Ultrafiltration Management in Peritoneal Dialysis

Peritoneal Dialysis International, Vol. 20, Suppl. 4

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Copyright © 2000 International Society for Peritoneal Dialysis

Evaluation and Management of Ultrafiltration

Problems in Peritoneal Dialysis

Salim Mujais, Karl Nolph, Ram Gokal, Peter Blake, John Burkart, Gerald Coles,

Yoshindo Kawaguchi, Hideki Kawanishi, Stephen Korbet, Raymond Krediet,

Bengt Lindholm, Dimitrios Oreopoulos, Bengt Rippe, and Rafael Selgas

For the International Society for Peritoneal Dialysis Ad Hoc Committee on

Ultrafiltration Management in Peritoneal Dialysis

Fluid balance management is one of the primary functions of renal replacement therapy. Peritoneal dialysis (PD), because of its continuous nature, has been considered an optimal approach to this therapeutic goal, avoiding fluctuant volume status and affording better homeostatic stability (1). This superior potential of PD has been illustrated in several studies showing, in discreet patient groups, better blood pressure control in PD compared to hemodialysis (HD) (2). This therapeutic advantage, however, has not been universally utilized and population surveys still show as high a prevalence of hypertension and cardiovascular mortality in PD as in HD populations (3_5). While the latter may be ascribed in both populations to an inherited disease burden from the pre end-stage renal disease (ESRD) phase of renal disease, it is clear that the full potential of PD for optimal volume homeostasis has remained underutilized (6). Several factors may be responsible for this underutilization and for the assumption prevalent among physicians that HD affords a more effective means of volume control. By its very nature as a continuous therapy, PD lacks the dramatic illustration of rapid volume removal observed with HD. Similarly, by its very nature as a home therapy, PD lacks the recurrent frequent examination by physicians/nurses of volume status afforded by three-times weekly HD, so the opportunities for triggered interventions are more temporally spaced than in HD. These two contrasting phenomena (dramatic volume removal and frequent examination) may also explain why the concept of "dry weight," a cornerstone clinical operating indicator in HD, is not widely used in the approach to volume management in PD. Patients on PD are routinely instructed to measure their weight on a daily basis. Guidelines on therapy modifications based on changes in weight can be safely taught to most patients.

Goals of Fluid Management in Residual Renal Therapy

In HD, the replacement of the volume homeostatic function of the native kidney is done by rapid removal of accumulated fluid to a target weight ("dry weight") that errs conceptually on the side of mild intravascular hypovolemia (7,8). This is done under the presumption that subsequent fluid accumulation is unavoidable in the interdialytic interval, and hence such mild intravascular hypovolemia safeguards against dangerous hypervolemic deviations. The usual homeostatic profile of a HD patient is to travel from a state of mild intravascular hypovolemia immediately after a dialysis session to mild/moderate hypervolemia immediately before the next dialysis session (7,8). The goal of attaining "dry weight" is to position the patient in a homeostatic safety state where the inevitable fluid accumulation is handled safely. In HD, the correspondence between "dry weight" and euvolemia is at best approximate, and in most clinical situations "dry weight" is determined empirically by clinical skill and trial and error. This absence of rigor in the prevalent clinical approach has been blamed for the persistence of volume-related complications in HD patients; hence the proliferation of experimental, clinical remedial approaches (7,8). A variety of volume markers have been proposed for use, varying from hormonal measurements (ANP, cGMP, renin, etc.), to vena cava diameter by ultrasonographic techniques, to bioimpedance measurements (7,8). While initial descriptions are uniformly promising, wider application frequently uncovers the proverbial "initial description bias." Further, logistic burdens have limited the wide and repetitive use of these techniques in clinical practice. Another variant of this approach is the proliferation of volume removal indicators for use during dialysis. Despite initial enthusiasm for their use (and imminent universal availability in new hardware), these devices seem to be succumbing to the inevitable life cycle of any new methodology (7,8). In the majority of HD patients, "dry weight" remains a goal defined by clinical criteria.

In PD patients attainment of target weight has been based on clinical indicators. The continuous nature of PD precludes the need for anticipatory, relative intravascular hypovolemia; hence the need to avoid the concept of "dry weight" and its replacement in PD by "target weight" or "desired weight." The avoidance of intermittent intravascular hypovolemia and its attendant complications has been considered to play an important role in the better preservation of renal function in PD patients compared to HD patients (9). Nevertheless, there is a need for a more rigorous approach to the definition and the evaluation of a target weight. For practical reasons, the definition of target weight and its continuous evaluation need to be addressed clinically. Further, it should be stressed that the determination of a target weight in a particular patient needs to be a dynamic continuous process taking into account changes due to nutritional status and cardiovascular profile that may occur over time.

Attainment of an edema-free state is a readily acceptable and definable target. It should be recognized, however, that because of the limitations inherent in clinical evaluations, an edema-free state is not synonymous with euvolemia. Significant fluid overload can be present in the absence of clinically detectable signs. The desirable target weight in a PD patient should ideally be that weight at which the patient is euvolemic. However, as discussed above, clinical determinations of euvolemia are at best approximate. There is a need then to base the clinically workable definition of target weight on exclusion clauses explored in a dynamic clinical process. Hence, the target weight that best approaches euvolemia is that weight at which the patient is clinically edema-free and below which undesirable clinical signs and symptoms of hypovolemia occur (hypotension, cramp, etc.). Reliance on clinical symptoms is less misleading in PD than it would be in HD. In the latter, clinical symptoms may appear when total extracellular fluid volume is still abnormally high because of the rapidity of fluid removal from the intravascular compartment. In PD, however, the gradual nature of fluid removal facilitates a concordance between intravascular and total extracellular volume changes. This definition implies that weight reduction needs to be pursued beyond the edema-free state. It also implies that the occurrence of undesirable clinical signs and symptoms during the process of fluid removal before the attainment of edema-free state is not sufficient.

To illustrate these two exclusion clauses, it is useful to consider the hypertensive patient. Attainment of clinically edema-free status does not guarantee that the volume-dependent component of the hypertensive state has been corrected. The edema-free state can be considered the necessary but not sufficient minimum bracket of desirable weight. Undesirable clinical signs and symptoms can then be viewed as the ceiling or upper bracket for fluid removal. The weight range between these two brackets is highly variable in individual patients. In a few clinical situations, the relation between these two brackets is complex. Patients with baseline hypotension, or patients with underlying autonomic insufficiency may cross the symptomatic threshold long before they are edema free, hence the need for flexibility and deliberate individualization of the approach to fluid removal. In the absence of validated readily applicable indicators of volume status, reliance on clinical judgement remains the physician's best guide.

