A schematic concept of Kt/V urea and creatinine clearance . D dialysate, P plasma, V urea volume of distribution of urea, CrCl creatinine clearance, Cr creatinine, BSA body surface area
Formulas for Kt/V urea and CrCl
Kt/ V urea
Peritoneal Kt = Total drained volume (L) × (24-h dialysate effluent urea concentration/blood urea nitrogen level)
Renal Kt = Total urine volume (L) × (24-h urinary urea concentration/blood urea nitrogen level)
Total Kt = peritoneal Kt + renal Kt
Watson formula for estimating V
V (L, in males) = 2.447–0.09516 × (age, years) + 0.1704 × (height, cm) + 0.03362 × (weight, kg)
V (L, in females) = −2.097 + 0.1069 × (height, cm) + 0.2466 × (weight, kg)
Daily Kt/V = (peritoneal Kt + renal Kt)/V
Weekly Kt/V = 7 × daily Kt/V
Peritoneal CrCl = Total drained volume (L) × (24-h dialysate effluent creatinine concentration/serum creatinine concentration)
Renal CrCl = Total urine volume (L) × ([24-h urine creatinine concentration/serum creatinine concentration] + [24-h urine urea concentration/blood urea nitrogen level])/2
Daily CrCl = (peritoneal CrCl + renal CrCl)/1.73 m2 BSA
The DuBois formula for calculation of BSA
BSA (m2) = 0.007184 × (weight, kg)0.425 × (height, cm)0.725
Weekly CrCl = 7 × daily CrCl (L/week)
Because CAPD is a continuous therapy, blood urea nitrogen concentration is relatively constant throughout the day, thus sampling timing is not a major concern. However, in intermittent PD such as CCPD and NIPD , plasma urea concentration differs between daytime and nighttime. The general rule regarding sampling time in patients treated with these modalities is to take blood sample in the middle of the non-cycling daytime period when urea concentration represents the average value of blood urea for a day. This is usually between 1:00 and 5:00 p.m.
15.1.2 Measurement of Creatinine Clearance (CrCl)
Molecular weight of creatinine is slightly higher than urea (113 D vs. 60 D). Although urea and creatinine are well dialyzed by diffusion , creatinine equilibration is relatively lower than urea equilibration (Fig. 15.2). Therefore, monitoring both Kt/V urea and CrCl is recommended in clinical practice. CrCl is calculated in the same manner as in the measurement of Kt/V. For peritoneal CrCl, creatinine concentration is measured in the effluent from the 24-h collection of dialysates and in the plasma. For renal CrCl , creatinine concentration is also measured in the 24-h collection of urine. However, it is well known that renal CrCl overestimates true GFR because creatinine is exceedingly secreted by the proximal tubules in advanced stages of CKD. Therefore, renal CrCl is generally expressed as an average of the urinary urea clearance and creatinine clearance . Total CrCl is calculated as a sum of peritoneal CrCl and renal CrCl and is then normalized for 1.73 m2 body surface area (BSA). BSA can be estimated using the DuBois formula, which is most commonly used worldwide. These are summarized in Table 15.1.
Urea and creatinine equilibration. Urea diffuses rapidly into PD solution compared with creatinine. Rate of entry of a larger molecule, vitamin B12, is slower than urea and creatinine. D/P ratio indicates dialysate concentration of urea, creatinine, and vitamin B12 divided by plasma urea concentration of each molecule
15.1.3 Clinical Examples of Measurement of Kt/V Urea and CrCl
PD adequacy can numerically be determined by Kt/V urea and CrCl. Therefore, physicians should be familiar with these formulas. Examples of how the formulas are calculated and how we put these into clinical practice are presented as follows:
A 60-year-old female started PD due to hypertensive nephrosclerosis. She underwent three exchanges of a 1.5% 2 L glucose PD solution. A daily net peritoneal ultrafiltration and urine volume were 1 L per day and 500 mL per day, respectively. She was 165 cm tall and weighed 62 kg. Laboratory findings were as follows:
Dialysate (24-h collection): Urea, 55 mg/dL; creatinine, 6 mg/dL
Plasma: BUN, 75 mg/dL; creatinine, 8 mg/dL
Urine (24-h collection): Urea, 600 mg/dL; creatinine, 48 mg/dL
What is a total weekly Kt/V urea and CrCl?
22.214.171.124 Kt/V Urea
Step 1 Calculate peritoneal Kt/V.
