Peritoneal Dialysis Solutions, Prescription and Adequacy

31 Peritoneal Dialysis Solutions, Prescription and Adequacy Angela Yee-Moon Wang, MD, PhD OUTLINE Peritoneal Dialysis Solutions, 480 Constituents of Peritoneal Dialysis Solutions, 480 Dialysate Buffer, 482 Dialysate Calcium, 482 Glucose-Based Solutions, 483 Non–Glucose-Based Peritoneal Dialysis Solutions, 485 Future Development in Peritoneal Dialysis Solutions, 492 Conclusions, 492 Dialysis Adequacy and Prescription, 493 Defining Dialysis Adequacy, 493 Measuring Biochemical Indices of Dialysis Adequacy, 493

Normalization Factor for Urea and Creatinine Clearance, 495 Estimation of Residual Kidney Function, 495 Frequency of Monitoring of Biochemical Indices of Dialysis Adequacy, 495 Peritoneal Equilibration Test, 495 Conclusions, 504 Residual Kidney Function, 504 Importance of Residual Kidney Function in Peritoneal Dialysis, 504 Decline of Residual Kidney Function, 506 Conclusion, 508

The use of a novel portable or wearable equilibrium peritoneal dialysis (PD) technique was first described by Moncrief et al.1 in 1976 and named as continuous ambulatory peritoneal dialysis (CAPD) 2 years later. In the last 40 years, significant advances have been made in the understanding of peritoneal membrane function, residual kidney function (RKF), and dialysis adequacy and in the development of PD technology, solutions, and prescription. A significant growth in PD use has been reported worldwide, with some countries, such as Hong Kong and Thailand, adopting a “PD first policy.” A more thorough understanding of PD solutions, adequacy, and prescription is therefore essential for successful delivery of PD programs worldwide. This chapter covers three major issues in relation to PD: 1. PD solutions. This includes conventional standard glucose PD solutions, more biocompatible PD solutions, and solutions using alternative osmotic agents as well as other novel solutions that are under development. Various other constituents of PD solutions are also reviewed and their importance discussed in light of more recent studies. 2. PD adequacy and prescription. This section defines standard indices of dialysis adequacy, peritoneal membrane function and their measurements. Prescription strategies used to increase PD dose are reviewed. Specific discussions will be made on ultrafiltration failure (UFF) and management of volume overload. 3. Residual kidney function. This section reviews the importance of RKF in its contribution to the overall clearance and clinical outcomes in PD patients. Potential strategies in retarding loss or decline of RKF are discussed.

PERITONEAL DIALYSIS SOLUTIONS

480

Constituents of Peritoneal Dialysis Solutions Conventional commercially available PD solutions contain sodium (132 to 135 mmol/L), calcium (1.25 to 1.75 mmol/L), magnesium (0.5 mmol/L), chloride (95 to 103.5 mmol/L), and lactate (35 to 40 mmol/L) and varying concentrations of glucose/dextrose ranging from 1.36%/1.5% to 2.27%/2.5% and 3.86%/4.25%. This results in an overall osmolality of 344 to 347, 395 to 398, and 483 to 486 mOsmol/L, respectively (Table 31.1). The concentrations of various components of PD solutions were designed to facilitate ultrafiltration and removal of water-soluble uremic toxins while maintaining electrolyte and acid–base balance of PD patients. The various glucose concentrations of PD solutions provide an osmotic gradient of different degrees that allows ultrafiltration to take place across the peritoneum. However, standard glucose-based PD solutions are acidic in pH (5.0 to 5.8) to prevent dextrose caramelization during the sterilization procedure. As a result of their high lactate, high glucose concentration, high osmolality, and high levels of glucose degradation products (GDPs), long-standing use of these standard glucose PD solutions has been associated with progressive peritoneal membrane injury, neovascularization, peritoneal sclerosis, and fibrosis.2 Furthermore, the low pH, high osmolarity, and glucose content of standard glucose PD solutions inhibit phagocytic functions of peritoneal leukocytes and impair host immune defense mechanisms.3,4 Instillation of these solutions may also be associated with inflow pain in some patients.5 

TABLE 31.1  Composition of Various Current Commercially Available Peritoneal Dialysis (PD) Solutions Amino acid or Nutrineal or 1.1% StaySafe Standard Solution Glucose PD Solutions

StaySafe Balance

Bica Vera

132

133

132

134

134

134

1.25 (PD-2) 1.75 (PD-4) 1.00 (PD-1) 0.25 96

1.25 1.75 — 0.25 95 (Physioneal-40) 101 (Physioneal-35)

— 1.75 — 0.25 96

1.25 — — 0.25 105

1.25 1.75 — 0.5 103.5

— 1.75 — 0.5 104.5

Lactate (mmol/L)

40

40

40

35

Bicarbonate (mmol/L) Glucose (mmol/L)

— 1.36%, 76 2.27%, 126 3.86%, 214 0 0 5.5 PD-2 1.36%, 346 mOsm 2.27%, 396 mOsm 3.86%, 485 mOsm PD-4 1.36%, 345 mOsm 2.27%, 395 mOsm 3.86%, 483 mOsm PD-1 1.36%, 344 mOsm 2.27%, 394 mOsm 3.86%, 484 mOsm

15 (Physioneal-40) 10 (Physioneal-35) 25 1.36%, 75.5 2.27%, 126 3.86%, 214 0 0 7.4 1.36%, 344 mOsm 2.27%, 395 mOsm 3.86%, 483 mOsm

1.25 1.75 — 0.5 100.5 for 1.25 mmol Ca 101.5 for 1.75 mmol Ca 2

0 0

0 0

0 87a 6.6 365 mOsm

35 1.5%, 83.2 2.3%, 126.1 4.25%, 235.8 0 0 7 1.25 mmol/L Ca solution 1.5%, 356 mOsm 2.3%, 399 mOsm 4.25%, 509 mOsm 1.75 mmol/L Ca solution 1.5%, 358 mOsm 2.3%, 401 mOsm 4.25%, 511 mOsm

35 1.5%, 83.25

75 0 5.2 284 mOsm

0 1.5%, 83.2 2.3%, 126.1 4.25%, 235.8 0 0 7 1.25 mmol/L Ca solution 1.5%, 356 mOsm 2.3%, 399 mOsm 4.25%, 509 mOsm 1.75 mmol/L Ca solution 1.5%, 358 mOsm 2.3%, 401 mOsm 4.25%, 511 mOsm

Sodium (mmol/L) Calcium (mmol/L) Low Standard Ultralow Magnesium (mmol/L) Chloride (mmol/L)

132

Icodextrin (g/L) Amino acids (mmol/L) Overall pH Approximate osmolality

aThe

0

0 0 7.4 358 mOsm

1.1% solutions consist of a combination of amino acids, including histidine, valine, isoleucine, alanine, leucine, arginine, lysine, glycine, methionine, proline, phenylalanine, serine, threonine, tyrosine, and tryptophan.

CHAPTER 31  Peritoneal Dialysis Solutions, Prescription and Adequacy

Physioneal

Icodextrin or Extraneal or 7.5% Solution

Dianeal Standard Glucose PD Solutions

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SECTION III  Dialysis

Dialysate Buffer The buffer present in standard PD solutions is lactate, with concentrations varying between 35 to 40 mmol (see Table 31.1). In patients with normal liver function, lactate is rapidly converted to bicarbonate such that 1 mM lactate absorbed generates 1 mM bicarbonate. The rapid metabolism of lactate to bicarbonate maintains the high dialysate to plasma lactate concentration gradient necessary for continued absorption without accumulation of lactate in the circulation.6 Absorption may be reduced with hypertonic glucose PD solution, because increased ultrafiltration may dilute the concentration of lactate in the peritoneal cavity, thus decreasing the concentration gradient for diffusion. Lactate in standard PD solution is normally present in a racemic mixture of approximately equimolar concentration of d-lactate and l-lactate isomers. l-Lactate was suggested to be more rapidly absorbed than d-lactate.6 Bicarbonate is regarded as the most physiological and biocompatible buffering system. However, calcium and magnesium precipitate in the presence of bicarbonate and with an alkaline pH. Thus magnesium and calcium must be omitted from bicarbonate-containing dialysate. Patients doing PD with these calcium-free and magnesium-free solutions may develop deficits of calcium and magnesium. A dual-chamber dialysate bag in which one chamber contains the bicarbonate buffer of 34 mmol/L and the other contains a solution with calcium and magnesium has therefore been designed. The two solutions are mixed together only before instillation into patients’ abdomen, thus preventing calcium and magnesium carbonate precipitation. The neutral pH bicarbonate solution has been found to be well tolerated and effective in ameliorating metabolic acidosis7 and is currently used in daily clinical practice in some parts of the world. Treatment of metabolic acidosis is well known to be associated with downregulation of muscle ubiquitin–proteasome complex and inhibition of muscle degradation.8 More details are discussed in the Biocompatible Peritoneal Dialysis Solutions section. Bicarbonate-containing solutions (e.g., 25 mmol/L) may also be available in a mixture form with lactate (15 mmol/L), because solutions with pure supraphysiological concentration of bicarbonate have been associated with more abdominal pain than mixed bicarbonate and lactate solution.5 

Dialysate Calcium Patients treated with PD may be in negative, positive, or neutral calcium balance, depending on various factors, including dialysate calcium concentration, dietary calcium intake, dose of calcium-based phosphorus binders used, and use of vitamin D analogs. Hou et al.9 found that a high dialysate calcium concentration of 1.75 mM may lead to positive calcium balance and increased plasma calcium, whereas a low dialysate calcium concentration of 0.75 mM may lead to negative calcium balance and decreased plasma calcium. A dialysate calcium concentration of 1.25 mM maintained neutral calcium balance with minimal perturbation in plasma calcium9 (Fig. 31.1). However, plasma calcium does not reflect body calcium balance because 99% of calcium resides in the bone.10

Plasma calcium concentration (mmol/L)

482

+ 21.9 mmol (879 mg)

2.74 1.75 mM Ca

2.62 2.50

1.25 mM Ca

2.37 2.25 2.12

-5.8 mmol (231 mg) 0.75 mM Ca

2.00 1.87 1.75 0

30

60

90 120 150 180 210 240 Time (minutes)

300

FIG. 31.1 Changes in plasma calcium concentration over a 4-hour dwell of PD fluid with different dialysate calcium concentrations, namely 0.75 mM, 1.25 mM, and 1.75 mM. (Reproduced with permission from Hou SH, Zhao J, Ellman CF, Hu J, Griffin Z, Spiegel DM, et al. Calcium and phosphorus fluxes during hemodialysis with low-calcium dialysate. Am J Kidney Dis. 1991;18(2):217-224.)

The addition of vitamin D analogs and calcium-based binders may increase extracellular calcium and increase the risk for positive calcium balance even when 1.25 mM calcium dialysate is used.10 In fact, it is somewhat of a misnomer that current commercially available high-calcium (1.75 mM) PD solution is termed standard calcium solution, whereas 1.25 mM calcium concentration solution is termed low-calcium solution but in fact is the more physiological calcium concentration (see Table 31.1). As nicely demonstrated in two calcium balance studies, an elemental calcium intake of 1.5 to 2 g induced positive calcium balance in patients with chronic kidney disease (CKD).11,12 There are concerns that high-calcium dialysate may induce low parathyroid hormone and has been associated with a higher risk for cardiovascular death in hemodialysis patients.13 On the other hand, low-calcium dialysate may stimulate an increase of parathyroid hormone and worsen secondary hyperparathyroidism.14-16 Although an earlier study17 suggested that low-calcium (1.25 mM) dialysate use may increase parathyroid hormone in the short term, addition of calcium-based phosphorus binders and vitamin D analogs appeared to inhibit parathyroid hormone increase and stabilize its level over time. Furthermore, use of lowcalcium (1.25 mM) dialysate may be associated with a lower incidence of hypercalcemia in PD patients.18,19 A previous small randomized controlled trial15 (RCT) found no difference in bone histomorphometry for PD patients randomly assigned to receive 1.25 mM or 1.75 mM calcium solution for 1 year. There were some suggestions that PD patients using 1.25 mM calcium dialysate may have less progression in arterial stiffness than those receiving 1.75 mM calcium dialysate.20,21 In a 2016 prospective RCT,22 425 hemodialysis patients with intact parathyroid hormone ≤ 300 pg/mL were randomly assigned to receive either 1.25 mM or 1.75 mM calcium dialysate; those receiving 1.75 mM calcium dialysate had significantly more progression in coronary artery calcium score over 24 months than those using 1.25 mM calcium dialysate.

CHAPTER 31  Peritoneal Dialysis Solutions, Prescription and Adequacy

483

Intraperitoneal Glucose

Systemic Effects

Intraperitoneal (local) Effects

Glucotoxicity

Glucose Degradation Products

Glycemic Control

Hyperosmolality

Carbohydrate/caloric load 100-200 g glucose/day 320-640 kCal/day

Polyol pathway Hexosamine pathway

Changes to Peritoneal Membrane Structure and Function

Protein kinase C pathway

↑ Visceral Fat Mass Dyslipidemia

AGE pathway Fluid overload Inflammation

Increased Cardiometabolic Risk? FIG. 31.2 Local and systemic effects of PD glucose solutions. (Reproduced with permission from Holmes CJ. Reducing cardiometabolic risk in peritoneal dialysis patients: role of the dialysis solution. J Diabetes Sci Technol. 2009;3(6):1472-1480.)

Subgroup analysis indicated that progression of coronary artery calcification was found mainly in the subgroup with poor phosphorus control, namely serum phosphorus level ≥ 4.7 mg/dL. Furthermore, the 1.25-mM low-calcium dialysate group had a significant decrease in the prevalence of histologically diagnosed low bone turnover, from 85% to 41.8%, whereas the prevalence of low bone turnover did not change over 24 months in the 1.75-mM high-calcium dialysate group. Although a similar study is not available in PD patients, both the Kidney Disease Improving Global Outcomes 2017 CKD-mineral bone disease (MBD) guideline23 and the International Society of Peritoneal Dialysis (ISPD) Adult Cardiovascular and Metabolic guidelines24 suggested a 1.25-mM calcium-containing PD solution be used to avoid positive calcium balance or hypercalcemia. 

Glucose-Based Solutions One study25 found that initial ultrafiltration rate across the peritoneum is directly proportional to the initial glucose osmotic gradient. Generally, 1.36%/1.5% glucose/dextrose solution generates a 100 to 200 mL ultrafiltration, 2.27%/2.5% glucose/dextrose solution generates a 200 to 400 mL ultrafiltration, and 3.86%/4.25% glucose/dextrose solution generates more than 400 mL ultrafiltration. A 4-hour dwell of 2.5% PD dextrose solution has been used as the standard for peritoneal membrane equilibration test (PET).26 A net ultrafiltration of more than 200 mL from a standard 4-hour dwell of 2.27%/2.5% glucose/dextrose or more than 400 mL from a standard 4-hour dwell of 3.86%/4.25% glucose/dextrose solution is regarded as sufficient ultrafiltration. Values less than this indicate relative UFF.27 Symptoms of UFF may

not manifest overtly until RKF has declined significantly or is completely lost. Other than serving as an osmotic agent to facilitate ultrafiltration, glucose in the PD solution provides an important source of energy. The amount of glucose absorbed varies proportional to the concentration of glucose in the dialysate. The amount of glucose absorbed per liter of dialysate (y) can be predicted using the equation of Grodstein et al.28 as y = II.3 × x – 10.9, r = 0.96, in which x denotes the concentration of glucose from the dialysate. With an average peritoneal solute transport rate (PSTR), it is estimated that almost two-thirds of the PD fluid glucose is absorbed during a 4-hour dwell and more than 85% in an 8-hour dwell. This translates to an obligatory absorption of 43 g and 73 g of glucose with an 8-hour dwell of 2.5% and 4.25% solutions, respectively. Patients receiving four PD exchanges with three exchanges of 1.5% dextrose and one exchange of 2.5% were estimated to have absorbed 88 g glucose in a day. Typically glucose absorbed from PD fluids may amount to 100 to 300 g/day and may account for approximately 12% to 34% of total energy input. Thus it may lead to weight gain in some patients,29 although this has not been reproduced in other studies.30,31 Hypertonic glucose solutions may also add satiety and reduce appetite in PD patients. Glucose-based PD solutions have various other local and systemic adverse effects (Fig. 31.2).