The changing nature of target weight needs to be emphasized. Fluctuations in weight secondary to changes in lean body mass or fat do occur, and re-evaluation of target weight at regular intervals is necessary, guided by changes in nutrition and cardiovascular status.

Recommendations:

Guidelines for Fluid Management in Peritoneal Dialysis

TABLE 1
General Guidelines
  • Routine standardized monitoring including awareness of peritoneal equilibration test status
  • Dietary counseling concerning appropriate salt and water intake
  • Protection of residual renal function
  • Loop diuretics if residual renal function present
  • Enhanced compliance via education
  • Preservation of peritoneal membrane function
  • Hyperglycemia control

General guidelines on fluid management in PD patients are summarized in Table 1. Routine standardized monitoring and evaluation of volume status should be considered a necessary component of dialysis prescription and dialysis adequacy. The appropriateness of a patient's body weight has to be judged from two essential standpoints: the nutritional and the cardiovascular. Control of the volume component of hypertension, for example, needs to be titrated, patiently taking into account the need to balance volume removal with antihypertensive dosing. The importance of dietary counseling cannot be overemphasized. The general assumption that patients on PD tolerate greater dietary salt and fluid indiscretion should not be construed as an endorsement for such indiscretion (10). Tepid indifference that allows patients to hover close to mild edema may have pernicious long-term consequences (3). It is recognized that dietary interventions are the hardest to implement because they involve an elaborate process of education and lifestyle modification.

Residual renal function (RRF) plays an important role in both small solute adequacy and volume control. The protective zeal that has become a cornerstone of nephrologic management in the pre-ESRD phase needs to be sustained after initiation of dialysis. This is particularly important in the context of the new directions in dialysis initiation where patients are started on dialytic therapy at higher levels of RRF than previously (11).

Attention to the nephrotoxic potential of over-the-counter medications should become a component of regular patient interviews. Further, the use of aminoglycosides in the management of peritonitis should be limited to cases where no safer effective alternative is available. Protection from the nephrotoxic potential of contrast agents is limited by the obvious inability to use hydration methods. The promise of adenosine antagonists (e.g., aminophylline) has not been explored in this population and may be considered by inference until tested. Urine volume can be successfully increased even in advanced renal failure by the use of large doses of loop diuretics, alone or in combination with thiazides (12). While these agents do not help preserve RRF, they do increase urine output. Concern over potential ototoxicity finds its origin in experience with large intravenous doses. Oral administration seems not to carry the same risk. As with all other aspects of therapy, success is dependent on the patient's collaboration, which is usually enhanced by continuing education and positive re-enforcement. In cases of failure of a therapeutic approach, it is always useful to ponder whether the failure is due to the inappropriateness of the regimen, the overwhelming effect of underlying pathology, or the noncompliance of the patient.

Finally, because ultrafiltration (UF) is dependent on the glucose gradient across the peritoneal membrane, systemic hyperglycemia can interfere with fluid removal by reducing the gradient. The effects of hyperglycemia on thirst and excessive fluid intake need to be considered as well.

TABLE 2
Guidelines for Improved Fluid Removal in Peritoneal Dialysis (PD)
CAPD
  • Avoidance of long dwells with low glucose concentrations
  • Use of nighttime exchange device
  • Tailoring prescription to transport profile determined by peritoneal equilibration test
Automated PD
  • Avoidance of long dwells with low glucose concentrations
  • Use of short day dwells even when no additional exchange is needed for clearance

Fluid removal in PD follows principles that are detailed in the accompanying review by Krediet, Lindholm, and Rippe. Table 2 summarizes a few of the clinical guidelines useful in designing PD prescriptions for optimal fluid removal. The most frequently ignored principles are the need to avoid long dwells in high transporters, and balancing glucose concentration and dwell time (13).

Recommendations:

Diagnostic Approach to Fluid Balance Problems

Definition of the Clinical Syndrome

Figure 1 — Timeline of evaluation of fluid overload syndrome is depicted.
A structured diagnostic approach to the evaluation of suspected UF problems is presented in Figure 1. Patients presenting with the clinical syndrome of inability to maintain target weight and edema-free state need to be carefully evaluated according to the diagnostic process described below, prior to being labeled "ultrafiltration failure" (14_21). Indeed, there is a need for circumspection in the utilization of clinical labels in the absence of thorough delineation of causation. The term "ultrafiltration failure" has been liberally assigned in the past to cases where the main fault may have been either with the prescription or with the patient's nonadherence to clinical directives. Deficiency in tailoring PD prescription to transport type as determined by PET can readily lead to failure in fluid removal that should not be blamed on the therapy, but rather on its application. Low dialysate glucose concentrations and long dwell times will inevitably lead to inadequate fluid removal in patients with high transport profile. The need for precision in clinical labeling can be illustrated by the following example: Low small solute clearance because of inappropriately small fill volumes cannot be labeled "clearance failure." Similarly, low clearance because of a high residual peritoneal fluid volume from a malfunctioning catheter is also not "clearance failure." A parallel rigor in definition is required for fluid removal and, in the same vein, the concept of adequacy should be expanded to include fluid balance.

Initial Evaluation of Clinical Syndrome

Figure 2 — Categories and possible etiologies of reversible causes of fluid overload are depicted.

In the workup of the syndrome of inability to maintain target weight and edema-free state, it is important to consider the multitude of factors that can alter fluid balance (Figure 2) (20,21). The clinical history may readily disclose the probable causation, which can then be pursued with definitive diagnostic testing. A history of noncompliance with either dietary advice or PD prescription may direct the evaluation to more interventional pathways and preclude the need for expensive and tedious diagnostic workup. Understandably, the detection and resolution of patient noncompliance are not easy tasks. Parallel evidence for noncompliance in other aspects of the therapy, or generalized evidence for nonadequacy of the therapy may be helpful. Concomitant small solute inadequacy and inadequate fluid removal are rarely due to true peritoneal membrane pathology. The clinical profile of the syndrome is also helpful when it is associated with a persistent reduction in drain volume. Reductions in drain volume due to mechanical problems have a more acute presentation (22). A positional dialysate flow suggests a malpositioned catheter, whereas sluggish outflow (and/or inflow) may result from a partially obstructed or entrapped catheter. Findings of edema localized to the abdomen or inguinal area on clinical examination can be important clues to the presence of a peritoneal leak.

