important predictor of hospitalization in HD patients. Gotch and Seargent converted the time-averaged concentration of BUN in NCDS to the dimensionless Kt/V urea. The PD community followed and applied urea kinetics to PD. Since then, multiple studies (including reanalysis of CANUSA and ADEMEX ) have shown no association between increasing small solute clearance and outcome.

NCDS study is a good example of how overemphasis on a p-value changed the way we approached the clearance issues with regards to dialysis. It is no wonder that Steven Goodman wrote:

“The p-value is probably the most ubiquitous and at the same time, misunderstood, misinterpreted, and occasionally miscalculated index in all of biomedical research.”

Solute removal is important. There is likely a Kt/V urea below which patients do poorly. However, in large randomized controlled trials, maximizing small molecule clearance does not provide measurable patient benefits. Could this be due to an overemphasis on small molecule clearance at the expense of middle molecule clearance? A nice commentary on this controversy, entitled “Mistakes We Make in Dialysis” in Seminars in Dialysis is provided by @JoanneBargman.

Culture-Negative Peritonitis

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Peritonitis is a serious complication of PD. It is a major cause of technique failure and mortality. Rates of PD peritonitis range from 0.06-1.66 episodes/patient in single-center studies, but reports tend to be higher in multi-center studies. Peritonitis remains a major reason that ESRD patients to switch to hemodialysis, and early diagnosis and treatment is essential to ensure successful management. Treatment is guided by the PD fluid culture report, and appropriate antibiotics can be used in culture positive patients. But what if cultures remain negative?  

While most cases of culture-negative peritonitis are due to infectious causes not detected by microbiology, non-infectious causes must also considered, particularly in the absence of an antibiotic response. Culture-negative peritonitis represents 12% to 40% of all peritonitis episodes. One of the largest observational cohort studies of peritonitis from ANZDATA reported a culture negative peritonitis rate of 12%.

ISPD defines culture-negative peritonitis as having the following characteristics:

• Clinical features of peritonitis (abdominal pain or cloudy dialysate)
• Dialysate leukocytosis (white blood cell count > 100/mL with > 50% neutrophils)
• Negative dialysate culture result

One of the most important causes of culture-negative peritonitis is suboptimal sample collection or culture method. A UK survey of culture-negative peritonitis found that most centers used sediment cultures, but only 9% (5/53) of centers routinely used large culture volumes of 50 mL effluent (despite ISPD guidelines recommending to do so).

Sampling by a non-specialist nurse and prior antibiotic use also led to higher rates of culture-negative peritonitis. Infection due to unusual organisms such as fungus, mycobacteria, legionella, Campylobacter species, Ureaplasma species, Mycoplasma, or enterovirus require special culture media and prolonged incubation periods and may also lead to culture-negative peritonitis.

Exposure to antibiotics prior to the cultures being obtained can also cause culture-negative peritonitis. Non-infectious causes of culture negative peritonitis include chemical peritonitis (eg due to icodextrin), collection from a “dry” abdomen, chylous ascites, effluent eosinophilia, hemoperitoneum and rarely malignancy.

ISPD recommends that the rates of culture-negative peritonitis be no more than 20% of episodes. Even rates of less than 10% can be achieved at centers of excellence by improving culture techniques. Bedside inoculation of 5 mL – 10 mL effluent in 2 (aerobic and anaerobic) blood-culture bottles can reduce the culture-negative rate to around 10% – 20%. Centrifugation (50 mL peritoneal effluent spun at 3000g for 15 minutes) followed by resuspension of the sediment in 3 mL – 5 mL of sterile saline, inoculation on solid culture media, and into a standard blood-culture medium reduces culture negative rates to less than 5%.

An optimal culture technique involves culturing 50 mL of effluent and inoculating 5 mL – 10 mL effluent in two blood culture bottles at the bedside. The specimens should arrive at the laboratory within 6 hours. If immediate delivery to the laboratory is not possible, the inoculated culture bottles should ideally be incubated at 37°C. Solid media should be incubated in aerobic, microaerophilic, and anaerobic environments.

Most culture-negative peritonitis is thought to be due to non-Staphylococcus aureus gram positive organisms, as they behave similar clinically. If cultures remain negative at 72 hours but the patient is clinically improving, it is recommended to stop gram negative coverage and continue gram positive coverage for a total of 14 days. If the patient fails to improve, special culture methods should be used to try to identify the organisms. If there is still no growth and patient continues to deteriorate, it is advisable to remove the PD catheter.

Treatment approach to culture negative peritonitis. Li et al, Perit Dial Int.

ANZDATA of an observational cohort of 435 cases reported that culture-negative peritonitis was a common complication with benign outcomes. As compared to culture-positive peritonitis, culture-negative peritonitis was associated with better antibiotic response and lower risks of hospitalization, catheter removal, transfer to hemodialysis, or death. Chen et al also reported a better rate of antibiotic response and a lower rate of relapse, catheter removal, and mortality in 202 episodes of culture-negative peritonitis in 902 patients over a 16-year period at a single center. However, this data was not compared to culture-positive patients in the same cohort.