Local Effects Glucose exerts direct cytotoxic effects on peritoneal mesothelial cells and causes diabetiform changes in the postcapillary venules, leading to changes in peritoneal membrane

484

SECTION III  Dialysis

structure and function.32 The standard heat sterilization of glucose-based PD solutions accelerates the generation of GDPs.33-35 The formation of GDPs during heat sterilization may be reduced by lowering the pH of the solution.36 GDPs are locally cytotoxic and glycated local proteins form advanced glycation end-products (AGEs)37 and contribute to the long-term bioincompatibility of PD solutions. GDP and AGEs exert damaging effects on the peritoneal membrane by causing mesothelial cell loss, inflammation, submesothelial fibrosis, calcification, vasculopathy, and diabetiform neoangiogenesis.38,39 Data from the Peritoneal Biopsy Registry indicated a thickening of the submesothelial compact zone and development of a diabetiform occlusive vasculopathy of small arterioles and postcapillary venules with neovascularization with increasing time on PD.40 Peritoneal biopsy specimens taken from PD patients with low ultrafiltration capacity demonstrated that AGE accumulation in the peritoneal membrane was positively correlated with the development of severe interstitial fibrosis and microvascular sclerosis.41 All these negative effects on the peritoneum decrease the effectiveness of the peritoneum as a dialysis membrane, resulting in an increased PSTR with time on dialysis and intensifying the need for using hypertonic glucose solutions.42 This may eventually lead to peritoneal membrane failure (PMF), increased risk for fluid overload, and protein energy wasting (PEW). Several studies43-47 reported that a high PSTR was associated with worse patient survival, and some studies43,44 also reported a trend toward worse PD technique survival with high PSTR. A more contemporary analysis based on a nationally representative cohort of PD patients in the United States, of whom 87% were treated with automated peritoneal dialysis (APD), reinforced a similar finding; that is, the dialysate to plasma (D/P) creatinine ratio was associated with survival outcome and linearly associated with mortality. For every 0.1 unit increase in the D/P creatinine ratio, the adjusted mortality risk increased by 7% (95% confidence interval [CI], 1.02 to 1.13), the adjusted hospitalization risk increased by 5% (95% CI, 1.03 to 1.06). On the other hand, ultrafiltration volume was inversely related with hospitalization rate but not with all-cause mortality.46 

Systemic Effects of Glucose-Based Peritoneal Dialysis Solutions The cumulative, systemic PD glucose absorption through the peritoneum may aggravate various metabolic disturbances, including insulin resistance, hyperglycemia, accumulation of atherogenic visceral fat, weight gain, and dyslipidemia, and worsen glycemic control in PD patients with diabetes.48 Insulin resistance has been found to be associated with a higher cardiovascular mortality and worse clinical outcomes in dialysis patients.49 New-onset hyperglycemia has been reported in end-stage renal disease (ESRD) patients sometime after commencing PD treatment. Intraperitoneal glucose absorption gives rise to higher plasma glucose levels as well as a more extended period of hyperinsulinemia compared with an equivalent dose of oral glucose.48 Hyperglycemia not only

stimulates hyperinsulinemia but also increases mitochondrial superoxide generation, which activates four key pathways— namely, the polyol pathway, hexosamine pathway, protein kinase C pathway, and AGE pathway—causing hyperglycemic damage.50,51 Activation of these pathways induces the expression of endothelin 1, vascular epithelial growth factor, transforming growth factor beta, fibronectin, collagen, and leptin genes and at the same time downregulates endothelial nitric oxide synthase and upregulates transcription factor nuclear factor kappa B. Together with an increased oxidative stress, this results in a heightened inflammatory response, insulin resistance, and peritoneal membrane damage as well as a higher risk for accelerated atherosclerosis.52,53 Derangements in glucose and insulin metabolism are evident in early CKD.54 With progression of CKD, peritubular insulin uptake increases, which compensates for the decline in the metabolism of filtered insulin. As kidney function further deteriorates, insulin clearance also decreases. In addition, insulin resistance and tissue insensitivity to insulin increase, resulting in suboptimal insulin secretion in response to a glucose load or hyperglycemia.55,56 Usually around 60% of the glucose in PD solutions may be reabsorbed during the dwell, thus causing disturbed carbohydrate metabolism even in nondiabetic PD patients, further aggravating insulin resistance. Hyperinsulinemia also contributes to hypertriglyceridemia. Insulin enhances hepatic triglyceride synthesis and indirectly reduces the metabolism of very-low-density lipoprotein cholesterol. Use of glucose-based PD solutions has been associated with more weight gain and fat mass increase than non– glucose-based PD solutions.57,58 Increased truncal fat mass and visceral adiposity over time using glucose-based PD solutions has been positively associated with serum leptin and inflammation and negatively associated with serum adiponectin,59,60, providing indirect evidence of an important link between truncal fat mass and cardiometabolic risk markers. Increased abdominal adiposity has been implicated to contribute significantly to a higher cardiovascular risk in PD patients.61 An in  vitro study62 found that leptin secretion is directly stimulated in adipocytes being exposed to glucose-based PD solutions via activation of the hexosamine pathway. The degree of leptin secretion correlated directly with the amount of glucose being exposed. Similar stimulation on leptin secretion was not noted with non–glucose-based solutions.62 In keeping with these experimental data, higher leptin levels were reported in PD patients than in hemodialysis patients.63 Several studies have examined whether long-standing exposure to glucose-based PD solutions may be associated with worse clinical outcomes. So far, most available studies were retrospective and results were inconsistent. A retrospective analysis from Taiwan64 suggested that a higher initial glucose load within the first 6 months of initiation of PD was associated with higher prevalent diabetes mellitus, lower serum albumin, and lower RKF and a higher risk for technique failure but not mortality. Another extended follow-up study65 using timedependent covariate analysis reported that long-term glucose exposure was associated with a greater risk for mortality and

CHAPTER 31  Peritoneal Dialysis Solutions, Prescription and Adequacy technique failure. In keeping with these observations, a retrospective analysis from China66 found that use of PD solutions of higher glucose concentration over the initial 6 months of PD treatment was associated with a greater risk for all-cause and cardiovascular disease mortality. Metabolic syndrome, which consists of a constellation of clinical features including central obesity, hypertension, atherogenic dyslipidemia, hyperglycemia, and insulin resistance, has been found to be associated with adverse cardiovascular outcomes in nondiabetic PD patients.67 Hyperglycemia and hyperinsulinemia induced by hypertonic glucose PD solutions may also be associated with short-term adverse hemodynamic changes. A 4.25% dextrose solution has been found to increase blood pressure and cardiac output acutely in the absence of any acute changes in left ventricular diameter, whereas non–glucose-based PD solution was not associated with similar hemodynamic disturbance.68 

Non–Glucose-Based Peritoneal Dialysis Solutions Glucose Polymer Solutions Icodextrin is a starch-derived, branched, water-soluble glucose polymer with an average molecular weight between 13,000 and 19,000 Da. The current commercially available formulation is a 7.5% icodextrin solution with a sodium concentration of 133 mmol/L and a lactate concentration of 40 mmol/L and is isoosmotic (284 mOsmol/L) (see Table 31.1). Icodextrin is not significantly metabolized in the peritoneum. Instead it is slowly absorbed into the bloodstream via the lymph vessels, with around 40% being absorbed after a 12-hour period, and is metabolized into oligosaccharides and maltose by circulating α-amylase. The maltose cannot be metabolized in the circulation of humans because maltase is not in the circulation but is present in the kidney and intracellularly in the body. Nevertheless, there is no evidence to date that maltose accumulates within patients treated with icodextrin. Because icodextrin stays in the peritoneal cavity for a considerable period and very little gets reabsorbed, icodextrin is a superior osmotic agent and has better ultrafiltration capacity compared with conventional glucose, especially with longer dwell hours. Icodextrin was approved for use by the Food and Drug Administration of the United States in 2002 to increase ultrafiltration in PD patients. Effects on ultrafiltration, volume status, and technique survival.  Over the years, considerable clinical data demonstrated the efficacy of icodextrin in increasing ultrafiltration in PD patients compared with standard glucose solutions.69-72 When used as once-daily overnight long dwell in CAPD or long day dwell in continuous cycler PD (CCPD), icodextrin can achieve a net ultrafiltration equivalent to or even more than that of 2.27% or 3.86% glucose solution, depending on the peritoneal membrane transport characteristics and length of dwell.71,73,74 Generally the ultrafiltration, relative to glucose, is greater in patients with high PSTR. In patients with high or high-average peritoneal membrane transport, the ultrafiltration volume with icodextrin is significantly larger than that

485

with 2.27% or 3.86% PD solution.71,75 As a result of better ultrafiltration, more sodium is also removed by convection using icodextrin compared with 2.27% glucose PD solution.76 Thus it has been used as a salvage therapy in patients with clinically inadequate ultrafiltration or PMF. There is a suggestion that icodextrin may extend the life of PD treatment.77 Two earlier short-term RCTs both demonstrated better overall ultrafiltration with icodextrin compared with conventional glucose solution, resulting in better volume status as assessed by bioimpedance.69,70 Konings et  al.70 also suggested a decrease in left ventricular mass index with icodextrin. Davies et  al.69 reported that an icodextrin group had weight loss, whereas a standard glucose solution group had weight gain. This may be explained by more fluid removal or less fat mass gain with icodextrin. Another prospective RCT found that icodextrin improved technique survival rate in PD patients with background diabetic nephropathy, though a more rapid decline in RKF was found over a 24-month follow-up period.78 Several meta-analyses have reviewed the use of icodextrin versus standard glucose PD solutions in relation to peritoneal ultrafiltration and small solute clearance (Table 31.2).79-82All studies showed significantly better daily peritoneal ultrafiltration with icodextrin than standard glucose PD solutions. The systemic review by Cho et  al.79,80 additionally found a significantly lower incidence of uncontrolled fluid overload with icodextrin compared with standard glucose PD solutions without compromising RKF. Icodextrin may be a useful salvage therapy in PD patients with refractory fluid overload or UFF and may prolong technique survival.77,83,84 However, so far there are no prospective trials examining the effects of icodextrin on patients’ survival as the primary endpoint. Based on available evidence, the ISPD Adult Cardiovascular and Metabolic Guidelines 201524 recommended that oncedaily icodextrin be considered as an alternative to hypertonic glucose PD solutions for long dwells in those experiencing difficulties to maintain euvolemia as a result of insufficient peritoneal ultrafiltration, taking into account the PSTR. The level of recommendation for the statement was given a grading of 1B.24 Similarly, the European Best Practice Working Group (EBPG) recommended icodextrin be used as the long dwell in high transporter patients with a net peritoneal ultrafiltration <400 mL during a PET with a 3.86% glucose solution.85  Effects on metabolic profile.  Use of icodextrin as the long-dwell solution also minimizes glucose exposure and incurs less metabolic derangement compared with standard glucose PD solutions. Changes in triglycerides level have been suggested to correlate with the amount of peritoneal glucose absorption.86 Several prospective RCTs found that icodextrin, by minimizing glucose absorption, may improve glucose metabolism, improve insulin sensitivity, and reduce dyslipidemia compared with standard glucose PD solutions. An earlier prospective open-label multicenter study from Japan87 found that switching PD patients from standard glucose PD solutions to icodextrin reduced triglycerides and mean total and low-density lipoprotein cholesterol levels. Among

486

SECTION III  Dialysis

TABLE 31.2  Table Summarizing Systemic Reviews on Clinical Trials With Icodextrin Author, Year

No. of Studies (N)

He et al., 201182

Total nine trials: Two trials (n = 131), peritoneal creatinine clearance Five trials (n = 528), peritoneal creatinine clearance rate Four trials (n = 508), peritoneal urea clearance rate Total 11 trials: Four trials (n = 102), peritoneal ultrafiltration Two trials (n = 100), fluid overload episodes Four trials (n = 114), RKF Three trials (n = 69), urine volume (n = 69)

Cho et al., 201379 and Cho et al., 201480 (same findings)

Key Results Significant ↑ in peritoneal efficiency ratio with icodextrin vs. control (MD 6.84, 95% CI, 4.43–9.25) Significant ↑ in peritoneal creatinine clearance rate with icodextrin vs. control (MD 0.51, 95% CI, 0.35–0.67) Significant ↑ in peritoneal urea clearance rate with icodextrin vs. control (MD 0.43, 95% CI, 0.26–0.61) Significant ↑ in peritoneal ultrafiltration with icodextrin vs. control (MD 448.54, 95% CI, 289.28–607.80 mL/d) Significant ↓ in uncontrolled fluid overload episodes with icodextrin vs. control (RR 0.30, 95% CI 0.15–0.59) Did not compromise RKF (standardized MD 0.12, 95% CI, −0.26 to 0.49) or urine output (three trials; 69 patients; MD −88.88, 95% CI, −356.88 to 179.12 mL/d) with icodextrin use for up to 2 years

MD, Mean difference; RKF, residual kidney function; RR, relative risk.

those with glycated hemoglobin ≥6.5%, glycemic control also improved with icodextrin.87 A randomized study from Mexico found that diabetic PD patients using icodextrin as the long dwell had reduced insulin requirement, lower fasting glucose, lower glycated hemoglobin, lower serum triglycerides, and fewer adverse events compared with a standard glucose group.75 IMPENDIA and EDEN trials evaluated the clinical effects of a glucose-sparing PD regimen, namely icodextrin and amino acid–based PD solutions, in a multicenter study of 251 diabetic PD patients.88 The study88 reported an average of 0.5% improvement in glycated hemoglobin (as the primary study outcome) in the intervention group versus standard glucose group at 6 months. The mean glycated hemoglobin reduced from 7.7% to 7.2%. Secondary outcomes included a significant reduction in very-low-density lipoprotein cholesterol, serum triglyceride, and apo-B levels in the intervention group compared with control group. However, a significantly higher incidence of treatment-related adverse events, serious adverse events, hypoglycemia, and volume overload as well as study withdrawal were reported in the intervention group.88 Icodextrin may also have favorable effects on plasma adipokines.89 Another prospective open-label RCT from Japan78 failed to find a significant benefit of icodextrin on glycemic control or lipid profile in diabetic PD patients, but both glycemic control and lipid profile were secondary study outcomes. A more recent multicenter open-label short-term (90 days) RCT90 of 60 nondiabetic automated PD patients found that icodextrin use as the long dwell significantly reduced insulin resistance as denoted by homeostatic model assessment (HOMA) index. There are some suggestions that using twice-daily exchanges of icodextrin in place of standard glucose PD solution may reduce peritoneal glucose exposure by up to 50%, thus lowering systemic glucose absorption by 60%.91 Longer-term studies are needed to evaluate the safety of this approach because icodextrin metabolite levels will be higher than a single daily exchange. 