TABLE 3
Peritoneography
  • Take flat-plate radiogram of the abdomen.
  • Place 100 _ 200 mL of nonionic contrast in dialysate (2L bag).
  • Infuse 1 _ 2 L dialysate into the supine patient.
  • Have the patient change positions for mixing.
  • Repeat flat-plate radiogram of the abdomen.

At the time of the initial office evaluation, a quick "fill and drain" with 2 L dialysate is beneficial in order to directly observe the nature and rate of inflow and outflow. The presence of fibrin clots may explain abnormalities with flow that reduce the efficiency of drainage and volume removal, and can often be resolved with intraperitoneal heparin. If incomplete drainage or positional drainage is observed, a flat-plate radiograph of the abdomen will assess the possibility of a malpositioned catheter. When an entrapped catheter or peritoneal leak is suspected, peritoneography or peritoneal computerized tomography (Tables 3 and 4) are valuable in their diagnosis (23_26). It is extremely important to communicate to the radiologist the purpose of any radiographic procedure used in assessing problems with PD, as well as personally reviewing the radiograph(s).

TABLE 4
Peritoneal Computerized Tomography (CT)
  1. Take plain CT of abdomen.
  2. Place 100 _ 200 mL nonionic contrast in dialysate (2L bag).
  3. Infuse 1 _ 2 L dialysate into the supine patient.
  4. Have the patient change positions for mixing.
  5. Ambulate the patient for 30 minutes.
  6. Repeat CT of abdomen at 1 and 4 hours post instillation. Cuts through the pelvic floor and genitalia need to be obtained.

Dialysate Leaks: Dialysate leaks from the abdominal cavity result in a decrease in drain volume and net fluid removal. In the case of external leaks, the impact is greater on drain volume. In leaks into the abdominal wall or pleural space, net fluid removal is diminished either because of reabsorption from the interstitial spaces or sequestration in the pleural space. Leaks into the interstitial space are commonly accompanied by abdominal wall edema with or without genital edema. Leaks can occur at anytime but are often seen after being on PD for several months (>4 _ 6 months) and usually occur at the catheter insertion site, but can also be associated with an abdominal wall hernia or a history of multiple abdominal surgeries (23,24,27). Localized abdominal wall edema or subcutaneous fluid collections are often evident. Diagnosis is confirmed by utilizing radiographic techniques that include intraperitoneal infusion of a dialysis solution in which radiographic contrast has been added (with computed tomography) (Table 4), or through the intraperitoneal infusion of radioisotope with peritoneal scintigraphy (23_26, 28_31).

Peritoneal membrane function is not compromised and therefore peritoneal transport as evaluated by the PET is not changed compared to baseline, but the secondary increase in lymphatic absorption leads to reduced fluid removal. Leaks associated with hernias usually require surgical repair and a temporary transfer to HD until adequate healing has occurred. Leaks occurring in the absence of a hernia usually represent a tear in the parietal peritoneum. In this situation there is frequently a history of multiple abdominal surgeries, pregnancies, recent corticosteroid usage, or abdominal straining (coughing, Valsalva maneuver). Small leaks may respond to peritoneal rest with HD support or the use of intermittent PD without the need for surgical repair. Recurrence may require surgical repair (27).

Catheter Problems: Catheter-related problems contributing to poor drain volumes include obstruction, entrapment, or malposition. Catheter obstruction, either partial or complete, often results from fibrin plugs or buildup within the catheter lumen, but can be due to omentum obstructing the catheter ports, or even a kinked catheter. These lead to sluggish or intermittent inflow/outflow of dialysate and thus alter the efficiency of fluid removal. Fibrin strands seen in the dialysate should raise suspicion of the problem, but the diagnosis is otherwise one of exclusion because radiographic evaluation is generally not helpful except in identifying kinked catheters. Treatment consists of aggressive "flushing" of the catheter with a dialysate-filled syringe and, if this is unsuccessful, the use of fibrinolytic agents when fibrin-related occlusion is suspected.

The intra-abdominal portion of the catheter may become "entrapped" in a compartment formed by adhesions. This can lead to a reduction in intraperitoneal capacity resulting in pain on inflow once the compartment volume has been surpassed. With the use of peritoneography (Table 3) the compartment can be demonstrated. Treatment may be attained with surgical lysis of the adhesions if they are not too extensive.

Catheter malposition may occur because of improper placement, but it often results from migration of catheters originally in good position (32). A malpositioned catheter has positional outflow and does not drain the peritoneal cavity effectively, leading to an increase in residual volume. A normal residual volume (R) is approximately 200 _ 250 mL (33) and can be measured from information obtained during the PET using the following equation:

R = Vin(S3 _ S2)/(S1 _ S3)

where Vin = instillation volume, S1 = solute concentration (urea or creatinine) in the pretest drain, S2 = solute concentration of the instilled fluid (0 for urea or creatinine), and S3 = solute concentration immediately following instillation (33). An increase in residual volume dilutes the glucose concentration in freshly instilled dialysate. The effect is usually less than 10%. This decreases the osmotic gradient and thus reduces the rate of transcapillary UF without any significant effect on solute transport. Net UF is decreased while the dialysate-to-plasma (D/P) creatinine ratio remains essentially unchanged. An increase in the calculated residual volume should raise the suspicion of a malpositioned catheter. However, the presence of this problem is often clinically apparent and the diagnosis is easily made with the aid of simple radiographic techniques (flat-plate of the abdomen) because PD catheters have radiopaque material imbedded within.

Recommendations:

Evaluation of Peritoneal Membrane Function

Figure 3 — Components of the evaluation of peritoneal membrane function are depicted.

The exclusion of rapidly resolvable causes of impaired fluid removal has diagnostic and therapeutic advantages. The causes discussed above can be frequently resolved with standard therapeutic approaches and the clinical syndrome hence resolved. Streamlining of the diagnostic approach is also aided by exclusion of mechanical causes. The next diagnostic step is to evaluate the UF and transport functions of the peritoneal membrane (Figure 3).