Daily peritoneal Kt = total ultrafiltration × (dialysate urea nitrogen/serum BUN) = 7 (L) × (55/75) = 6.4 L per day.
Weekly peritoneal Kt = 7 (days) × 6.4 L/day = 44.8 L.
By the Watson formula, V = 30.8 L.
Weekly peritoneal Kt/V = 44.8/30.8 = 1.45.
Step 2 Calculate renal Kt/V.
Daily renal Kt = urine volume × (urinary urea nitrogen/serum BUN) = 0.5 (L) × (600/60) = 5.0 L per day.
Weekly renal Kt = 7 (days) × 5.0 L/day = 35 L.
Weekly renal Kt/V = 35/30.8 = 1.14.
Step 3 Calculate weekly Kt/V.
Weekly Kt/V = peritoneal Kt/V + renal Kt/V = 1.45 + 1.14 = 2.59.
Step 1 Calculate peritoneal CrCl.
Daily peritoneal CrCl = total ultrafiltration × (dialysate creatinine/serum creatinine) = 7 (L) × (6/8) = 5.25 L per day.
Weekly peritoneal CrCl = 7 (days) × 5.25 L/day = 36.75 L.
By the DuBois formula,
BSA = 1.68.
BSA corrected to 1.73 m2 = 1.73/1.68 = 0.97.
Weekly peritoneal CrCl normalized to 1.73 m2 BSA = 36.75/0.97 = 37.9 L.
Step 2 Calculate renal CrCl.
Daily renal CrCl = urine volume × ([urinary urea nitrogen/serum BUN] + [urinary creatinine/serum creatinine])/2 = 0.5 (L) × (600/60 + 48/8)/2 = 4.0 L per day.
Weekly renal CrCl = 7 (days) × 4.0 L/day = 28 L.
Weekly renal CrCl normalized to 1.73 m2 BSA = 28/0.97 = 28.9 L.
Step 3 Calculate weekly CrCl.
Weekly CrCl = peritoneal CrCl + renal CrCl = 37.9 + 28.9 = 66.8 L/week
She had been well maintained on CAPD without symptoms and signs of uremia until 1.5 years after commencing dialysis. At 2 years, urine volume was decreased to 100 mL per day, and she was not quite well and could not eat much. Her body weight decreased to 60 kg. Laboratory findings revealed dialysate urea of 72 mg/dL, serum BUN of 80 mg/dL, and urinary BUN of 350 mg/dL. Assuming the same net peritoneal ultrafiltration , calculate Kt/V and what should physicians do?
Using the same steps above, weekly total Kt/V is calculated as a sum of peritoneal and renal Kt/V: peritoneal Kt/V = 44.1/30.3 = 1.46; renal Kt/V = 3.08/30.3 = 0.1. Thus, weekly Kt/V is 1.56.
In this case, the patient does not meet the optimal target value of Kt/V as recommended by the current guidelines (see Sect. 15.2). Her symptoms and signs are most likely to be caused by inadequate dialysis. This is attributed to a significantly decreased RRF. She needs to do one more exchange of PD solution, four exchanges in total.
A 55-year-old male patient had been treated with APD for 3 years. Using a cycler, he underwent 8.0 L during nighttime only, and the abdomen was dried during daytime. He became anuric 6 months ago. At that time, Kt/V urea and CrCl were 1.8 and 48 L/week per 1.73 m2. This time, laboratory tests showed dialysate urea of 55 mg/dL, serum BUN of 65 mg/dL, dialysate creatinine of 4.8 mg/dL, and serum creatinine of 7 mg/dL. Total mean drained volume was 9.0 L. He weighed 68 kg and was 172 cm tall. How would you like to adjust dialysis prescription?
Following the steps above, peritoneal Kt/V urea = 1.61 and peritoneal CrCl = 41.5 L/week per 1.73 m2. We have several options to increase Kt/V urea and CrCl to the target levels. These can be (1) adding daytime dwell, (2) increasing dwell volume during nighttime, or (3) increasing frequency of exchanges on a cycler. Strengths and problems of each strategy are discussed below in Sect. 15.3.2 .