Effects on residual kidney function.  Although there were some earlier suggestions that increased ultrafiltration with icodextrin may jeopardize RKF, a systematic review by Cho et  al.79,80 did not find any significant difference between icodextrin and standard glucose PD solution in relation to decline in RKF and urine volume. However, RKF and urine volume were not primary outcomes in these studies. In a prospective multicenter RCT from Korea92 examining changes in residual glomerular filtration rate (GFR) and urine volume as the primary outcomes, there were some suggestions that icodextrin may be associated with slower residual urine volume loss compared with standard glucose PD solutions over a period of 12 months in both the intention-to-treat analysis and per-protocol analysis.  Potential adverse effects.  Use of icodextrin may be associated with potential adverse events such as sterile peritonitis or skin rash as a result of allergy to starch. Sterile peritonitis with icodextrin has been described and was related to contamination of icodextrin by peptidoglycan, which is a constituent of bacterial cell walls.93,94 Clinically, patients with sterile or chemical peritonitis may remain well despite having cloudy effluent. The differential cell count of PD fluid is associated with leukocytosis with predominantly eosinophilia but not neutrophils.95 PD effluent usually clears up rapidly on withdrawal of icodextrin. According to the systematic review by Cho et  al.,79,80 the incidence of chemical peritonitis was not increased with icodextrin compared with standard glucose PD solutions. The reported incidence of skin rash with icodextrin use is around 10% but may be up to 18.9%.96,97 It is usually mild and localized to the palm of hands. Occasionally, a more severe form of exfoliating dermatitis may occur, requiring withdrawal of icodextrin.98 The presence of icodextrin and its metabolites in plasma may interfere with some laboratory analytical methods on glucose measurements. For example, certain glucometers that use glucose dehydrogenase–pyrroloquinoline quinone will overestimate blood glucose in patients using icodextrin.99,100 

CHAPTER 31  Peritoneal Dialysis Solutions, Prescription and Adequacy Biocompatible Peritoneal Dialysis Solutions Neutral pH, low-GDP solutions.  Epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells is a hallmark feature in the peritoneum of PD patients101 and was suggested in earlier studies to play an essential role in the initiation of peritoneal fibrosis,102 leading to peritoneal membrane function decline and failure.103,104 In vitro experiments found that mesothelial cells culturing in neutral pH, low-GDP solutions had less EMT than in standard glucose solutions.105 Effluent mesothelial cells grown ex  vivo from patients treated with neutral pH, low-GDP solutions also had a trend toward maintaining more of an epitheloid phenotype with less induction of proinflammatory cytokine production, whereas mesothelial cells from patients treated with lactate-buffered standard glucose PD solution invariably transdifferentiated into a nonepithelial phenotype by 24 months.105 This led to the development and clinical application of more “biocompatible” PD solutions to minimize adverse effects to the peritoneum. However, a later experimental study106 used inducible genetic fate mapping and demonstrated type I collagen–­producing submesothelial fibroblasts as specific progenitors of α-smooth muscle actin–positive myofibroblasts that accumulated progressively in various models of high-glucose solutions or transforming growth factor β1–induced peritoneal fibrosis. Notably, only submesothelial fibroblasts but not mesothelial cells expressed α-smooth muscle actin after induction of peritoneal fibrosis in mice. Furthermore, pharmacological inhibition of platelet derived growth factor receptor, which is expressed by submesothelial fibroblasts but not mesothelial cells, attenuated peritoneal fibrosis. These data provide important novel evidence that submesothelial fibroblasts may be the key cell source of myofibroblasts driving peritoneal injury and fibrosis.106 For the glucose-based PD solutions to be more biocompatible clinically, a dual-chamber bag system was designed to allow heat sterilization and storage to occur at a lower pH in a separate bag to minimize GDP generation. Some of the low-GDP solutions used bicarbonate instead of lactate as the buffering system to minimize exposure to lactate as well. Thus mixing the contents of the two chambers just before use would produce a more physiological and neutral pH of around 7.0 (see Table 31.1). Earlier preclinical studies found that use of neutral pH, low-GDP solutions was associated with better preserved peritoneal membrane morphology and function40 and better host immune defense.107 Several subsequent observational studies also suggested similar findings, that use of neutral pH, low-GDP solutions may be associated with more favorable peritoneal membrane morphology,108 less systemic inflammation,109 and better patient survival outcomes.110,111 Numerous RCTs112-122 were conducted in the last 10 years on neutral pH, low-GDP solutions; these are summarized in Table 31.3.  Effects on residual kidney function and urine volume.  The Euro Balance Trial123 was the first RCT that examined the effects of neutral pH, low-GDP solutions on the peritoneal membrane and RKF in a crossover design. The study found that use of neutral pH, low-GDP solutions is accompanied by

487

a significant improvement in peritoneal membrane integrity as reflected by higher levels of peritoneal cancer antigen 125 (CA125) and procollagen peptide and significantly decreased circulating AGE levels compared with standard glucose solution over a 12-week time frame. Renal urea and creatinine clearance (CrCl) and urine volume also increased after exposure to neutral pH, low-GDP solutions.123 To date, the balANZ trial represents the largest RCT with the longest follow-up (2 years) that examined the effect of neutral pH, low-GDP solution on RKF and various other patient outcomes. It was an investigator-initiated, multicenter, multicountry, open-label, parallel-design RCT including 185 incident PD patients. The primary outcome of the study was slope of RKF decline, which did not have a significant difference between the neutral pH, low-GDP solution group and the control group (standard glucose solution) up to 2 years. However, the biocompatible group had significantly longer times to anuria (P = 0.009), longer time to first peritonitis episode (P = 0.01), and lower rates of peritonitis (0.30 vs. 0.49 episodes per year, P = 0.01) compared with the standard glucose solution group. Nevertheless, these were secondary outcomes. No significant difference was reported between the two groups in relation to technique survival and patient survival.118 In keeping with the findings from the balANZ trial, several other investigators found that neutral pH, low-GDP solutions attenuated decline of RKF in incident PD patients in an RCT setting.116,117,120,122 However, some other controlled trials did not reproduce similar results,112,114,115 which may be related to the rather short study durations of up to 12 months and relatively small sample sizes. The findings from these RCTs were summarized in the systematic review by Cho et  al.80,124-127 Essentially, the use of neutral pH, low-GDP solutions appeared to produce better preservation of RKF and greater urine volumes. In the Cochrane review, the benefit of low-GDP solutions in preserving RKF was found most significantly between 12 to 23 months (P = 0.0005) but also from 24 months and beyond, though less significant (P = 0.04). Similarly, low-GDP solutions were beneficial in preserving urine volume between 12 to 23 months (P = 0.0005) and from 24 months and beyond (P = 0.04)80 (Fig. 31.3). In addition, in 2016 the Trio study128 involving 67 incident PD patients also reported significantly slower decline in RKF in the lactate-buffered low GDP solution (Gambrosol Trio) group compared with the standard glucose PD solution (see Table 31.3). Based on these data, the 2015 ISPD Adult Cardiovascular and Metabolic Guidelines recommended that neutral pH, low-GDP solutions be considered for better preservation of RKF if used for 12 months or more (grading 2B).24  Effects on peritonitis risk.  In the balANZ trial, the time to first peritonitis episode was longer and overall peritonitis rates were lower with neutral pH, low-GDP solution compared with standard glucose solutions.118 A separate analysis on the same trial suggested a broad reduction in peritonitis caused by gram-positive, gram-negative, and specifically non-Pseudomonas gram-negative organisms as well as less severe peritonitis in patients using biocompatible solutions.129

488

SECTION III  Dialysis

However, similar findings were not reported in other trials. The Cochrane review did not find any difference in peritonitis rates between neutral pH, low-GDP solutions and standard glucose PD solutions.80  Effects on peritoneal solute transport and ultrafiltration volume.  The effects of biocompatible solutions on ultrafiltration volume were inconclusive. Several studies suggested lower ultrafiltration volume with neutral pH, low-GDP solutions compared with standard glucose solutions.118,122 In a separate analysis of the balANZ trial, the mean D/P creatinine ratio at 4 hours remained stable in the neutral pH, low-GDP solutions group but increased significantly in the control group over 2 years.130 Ultrafiltration volume was lower in the neutral pH, low-GDP solution group compared with the control group up to 6 months. However, over 2 years, ultrafiltration volume increased significantly in the neutral pH, low-GDP solution group but remained stable in the control group.130 The differential effects of neutral pH, low-GDP

solutions on peritoneal solute transport and ultrafiltration over time remain poorly understood. Another study115 suggested that neutral pH, low-GDP solution may be associated with a higher ultrafiltration volume. Overall the recent Cochrane and Canadian systematic reviews suggested a trend toward lower ultrafiltration volume with biocompatible PD solutions compared with standard glucose solutions but not reaching statistical significance. No significant difference was found in the peritoneal creatinine clearance.80,124  Other clinical outcomes.  Earlier studies suggested a potential benefit in reducing inflow pain with more biocompatible PD solutions.5,131 However, a recent Cochrane review suggested that the trend toward lower incidence of inflow pain with neutral pH, low-GDP solutions did not reach statistical significance. There is no convincing evidence to indicate that use of neutral pH, low-GDP solutions improve patients’ survival and technique survival.80 So far, no studies have been

Comparison: 1 Low-GDP (all buffer types) versus standard glucose dialysate Outcome: 5 Residual renal function: PD fluid types

Study or subgroup 1 Balance Bajo 2011 balANZ Trial 2006 Choi 2008 Kim 2003 Kim 2008 Szeto 2007 Subtotal (95% CI)

Neutral pH, low GDP N 9 40 38 16 25 24 152

Mean (SD)

Standard glucose N

4.2 (2.6) 3.4 (2.79) 4.7 (10.7) 2.3 (1.2) 3.5 (3.4) 2.72 (2.08)

Std. Mean Difference IV, Random, 95% CI

Mean (SD)

Weight

Std. Mean Difference IV, Random, 95% CI

3 48 30 10 21 24 136

4.2 (4) 3.2 (2.82) 1.86 (6.44) 1.8 (2.2) 1.65 (1.97) 2.81 (2.87)

1.6% 15.8% 12.0% 4.4% 7.9% 8.7% 50.5%

0.0 [–1.31, 1.31] 0.07 [–0.35, 0.49] 0.31 [–0.17, 0.79] 0.29 [–0.50, 1.09] 0.64 [0.04, 1.24] –0.04 [–0.60, 0.53] 0.22 [–0.02, 0.45]

Heterogeneity: Tau2 = 0.0: Chi2 = 3.45, df = 5 (P = 0.63): I2 = 0.0% Test for overall effect: Z = 1.79 (P = 0.073) 2 Purely bicarbonate buffered Fernandez-Perpen 2012 5 6 (4.4) Schmitt 2002 13 2.54 (2.62) Weiss 2009 15 4.77 (3.78) Subtotal (95% CI) 33

3 11 11 25

4.2 (4) 2.92 (1.98) 4.1 (2.8)

1.3% 4.3% 4.6% 10.2%

0.37 [–1.09, 1.82] –0.16 [–0.96, 0.65] 0.19 [–0.59, 0.97] 0.07 [–0.46, 0.59]

Heterogeneity: Tau2 = 0.0: Chi2 = 0.55, df = 2 (P = 0.76): I2 = 0.0% Test for overall effect: Z = 0.25 (P = 0.80) 3 Multiple fluid types in treatment group Fan 2008 44 5.1 (4.08) Lai 2012a 58 2.3 (2.74) Subtotal (95% CI) 102

49 67 116

5.38 (3.75) 1.69 (2.29)

16.8% 22.4% 39.3%

–0.07 [–0.48, 0.34] 0.24 [–0.11, 0.59] 0.10 [–0.20, 0.41]

Heterogeneity: Tau2 = 0.01: Chi2 = 1.29, df = 1 (P = 0.26): I2 = 23% Test for overall effect: Z = 0.66 (P = 0.51) Total (95% CI) 287

277

100.0%

0.16 [–0.01, 0.32]

Heterogeneity: Tau2 = 0.0: Chi2 = 5.78, df = 10 (P = 0.83): I2 = 0.0% Test for overall effect: Z = 1.85 (P = 0.064) Test for subgroup differences: Chi2 = 0.47, df = 2 (P = 0.79): I2 = 0.0%

A

–2

–1

Favors standard glucose

0

1

2

Favors low GDP

FIG. 31.3  Cochrane systematic review on studies comparing low-GDP (all buffer types) solutions versus standard glucose solution in relation to (A) residual kidney function, (B) urine volume, (C) analysis of residual kidney function from 12 to 24 months, and (D) residual kidney function up to 12 months. (Reproduced with permission from Cho Y, Johnson DW, Craig JC, Strippoli GF, Badve SV, Wiggins KJ. Biocompatible dialysis fluids for peritoneal dialysis. Cochrane Database Syst Rev. 2014(3):CD007554.)

CHAPTER 31  Peritoneal Dialysis Solutions, Prescription and Adequacy

489

Review: Biocompatible dialysis fluids for peritoneal dialysis Comparison: 1 Low-GDP (all buffer types) versus standard glucose dialysate Outcome: 6 Urine volume

Study or subgroup

Neutral pH, low GDP N

1 3 months Fan 2008 Weiss 2009

Subtotal (95% Cl)

Mean (SD)[mL.AD]

Standard glucose N

44

800 (663.3)

49

15

1346.1 (870.8)

12

59

Mean Difference Mean (SD)[mL.AD] IV, Random 95% Cl

Weight

Mean Difference IV, Random 95% Cl

1000 (700)

109%

–200.00 [–477.1R, 77.18]

1000.6 (770)

25%

345.50 [–774.17, 965.17]

13.4%

–0.54 [–515.46, 514.38]

61

Heterogeneity: Tau2 = 88804.91: Chi2 = 2.48, df = 1 (P = 0.12): I2 = 60% Test for overall effect: Z = 0.00 (P = 1.0) 2 12 months 290 (236.6 30 38 Choi 2008 Kim 2008 Szeto 2007

36

750 (6.79)

24

800 (600)

143 (172.9)

41.8%

137.00 [39.60, 234.40]

33

532 (408)

12.0%

218.00 [–43.87, 479.87]

24

690 (520)

8.6%

110.00 [–207.65, 427.65]

62.4%

144.03 [56.29, 231.77]

Subtotal (95% Cl)

98

87

Subtotal (95% Cl)

42

48

Heterogeneity: Tau2 = 0.0: Chi2 = 0.37, df = 2 (P = 0.83): I2 = 0.0% Test for overall effect: Z = 3.22 (P = 0.0013) 3 24 months balANZ Trial 2006 42 814 (624) 48 Heterogeneity: not applicable Test for overall effect: Z = 0.86 (P = 0.39) 4 3 years + 745.7 (819.23) Lai 2012a 58

Subtotal (95% Cl)

58

Heterogeneity: not applicable Test for overall effect: Z = 2.04 (P = 0.041)

Total (95% Cl)

257

699 (639)

475.1 (635.92)

12.0%

115.00 [–146.33, 376.33]

12.0%

115.00 [–146.33, 376.33]

12.1%

220.60 [1053, 530.67]

67

12.1%

270.60 [10.53, 530.67]

263

100.0%

126.39 [26.73, 226.05]

67

Heterogeneity: Tau2 = 3711.80: Chi2 = 7.51, df = 6 (P = 0.28): I2 = 20% Test for overall effect: Z = 2.49 (P = 0.043) Test for subgroup difference: Chi2 = 1.24, df = 3 (P = 0.74), I2 = 0.0% –1000 –500

B

0

500 1000

Favors standard glucose

Favors low GDP

Review: Biocompatible dialysis fluids for peritoneal dialysis Comparison: 1 Low-GDP (all buffer types) versus standard glucose dialysate Outcome: 2 Residual renal function: 24 months and beyond Neutral pH, low GDP N

Weight

Std. Mean Difference IV, Random, 95% CI

4.2 (4)

3.3%

0.0 [–1.31, 1.31]

48

3.2 (2.82)

32.3%

0.07 [–0.35, 0.49]

3

4.2 (4)

2.7%

0.37 [–1.09, 1.82]

21

1.65 (1.97)

16.0%

0.64 [0.04, 1.24]

54.3%

0.25 [–0.07, 0.57]

45.7%

0.24 [–0.11, 0.59]

45.7%

0.24 [–0.11, 0.59]

100.0%

0.25 [0.01, 0.48]

Mean (SD)

Standard glucose N

Mean (SD)

9

4.2 (2.6)

3

40

3.4 (2.79)

5

6 (4.4)

Kim 2008

25

3.5 (3.4)

Subtotal (95% CI)

79

Study or subgroup 1 24 months Bajo 2011 balANZ Trial 2006 Fernandez-Perpen 2012

75

Heterogeneity: Tau2 = 0.0: Chi2 = 2.51, df = 3 (P = 0.47): I2 = 0.0% Test for overall effect: Z = 1.51 (P = 0.13) 2 3 years + Lai 2012a 58 2.3 (2.74)

67

Subtotal (95% CI)

67

58

Std. Mean Difference IV, Random, 95% CI

1.69 (2.29)

Heterogeneity: not applicable Test for overall effect: Z = 1.34 (P = 0.18) Total (95% CI) 137 142 Heterogeneity: Tau2 = 0.0: Chi2 = 2.51, df = 4 (P = 0.64): I2 = 0.0% Test for overall effect: Z = 2.02 (P = 0.044) Test for subgroup differences: Chi2 = 0.00, df = 1 (P = 0.98), I2 = 0.0% –2

C

–1

Favors standard glucose

0

1

2

Favors low GDP

FIG. 31.3, cont’d. Continued

490

SECTION III  Dialysis

Review: Biocompatible dialysis fluids for peritoneal dialysis Comparison: 1 Low-GDP (all buffer types) versus standard glucose dialysate Outcome: 2 Residual renal function: 24 months and beyond Neutral pH, low GDP N

Study or subgroup 1 24 months Bajo 2011

Mean (SD)

Standard glucose N

Mean (SD)

Std. Mean Difference IV, Random, 95% CI

Std. Mean Difference IV, Random, 95% CI

Weight

9

4.2 (2.6)

3

4.2 (4)

3.3%

0.0 [–1.31, 1.31]

40

3.4 (2.79)

48

3.2 (2.82)

32.3%

0.07 [–0.35, 0.49]

5

6 (4.4)

3

4.2 (4)

2.7%

0.37 [–1.09, 1.82]

Kim 2008

25

3.5 (3.4)

21

1.65 (1.97)

16.0%

0.64 [0.04, 1.24]

Subtotal (95% CI)

79

54.3%

0.25 [–0.07, 0.57]

45.7%

0.24 [–0.11, 0.59]

45.7%

0.24 [–0.11, 0.59]

100.0%

0.25 [0.01, 0.48]

balANZ Trial 2006 Fernandez-Perpen 2012

75

Heterogeneity: Tau2 = 0.0: Chi2 = 2.51, df = 3 (P = 0.47): I2 = 0.0% Test for overall effect: Z = 1.51 (P = 0.13) 2 3 years + Lai 2012a 58 2.3 (2.74)

67

Subtotal (95% CI)

67

58

1.69 (2.29)

Heterogeneity: not applicable Test for overall effect: Z = 1.34 (P = 0.18) Total (95% CI) 137 142 Heterogeneity: Tau2 = 0.0: Chi2 = 2.51, df = 4 (P = 0.64): I2 = 0.0% Test for overall effect: Z = 2.02 (P = 0.044) Test for subgroup differences: Chi2 = 0.00, df = 1 (P = 0.98), I2 = 0.0% –2

–1

Favors standard glucose

D

0

1

2

Favors low GDP

FIG. 31.3, con’d.