Traditionally, peritoneal membrane function has been assessed by the PET. The PET has been standardized both procedurally and interpretably to classify membrane function (33). It is directed, however, primarily at small solute clearance and, although UF capacity is closely linked to the latter, the current PET has not addressed the issue of quantifying pathologic variations in UF. For the purposes of diagnosing presence and causation of impaired fluid removal, the required test is one which will (1) measure UF under optimal conditions (to avoid false positive results), (2) evaluate small solute transport to aid in defining causation, and (3) have validated criteria that correlate with clinical behavior (to avoid both false negative and false positive results). Regrettably, a fully validated test that satisfies all the above criteria is not currently available and efforts to develop it and standardize it are urgently required. The current PET does provide a thorough evaluation of small solute transport, but because of the modest osmotic challenge of the 2.5%/2.27% dextrose concentration utilized in the test, the osmotic drive for UF is not optimal. Further, the normal ranges for UF volume expected for each transport category have not been fully defined nor have they been validated against clinical behavior.

A modification of the standard PET introduced by Krediet and his colleagues (34,35) offers a reasonable alternative, albeit with remaining shortcomings. The modification consists of replacing the 2.5%/2.27% dextrose solution of the standard PET with a 4.25%/3.86% dextrose solution, thereby satisfying the criterion of maximal osmotic drive defined above as required for proper evaluation of UF capacity. A value of less than 400 mL net UF in a 4-hour dwell correlates well with clinical behavior and avoids any false positive results.

An additional advantage of this approach is that it allows for determination of sodium sieving by profiling the changes in dialysate Na+ concentration induced by osmotically driven water flow. Because water influx into the peritoneal cavity is mediated in part by aquaporins, the enhanced osmotic drive will draw water into the peritoneal cavity, thereby diluting the Na+ concentration. The greater the influx of water via aquaporins, the greater the decline in dialysate Na+. Impaired aquaporin-mediated water transport will lead to obliteration of the decline in dialysate Na+. Hence, measurement of Na+ sieving will allow better diagnostic discrimination of the causes of impaired UF. The major limitation of this modification of the standard PET is that its characterization of small solute transport has not been fully examined and related to the results of the standard PET with 2.5%/2.27%. A few studies have compared the creatinine profile with 1.5%/1.36% and 4.25%/3.86% and found no difference in D/P creatinine (36,37). Further, preliminary results in 47 patients studied with both 2.5%/2.27% and 4.25%/3.86% reveals no major discrepancies in patient allocation to different transport groups on the basis of D/P creatinine (Burkhart et al., unpublished observations). For the purpose of the diagnostic endeavor at hand, the use of the modified PET appears adequate.

TABLE 5
Modified Peritoneal Equilibration Test (4.25% Dextrose)
  1. On the evening prior to the test, the patient should perform a standard CAPD 8- to 12-hour overnight dwell.
  2. With the patient upright, drain the overnight dwell over 20 minutes and note volume drained. Save sample for creatinine and glucose to allow for determination of residual volume.
  3. With the patient supine, infuse 2.0 L 4.25% dialysis solution over 10 minutes. The patient should roll from side to side after each 400 mL of solution is infused.
  4. Note time the infusion is complete: this is the "zero hour" dwell time.
  5. At 0-hour, 1-hour, and 2-hour dwell times:
    • Drain 200 mL effluent into bag.
    • Mix bag by inverting 2 _ 3 times.
    • Using aseptic technique, draw a 10 mL sample from medication port.
    • Reinfuse the 190 mL of effluent into the patient.
    • Transfer 10 mL sample to red-top tube and label appropriately.
  6. At 2-hour dwell time, draw blood sample for creatinine, sodium, and glucose measurements.
  7. At 4-hour dwell time:
    • With patient upright, drain exchange over 20 minutes.
    • Mix bag by inverting 2 _ 3 times.
    • Using aseptic technique, draw a 10 mL sample from medication port.
    • Measure and record volume drained.
    • Transfer 10 mL sample to red-top tube and label appropriately.
  8. Send all effluent samples and one blood sample to laboratory for creatinine, sodium, and glucose measurements.

Discrimination by UF Response: Subsequent to initial exclusion of mechanical, compliance, dietary, and other relevant clinical causes of impaired fluid removal, and the limitations of the modified PET (4.25%/3.86% dialysate dwell) notwithstanding, the patient needs to undergo an evaluation of UF response (Figure 4). The details of the test are summarized in Table 5.

As can be gleaned from the detail of the test, both fluid removal and small solute profiles are obtained during the test. The former is the primary discriminating measurement, and determination of small solute profile becomes relevant only if fluid removal is deemed abnormal. The rationale of sampling for small solute profile in the test in parallel with UF assessment, and prior to determination of fluid removal adequacy, is to have at hand the means to proceed with the diagnostic workup without the need to subject the patient to further testing.

The primary intent of the test is to quantify net UF in response to a 4.25%/3.86% dextrose dialysis solution challenge. If net UF is greater than 400 mL/4 hours (drain volume greater than 2400 mL/4 hours), the subsequent diagnostic sequence needs to focus on the following possible etiologies: (1) dietary indiscretion or dialysis noncompliance, (2) inappropriate prescription, and (3) recent loss of RRF for which no adjustments were made in prescription. In effect, a net UF greater than 400 mL/4 hours (a drain volume greater than 2400 mL/4 hours) effectively rules out any alterations in peritoneal functional parameters as responsible for the inadequate fluid removal and the ensuing clinical syndrome. If net UF is less than 400 mL/4 hours (drain volume lower than 2400 mL/4 hours), the subsequent diagnostic sequence is dependent on an examination of the results of small solute profile measurement. Once it has been determined that net UF is lower than the discriminatory value, then the samples obtained during the test can be assayed for small solute concentrations. When using the values for net UF or drain volume indicated above, the physician should keep in mind the possibility of overfill of dialysis bags, which may be in the order of 50 mL, and account for this volume in their evaluation of the observed response.

Figure 4 — Evaluation method of the ultrafiltration response is depicted.