Iranian CAPD registry data from 26 CAPD centers and approximately 1,500 patients revealed better patient survival and technique survival in culture-negative peritonitis patients compared to culture positive patients at 6 years:

Comparison of patient and technique survival in patients with culture-positive and culture-negative peritonitis. Najafi I et al, Iran J Kidney Dis.

In contrast to the above data, Szeto et al reported inferior outcomes of culture-negative peritonitis during a six-year study at a single center. In addition to imprecise definitions of cure as the outcome, the study also included patients who experienced delays in initiation of antibiotic therapy as well as those with higher rates of antibiotic use 30 days prior to the onset of peritonitis.

Overall, culture negative peritonitis is associated with better outcomes as compared to culture-positive peritonitis. However, improvement in sampling and culture methods is needed to improve culture positivity rates and avoid long term exposure to broad spectrum antibiotics.

Catheter Dysfunction in PD

Access remains the achilles heel of dialysis. Every year, 10% of PD patients switch to HD. After infectious-related PD complications, catheter-related issues are the second most common reason for technique failure. Catheter-related issues tend to lead to an earlier, rather than later switch to HD. The International Pediatric Peritoneal Dialysis Network (IPPN) database reported that mechanical PD catheter dysfunction was the main cause for access revision surgeries in 60% of pediatric patients, especially within the first year of PD. Catheter dysfunction doubled the risk of technique failure.

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Two common causes of catheter dysfunction in the early period after placement include obstruction and peritonitis. One-way outflow obstructions are the most common types of obstruction and are reported in 4% – 35% of PD patients. These obstructions are caused by adhesions or the closeness of the distal portion of the catheter to the omentum or bowel loops. Migration of the catheter to the upper abdominal quadrants due to catheter spatial memory also results in outflow obstruction. This is a consequence of poor orientation of the catheter tunnel. Catheter manipulation under fluoroscopy, using titanium weight at the end of the catheter or laparoscopic salvage with an omentopexy, can correct this problem. Omental wrapping can cause early or late obstruction and is reported in 5% – 15% of patients. Omental wrapping typically requires a surgical repair with either catheter repositioning, omental folding, omentolysis, omentopexy, or omentectomy to relieve the obstruction.

Catheter kinks during insertion can lead to total obstruction. Manipulation with a flexible probe or surgical repositioning can help. Blood clots or fibrin-related obstructions can be treated with heparin. Rarely, stiff wire manipulation under fluoroscopy is required for persistent obstructions. Intraoperative contamination can lead to early peritonitis and catheter dysfunction. Appropriate antibiotic therapy can salvage the catheter.

There are similar causes of catheter dysfunction in both the early and late-stage post-insertion periods. Late obstruction due to omental wrapping and catheter migration are treated in the ways discussed above. Obstruction due to recurrent fibrin strands can be treated with intermittent heparin use in PD fluid.  

Encapsulating peritoneal sclerosis (EPS) is a rare but serious cause of catheter dysfunction associated with prolonged exposure to glucose-containing PD fluids. Other risk factors for EPS include length of time spent on PD and recurrent, severe episodes of peritonitis. EPS leads to ultrafiltration failure and bowel obstruction and is associated with increased mortality. Treatment requires immediate cessation of PD, removal of the catheter, surgery for bowel obstructions, and the use of tamoxifen.

Infectious causes of catheter dysfunction include chronic relapsing peritonitis with indolent and fastidious organisms, chronic exit site infections, cuff erosions, and extrusions. Aggressive and prolonged antibiotic therapy may be needed in such cases, and rarely, the catheter may need to be changed.

Certain features known to influence catheter performance include catheter type, placement technique, exit site orientation, timing of first catheter use, and exit site care. According to the IPPN database, swan neck catheters needed more revisions due to mechanical complications and peritonitis than other types of catheters. Even in adults, curved intraperitoneal segments of PD catheters were associated with a greater risk of migration and access dysfunction. In a meta-analysis of 13 randomized-controlled trials, surgically-inserted straight catheters had a higher survival rate at one year compared to those with a curved intraperitoneal segment. Laparoscopic-assisted PD catheter insertion has been shown to reduce PD catheter complications such as catheter tip migration, omental wrap, and tissue entrapment. In urgent start PD, automated PD decreases the incidence of catheter dysfunction compared to the intermittent PD technique:  

Catheter dysfunction incidence for patients with different initiation PD modalities. Catheter dysfunction including malposition, leakage, omental wrap, and obstruction; the dysfunction incidence was significantly lower in the Automatic PD group than that in the Intermittent PD group (p = 0.077). Wang C et al, Am J Nephrol.

Catheter dysfunction is a major cause of technique failure in PD and can generally be prevented with care taken at the time of catheter placement. However, failure to recognize the issue in a timely fashion and an inability to fix the problem can lead to technique failure and switch to hemodialysis.

– Post prepared by Amit Langote. Follow him @LangoteAmit.

How to Claim CME
US-based physicians can earn 1.0 CME credit for reading this region. Please register/log in at the NKF PERC portal. Click on “Continue,” click on the “Peritoneal Dialysis Region,” then click on “Continue” to access the evaluation. You’ll need to click on “Continue” again to complete the evaluation, after which you can claim 1.0 credit and print your certificate. The CME activity will expire on June 15th, 2018.

Submit your picks! | NephMadness 2018 | #NephMadness |#PDRegion