TABLE 31.3  An Overview of Randomized Controlled Trials of Neutral pH, Low-GDP

Solutions in Relation to Residual Kidney Function (RKF) or Urine Volume Reference

n

I/P

Follow-up Duration

Results

69

I

24 weeks

Szeto et al., 2007114

50

1

12 months

Choi et al., 2008115

104

1

12 months

Fan et al., 2008112

93

I

12 months

Kim et al., 2009116

91

1

12 months

Haag-Weber et al., 2010117

69

I

18 months

Johnson et al., 2012118

185

I

2y

No significant difference was found in decline in residual renal clearances between biocompatible, 2.7 ± 2.8–2.8 ± 4.4 mL/min, and standard glucose group, 3.6 ± 4.1–3.0 ± 3.3 mL/min. No significant difference was found in the rate of decline of RKF between neutral pH, low-GDP solutions (–1.19 ± 2.23 mL/ min/1.73 m2) and control group (–1.02 ± 3.27 mL/min/1.73 m2). No significant difference was found in the change in renal clearances or urinary volume between neutral-pH, low-GDP solution and standard glucose group. No significant difference was found in the change in RKF between biocompatible and standard glucose groups. No significant difference was found in urine volume in the two groups at any time point. Using a mixed-models method and adjusting for baseline differences in kidney function, the residual GFR at 12 months was significantly higher in the neutral pH, low-GDP solution group (P = 0.048). The rate of decline in RKF was significantly slower with biocompatible PD solution Gambrosol Trio (–1.5%/month [95% CI, –3.07% to 0.03%]) vs. standard glucose solution (–4.3%/month [95% CI, –6.8% to –2.06%, P = 0.04]); also, there was a slower decline in 24-hour urine volume (12 vs. 38 mL/month, P = 0.02) No significant difference was found in the slope of decline in RKF in either year 1 (–0.22 vs. –0.28 mL/min/1.73 m2) or year 2 (–0.09 vs. –0.10 mL/min/1.73 m2). A significantly longer time to anuria was reported in individuals assigned to neutral pH, low-GDP solution (P = 0.009).

Feriani et al.,

1998113

CHAPTER 31  Peritoneal Dialysis Solutions, Prescription and Adequacy

491

TABLE 31.3  An Overview of Randomized Controlled Trials of Neutral pH, Low-GDP

Solutions in Relation to Residual Kidney Function (RKF) or Urine Volume—cont’d Reference

n

I/P

Follow-up Duration

Results

Lai et al., 2012119

125

I

Mean, 2.3 years

Lui et al., 2012120

150

I

12 months

Park et al., 2012121

146

I

12 months

Cho et al., 2013122

60

I

12 months

No significant difference was found in RKF in patients at end of follow-up (2.30 ± 0.36 vs. 1.69 ± 0.28 mL/min/1.73 m2); urine volume was higher in neutral pH, low-GDP solution group (745.7 ± 107.57 vs. 475.1 ± 77.69 mL/d). No significant difference was found in the rate of decline in RKF between the group using 1.5%/1.1%/7.5% vs. standard solutions (–0.76 ± 1.77 vs. –0.91 ± 1.92 mL/min/1.73 m2 per year; P = 0.60); patients using the biocompatible PD fluids had better preservation of daily urine volume (959 ± 515 vs. 798 ± 615 mL/d; P = 0.02). No significant difference was found in RKF (2.9 ± 2.3 vs. 2.9 ± 3.1 mL/min) or urine volume (625 ± 488 vs. 644 ± 575 mL) in neutral pH, low-GDP solutions vs. standard solutions group. No significant difference was found in RKF (2.4 ± 1.7 vs. 2.2 ± 2.1 mL/min) or urine volume (714 ± 537 vs. 682 ± 460 mL) in neutral pH, low-GDP solution vs. standard glucose solution group.

GDP, Glucose degradation products; I, incident; P, prevalent.

adequately powered to examine the impact of neutral pH, low-GDP solutions on clinical hard outcomes such as hospitalizations or cardiovascular events. 

Amino Acid Peritoneal Dialysis Solutions Amino acid PD solution was launched back in the 1990s with an aim to supplement and replace nitrogen losses in PD patients. PD patients may lose up to 3 to 4 g/day of amino acids and 4 to 15 g/day of proteins even in the stable condition. The amount of peritoneal protein and amino acids loss may increase further with peritonitis. The only commercially available amino acid PD solution is 1.1% solution, which contains 87 mmol/L of amino acids, the majority (61%) of which is essential amino acids (see Table 31.1). A 1.1% amino acid solution exerts a similar osmotic force to 1.36% glucose solutions, thus providing an ultrafiltration volume comparable to that achieved with 1.36% glucose solutions. The peak plasma amino acid concentration is usually achieved around an hour. Usually approximately 72% to 82% of amino acids are absorbed in a single daily dwell and this may amount up to 18 g/day, thus providing a good source of protein supplement without adding phosphorus load.132 The 1.1% amino acid solution has been found to have a very small vasodilatory effect on peritoneal blood flow and may increase small solute transport.133 Earlier balance studies suggested that the nitrogen absorbed from a single daily dwell of 1.1% amino acid solution is sufficient to offset the daily losses of amino acids and protein from the peritoneum.132 Compared with using glucose solution only, combined amino acids and glucose PD solutions have been found to improve protein kinetics and whole-body protein synthesis in PD.134,135 Nevertheless, this was not accompanied by a parallel increase in serum albumin, suggesting different pathways involved in albumin and skeletal muscle protein synthesis.136

Several RCTs have been conducted to evaluate the safety of 1.1% amino acid solution and its efficacy in treating malnutrition, or what is now called protein-energy wasting, in PD patients.137 An earlier 12-week multicenter study138 reported an increase in circulating insulin growth factor I in PD patients randomly assigned to 1.1% solution compared with controls, suggesting an increase in protein synthesis. A subgroup analysis indicated an increase in plasma prealbumin and transferrin levels, yet no change in midarm muscle circumference levels among those with plasma albumin <35 g/L.138 Another RCT139 using 1.1% amino acid solution was conducted in Chinese malnourished PD patients. In the 3-year study, participants who were randomly assigned to use 1.1% solution had an improvement in serum albumin, triglyceride, and total cholesterol level as well as a reported increase in dietary protein intake and an increase in normalized protein equivalent of nitrogen appearance (nPNA). Some anthropometric markers improved, although composite nutrition scores did not differ between treatment and control groups. Interestingly, the nutritional benefits appeared more prominent in women, whose lean body mass and body mass index were well maintained with combined amino acids and glucose PD solution but not with glucose solutions. The study was not powered to detect a difference in survival outcomes because only 60 participants were included. No significant difference was noted in inflammatory profile, mortality rates, and duration of hospitalization.139 Another 6-month crossover study140 failed to find any positive benefit on lipid metabolism with 1.1% amino acid solution in PD patients. In relation to peritoneal membrane function, preliminary data suggested that 1.1% amino acid solution may be more biocompatible to the peritoneal membrane and mesothelial cells than standard glucose solutions, as reflected by both in vitro and in vivo response of peritoneal CA125.141

492

SECTION III  Dialysis

In summary, the overall clinical value of 1.1% amino acid solution in PD patients has remained equivocal and uncertain. Generally, 1.1% amino acids PD solution is safe. Potential adverse effects include increased nausea and anorexia. Some patients may develop mild metabolic acidosis.142 This may be ameliorated by adjusting to use a bicarbonate-based buffer in the remaining PD exchanges. 1.1% amino acids solution may be reserved as a glucose-sparing solution in PD subjects and also for use in subjects at risk or exhibit features of PEW syndrome. Adequately powered randomized studies are needed to better define the outcome benefits of this solution. 

Low-Sodium Peritoneal Dialysis Solutions Sodium removal is largely achieved by convection in PD through ultrafiltration. The concept of using low-sodium dialysate is to enhance sodium removal by diffusion, given the larger concentration gradient between plasma and dialysate sodium. However, low-sodium dialysate is currently not in use in clinical practice. In a 2009 nonrandomized controlled trial by Davies et  al.,143 two novel solutions designed from predictions using the three-pore model were compared. In one group, sodium concentration was 115 mmol/L and glucose concentration was increased to 2.0% to compensate for reduced osmolality. In the other group, sodium concentration was 102 mmol/L and glucose concentration was unchanged (2.5%). Both solutions were substituted for one 3- to 5-hour exchange per day and no change was made to the rest of the PD regimen. The results indicated that use of the compensated low-sodium dialysate increased the diffusive component of sodium removal while maintaining ultrafiltration. This in turn translated to an improvement in blood pressure, thirst, and fluid status. However, uncompensated low-sodium dialysate had no effect at all on blood pressure, thirst, and fluid status, suggesting that these benefits cannot be achieved just by manipulating the dialysate sodium level alone.143 In a prospective multicenter double-blind RCT conducted to prove noninferiority of total weekly urea clearance (Kt/V) with low-sodium versus standard-sodium PD solutions, 108 patients were randomly assigned to low-sodium dialysate (sodium concentration 125 mmol/L) versus standard sodium dialysate (sodium concentration 134 mmol/L) for a 12-week treatment. The noninferiority of low-sodium PD solution for total Kt/V could not be confirmed. Although no difference was found in PD Kt/V, renal Kt/V was different between the two groups, being higher in standard-sodium than in lowsodium group. Low-sodium group showed higher mean daily dialysate sodium removal than high-sodium group. Blood pressure also decreased more with the low-sodium group, resulting in less antihypertensive medication use.144 Freida et  al.145 created their own compensated “bimodal solution” using a combination of icodextrin and glucose solution. The combination solution had a sodium concentration of 121 mmol/L, and a 15-hour dwell was associated with enhanced net ultrafiltration (mean 990 mL) and sodium removal (mean 158 mmol) compared with 7.5% icodextrin (mean net ultrafiltration 462 mL, mean net sodium removal 49 mmol) or 3.86% glucose-based PD solution (mean net ultrafiltration –85 mL,

mean net sodium removal 16 mmol). Compared with 7.5% icodextrin, the combination solution was also associated with significantly higher urea and creatinine clearances, by 41% and 26%, respectively.145 Another nonrandomized trial from the same group of investigators146 using the bimodal solution combining colloids and crystalloids solution found that over a 4-month period, net ultrafiltration and peritoneal sodium removal using bimodal solution as the long dwell increased more than twofold compared with baseline. The estimated change (95% CI) from baseline in net daytime ultrafiltration was 150% (106% to 193%) for the bimodal solution versus 18% (–7% to 43%) for icodextrin and was highly significant. The estimated change from baseline in peritoneal sodium removal was 147% (112% to 183%) for the bimodal solution versus 23% (–2% to 48%) for icodextrin (P < 0.001). The estimated change from baseline in ultrafiltration efficiency was also significantly higher with bimodal solution than icodextrin (71% vs. –5%).146 These data suggest that a bimodal solution based on a mixture of glucose (2.6%) and icodextrin (6.8%) significantly improved both ultrafiltration and peritoneal sodium removal and warrants further evaluation. 

Future Development in Peritoneal Dialysis Solutions

Hyperbranched polyglycerol (0.5 to 3 kDa) is a nontoxic, nonimmunogenic, water-soluble polyether polymer and has been found to be an efficacious and biocompatible osmotic agent in a rodent model of PD.147 Preclinical data suggested that hyperbranched polyglycerol functioned as colloids and induced osmosis mainly through capillary small pores and provided superior fluid and waste removal compared with Physioneal solution.148 More recent animal data indicated that hyperbranched polyglycerol solution may preserve peritoneal membrane function and structure better than standard glucose solution in a rat model of chronic PD.149 Pyruvate has been suggested as the other alternative buffer. However, all these alternative solutions require further testing and evaluation before clinical application. 

CONCLUSIONS The standard glucose-based PD solutions have adverse effects both locally to the peritoneal membrane and systemically to the metabolic profile of PD patients. There is a need to move to a glucose-sparing regimen for PD patients. Preclinical and observational studies suggested that biocompatible neutral pH, low-GDP solutions may improve peritoneal membrane morphology. However, this was not confirmed in the RCT setting. Data from RCTs indicated that the biocompatible neutral pH, low-GDP solutions preserved RKF and urine volume better than standard glucose solutions without finding any increase in adverse events and thus should be adopted more readily clinically in patients with preserved RKF. The latest evidence from a systematic review of RCTs suggested that glucose polymer solution significantly increased peritoneal ultrafiltration and reduced episodes of uncontrolled

CHAPTER 31  Peritoneal Dialysis Solutions, Prescription and Adequacy Multidimensional Assessment of Optimal Dialysis: Potential Measures

Potential Dialytic Strategies to Achieve

493

Goals of ESRD Care

Evidence

• Treatment duration • • • • •

• • • •

Patient reported outcomes Small solute removal Residual kidney function Left ventricular geometry Ultrafiltration rate and extracellular fluid volume management Higher weight range middle molecule removal Phosphorus HR and BP variability Serum potassium control

• Treatment frequency

• Maximize quality of life

• Incremental dialysis • Preservation of residual kidney function

• Maximize survival

• Consideration of home dialysis Abbreviations: HD – hemodialysis, HR – heart rate, BP – Blood pressure

FIG. 31.4  Multidimensional measure of optimal dialysis. (Reproduced with permission from Perl J, Dember LM, Bargman JM, Browne T, Charytan DM, Flythe JE, et al. The use of a multidimensional measure of dialysis adequacy-moving beyond small solute kinetics. Clin J Am Soc Nephrol. 2017;12(5):839-847.)

volume overload compared with standard glucose solutions. None of these solutions produced a difference in the peritonitis risk compared with standard glucose solutions. 

DIALYSIS ADEQUACY AND PRESCRIPTION Defining Dialysis Adequacy Starting in the 1990s, the term peritoneal dialysis adequacy was used to denote small solute clearance, namely Kt/V normalized to total body water and CrCl normalized to body surface area.150 Total weekly Kt/V and CrCl are each composed of two components, namely clearance from RKF and clearance from PD. The dialysis component is modifiable. Thus the term dialysis prescription was introduced to denote the prescription of PD therapy to optimize dialysis adequacy to reach adequacy targets. The United States Centers for Medicare and Medicaid Services ESRD Dialysis Incentive Program included Kt/V as a dialysis adequacy comprehensive clinical measure. However, there is increasing recognition that the term dialysis adequacy should encompass more than small solute clearance, Kt/V. Adequacy of dialysis should reflect measures that maximize the sum of survival, cardiovascular outcomes, extracellular volume status, CKD-MBD control, and patient-centered outcomes such as quality of life, appetite, nutrition status, and sleep, in addition to biochemical indices of dialysis adequacy. The American Society of Nephrology Dialysis Advisory Group recently proposed a multidimensional measure that moves beyond small solute clearance and that aims to quantify dialysis adequacy. This multidimensional measure of

optimal dialysis encompasses not only small solute removal, ultrafiltration rate, and extracellular volume overload but also left ventricular geometry, higher weight range middle molecule and phosphate removal, blood pressure variability, serum potassium control, anemia management, and, most importantly, patient-reported outcomes151 (Fig. 31.4). There are evolutionary changes coming from the concept of adequacy of dialysis to optimal dialysis in the Standardised Outcomes in Nephrology (SONG)–PD Initiative, which accounts more for patient-centered outcomes such as self-reported quality-of-life measures152 (Fig. 31.5). Adequacy of dialysis should not just include numerical indices of biochemical or clinical parameters but also, more importantly, how patients themselves feel with the therapy received. 