A similar approach may be followed using a standard PET with 2.5%/2.27% dialysate dextrose with the following caveats: (1) since the osmotic challenge is not maximal, there is a potential for false positive results; (2) the discriminatory value is adjusted downward to 100 mL/4 hours of net UF (2100 mL/4 hours drain volume). Further, if the standard PET is to be used, no 4.25%/3.86% dextrose dialysate could have been used immediately prior to the test. There is no immediately obvious reason why a standard PET is to be used in this diagnostic sequence, except the remote possibilities of unavailable proper concentration of dialysate test solutions or human error. In the latter case, the results of the test can still be interpreted based on the above caveats, and the patient is not subjected to additional testing. Nevertheless, it is the recommendation of the committee, based on the argument of the need to maximize osmotic challenge, that the 4.25%/3.86% dextrose PET be used in this setting.

Figure 5 — Categories and possible etiologies for an impaired ultrafiltration response are depicted.
Discrimination by Small-Solute Transport Characteristics: The peritoneal conditions that would result in a drain volume of less than 2400 mL/4 hours can be separated by examination of the small solute characteristics (Figure 5). In the following discussion, three categories based on D/P creatinine need to be considered: high transporters, low transporters, and high-average and low-average transporters. The overall separation into these three categories is based on creatinine and glucose handling and follows standard values with which physicians are familiar. In a few cases, however, the profile of Na+ handling becomes crucial and this will be discussed where relevant.

Several alternatives can be considered for patient classification by small solute characteristics. In patients who have had a recent standard PET (within 3 months of current evaluation), there is no need to repeat the profiling; the previously determined profile would suffice if no intervening peritonitis has occurred. In most other patients, a renewed evaluation of small solute transport may be in order. As discussed above, a small solute profile obtained during the modified PET with 4.25%/3.86% dextrose can substitute for a repeat standard PET. The conditions discussed below may coexist in the same patient. While this may be rare, it is important nevertheless to recognize the possibility, particularly when diagnostic findings are mixed. Adherence to a systematic diagnostic approach will usually help resolve the issue. Finally, this classification for purposes of clarity and precision diverges from previous approaches that categorized patients as having type I or type II or type III "ultrafiltration failure." While the previous categories are included in the following discourse, it is preferable to abandon the old nomenclature and adopt the more descriptive terms utilized herein.

Recommendations:

Low Drain Volume and High Transport: Patients with a low drain volume (<2400 mL/4 hours with a 4.25%/3.86% modified PET) and D/P creatinine greater than 0.81 likely represent the largest group of patients with inadequate filtration due to peritoneal membrane characteristics. These patients fall into 3 groups: (1) patients with an inherent high small-solute transport profile at initiation of dialysis, (2) patients with peritonitis, and (3) patients who develop a high transport profile in the course of long-term PD. These patients tend to have good low molecular weight solute transport, but have poor UF during standard CAPD or continuous cycling PD using glucose-containing dialysate, due to rapid absorption of glucose and dissipation of the osmotic gradient. If their dwell times are mismatched for their membrane transport characteristics, they often appear to have inadequate UF as they lose RRF and no longer have urine flow to supplement net daily peritoneal fluid removal.

TABLE 6
Proportion of Peritoneal Equilibration Test Profiles in Different Populations
U.S.A.StockholmAmsterdamJapan
High (%)10151513
High average (%)53443646
Low average (%)31283533
Low (%)613148

Inherent high transport: Ten percent of patients starting PD display this transport profile. This proportion appears to be constant in various population groups (Table 6) and stable over medium periods of observation (38). Patients in this group have very efficient membranes for small solute clearance but may have difficulty in UF, particularly in long dwell cycles. These patients are at risk of high protein losses in the peritoneum. A high level of technique failure has been described on CAPD therapy, likely related to fluid management. Retrospective analysis also suggests higher mortality in this group (39_41). These patients typically do well on CAPD until residual renal volume decreases, at which time it may become difficult to maintain euvolemia and blood pressure control on standard CAPD with glucose-containing solutions. Automated peritoneal dialysis (APD) and icodextrin for the long dwell are recommended therapeutic approaches in this group (see below).

Recent peritonitis: It is a common clinical experience for PD patients to experience fluid retention during episodes of peritonitis (42_45). These patients often need a temporary change in their standard dialysis prescription (shorter dwell times, increased tonicity of fluids, or use of icodextrin) to achieve net UF. When compared to baseline, PET data during peritonitis reveal an increase in the D/P ratio for creatinine and a decrease in the D/D0 ratio for glucose. There is also an increase in protein losses and a significant decrease in net UF. These clinical and physiological changes associated with peritonitis are usually reversible and, after recovery from the episode, membrane transport usually returns to baseline. Several studies have indicated that UF during an episode of peritonitis can be satisfactorily achieved with the use of icodextrin (46).

High transport during long-term PD: An increase in small solute transport during the course of long-term therapy on PD is thought to be due to an increase in peritoneal membrane functional surface area (47_52). This process is diagnosed in patients whose D/P creatinine at 4 hours on PET changes from baseline. Peritoneal equilibration testing confirms an increase in D/P ratio for creatinine, a decrease in the D/D0 ratio for glucose, and a smaller than usual decrease in dialysate Na+ during the dwell. In contrast to the situation seen with peritonitis, where transport changes are usually transient and protein losses are increased, the small solute transport changes in this group tend to be permanent and protein mass transport does not change. It is often easy to maintain minimal total solute clearance goals in these patients despite a tendency toward clinical volume overload.

This was originally described with acetate-containing dialysis solutions (14,53) but has also been seen in patients who have only used lactate-containing dialysis. A history of recurrent peritonitis and extensive use of hypertonic exchanges has been observed in some, but not all studies. The incidence seems to increase with time on PD, implicating repeated exposure of the peritoneum to dialysis solution as a cause (17).

The natural history of peritoneal membrane transport over time has been debated (38,52,54_58), due mainly to noncomparability of the methods used. A small number of studies used standardized 4hour dwell evaluations with examination of both UF and solute transport, while a larger number utilized clearance monitoring. The latter may mask opposing directional changes in solute and fluid transport. The potential increase in solute clearance due to an increase in D/P creatinine may be masked by the potential decline due to lower UF. The emerging picture, however, is that during long-term observations (greater than 2 years) some degree of increase in D/P creatinine does occur in patients on PD.