Measuring Biochemical Indices of Dialysis Adequacy

The measurement of biochemical indices of dialysis adequacy requires the simultaneous collection of all PD effluent drained out and all urine output passed within the same 24-hour period together with a blood sample for serum urea and creatinine collected around the same time frame. In practical terms the blood sample is usually collected at the time when patients return both the 24-hour PD effluent and simultaneous 24-hour urine to the dialysis center. The PD component of Kt/V and CrCl is calculated by measuring urea and creatinine quantity in a 24-hour collection of PD fluid, respectively (Table 31.4). These values are divided by serum urea and creatinine levels to give the PD Kt/V and CrCl, respectively. The PD and residual renal component of urea and CrCl are then added to give a total weekly Kt/V and CrCl, respectively. Both

494

SECTION III  Dialysis

Research Agenda

Outer Core

Core Outcomes

All outcomes identified to be important by either stakeholder group. Consider for trials. Prioritized to be of “critical importance” by either stakeholder group. Include in some trials. Prioritized to be of “critical importance” by both stakeholder groups. Include in all trials.

FIG. 31.5  Standardised Outcomes in Nephrology–Peritoneal Dialysis aims to identify outcome measures that are important to patients and caregivers in PD and establish a set of core outcome domains for trials conducted in PD. (Reproduced with permission From Tong A, Manns B. Establishing Core Outcome Domains in Hemodialysis: Report of the Standardized Outcomes in Nephrology -Hemodialysis (SONG-HD) Consensus Workshop. Am J Kidney Dis. 2017 Jan;69(1):97-107.)

TABLE 31.4  Formulas for Calculation of Indices of Dialysis Adequacy Indices of Dialysis Adequacy

Formulas

Total weekly Kt/V Daily PD Kt/V

= (Daily PD + renal urea clearance) × 7 and normalized by V = [(24-hour PD volume in L) × (24-hour PD fluid urea concentration in mmol/L) / Plasma urea concentration in mmol/L] and normalized by V = [(24-hour urine volume in L) × (24-hour urine urea concentration in mmol/L) / Plasma urea concentration in mmol/L] and normalized by V = (Daily PD + renal creatinine clearance) × 7 and normalized by BSA = [(24-hour PD volume in L) × (24-hour PD fluid creatinine concentration in umol/L) / Plasma creatinine concentration in μmol/L] and normalized by BSA = [(24-hour urine volume in L) × (average of 24-hour urine urea and creatinine concentration in μmol/L) / Plasma creatinine concentration in μmol/L] and normalized by BSA

Daily renal Kt/V Total weekly CrCl Daily PD CrCl Daily renal CrCl nPNA (g/d) equations* Bergstrom formula I Bergstrom formula II Randerson I Randerson II Teehan Blumenkrantz I Blumenkrantz II Residual GFR (mL/min/1.73m2) Normalization factor V (L) V (L) BSA

= 20.1 + (7.5 × UNA in g/d) = 15.1 + (6.95 × UNA in g/d) + (dialysate + urine protein in g/24 h) = 10.76 × (UNA/1.44 + 1.46) and UNA is in g/d = 10.76 × (UNA + 1.46) and UNA is in mg/min = 6.25 × (UNA + 1.81 + 0.031*BW) and UNA is in g/d = 34.6 + 5.86 × UNA in g/d = 22.5 + 6.16 × UNA in g/d = Average of (24-h urine urea clearance + creatinine clearance in mL/min) Formulas = 2.447 + (0.3362 × BW in kg) + (0.1074 × BH in cm) – (0.09516 × age in years) for male patients = –2.097 + (0.2466 × BW in kg) + (0.1069 × BH in cm) for female patients = 0.007184 × BW in kg0.425 × BH in cm0.725

BH, Body height; BSA, body surface area; BW, body weight; CrCl, creatinine clearance; Kt/V, urea clearance; PD, peritoneal dialysis; UNA, urea nitrogen appearance; V, total body water estimated by Watson method. *These equations make the assumption that the patient is in steady state, where urea nitrogen output equals urea generation. The Randerson equation also assumes that the average daily protein loss in the dialysate is 7.3 g/day. In PD patients with substantial protein losses in dialysate or urine, these losses must be added to the equation in calculating nPNA.

Kt/V and CrCl values are conventionally expressed as weekly rather than daily to allow comparisons with hemodialysis. Notably, when 24-hour PD fluid and urine collections are repeated on separate occasions in the same patient receiving the same PD prescription, significant intraindividual variations occur, especially in the renal component of clearance.154 These variations may be accounted for by inaccuracies in the 24-hour urine and dialysate collection because they are

cumbersome to do or by the timing of blood sampling. There could also be genuine day-to-day variation in the amount of dietary protein intake and fluid intake; urine volume, peritoneal ultrafiltration volume, and degree of equilibration of PD fluids; timing of PD exchanges; and concentrations of PD glucose solutions used. In CAPD either the patient is asked to bring all the dialysate drained out over the 24-hour period to clinic and the total 24-hour dialysate volume is measured

CHAPTER 31  Peritoneal Dialysis Solutions, Prescription and Adequacy in the laboratory, or the patient can measure the volumes of all dialysate drained out over a 24-hour period, mix up all the dialysates drained out well, and bring back a representative volume to the dialysis center. In automated PD the dialysate volumes involved are even larger. APD patients are usually trained to record or measure total cycler effluent volumes at home using the machine reading and bring back a representative aliquot of the dialysate to clinic for measurement of urea and creatinine concentrations. In CAPD the timing of blood sampling for urea and creatinine may not be as critical because generally serum urea and creatinine do not fluctuate significantly during the day. In automated PD, however, there may be a 10% or greater variation in serum urea and creatinine from a trough value after completion of PD cycles in the morning to a peak value before the patient resumes PD cycles in the evening. This may be a problem especially if patients have no PD fluids dwell during daytime. Thus in patients receiving APD with no PD fluids during daytime, serum samples should be taken approximately halfway through the noncycling period, which means mostly in the early afternoon. The target total weekly Kt/V values achieved in PD are usually around half to two-thirds of those in hemodialysis. This difference may be explained by the fact that, in contrast to hemodialysis, PD provides a continuous removal of small solute clearance and thus is greater than intermittent hemodialysis that delivers a similar quantity of clearance.155,156 Furthermore, the continuous nature of PD avoids the day-to-day fluctuations in small solute clearance as found in intermittent hemodialysis. The concept of a “peak concentration hypothesis” put forward by Keshaviah et  al.155 suggested that peak levels rather than mean levels of small solutes determined uremic toxicity. Theoretically, continuous modalities may be better, because peak levels of uremic waste solutes should be lower for a given clearance than as in the case of intermittent modalities.155,156 

Normalization Factor for Urea and Creatinine Clearance

Total weekly Kt/V is normalized to total body water, V, which can be estimated using anthropometric formulas such as Watson157 or Hume,158 which are based on age, gender, body weight, and height information. Estimates of V using the Watson formula are on the average slightly lower compared with the gold standard methods for estimating total body water such as deuterium oxide dilution.159 However, the discrepancy varies substantially in patients with extreme body weight, such as obesity. By far, the Watson formula remains the most commonly adopted equation used to calculate V. Total weekly CrCl is normalized to body surface area (BSA), which is usually estimated by the du Bois formula.160 In general, edema-free body weight should be used in the formulas to calculate V and BSA153 (see Table 31.4). If patients have significant weight loss as a result of PEW, the ideal body weight rather than actual body weight has been suggested to be used in the formula. This is because wasted patients would have a misleadingly high normalized clearance value as a result of significant weight loss, whereas obese patients would have a misleadingly low value because of overweight. Ideal body weights provided by the

495

National Health and Nutrition Evaluation Survey tables give the median body weight of North Americans of the same age, sex, height, and frame as the patient and are regularly updated. However, it is uncertain whether these values are also directly applicable to non-white populations. 

Estimation of Residual Kidney Function The renal component of urea and CrCl is calculated in the same way as with a 24-hour urine collection, except that in the case of creatinine clearance, an average of residual renal urea and CrCl is typically used (see Table 31.4). This is because unmodified urine CrCl substantially overestimates the true GFR because of tubular secretion of creatinine, whereas using renal Kt/V underestimates GFR.164 Both creatinine and urea are freely filtered by the glomeruli. As part of the biochemical indices of dialysis adequacy, residual GFR is estimated using the average of 24-hour urine urea and CrCl and is normalized to BSA164 (see Table 31.4). It is important to take into account both the peritoneal membrane transport characteristics and RKF of each patient when doing PD prescription and interpreting biochemical indices of dialysis adequacy. 

Frequency of Monitoring of Biochemical Indices of Dialysis Adequacy

For all CAPD or APD patients, total weekly Kt/V and RKF should be measured around 4 weeks after initiation of PD therapy. Thereafter, they should ideally be monitored at least once every 6 months to allow for prescription modification if necessary. 

Peritoneal Equilibration Test PET is a simple clinical method that assesses the diffusive transport capacity of urea, creatinine, and other solutes across the semipermeable membrane, as well as ultrafiltration, in different patients.26 Patients who are high transporters equilibrate very quickly and have excellent diffusive transport capacity. However, they tend to have a low ultrafiltration volume using standard glucose PD solutions because the osmotic gradient for glucose dissipates relatively quickly (Fig. 31.6). These patients may do better with short dwell times as in APD. However, long hours’ day dwell in APD using standard glucose solution may be a problem in high transporters because PD fluids will be largely reabsorbed. Glucose polymer solution or icodextrin would be preferred as the long day dwell solution for high transporters receiving APD.72 In contrast, low transporters ultrafiltrate well but equilibrate slowly. Thus longer dwell times may be more effective in removing small solutes in low transporters. Generally, Kt/V is much less affected by peritoneal transport characteristics than CrCl in CAPD because more than 90% of Kt/V and equilibration occurs with the long dwell hours of CAPD, regardless of peritoneal transport characteristics. This differs from creatinine clearance, which may have two to three times difference between low and high transporters even after a 4- to 6-hour dwell (see Fig. 31.6). In APD, dwell time is usually shorter than CAPD except for the long day dwell. Thus peritoneal membrane transport characteristics may be considered in the prescription of PD modality and regimen.

496

SECTION III  Dialysis High transport Low transport

D/P creatine

1.0 0.8 0.6 0.4 0.2 0.0

3000

2.5 CrCL/exchange (mL/min/exchange)

Total dialysate volume (mL)

1.2

2500 2000 1500 1000 500 0

0 1 2 3 4 5 6 7 Dwell time (hours)

2.0 1.5 1.0 0.5 0.0

0 1 2 3 4 5 6 7 Dwell time (hours)

0 1 2 3 4 5 6 7 Dwell time (hours)

FIG. 31.6  Solute and fluid transport in low transporters versus high transporters in PD. High transporters reach equilibrium for creatinine more quickly than low transporters (left panel) and have a gradual reduction in dialysate drain volume after 2 hours or so as a result of glucose absorption and loss of osmotic gradient (middle panel). Creatinine clearance also gradually decreases after 4 hours as a result of continued absorption of creatinine with the glucose and fluid (right panel). This is in contrast to the low transporters, who have a very gradual increase in creatinine clearance, dialysate-to-plasma creatinine ratio, and dialysate drain volume over the 4-hour dwell. (Reproduced with permission from Twardowski ZJ. Nightly peritoneal dialysis. Why, who, how, and when? ASAIO Trans. 1990;36(1):8-16.)

In patients with complete loss of RKF, there could be limitations in achieving optimal clearance targets, depending on the peritoneal transport characteristics.

Importance of Dialysis Adequacy and Defining Numerical Targets for Biochemical Indices of Dialysis Adequacy The CANUSA (Canada-USA) study43 was a prospective multicenter cohort study of 680 incident CAPD patients from Canada and United States that examined the importance of adequacy. Over a 2-year period of follow-up, a significant positive association was identified between the total weekly Kt/V and CrCl and clinical outcomes including overall survival. For every 0.1 unit higher total weekly Kt/V, the relative risk for mortality was lower by 6%, and for every 5 L higher total weekly CrCl, the relative risk for mortality was lower by 7%. Subsequent to the CANUSA study, Maiorca et al.168 also reported an association between weekly Kt/V >1.96 and better survival in another prevalent cohort of CAPD patients followed over 3 years.168 These two important studies formed an important basis for the recommended total weekly Kt/V target of at least 2.0 and a CrCl target of at least 60 L/week/1.73 m2 for those receiving CAPD with high and high-average transporters and a CrCl target at least 50 L/week/1.73 m2 for those with low and low-average transporters by the National Kidney Foundation Dialysis Outcome Quality Initiative (K/ DOQI) Guidelines in 1997 and 2000.169 If there is discordance in achieving these targets, Kt/V was recommended to be the immediate determinant of dialysis adequacy because it directly reflects protein metabolism and is less affected by extreme variations in RKF. However, a cause for the discrepancy should be looked for and the patient should be followed

closely for signs of underdialysis. One potential explanation for the discrepancy could be patients being underweight, which may result in a small V and overall a higher Kt/V. Subsequent to these studies, two large prospective RCTs found no significant difference in the mortality risk for PD patients by increasing peritoneal small solute clearance. In the ADEquacy of PD in MEXico (ADEMEX) study,170 increasing weekly peritoneal Kt/V from 1.62 to 2.13 (weekly CrCl from 46.1 to 56.9 L/week/1.73 m2) had no significant effect on mortality risk (relative risk 1.00, 95% CI, 0.8 to 1.24). In another randomized trial from Hong Kong,171 320 PD patients with baseline renal Kt/V <1.0 were randomly assigned to three groups of different Kt/V targets, namely 1.5 to 1.7, 1.7 to 2.0, and >2.0. Patients in the group with the lowest Kt/V target 1.5 to 1.7 had more clinical problems and were more likely to be withdrawn from the study by their physicians based on clinical ground. The overall 2-year survival was 84.9% with no significant difference reported between the group with a Kt/V target of 1.7 to 2.0 and the group with a Kt/V target >2.0.171 Another retrospective analysis from an administrative database of anuric PD patients in the United States demonstrated higher mortality rates in patients with a weekly Kt/V <1.7.172 With the exception of the study from Hong Kong, all the other studies failed to find a relationship between peritoneal small solute clearance and survival in PD patients. The ADEMEX RCT and the Hong Kong PD RCT formed the key basis for a subsequent revision of the 2006 K/DOQI, 2005 EBPG, and 2006 ISPD guidelines, all recommending a minimum weekly Kt/V target of 1.7 in CAPD patients.169,173,174 There are no trial data to support benefit of further increasing dialysis to reach a total weekly Kt/V beyond 2.0 or a CrCl of more than 60 L/week/1.73 m2. Furthermore, there are trial

497

CHAPTER 31  Peritoneal Dialysis Solutions, Prescription and Adequacy 1.0

1.0

Group IV

0.9

0.9

Group III

0.8

Group III

0.8 Group II Group I

0.6 0.5 0.4 0.3

Group II

0.7 Cumulative survival

0.7 Cumulative survival

Group IV

Group I

0.6 0.5 0.4 0.3

Sodium Removal (mmol/24 h/1.73 m2) group I, <130 group II, 130 to 181 group III, 181 to 232 group IV,> 232

0.2 0.1

Fluid Removal (mL/24 h/1.73 m2) group I, <1265 group II, 1265 to 1570 group III, 1570 to 2035 group IV,> 2035

0.2 0.1

0.0

0.0 0

6

12

18 24 Time, months

30

36

42

0

6

12

18 24 Time, months

30

36

42

FIG. 31.7 Effects of sodium and fluid removal on survival in PD patients. (Reproduced with permission from Ates K, Nergizoglu G, Keven K, Sen A, Kutlay S, Erturk S, et al. Effect of fluid and sodium removal on mortality in peritoneal dialysis patients. Kidney Int. 2001;60(2):767-776.)

data to suggest that a weekly total Kt/V <1.7 was associated with more clinical problems and greater need for erythropoietin.171 In the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) study, peritoneal Kt/V <1.5 and CrCl <40 L/week/1.73 m2 were associated with higher mortality.175 The 2005 EBPG guideline, 2006 ISPD guideline update, and K/DOQI 2006 guideline suggested a minimum weekly peritoneal Kt/V of 1.7 for anuric PD patients. In APD a cycler is used to perform multiple overnight exchanges. A minimum weekly Kt/V target of ≥1.7 per week is recommended and is in line with the 2006 K/DOQI guideline.169,173 In APD patients who are anuric or have minimal urine volume, an additional manual day exchange is suggested to increase PD clearance, because the recommended Kt/V targets for APD patients are based on studies in CAPD patients who underwent continuous PD over a 24-hour period. In the 2006 ISPD guideline, a separate target for CrCl was not suggested for CAPD. In APD, because of more variable relations between Kt/V and CrCl, an additional target of 45 L/week/1.73 m2 for CrCl was recommended. Novel concepts in defining dialysis adequacy or optimal dialysis.  The minimum target Kt/V defines the minimum but not necessarily the optimal dose of dialysis that should be performed. Optimal dialysis prescription should be personalized, based on an assessment of RKF, peritoneal membrane function, status of clinical and biochemical parameters, acid–base status, uremic symptoms, volume status, nutrition profile, control of mineral metabolism, and patients’ selfperceived well-being on dialysis (see Fig. 31.4). In some situations, dialysis dose may need to be increased despite achieving the minimum weekly Kt/V target of 1.7. Examples of these situations are persistent acidosis, persistent uremic symptoms such as nausea and anorexia, clinical manifestations of PEW,

and hyperphosphatemia despite dietary restriction and use of phosphorus binders. 

Ultrafiltration and Volume Control as a Target for Dialysis Adequacy Ultrafiltration is an important parameter for assessing adequacy of dialysis, and ultrafiltration has been found to be associated with survival in anuric APD patients; ultrafiltration volume less than 750 mL/day was associated with a higher mortality.176 However, a numerical target for daily ultrafiltration volume was not formulated or recommended by different guideline bodies. It is because the overall volume status depends also on the residual urine volume as well as salt and fluid intake of patients and there may be substantial intraindividual variation. Both the 2006 ISPD guidelines and the recent 2015 ISPD Cardiovascular and Metabolic guidelines emphasized the importance of maintaining euvolemia in PD patients as one of the treatment goals in PD and recommended that attention be paid to both the urine volumes and PD ultrafiltration volumes.24,169 The negative findings from the ADEMEX study that increasing small solute clearance did not improve survival of PD patients170 suggested the need to look for factors other than small solute clearance that may be important in determining clinical outcomes of PD patients. A reanalysis of data from the CANUSA study indicated that every 250 mL of urine output was associated with a 36% lower mortality risk, suggesting the importance of urine volume in determining the clinical outcome of PD patients.177 Sodium and fluid removal are associated with survival in PD patients. The lower the sodium and fluid removal from PD, the greater the mortality risk178 (Fig. 31.7). Extracellular volume overload is a highly prevalent complication in PD patients.

498

SECTION III  Dialysis

BOX 31.1  Clinical Evaluations and Checklist for Patients With Volume Overload 1. W  hat is the PD outflow pattern lately? Has there been a recent change in PD ultrafiltration or drain volume? Any recent change in PD prescription? What’s the outflow volume for each bag of PD exchanges used? 2. What’s the daily amount of urine volume lately? Has there been a recent decrease in urine volume? 3. Are there any nonadherence issues related to salt and fluid restriction? 4. Has the patient been dining out often or eating high-salt or -fluid meals? 5. Is there any nonadherence to dialysis prescription? Or missed exchanges by patients? 6. Does the patient have undiagnosed cardiovascular disease or heart failure? Any features to suggest silent myocardial ischemia? 7. What kind of peritoneal transport characteristics does the patient have? 8. Does the patient reach the minimum target for Kt/V and CrCl? 9. If drain volume is low: (i) Are there any mechanical issues with PD outflow that may explain low drain volume? (ii) Does the patient have constipation? (iii) Is outflow position related? (iv) Is the catheter positioned correctly? (v) Are fibrin clots present that may obstruct outflow? (vi) Is there omental wrap? (vii) Are there clinical features to suggest peritoneal adhesions or encapsulating peritoneal sclerosis? CrCl, creatinine clearance; Kt/V, urea clearance; PD, peritoneal dialysis.

Using bioimpedance spectroscopy, the estimated prevalence of extracellular volume overload was at least more than 50%179,180 and was even higher when patients completely lost their RKF.179 Extracellular volume overload is associated with a higher risk for mortality in PD patients.181 Apart from loss of RKF, UFF with low drain volume is another important cause of volume overload (see Ultrafiltration Failure). Other non–membrane-related causes of volume overload include dietary nonadherence with excess salt and fluid intake, nonadherence to dialysis prescription, and inappropriate choice of PD solution strengths that may affect the PD outflow. Mechanical complications such as dialysate leaks, hernias, catheter malposition, and loculations in the peritoneal cavity may also cause low drain volume. In fact, retroperitoneal dialysate leaks have been suggested to be an important cause of acute UFF and can be diagnosed using computed tomography peritoneogram.182 Hyperglycemia may also contribute to low drain volume by decreasing the glucose osmotic gradient–driven ultrafiltration.183 It is therefore essential to take a thorough history and physical examination and review the PD outflow records and dietary intake pattern in the preceding days before the episode of volume overload to identify the exact cause. Box 31.1 details a checklist of questions to be asked when assessing a patient with volume overload. Fig. 31.8 provides an algorithm on the clinical evaluation of patients who present with volume overload. 

Nutrition Status as a Target for Dialysis Adequacy The importance of nutrition status in clinical outcomes and survival of dialysis patients has long been recognized. A study by Owen et al.184 found that serum albumin concentration was at least 20-fold more powerful than urea reduction ratios in its association with a higher risk for mortality in dialysis patients.184 In PD patients, various nutritional indices, including subjective global assessment, serum albumin, handgrip strength, and lean body mass, have been found to be associated with survival and cardiovascular outcomes.185-187

In 2008 the International Society of Renal Nutrition and Metabolism (ISRNM) commissioned an expert panel to standardize the definition and terminology used. The term protein-energy wasting was recommended to denote loss of body protein mass and fuel reserves. The diagnosis of PEW is made based on the presence of three out of the four characteristics, namely (1) at least one biochemical parameter of the following: low serum levels of either albumin, transthyretin, or cholesterol; (2) reduced body mass (low or reduced body fat mass or weight loss with reduced intake of protein and energy); and (3) reduced muscle mass (muscle wasting or sarcopenia, reduced midarm muscle circumference) (Box 31.2). Unintentional weight loss should lead one to consider the presence of PEW. The panel regarded loss of 5% of nonedematous weight within 3 months or an unintentional loss of 10% of nonedematous weight over the past 6 months as an indicator of PEW, independent of weight-for-height measures. Loss of body fat and muscle mass are considered important criteria for diagnosing PEW. Other potential tools such as a nutrition scoring system (e.g., subjective global assessment, malnutrition-inflammation scoring, appetite assessment, dietary intake assessment) or body composition assessment may also be used, though they are not included as a diagnostic criteria for PEW.188 In fact, a simple questioning of appetite has been found to be useful in predicting clinical outcome and hospitalization in dialysis patients.189 Inflammatory markers such as C-reactive protein are usually elevated in the setting of PEW.188 Various urea kinetics equations have been used to estimate nPNA, a surrogate for protein intake in PD patients. However, these equations made the assumption that the patient was stable and urea generation, excretion, and other nitrogen losses were proportional and in equilibrium to the amount of protein intake. Among the various equations, the best validated is the Bergstrom formula. Both the Randerson and Bergstrom formulas are often used (see Table 31.4). These formulas are derived using the same variables as Kt/V. In the early 1990s, the cross-sectional association between solute clearance Kt/V

CHAPTER 31  Peritoneal Dialysis Solutions, Prescription and Adequacy

499

Fluid Overload

Check for causes:1. 2. 3. 4. 5. 6.

Low drain volume Diet and fluid adherence issues Loss of RKF Dialysate leaks Catheter malposition Non-adherence to PD prescription

Check PET and Kt/V results Do a rapid 2L exchange, check drain volume AXR if catheter malposition suspected Check if any adherence issues Check dietary salt and fluid intake pattern If cause of fluid overload remains unexplained

If drain volume low, then True Loss of Ultrafiltration

Review PET D/P Cr ratio

Decreased D/P Cr

-Sclerosing peritonitis -Peritoneal adhesions

Increased D/P Cr

-Type 1 UFF -Recent peritonitis

If drain volume not low, then look for other causes such as non-compliance to dialysis prescription and to diet, loss of residual kidney function

Stable D/P Cr

- lymphatic absorption -Catheter malposition -Dialysate leaks -Decreased transcellular transport

FIG. 31.8  Algorithm of clinical evaluation of patients with volume overload.

BOX 31.2  ISRNM Consensus Statement on Diagnosis of Protein-Energy Wasting (PEW)188 A diagnosis of PEW requires that at least three out of the four listed categories be met and at least one test in each of the selected category should be included. Serum Chemistry • Serum albumin level (measured using the bromocresol green method) <38 g/L • Serum prealbumin level (transthyretin) <30 mg/dL • Serum cholesterol level <2.59 mmol/L (not valid if low concentrations are caused by abnormally high urinary or gastrointestinal protein losses, liver disease, or cholesterol-lowering medicines)  Body Mass • BMI <22 kg/m2 ≤65 years, <23 kg/m2 >65 years (a lower BMI might be desirable for certain Asian populations; weight must be edema-free mass) • Unintentional weight loss over time: ≥5% over 3 months or ≥10% over 6 months • Total body fat percentage <10% 

Muscle Mass • Muscle wasting: reduced muscle mass ≥ 5% over 3 months or ≥10% over 6 months • Reduced MAMC area as measured by a trained anthropometrist (reduction >10% in relation to the 50th percentile of the reference population) • Creatinine appearance (of note, appearance is influenced by muscle mass and meat intake)  Dietary Intake • Unintentionally low DPI <0.80 g/kg per day for at least 2 months (which can be assessed by dietary diaries and interviews, or for protein intake by calculation of the normalized protein equivalent of total nitrogen appearance [normalized protein nitrogen appearance or normalized protein catabolic rate] as determined by urea kinetic measurements) • Unintentional low DEI <25 kcal/kg/d for at least 2 months

BMI, Body mass index; DEI, dietary energy intake; DPI, dietary protein intake; MAMC, midarm muscle circumference.

500

SECTION III  Dialysis

and dietary protein intake, nPNA, led to the conclusion that dialysis dose was one of the important determinants of dietary protein intake.187 However, subsequent concerns were raised that the close correlation reported between Kt/V and nPNA may have been due to mathematical coupling because these two parameters contained some common variables.190 Wang et al. found that total weekly Kt/V and CrCl had important associations with actual intake of dietary protein, energy, macronutrients, and micronutrients, estimated using a 7-day food frequency questionnaire, independent of other confounding clinical and biochemical covariates. The associations with intake of various dietary components including protein and energy were essentially contributed by RKF but not PD clearance.191,192 These data provided important evidence that the correlations reported between small solute clearance and protein intake were not simply the result of mathematical coupling. RKF but not PD clearance contributed significantly to the overall nutrition status and dietary intake of PD patients. In keeping with this finding, the ADEMEX RCT reported no difference in nutrition status and dietary protein intake with increasing PD clearance to 60 L/week/1.73 m2 compared with the control group with average PD clearance of 45 L/ week/1.73 m2, suggesting that increasing PD dose to 60 L/ week/1.73 m2 did not further improve nutrition status.170 The current recommended protein intake nPNA for stable PD patients is ≥1.2 g/kg body weight per day and energy intake is ≥30 to 35 kcal/kg/day including energy derived from peritoneal glucose absorption.193 Other than loss of RKF, a multitude of other factors may contribute to lower dietary intake and increased catabolism, causing PEW in PD patients (Box 31.3). Some of these factors included uremic anorexia, inflammation, metabolic acidosis, insulin resistance, resistance to growth hormone/insulin growth factor I, impaired protein anabolism, volume overload, and associated comorbidities. In PD, dialysate protein losses, impaired gastric emptying as a result of diabetes or peritoneal fluids, and infections such as peritonitis may additionally predispose patients to PEW. Fig. 31.9 provides a conceptual model of the etiology and consequences of PEW. The current estimated prevalence of PEW in PD patients ranges from 18% to 55%.191,194 Regular monitoring of nutrition status and screening for PEW are therefore essential in PD patients and in particular when complication sets in. Serum albumin alone is not a reliable marker of PEW because systemic inflammatory processes lower serum albumin. Hypoalbuminemia may also be a marker of overhydration.195 In managing PD patients with PEW, it is essential to identify and treat the underlying cause of PEW. Oral nutrition supplement (ONS) and enteral nutrition supplement should be considered in patients who fail to achieve the recommended level of protein and energy intake and have features of PEW such as unintentional weight loss, low serum albumin, and loss of body fat mass and muscle mass. Trials on ONS have been lacking in the PD population. Nevertheless, in hemodialysis, small RCTs have reported that ONS improved various nutritional parameters.193 Other potential treatments for PEW, such as growth hormone and anabolic steroids, that may stimulate net muscle protein synthesis or appetite

BOX 31.3  Causes of Protein-Energy

Wasting in Peritoneal Dialysis Patients Protein and Nutrient Losses in Dialysate • Increased loss during peritonitis  Decreased Intake of Dietary Protein, Energy, and Other Nutrients • Uremic anorexia • Loss of residual kidney function • Accumulation of uremic toxins • Dietary restrictions • Abdominal distension as a result of peritoneal fluids in situ • Early satiety as a result of peritoneal glucose • Encapsulating peritoneal sclerosis • Peritoneal collections and adhesions • Diabetes mellitus •  Atherosclerotic vascular disease and peripheral vascular disease • Heart failure and volume overload • Infections (e.g., peritonitis, exit site infections, pneumonia) • Psychological factors such as depression • Poor dentition or dental caries, periodontitis  Hypermetabolism • Inflammation relating to comorbidities (such as atherosclerotic vascular disease, peripheral vascular disease, heart failure, volume overload, MIA syndrome) •  Inflammation relating to infections (e.g., peritonitis, exit site infections, pneumonia) • Loss of residual kidney function • Insulin resistance • Increased glucocorticoid activity • Sympathetic overactivity • Dialysis-related inflammation • Dialysis-related hypermetabolism • Metabolic acidosis • Inflammation caused by periodontitis  Decreased anabolism • Resistance to growth hormone/insulin growth factor 1 • Testosterone deficiency • Low thyroid hormone levels • Decreased nutrient intake

need further evaluation in PD patients. Fig. 31.10 provides an algorithm proposed by ISRNM on nutrition management and support in CKD, including patients receiving PD treatment.193 Detailed discussion on management of PEW in CKD is provided in another section. 

Initial Peritoneal Dialysis Prescription The initial CAPD prescription may need to be empirically set based on patients’ weight, degree of RKF, and lifestyle constraints even before information on peritoneal transport status is available. Generally, PET is recommended to be conducted at least 4 to 6 weeks after long-term continuous PD initiation. CAPD or APD may be initiated incrementally or as a full therapy, depending on the degree of RKF at the time of dialysis initiation. 

CHAPTER 31  Peritoneal Dialysis Solutions, Prescription and Adequacy Causes of PEW

501

Consequences of PEW

Dietary nutrient intake

Infection

(–)

Loss of kidney function Uremic toxins

(+) (–)

Comorbid conditions (IR, diabetes, CVD depression)

(–) Protein energy wasting

(–)

(–) Dialysis-associated catabolism

Cardiovascular disease (+)

(–)

(–)

(+)

(–)

Metabolic derangements (HPT, metabolic acidosis, hypogonadism, GH resistance)

Frailty, depression

Inflammation

FIG. 31.9  The conceptual model for etiology and consequences of protein energy wasting in chronic kidney disease. CVD, Cardiovascular disease; GH, growth hormone; HPT, hyperparathyroidism; IR, insulin resistance. (Reproduced with permission from Ikizler TA, Cano NJ, Franch H, Fouque D, Himmelfarb J, Kalantar-Zadeh K, et al. Prevention and treatment of protein energy wasting in chronic kidney disease patients: a consensus statement by the International Society of Renal Nutrition and Metabolism. Kidney Int. 2013;84(6):1096-1107.)