Recommendations:

Low Drain Volume and Low Transport: This combination of low drain volume in the face of adequate osmotic challenge and low small-solute transport is very rare and reflects a major disruption of the peritoneal membrane and/or intraperitoneal fluid distribution (59,60). It is usually due to adhesions, and the functional consequences may be related to fluid trapping in small spaces. Peritoneography may be helpful in making the diagnosis by identifying sequestered spaces. Poor UF in association with low transport is reported to occur in advanced stages of sclerosing peritonitis (60,61). It is important, however, to realize that a high transport rate has also been described prior to a diagnosis of sclerosing peritonitis (60_62). Unfortunately, no large prospective study of fluid problems in PD patients has been performed, so it is not possible to state how often UF failure, together with low transport, occurs. Because this condition results in both inadequate volume and inadequate solute removal, transfer to HD is required for adequate patient management (19) unless patients have some degree of RRF. Management of anuric patients in this category may be difficult by PD.

A caveat on the diagnostic criteria is in order: Patients with underlying low transport rate and leaks or mechanical problems or high lymphatic/tissue reabsorption may also present with the composite picture of low drain volume and low small-solute transport. It is therefore important to exclude these latter causes before accepting low transport as the reason for the difficulty with peritoneal fluid removal.

Recommendations:

Low Drain Volume and High-Average or Low-Average Transport: A low drain volume coupled with high-average or low-average transport can result from four possible etiologies: (1) mechanical problems, (2) lymphatic reabsorption and/or (3) tissue reabsorption, and (4) aquaporin deficiency.

Mechanical problems: The above profile of UF and small solute transport results should invite a reconsideration of mechanical problems as a cause of the inadequate volume removal. This is particularly true in patients in whom the workup for mechanical problems was cursory or not entertained in the initial evaluation. This possibility need not be considered if the initial evaluation was rigorous and mechanical problems were fully excluded.

Lymphatic reabsorption and/or tissue reabsorption: Increased lymphatic absorption (or overall peritoneal tissue reabsorption) can lead to a low drain volume despite adequate response to an osmotic challenge (63,64). Since enhanced lymphatic reabsorption is ongoing, the response to the osmotic challenge is obscured if one relies solely on final drain volume or even on peritoneal volume. Lymphatic absorption of peritoneal fluid negatively influences the overall removal of water (decreases net UF) and solute (partially negating the effect of diffusive and convective solute transport). Since the absorption of peritoneal fluid by lymphatics does not alter the concentration of solutes in the dialysate, the D/P creatinine ratio remains unchanged with increased lymphatic flow, even though net UF can be significantly decreased.

The relative contribution by increased lymphatic/tissue reabsorption to fluid removal problems has not been definitively established. Proper assessment of frequency of the condition will require further work. Impaired net UF associated with the disappearance of macromolecules administered intraperitoneally was found in 2 of the 9 patients with UF failure described by Heimbürger et al. (17). Krediet and his group (35) found a dextran disappearance rate exceeding 2 mL/min in 7 of 19 patients with inadequate UF (net UF < 400 mL/4 hours on 4.25%/3.86% glucose), often in combination with the presence of a large peritoneal surface area. Up to now, no evidence is present suggesting that the prevalence of this cause of impaired peritoneal fluid removal would increase with the duration of PD.

Definitive proof of the condition requires identification of high macromolecule clearance from the peritoneal cavity (65,66). In the absence of such a test, the diagnosis is made by exclusion of mechanical catheter problems, aquaporin deficiency, and increased hydraulic conductance. The rate of lymphatic absorption is estimated by measuring the disappearance of macromolecules, such as albumin or dextran 70, from the peritoneal cavity (molecules too large for transcapillary transfer by either diffusion or convection). As described by Pannekeet et al. (34), this can be done by adding 1 g dextran 70 per liter to a 2-L, 4hour, 4.25%/3.86% dextrose dwell. The dialysate would be sampled at 0, 10, 20, 30, 60, 120, 180, and 240 minutes and the lymphatic or tissue resorption rate of dialysate would be calculated from the dextran clearance from the peritoneal cavity.

Measurement of lymphatic flow is uncommon in clinical practice due to the complexity of the procedure. Since transcapillary UF is essentially normal in this situation, osmotically-mediated water transport into the intraperitoneal cavity results in the normal dilution of the Na+ concentration of the dialysate. (Because the sieving coefficient for Na+ is < 1.0, the Na+ concentration in ultrafiltrate is less than that of serum, leading to an increase in intraperitoneal Na+-free water which dilutes the initial dialysis solution Na+ concentration.) A 2 _ 4 mEq/L decrease in the dialysate Na+ concentration will normally be observed within 2 hours of a 2-L, 2.5%/2.27% dextrose dialysate dwell (this decrease in Na+ concentration can be augmented by the use of 4.25%/3.86% dialysate), and has been used as indirect evidence of normal transcapillary UF. In patients with reduced net UF secondary to increased lymphatic absorption, the normal decline in Na+ concentration is maintained.

Aquaporin deficiency: This is a relatively rare condition and only a small number of cases with proven diagnosis have been reported (67). Nevertheless, greater awareness and a more systematic evaluation may allow a more precise determination of its true prevalence. Further, this condition offers a very interesting model for understanding peritoneal transport and its alteration by pathologic states. The peritoneal capillary membrane is not freely permeable to solutes, but is a highly selective barrier with the ability to impede diffusion and convection of relatively small molecules while restricting large macromolecules, but to a lesser degree than standard HD membranes. This suggests that peritoneal capillaries contain populations of various sized "pores" that alter solute transport. This has led, through computer simulations (68_74) and animal work (75_77), to the "three-pore theory" of water and solute transport across the peritoneal membrane (mainly transcapillary movement of solute and fluid). This theory proposed three populations of pores: a large number of transcellular pores (radius 4 _ 5 Å), a large number of small pores (40 _ 50 Å), and a small number of large pores (200 _ 300 Å). This theory predicted that 40% _ 50% of the total ultrafiltrate is obtained through this transcellular path, and therefore will be solute free when driven by an osmotic-pressure differential. Animal work and indirect human research has strongly pointed to aquaporins 1 and 3 being the water-channel transcellular pores (ultrasmall pores). Aquaporin has been demonstrated by in situ techniques to be present in the human peritoneal capillary endothelium and mesothelium (78,79). The small pores are also involved in water transport through colloid osmosis and hydrostatic pressures that are in balance; these are also the pores through which most of the small solute transport occurs. Aquaporin deficiency is that situation where there is damage to or a diminished number of water-channel ultrasmall pores, which can lead to deficient crystalloid-induced UF. There are few reports of isolated aquaporin-mediated loss of UF, but it is possible for this to occur (67,80).

Various indirect methods can be applied in clinical practice to estimate the magnitude of aquaporin-mediated water transport. The so-called sieving of Na+ is the simplest one. The dialysate concentration of Na+ decreases during the initial phase of a dialysis dwell using a hypertonic glucose solution (4.25%/3.86% glucose) (36,67,81_83). The minimum value is usually reached after 30 _ 60 minutes. It is likely that the dissociation between the transport of Na+ and that of water is caused by aquaporin-mediated water transport. Consequently, the magnitude of the dip in D/P Na+ provides information on channel-mediated water transport. However, in situations of a large vascular surface area, the diffusion and/or convection of Na+ from the circulation to dialysate through small pores will also increase, thereby blunting the decrease of D/P Na+.

Another simple way to assess aquaporin-mediated transport is to calculate the difference in net UF obtained after a 4-hour dwell with 1.5%/1.36% glucose and with 4.25%/3.86% glucose dialysate. Using 1.5%/1.36% glucose induces only a small crystalloid osmotic pressure gradient, and therefore limited transport through water channels. On the other hand, using 4.25%/3.86% glucose induces a very high crystalloid osmotic pressure gradient and the net UF obtained with it is therefore much more dependent on the number and function of water channels. Consequently, DUF 4.25%/3.86% _ 1.5%/1.36% will decrease in situations with impaired aquaporin-mediated water transport. The D/P Na+ ratio or DNa+ are probably the simplest way for rough assessment of channel-mediated water transport, but a correction for diffusion should probably be applied when the difference between the plasma and the initial dialysate concentrations of Na+ exceeds, for example, 5 mmol/L.

Recommendations:

Therapeutic Approach to Fluid Balance Problems

General Guidelines

A summary of guidelines for the prevention of fluid overload is presented in Table 1.

Routine Standardized Monitoring: Routine standardized monitoring of desired weight, course of RRF, and achieved UF with current dialysis prescription should be emphasized in the care protocols of all patients on PD. This approach will allow for early detection of developing problems and early intervention with corrective measures. The volume status of patients on PD should be used as a core indicator of dialysis adequacy. Constant re-evaluation, by physicians and nurses, of the patient's target weight in the light of blood pressure and other features suggestive of fluid overload is required. Particular emphasis should be placed on the desirability of normalizing blood pressure by using fluid removal alone, without antihypertensive drugs, until it is proven that this strategy is not adequate. Routine performance of the PET, with a view to identifying high and high average transporters in whom monitoring of fluid status is particularly critical, is highly encouraged. Use of icodextrin for the long dwell, and utilization of APD may be the preferred approaches in these patients.

Dietary Counseling: Dietary counseling concerning appropriate salt and water intake is crucial. Avoidance of dietary indiscretion can be enhanced by detailed dietary counseling and regular re-enforcement of taught guidelines. The tendency to be more liberal in dietary restrictions with PD patients compared to patients on HD should be tempered by the need to maintain desired weight and reduction of cardiovascular risk (10).

Diuretic Use: Routine use of high-dose loop diuretics to maintain urine output in patients with RRF is a viable consideration (12). Usually, large oral doses are needed (furosemide range 250 _ 1000 mg) with or without the addition of a thiazide-like diuretic (metolazone 5 _ 10 mg given 30 minutes prior to the loop diuretic). The concern over ototoxicity is largely based on experience with large intravenous doses; it has rarely been seen with oral administration.

Protection of RRF: Protection of RRF should continue to be as high a priority in the ESRD phase as it is in the pre-ESRD phase. Avoidance of nephrotoxic agents (e.g., aminoglycosides, nonsteroidal anti-inflammatory drugs, radio contrast dye) that might cause accelerated loss of urine output should be practiced rigorously. In patients with diffuse vascular disease but not yet ESRD, angiotensin converting enzyme inhibitors may adversely affect renal function. Recent analysis of the United States Renal Data System data suggests that use of angiotensin converting enzyme inhibitors was associated with better preservation of RRF in patients on dialysis (84).

Enhanced Compliance and Education: During the initial training period, emphasis should be placed on the education of the patient in the diagnosis and significance of fluid overload (e.g., awareness of importance of hypertension, peripheral edema, shortness of breath). Additionally, patients should be provided appropriate education in what the indications are to use more-hypertonic PD solutions. Routine monitoring of patient compliance with PD exchanges, and education of the patient in the importance of this issue, are highly desirable. Better techniques to determine and detect noncompliance need to be developed.

Hyperglycemia Control: In diabetic patients, hyperglycemia can adversely affect the maintenance of an osmotic gradient across the peritoneal membrane. Control of hyperglycemia may allow improved UF without the need to use hypertonic glucose solutions unnecessarily. Because glucose control is, under current practice conditions, mostly monitored and modified by the patient independently, education of the patient on the relevance of this activity to the adequacy of dialysis is important.

Preservation of Peritoneal Membrane Function: The acute (and possibly chronic) impact of peritonitis on membrane function has been discussed above. Minimization of damage to the peritoneal membrane by implementation of strategies to decrease the peritonitis rate should be universally applied. The use of more-biocompatible solutions may also influence membrane preservation, partly via a reduction in the peritonitis rate. Temporary cessation of PD has been used in a few patients with high small-solute transport characteristics with some success, and may be a reasonable option to consider if other approaches are unsuccessful (85_87). Alternatively, reduction in exposure of the peritoneal membrane to glucose may lead to some improvement in transport parameters (88).

Therapeutic Guidelines for Specific Diagnostic Categories

Low Drain Volume and High Transport: In addition to the universal guidelines discussed above, therapeutic interventions in this constellation of diagnostic findings need to address the basic pathophysiologic mechanism of rapid dissipation of the osmotic gradient. The latter phenomenon is particularly prominent during the long overnight dwell in CAPD and the daytime dwell in APD. The most appropriate intervention is the use of high molecular-weight substitutes for glucose, such as icodextrin. Dialysate solutions containing this polyglucose have been shown to be superior to glucose-based solutions in achieving net UF during long dwells in a majority of patients, and particularly in high transporters (89_95). Icodextrin has also been shown to be effective during peritonitis (46). In areas of the world where icodextrin dialysis solutions are not available, shortening dwell time is the preferred approach. In CAPD patients, this can be achieved with the use of an automated nighttime exchange device. This approach will shorten dwell time and has the additional benefit of improving small solute clearance with little impact on patient lifestyle. Alternatively, patients can be switched to APD where the use of short dwell times in the night phase enhances UF (13). In patients on APD, foregoing the daytime exchange and optimizing the nighttime regimen may be sufficient. If small solute clearance suffers, then a short daytime exchange with midday drainage will supplement nighttime clearance without compromising UF. If the preceding options are insufficient, then high glucose concentrations may be required. In a few patients, adjunctive, temporary, or permanent HD may be required.