Clinical Evaluation of Patients With Low Delivered Urea Clearance In PD patients with a low Kt/V, evaluations should include the following potential causes: 1. Check if the dialysis prescription, namely the number of cycles and the concentration of PD solutions, is sufficient for the patient. 2. Check for nonadherence or nonadherence to the dialysis prescription or missed cycles. 3. Check if actual dwell times may differ from that prescribed. 4. Check for loss of RKF. 5. Check for incomplete draining. 6. Check for hypercatabolic conditions in the patient.  Adjusting Peritoneal Dialysis Prescription If kinetic modeling is not available, dialysis dose may be increased by increasing the instilling volume as tolerated, thereby maximizing mass transfer and dwell time. The other possibility would be to increase the number of daily PD exchanges while maximizing the dwell time. For example, for PD patients who are prescribed three exchanges daily of 2 L × 1.5% and have a low Kt/V because of loss of RKF, one may increase the dialysis dose by increasing to four exchanges daily of 2 L × 1.5% or by increasing the volume per exchange to 2.3 to 2.5 L × 1.5% as required and as tolerated. If there is a need to increase ultrafiltration volume as well, then one may consider replacing 1.5% with 2.5% solution. If computer-assisted kinetic modeling is available, then the kinetic modeling may be used to tailor PD prescriptions to individual’s transport type, RKF, body size, and lifestyle habits and thus enable a more personalized PD treatment to be

prescribed. Kinetic modeling is especially important for APD prescription because the dwell times are variable and may not be optimized for many patients. Computer-assisted kinetic modeling accurately and reliably predicts the delivered dose and facilitate the prescription process and achievement of the target delivered PD dose. Actual measurements will still need to be carried out to confirm that an adequate PD dose has indeed been delivered. In patients performing APD, an initial prescription may consist of three to four daily exchanges of 2 L × 1.5% or 2.5% in various combination, depending on the ultrafiltration volume and urine output of patients. A dry day may be considered in those who still have significant RKF, but this implies that the total daily number of hours of dialysis will be reduced by at least 8 to 10 hours, depending on the hours of the dry day. As patients lose their RKF or in patients who are underdialysed with dry day, usually a wet day or a single day dwell using 2 L exchange of 1.5%, 2.5%, or icodextrin solution will be required to achieve adequate dialysis. The use of icodextrin as the long day dwell has the advantage of achieving a better ultrafiltration volume compared with the standard glucose solutions. In patients who remain underdialysed with a single long day dwell, the prescription can be modified to using two shorter day dwells—for example, 2 × 2 L exchanges of 1.5% or 2.5%—to increase dialysis clearance. Other ways to increase dialysis clearance in APD patients include increasing the number of exchanges overnight to five exchanges or increasing the dwell volume—for example, from 2 L to 2.5 L as tolerated. In patients who are low transporters and in whom clearance critically depends on the dwell time, using cycler therapy shorter than 2-hour dwells may not achieve

502

SECTION III  Dialysis

Nutritional assessment (as indicated) SPrealb; SGA; anthropometrics

*Periodic nutritional screening SAIb, weight, BMI, MIS, DPI, DEI

Continuous preventive measures • Continuous nutritional counseling • Optimize RRT-Rx and dietary nutrient intake • Manage comorbidities (acidosis, DM, inflammation, CHF, depression)

Indications for nutritional interventions despite preventive measures • Poor appetite and/or poor oral intake • DPI<1.2 (CKD 5D) or <0.7 (CKD 3–4); DEI < 30 kcal/kg/day • SAIb < 3.8 g/dl or Sprealb∧< 28 mg/dl • Unintentional weight loss – > 5% of IBW or EDW over 3 months • Worsening nutritional markers over time • SGA in PEW range

Start CKD-specific oral nutritional supplementation SAIb > 3.8; SPrealb >28 weight or LBM gain

• CKD 3–4: DPI target of > 0.8 g/kg/day (± AA/KA or ONS) • CKD 5D: DPI target > 1.2 g/kg/day (ONS at home or during) dialysis treatment; in-center meals)

No improvement or deterioration

Maintenance nutritional therapy goals

Intensified therapy

Adjunct therapies

• SAIb > 4.0 g/dl • SPrealb > 30 mg/dl • DPI > 1.2 (CKD-5D) and > 0.7 g/kg/day (CKD 3–4) • DEI 30–35 kcal/kg/day

• Dialysis prescription alterations • Increase quantity of oral therapy • Tube feeding or PEG if indicated • Parenteral interventions: • IDPN (esp. if SAIb <3.0 g/dl) • TPN

• Anabolic hormones • Androgens, GH • Appetite stimulants • Anti-inflammatory inventions • Omega 3; IL-1ra • Exercise (as tolerated)

FIG. 31.10  A consensus statement from ISRNM on nutritional management and support in PD patients. AA, Amino adics; BMI, body mass index; CHF, congestive heart failure; CKD, chronic kidney disease; DEI, dietary energy intake; DM, diabetes mellitus; DPI, dietary protein intake; EDW, expected dry weight; GH, growth hormone; IBW, ideal body weight; IDPN, introdialytic parenteral nutrition; IL-1ra, interleukin-1 receptor anatogonist; KA, ketoanalog; LBM, lean body mass; MIS, malnutrition inflammation syndrome; ONS, oral nutrition supplement; PEG, percutaneous endoscopic gastrostomy; SAlb, serum albumin; SGA, subjective global assessment; SPrealb, serum prealbumin; RRT-Rx, renal replacement therapy prescription; TPN, total parenteral nutrition. (Reproduced with permission from Ikizler TA, Cano NJ, Franch H, Fouque D, Himmelfarb J, Kalantar-Zadeh K, et al. Prevention and treatment of protein energy wasting in chronic kidney disease patients: a consensus statement by the International Society of Renal Nutrition and Metabolism. Kidney Int. 2013;84(6):1096-1107.)

a higher dialysis clearance. Rather, increasing dwell volume without changing dwell time will help increase dialysis clearance. 

High Transporters High transporters have the highest rates of diffusive transport. Small solutes such as glucose, urea, and creatinine are transported quickly in these patients, leading to equilibration between dialysate small solute concentration and that of the blood relatively early in a dwell. As a result of rapid absorption of dialysate glucose, there is early dissipation of the osmotic gradient between dialysate and blood that is required for ultrafiltration to take place and so ultrafiltration ceases. Furthermore, there is a slow but continuous absorption of

fluid via the peritoneal lymphatics. Thus a major clinical problem encountered by rapid transporters is suboptimal ultrafiltration, low drain volume, and inadequate solute clearance (see Fig. 31.6). Some PD patients are high transporters at the start of dialysis, whereas others gradually become high transporters over increasing time on PD. A high peritoneal transport status is associated with a higher mortality in PD patients.43-45,203-205 

Factors Contributing to More Adverse Outcomes in High Transporters Several mechanisms have been proposed for the higher risk for mortality reported in high transporters, including fluid overload, chronic inflammation, increased protein loss through

CHAPTER 31  Peritoneal Dialysis Solutions, Prescription and Adequacy the peritoneum, and PEW.206,207 Some cross-sectional analyses indicated that peritoneal transport characteristics, namely the D/P creatinine ratio, had an inverse relationship with serum albumin, independent of dialysis dose.208 This may be explained by increased dialysate protein losses that may amount up to 15 g/day (generally, an average of 5 to 6 g of protein is lost in the dialysate per day in CAPD patients). The other possibility may relate to the chronic inflammation that is associated with high peritoneal transport status and that explains the associated hypoalbuminemia.207 A 2006 metaanalysis included mainly studies of patients receiving CAPD, which is a less favorable modality for high transporters as a result of poor ultrafiltration volume and solute clearances. In a small study comparing CAPD patients who were low transporters with those who were high transporters, patients who were high transporters were more likely to be hypertensive and had more left ventricular hypertrophy.209 In theory, high transporters would do best with short dwell times (up to 3 hours per dwell). Thus high transporters fare best with APD or NIPD with 3 hours per dwell overnight when using standard glucose solution and then either have a long day dwell using icodextrin or a day dwell with a midday exchange when using standard glucose solutions. In contrast, low transporters would do best with prolonged dwells such as CAPD or CCPD with fewer overnight exchanges. Patients with low average or low transport may need to use larger PD fluid volumes, which increase clearance by maximizing contact surface area with the peritoneum. In practice, most patients could be prescribed either CAPD or APD. Previous observational studies did not demonstrate any significant difference in the overall survival for patients doing CAPD or APD.210-212 Another analysis based on the Australia and New Zealand Registry suggested a better survival outcome for high transporters treated with APD versus CAPD.213 Summarizing current available data, there is no conclusive evidence to suggest one modality is superior to the other and thus modality of PD should be individualized according to patients’ need, peritoneal transporter characteristics, and RKF. 

Acute Membrane Injury Patients with acute peritonitis may develop acute peritoneal membrane dysfunction, resulting in reduced ultrafiltration volume and increased solute transport. This is usually the result of an increased effective surface and an increased vascular permeability. Usually, PET will not be conducted during or immediately after peritonitis because the acute membrane dysfunction will largely resolve after peritonitis.214,215 However, in the acute phase, a short-term adjustment of the PD prescription is usually required to improve ultrafiltration—for example, by using more hypertonic glucose solution or by shortening the dwell time of an exchange.  Ultrafiltration Failure UFF is classically defined as having a net ultrafiltration volume less than 400 mL with a standard 2 L 3.86% glucose solution during a 4-hour exchange.27 In fact, any patient

503

TABLE 31.5  Classification of Ultrafiltration

Failure Types

Characteristics

I

Inadequate ultrafiltration is caused by rapid solute transport, resulting in early dissipation of the osmotic gradient. Has been attributed to long-standing exposure of peritoneal membrane to glucose-based PD solutions or hypertonic glucose solutions, which resulted in submesothelial fibrosis, vasculopathic changes, and neovascularization of the peritoneum as well as an increase in the effective peritoneal surface area. Classically presents with a low drain volume in patient who has been on PD for some years. PET indicates a high D/P creatinine ratio. Decrease in peritoneal transport of small solutes and water is caused by loss of peritoneal surface area. Characterized by a decrease in the osmotic conductance to glucose and an attenuation of sodium sieving. Usually occurs in the context of peritoneal adhesions secondary to severe peritonitis, encapsulating peritonitis or postoperative complications. Classically presents with a low drain volume and PET indicating a low D/P creatinine ratio. Occurs when there is high lymphatic reabsorption of fluid from the peritoneal cavity that reduces ultrafiltration.

II

III

D/P, Dialysate to plasma; PD, peritoneal dialysis; PET, peritoneal equilibration test.

who requires three exchanges of 3.86% glucose PD solution to maintain dry weight is considered to have an inadequate ultrafiltration capacity. UFF is classified into three types (Table 31.5). Type I UFF is the most common, in which equilibration across the membrane is so rapid that the osmotic gradient for glucose dissipates before adequate ultrafiltration has occurred. It is characterized by inadequate ultrafiltration and increased solute transport and generally has a more gradual onset. The prevalence of high transport status may increase with increasing time on PD. In some cases, temporary cessation of PD or resting the peritoneal membrane may allow remesothelialization and may transiently improve ultrafiltration capacity.216 However, in some cases, encapsulating peritoneal sclerosis (EPS) may develop after switching to hemodialysis.217 According to some previous surveys, the cumulative incidence of UFF was 2.6% after 1 year on PD, rising to 9.5% after 2 years and to 30.9% after 6 years.218 The cumulative increase in the incidence of high peritoneal transport status over time on PD has been suggested to be partly attributed to the long-standing exposure of the peritoneal membrane to glucose-based PD solutions. In particular, exposure to hypertonic glucose solution has been implicated as one of the key culprits. Pathologically, peritoneal membrane of PD patients had increased submesothelial fibrosis, vasculopathic changes, and neovascularization compared with healthy controls and

504

SECTION III  Dialysis

hemodialysis patients.2 The neovascularization increases the effective peritoneal surface area, leading to more rapid peritoneal transport. In animal models of PD, glucose and GDPs of glucose solutions induced vascular endothelial growth factor (VEGF) expression, which in turn promoted vasculopathic changes and neovascularization of the peritoneal membrane through induction of nitric oxide. Treatment with neutralizing anti-VEGF monoclonal antibodies largely prevented the hyperglycemia-induced structural and functional microvascular alteration of the peritoneum and prevented deterioration of ultrafiltration in animal models of PD.219,220 Similarly, in human studies, patients who develop high peritoneal transport characteristics were noted to have more exposure to hypertonic glucose solutions for some years before its development, compared with other patients who maintained relatively stable transport characteristics. However, glucose exposure may not be the sole factor contributing to an increased peritoneal transport. There are some suggestions that patients who develop high peritoneal transport characteristics also had a faster decline in RKF.221 However, a causal link cannot be determined based on the cross-sectional study design. As reported in a longitudinal follow-up study, peritonitis may also partly influence the time course of small solute and solute-free water transport. Patients with previous peritonitis had an earlier and more pronounced increase in the mass transfer area coefficient for creatinine and glucose compared with the group with no peritonitis. A decrease in solute-free water transport and ultrafiltration rate occurred only in the peritonitis group. The decrease in ultrafiltration was evident after 1 year in patients with severe peritonitis. On the other hand, in long-term peritonitis-free PD patients, small solute transport decreased and ultrafiltration increased.222,223 Systemic inflammation may also be associated with high peritoneal transport in patients receiving PD for more than 6 months.224 Type II UFF occurs as decrease a result of loss of peritoneal surface area, resulting in a decrease in peritoneal transport of small solutes and water. This is less common and usually occurs in the context of peritoneal adhesions secondary to severe peritonitis or after surgical complications. As a result of the peritoneal adhesions, the surface area and capacity for peritoneal transport for both solutes and water are substantially reduced. There is some suggestion that type II UFF may be a manifestation of EPS, although in early stages of EPS, a high rather than a low peritoneal transport is usually seen.225 The diagnosis of EPS may be confirmed by a contrast-enhanced computed tomographic scan of the abdomen.218 Type III UFF occurs when lymphatic reabsorption of fluid from the peritoneal cavity is large enough to reduce ultrafiltration. Peritoneal fluid absorption occurs either by direct lymphatic absorption that occurs predominantly through the diaphragmatic stomata or by hydrostatic pressure into the anterior abdominal wall tissues. From there, peritoneal fluid is gradually reabsorbed by the lymphatics or into systemic capillaries. The total amount of fluid reabsorbed is approximated to be 60 to 120 mL/hour. The incidence of type III UFF is

not known and is a diagnosis of exclusion, because peritoneal lymphatic flow is not measured in most PD centers. There is some preliminary suggestion that peritoneal lymphatic flow may increase with increasing time on PD.226 To best assess UFF, a modified PET using 3.86% glucose solution is preferred over 2.5% dextrose solution to maximize osmotic drive.227 During the PET, the D/P sodium curve typically shows an initial fall because of the high ultrafiltration rate. Ultrafiltration is initially low in sodium concentration as a result of sodium sieving. Dialysate sodium concentration reduces, resulting in a fall in the D/P sodium ratio. With the cessation of ultrafiltration later in the dwell, dialysate sodium gradually equilibrates with that of plasma and the D/P sodium ratio gradually returns back to baseline. Absence of the initial fall in D/P sodium ratio is a feature of UFF and typically occurs in the early phase of EPS.228 

CONCLUSIONS There is an evolving concept to define adequate dialysis, or more preferably optimal dialysis, using a multidimensional measure that moves beyond urea and CrCl targets. Optimization of PD prescription also should be based on various other therapeutic targets, including ultrafiltration and volume control, nutrition status, uremic toxins removal, CKD-MBD control, blood pressure, left ventricular hypertrophy, and function as well as patient-centered outcomes. This multitargeted approach may be useful in improving clinical outcomes of PD patients. 