Preventive measures remain limited and speculative because of a lack of thorough understanding of the factors underlying high transport (96,97). In patients with inherent high transport, there are no clear associations with reversible conditions that can be therapeutically addressed. The possible association with higher indices of chronic systemic inflammatory response remains unproven. The clearest category for intervention is that of the transient, small-solute, high transport rate associated with infection. Approaches to reduce and/or prevent infections, using improved connectology, patient training, and local prophylaxis, have been successful but more remains to be achieved. In patients who develop a high transport profile in the course of chronic PD, the approach is more a question of considered opinion rather than evidence based. Reinforcing universal measures before relying on chronic intensive use of 4.25%/3.86% glucose dialysate is generally preferable. Further, where available, use of icodextrin in lieu of any high glucose dialysate for the long dwell is recommended.

Low Drain Volume and Low Transport: The combination of reduced solute clearance and diminished UF represents a state of significant shortcomings in delivery of appropriate renal replacement by PD. If therapeutic targets for both azotemia and volume homeostasis cannot be met, then adjunctive HD or permanent transfer to HD may be required in anuric patients. In subjects with RRF, use of high-dose loop diuretics may be beneficial.

Low Drain Volume and High-Average or Low-Average Transport: Aquaporin Deficiency: Adherence to the universal measures detailed above is necessary in all conditions, whatever the underlying etiology of the impaired UF. Patients with aquaporin deficiency continue to have significant UF via nonaquaporin pathways. This can be enhanced by the use of icodextrin in long dwells, allowing for sustained fluid removal (92,95,98,99). For glucose-based exchanges, short dwells are also preferable, as in patients with high transport profile, with the same provisions as far as optimizing maintained solute clearance is concerned.

Lymphatic Reabsorption and/or Tissue Reabsorption: When enhanced tissue reabsorption results in reduced net UF, interventions to maximize overall UF are required to reach a state favorable to fluid removal. Ultrafiltration needs to exceed reabsorption to allow proper volume homeostasis. All interventions that maximize UF (short dwell time, high tonicity of dialysate) need to be combined. Because tissue resorption is a continuous process, and because UF tends to decline with time, short-cycle therapy is required to keep the balance of operation earlier than the convergence of the two processes. Adjusting cycle number and overall cycler time in APD, or cycle number in CAPD, to the requirements of both UF and solute clearance needs to be done meticulously (13). Pharmacological reduction of lymphatic absorption has been attempted (100). Intraperitoneal administration of phosphatidylcholine has been found to increase net UF, in both CAPD patients with UF failure and patients with normal net UF (101_103). Alternatively, a cholinergic effect could lead to a decrease of lymphatic absorption, such as has been demonstrated in rats for neostigmine. The parasympathomimetic drug, bethanechol chloride, has been reported to increase UF after oral administration (104). An effect on lymphatic absorption was postulated, but not investigated. More studies are required to confirm its effect. Although there is a lot of promising investigative evidence that tissue resorption can be reduced, no pharmacological intervention can be recommended at this time due to the lack of definitive clinical studies.

Clinical Recommendations

  1. A systematic and thorough evaluation of fluid management should be considered a cornerstone of dialytic therapy. Routine monitoring and evaluation of volume status should be considered a necessary component of dialysis prescription and dialysis adequacy. Assessment, achievement, and maintenance of target weight are essential, with the aim of maintaining normotension with euvolemia. Regular assessment (annually, but more frequently if clinically indicated) of peritoneal function (PET modified), RRF, and solute clearance are essential.
  2. In the absence of validated readily applicable indicators of volume status, reliance on clinical judgment remains the physician's best guide.
  3. Adherence to sound physiologic principles in the design and implementation of PD prescriptions is essential to prevent the emergence of fluid overload. The most frequently ignored principles in PD that lead to UF difficulties are the need to avoid long dwells in high transporters and balancing glucose concentration and dwell time. Prescription setting must take them into account.
  4. In the evaluation of causes of fluid overload, screening for reversible causes, such as dietary indiscretion and noncompliance, problems in prescription design, and finally mechanical problems, is imperative. These factors may account for a large proportion of the causes of fluid overload.
  5. Evaluation of peritoneal membrane-related causes of fluid overload requires adherence to a structured diagnostic framework: The first step involves evaluation of UF response to an effective osmotic challenge. The second step refines the diagnostic approach with an evaluation of the small-solute transport profile.
  6. Evaluation of peritoneal membrane function in this context is best performed with a modified PET utilizing 4.25%/3.86% glucose. In effect, a net UF greater than 400 mL/4 hours (a drain volume greater than 2400 mL/4 hours) effectively rules out any alterations in peritoneal functional parameters being responsible for the inadequate fluid removal and the ensuing clinical syndrome.
  7. For patients with net UF less than 400 mL/4 hours and a high transport profile of small solute clearance, APD and icodextrin for the long dwell are the recommended therapeutic approaches. This profile can also be seen during peritonitis, and several studies have indicated that UF during an episode of peritonitis can be satisfactorily achieved with the use of icodextrin.
  8. Patients who are functionally anephric and have net UF less than 400 mL/4 hours and a low transport profile of small solute clearance have both inadequate volume and inadequate solute removal; transfer to HD may be required for adequate patient management. Functionally anephric patients in this category often cannot be managed by PD. However, if some degree of RRF is present, maintenance on this dialytic modality may be feasible.
  9. Patients with a net UF less than 400 mL/4 hours and low-average, average, or high-average transport profiles may have mechanical problems, high peritoneal absorption rates, or aquaporin deficiency.
Correspondence to: S. Mujais, Renal Division, Baxter Healthcare Corporation, 1620 Waukegan Road, MPGR-D1 McGaw Park, IL 60085-9815 U.S.A.

mujaiss@baxter.com

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