RESIDUAL KIDNEY FUNCTION Importance of Residual Kidney Function in Peritoneal Dialysis The importance of RKF in clinical outcomes of PD patients was first recognized in the 1990s when Maiorca et  al.168 reported that in a prospective cohort of hemodialysis and PD patients every 1 mL/min higher residual GFR was associated with a 40% lower mortality risk in the overall cohort and a 50% lower mortality risk in the PD patients. Subsequent to this study, several other investigators reported a similar association between residual GFR and overall survival in other prospective PD cohorts. A reanalysis of data from the CANUSA study confirmed notable differences in the contribution of RKF and PD to the overall total small solute clearance in PD patients. The predictive power of total weekly small solute clearance for survival of PD patients was attributed to RKF but not to PD clearance. Every 5 L/week/1.73 m2 higher residual GFR was associated with a 12% lower risk for mortality. However, no association was reported between the PD component of small solute clearance and survival of PD patients.177 These data suggest that the contribution of these two components of small solute clearance cannot be considered equivalent. Extending these observations in relation to hard outcomes, Wang et  al.229 reported an important inverse relationship between the degree of left ventricular hypertrophy and total

CHAPTER 31  Peritoneal Dialysis Solutions, Prescription and Adequacy

505

↓ Residual renal function

↑ Resting energy expenditure

↓ Removal of middle molecule uremic toxins, for example, p-cresol

Malnutrition

↓ Erythropoietin production and ↑ anemia

↑ Inflammation

Cardiac hypertrophy and heart failure

↓ Urea and creatinine clearance

Atherosclerosis and arteriosclerosis

↓ Sodium and fluid removal

↓ Phosphorus removal

Vascular and valvular calcification

↑ Overall and cardiovascular mortailty ↓ Quality of life and well-being

FIG. 31.11  Importance of residual kidney function in PD patients. (Reproduced with permission from Wang AY, Lai KN. The importance of residual renal function in dialysis patients. Kidney Int. 2006;69(10):1726-1732.)

small solute clearance and that this association was attributed to residual GFR but not to PD small solute clearance. Several factors have been suggested to explain the association between RKF and clinical outcomes of PD patients230 (Fig. 31.11), one of which was related to extracellular volume overload. Konings et  al.231 found that loss of residual GFR was associated with extracellular volume overload as determined by bromide dilution in PD patients. In keeping with this early observation, a 2008 study232 found that left ventricular filling pressure, estimated by echocardiography and tissue Doppler imaging–derived ratio of early diastolic transmitral flow velocity to early diastolic mitral annular velocity (E/Em), was inversely associated with residual GFR, independent of other clinical, biochemical, and echocardiographic factors. A higher left ventricular filling pressure as determined by E/Em ratio was predictive of a greater risk for mortality and cardiovascular events in PD patients.232 An increased inflammatory response also contributes to adverse clinical outcomes of PD patients and is in part attributed to the loss of RKF.233 C-reactive protein and interleukin 6, prototype markers of inflammation, are well-recognized predictors of a higher mortality and cardiovascular events in PD patients.47,233-236 Previous studies from Wang et  al.233,237 and other investigators found that PD patients with less residual GFR had more inflammation as denoted by different inflammatory parameters, including C-reactive protein, interleukin 6, and soluble vascular cell adhesion molecule 1. The loss of RKF together with more severe cardiac hypertrophy and more inflammation combined additively to increase the mortality and cardiovascular death risk for PD patients. Compared with patients who exhibited none of the risk factors, PD patients having all three risk factors had a

nearly sevenfold higher all-cause mortality risk and more than fivefold higher cardiovascular death risk.238 Accumulation of protein-bound uremic retention solutes and middle molecules has been suggested as the other key factor linking loss of RKF to more adverse clinical outcomes of PD patients.239 Higher circulating levels of uremic retention solutes such as free p-cresol and β2 microglobulin were associated with higher risk for mortality in dialysis patients.239,240 Accumulating evidence suggests that some of these uremic retention solutes, such as p-cresol sulfate, indoxyl sulfate, and p-cresol glucuronide, activate monocytes, macrophages, and endothelial cells that are pivotally involved in the process of atherosclerosis and mediated vascular injury by stimulating cross-talk between leukocyte and vascular endothelium.241,242 Furthermore, RKF appears to have a substantially greater contribution compared with PD clearance to the overall clearance of protein-bound uremic retention solutes and middle molecules such as free p-cresol and indoxyl sulfate.239,243,244 (Fig. 31.12). There are similar data from hemodialysis populations indicating that RKF contributes significantly to the clearance of β2 microglobulin.240 Thus the decrease in protein-bound uremic retention solutes and middle molecules clearance with decline in RKF may not be equivalently replaced by increasing PD.243 RKF also plays an important role in the CKD-MBD axis. Residual GFR was one of the most significant contributing factors to serum phosphorus control among those with preserved RKF, second only to nPNA. Its importance outweighed that contributed by PD clearance. Among anuric PD patients, PD clearance and nPNA were the most significant factor associated with serum phosphorus level.245 In keeping

506

SECTION III  Dialysis

Clearance, L/wk/1.73 m2

100 Peritoneal clearance 80 60 40 20 0

A

Renal clearance

UN

Cr

P

β2M

p-cresol

Clearances of p-cresol L/week/1.73 m2 20

20

15

15

10

10

5

5

0

B

0 time

20

Clearances of β2-microglobulin L/week/1.73 m2

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15

10

10

5

5

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0

C

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FIG. 31.12 Renal and peritoneal clearance of uremic retention solutes. (A) Important contribution of residual kidney function to middle molecular uremic toxins clearance (e.g., p-cresol sulfate and β2 microglobulin [β2M]) in PD patients. (B) Time course of renal (gray bars), peritoneal (white bars), and total clearances (black diamonds) (in liters per week per 1.73 m2) of β2M from visits 1 to 5 (N = 24). (C) Time course of renal (gray bars), peritoneal (white bars), and total clearances (in liters per week per 1.73 m2) of p-cresol from visits 1 to 5 (N = 24). Median values are shown. (Reproduced with permission from Bammens B, Evenepoel P, Verbeke K, Vanrenterghem Y. Time profiles of peritoneal and renal clearances of different uremic solutes in incident peritoneal dialysis patients. Am J Kidney Dis. 2005;46(3):512-519.)

with these observations, a greater prevalence of valvular calcification was reported in anuric PD patients compared with those with preserved RKF and appeared to be contributed to both by an increased inflammatory response and worse calcium phosphorus control.246 A combination of inflammatory

and calcification markers further increased the long-term mortality and cardiovascular event risk in PD patients.247 Loss of RKF also increased the prevalence of 25-hydroxyvitamin D deficiency in PD.248 A previous meta-analysis249 found that having a higher 25-hydroxyvitamin D level was associated with a better survival in patients with CKD. RKF was also associated with other parameters of CKD-MBD, such as fibroblast growth factor 23, which has also been found to be associated with mortality in dialysis patients. RKF contributes significantly to the nutrition status of dialysis patients.250 Bammens et al.251 found that retention of middle molecule uremic solutes may explain uremic symptoms in dialysis patients. In PD patients, better preserved RKF but not PD clearance has been associated with a greater amount of dietary protein, energy, other macronutrient and micronutrients intake, and better nutrition status as determined by subjective global assessment.191,192 On the other hand, loss of RKF was associated with increased catabolism in PD patients. This is evident by the strong, inverse, novel association between residual GFR and resting energy expenditure independent of other factors, including diabetes, cardiovascular disease, C-reactive protein, and serum albumin in PD patients. Having a better preserved RKF was associated with a lower resting energy expenditure, whereas PD patients who lost their RKF were associated with an increased resting energy expenditure.252 In keeping with these data, PD patients who lost their RKF were also noted to have more muscle wasting as reflected by less handgrip strength.186 Having less handgrip strength was associated with higher risk for mortality and cardiovascular death186 and was found to be predictive of higher risk for heart failure in PD patients.185 In conclusion, having a better preserved RKF was associated with better small solute clearance as well as middle molecule uremic retention solute clearance, better extracellular volume control, less inflammation, better control of the CKD-MBD axis, better dietary intake profile, less muscle wasting, and less resting hypercatabolism in PD patients, thus explaining a better survival and cardiovascular outcome (see Fig. 31.9). Having a better preserved RKF was also noted to be associated with a better quality of life in PD patients.253 Specifically, this included several dimensions of the Kidney Disease Quality of Life scale in PD patients: physical health, kidney disease issues, and patient satisfaction (unpublished observation of Wang et al.). 

Decline of Residual Kidney Function There have been some suggestions that PD may be associated with a slower rate of decline in RKF than hemodialysis.254-257 The rates of decline in RKF on average may be 24% to 80% faster in hemodialysis than PD patients,258 although there have also been studies that suggested similar rates of decline of RKF in PD and hemodialysis patients.259,260 However, it is important to caution that these studies were all observational and not randomized. Notably, there were some suggestions that the rate of decline of RKF matters in dialysis patients. PD patients with faster rates of decline in RKF were associated with worse patient survival and technique survival.261

CHAPTER 31  Peritoneal Dialysis Solutions, Prescription and Adequacy BOX 31.4  Potential Strategies Being

Studied for Better Preservation of Residual Kidney Function Avoid hypotension. Avoid nephrotoxins and radiocontrast use. Use low-GDP solutions (randomized trials and data suggest its use may keep RKF and urine volume better up to 24 months). Use icodextrin (no conclusive data to suggest icodextrin use increases RKF loss). Use angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (only two very small randomized trials available). Use oral N-acetylcysteine (only two pilot single-arm small studies available). Supplement with a low-protein diet (only one small randomized controlled trial available). Use diuretics (no data to suggest their use preserves RKF better). Consider PD vs. APD (no randomized studies, only observational studies; no conclusive data to suggest any difference in RKF decline between PD vs. APD). APD, automated peritoneal dialysis; GDP, glucose degradation products; PD, peritoneal dialysis; RKF, residual kidney function.

According to a marginal structural model analysis from the NECOSAD study group, dialysis patients who completely lost their RKF had a higher mortality risk compared with those who retained some degree of RKF.262 The importance of RKF and its rate of decline were further confirmed in a recent large nationally representative cohort of incident hemodialysis patients from Obi et al.263 reporting that the annual change in residual renal Kt/V and urine volume were associated with all-cause mortality. Patients with better preserved residual Kt/V and urine volume at 1 year had significantly lower hazards for mortality.

How Can We Better Preserve Residual Kidney Function in Peritoneal Dialysis Patients? Box 31.4 summarizes potential therapeutic strategies that may be useful to better preserve RKF in PD patients. It is generally recognized that avoiding overdehydration and hypotensive episodes may be important in preserving RKF in dialysis patients. As found in the analysis based on the NECOSAD cohort, having hypotensive or dehydration episodes was associated with a more rapid decline in residual GFR at the initial 3-month period of dialysis in both hemodialysis and PD patients, and that was independent of other confounding factors such as age, gender, background kidney disease, comorbidity, and dialysis urea clearance.259 On the other hand, there are also data to suggest that having extracellular volume overload did not help preserve RKF better in PD patients. In an earlier analysis based on the United States Renal Data System Dialysis Morbidity and Mortality Study Wave 2, factors that were found to hasten the loss of RKF included female gender, nonwhite race, background diabetes, and history of heart failure. Use of converting enzyme

507

inhibitors and calcium channel blockers as well as having a higher baseline residual GFR was associated with a lower risk for losing RKF in PD patients.264 Another, more observational analysis based on the International Pediatric PD Network found that background glomerulonephritis, use of icodextrin, and the ultrafiltration volume were associated with greater hazards of losing RKF, whereas use of diuretics may be associated with a lower hazard of losing RKF.265 Biocompatible low-GDP solutions.  The effects of biocompatible low-GDP solution on RKF have been examined in several RCTs (detailed earlier in Biocompatible Peritoneal Dialysis Solutions), the largest of which is the balANZ trial. Although the primary endpoint of this trial, rate of decline in RKF, was negative, the biocompatible group had a significantly longer time to anuria (P = 0.009) than the standard glucose solution group.118 In keeping with the findings from the balANZ trial, several other RCTs also reported that neutral pH, low-GDP solution attenuated the decline of RKF in incident PD patients.116,117,120,122 Some other controlled trials did not reproduce similar results,112,114,115 which may be explained by their rather short study durations of only up to 12 months and relatively small sample sizes. The findings from these randomized trials were summarized in two systematic reviews80,124-127 (see Fig. 31.2). Essentially, the systematic reviews suggested that use of neutral pH, low-GDP solutions resulted in better preservation of RKF and greater urine volumes. In the Cochrane review, the benefit of low-GDP solutions in preserving RKF was found most significantly between 12 to 23 months (P = 0.0005) but also from 24 months and beyond, though less significantly (P = 0.04). Similarly, low-GDP solutions also had significant benefit in preserving urine volume between 12 to 23 months (P = 0.0005) and from 24 months and beyond (P = 0.04).80 More recently, the Trio study of 67 randomly assigned incident PD patients also found significantly slower decline in RKF in the lactate-buffered low-GDP solution (Gambrosol Trio) group compared with the standard glucose PD solution group.128 Based on the cumulative evidence, the ISPD Adult Cardiovascular and Metabolic Guidelines made the recommendation that neutral pH, low-GDP solutions be considered for better preservation of RKF if used for 12 months or more. The grading of the recommendation was 2B.24  Renin-angiotensin system blockers.  The efficacy of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in preserving RKF were examined in two randomized open-label trials. In the RCT by Li et  al.,266 60 PD patients were studied. Residual GFR declined by 2.07 ± 1.12 with ramipril 5 mg daily versus 3.00 ± 1.86 mL/ min/1.73 m2 in the control group over a 12-month period (P = 0.03). In the study by Suzuki et al.,267 34 PD patients were randomly assigned to either valsartan or no valsartan. Valsartan 40 to 80 mg daily was associated with a change in residual GFR from 3.2 ± 0.3 to 4.3 ± 0.7 mL/min/1.73 m2, whereas the control group had a change in residual GFR from 5.9 ± 0.5 to 2.8 ± 0.4 mL/min/1.73 m2 (P < 0.01) over a treatment period of 24 months. It is important to caution that both studies were small and from a single center. Thus these findings can

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SECTION III  Dialysis

only be regarded as preliminary and need to be confirmed in larger, adequately powered studies.  Ketoacid-supplemented low-protein diet.  There is some preliminary suggestion that a ketoacid-supplemented lowprotein diet may be useful in preserving RKF in PD patients. In a small RCT conducted by Jiang et al.,268 60 PD patients were randomly assigned to a high-protein diet (1.0 to 1.2 g/kg/day protein diet), low-protein diet (0.6 to 0.8 g/kg/day protein diet), or ketoacid-supplemented low-protein diet (0.6 to 0.8 g/kg/day). Over a treatment period of 12 months, the ketoacid-supplemented low-protein diet group had significantly better preserved residual GFR and urine volume compared with the other two groups.268 These interesting preliminary findings warrant further confirmation in larger RCTs.  N-acetylcysteine.  Two small single-arm pilot studies, one in PD and one in hemodialysis patients, suggested that oral N-acetylcysteine 1200 mg twice daily for 2 to 4 weeks may be useful in increasing urine volume and residual GFR.269,270 These very preliminary findings need further evaluation in a longer-term RCT.  Diuretics.  The role of diuretics is mainly to increase urine volume and sodium excretion and minimize use of hypertonic PD glucose solutions without preserving RKF in PD patients. A previous prospective RCT in 61 PD patients found that patients randomly assigned to receive furosemide 250 mg daily had higher urine volumes at 6 and 12 months than those randomly assigned to no furosemide. However, both urea and CrCl declined at a constant rate in both groups.271  Aminoglycosides.  Given the nephrotoxicity of aminoglycosides, use of aminoglycosides should be cautioned in PD patients to minimize loss of RKF, although several studies reported no effect of aminoglycosides use on RKF decline.272 In a small RCT in which 50 PD patients with preserved RKF >1 mL/min/1.73 m2 were randomly assigned to receive cefazolin and netilmicin versus cefazolin and ceftazidime, residual GFR had transient reduction by day 14 but returned

back to baseline by day 42 with no significant difference between the two groups.273  Iodinated radiocontrast.  Because iodinated radiocontrast agents can cause acute tubular necrosis and acute kidney injury, its use is generally cautioned in PD patients because it may jeopardize RKF. Several observational studies reported no significant loss of RKF after radiocontrast agent administration. However, none of these studies were randomized or controlled.274,275 Thus one should cautiously weigh the risks versus benefits before subjecting PD patients to any contrast studies.  PD modality.  There has been some suggestion that APD might be associated with a more rapid decline in RKF than CAPD.276,277 However, other studies did not find any significant effect of PD modality on RKF loss in PD patients.278-280 So far, none of the studies were RCTs and thus it remains inconclusive whether the modality of PD, namely APD versus a continuous form of PD, may influence the decline of RKF differentially. Further confirmatory studies are required to answer this question. 

Monitoring of RKF The 2015 ISPD guideline recommended that monitoring of RKF be performed at least once every 6 months in PD patients with urine output.24 

CONCLUSION RKF contributes significantly to uremic toxins clearance and various metabolic and hemodynamic controls in PD patients and is not equivalent to that contributed by PD. Regular interval monitoring of RKF is essential in all patients who still have urine. Use of biocompatible low-GDP solutions may better preserve urine volume and RKF up to 24 months according to a systematic analysis. A full list of references is available at www.expertconsult.com.

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