15.2 Therapeutic Targets of Kt/V Urea and CrCl
Many studies have been conducted to find the optimal target values of small solute clearance by using Kt/V urea and CrCl. In1996, the Canada-USA (CANUSA) PD study group reported the results of the prospective cohort study of 680 patients commencing continuous PD in 14 centers in two countries (1996). They found a 5% increase in the relative risk of death in proportion to a decrease of 0.1 unit of Kt/V urea, suggesting the importance of small solute clearance. Two-year survival rates were 78 and 81% in patients with Kt/V urea of 2.1 and 2.3, whereas it was only 66% in patients with Kt/V urea of 1.5. Similarly, patients with CrCl of 80 L/week per 1.73 m2 had a higher 2-year survival rate than patients with CrCl of 40 L/week per 1.73 m2 (81% vs. 65%). In line with this finding, many observational studies consistently found a decreased risk of mortality as Kt/V urea or peritoneal CrCl increased. Encouraged by the results of the observational studies, two randomized controlled trials had been consecutively published in 2002 and 2003 (Table 15.2). Both studies aimed to evaluate whether higher target of small solute clearance could improve patient survival. The ADEMEX (Adequacy of PD in Mexico) study first addressed this issue in 965 patients from 24 centers in 14 Mexican cities (Paniagua et al. 2002). The participants were randomized into two arms, and a modified PD regimen to achieve a peritoneal CrCl of 60 L/week per 1.73 m2 was prescribed to the intervention group. Fifty-nine percent of the intervention group achieved this target value by either an increase in exchange volume or the addition of a nighttime exchange or both. Contrary to the findings of the previous observational studies, this study failed to show a better survival rate in patients with an increased peritoneal clearance than in control group. In the following year, another randomized controlled trial produced similar results. A total of 320 patients were recruited from six centers in Hong Kong and were randomized into three groups with total Kt/V targets of <1.7, 1.7–2.0, and >2.0 (Lo et al. 2003). The 2-year survival rates did not differ among the three groups (87.3% in patients with Kt/V of >2.0, 86.1% in patients with Kt/V of 1.7–2.0, and 81.5% in patients with Kt/V < 1.7). In addition, there were no significant differences in technique survival, nutritional score, and hospitalization rate. However, erythropoietin was more used in patients with the lowest Kt/V group, and more patients in that group dropped out from the study due to inadequate dialysis and inadequate ultrafiltration. Although survival rates were not statistically significant, p-value was 0.054 between patient with Kt/V of <1.7 and patients with Kt/V of 1.7–2.0, suggesting a poorer outcome in patients with lowest Kt/V.
Main findings of the ADEMEX and Hong Kong study
No. of patients
<60 L/week per 1.73 m2
>60 L/week per 1.73 m2
1.5 to 1.7
1.7 to 2.0
2-year patient survival
P = 0.9842
P = 0.9924
– No difference in hospitalization rates
– No differences in hospitalization rates and nutritional parameters
– More EPO requirement in group A
– More patients who withdrew from the study in group A
Consequently, many guidelines proposed by the National Kidney Foundation (Peritoneal Dialysis Adequacy Work 2006), the International Society of PD (Lo et al. 2006), the UK Renal Association (www.renal.org/guidelines/modules/peritoneal-dialysis-in-ckd#sthash.Re0T4XBR.dpbs), the European Best Practice Working Group (Dombros et al. 2005), the Canadian Society of Nephrology (Blake et al. 2011), and the Australian Society of Nephrology (Johnson et al. 2005) adopted the findings of these two randomized controlled trials and agreed on the minimum target for Kt/V urea of at least 1.7 per week (Table 15.3). Some groups suggest a minimum target for CrCl depending on dialysis modality or transport types. In fact, there has been concern about inadequate dialysis with respect to CrCl in patients with a slow transport-type peritoneal membrane. In general, patients on APD use short and frequent exchanges, thus the target value of CrCl may not be achieved particularly in patients with a slow transport status. It takes only several hours for urea to equilibrate between plasma and peritoneal fluid (Fig. 15.2). D/P urea ratio typically is 0.7 at 2 h and 0.9 at 4 h after the dwell, where D and P represent dialysate and plasma, respectively. Creatinine equilibration is relatively lower than urea equilibration. Therefore, in slow transporters, creatinine may not be adequately removed particularly when short and frequent exchanges are used. This phenomenon becomes more evident once RRF is lost. In this regard, some guidelines additionally suggest targets of CrCl and recommend a regular monitoring. Nevertheless, compared to relatively strong evidence for Kt/V target supported by the two previous randomized controlled trials, CrCl targets for slow transporters have weak evidence. To date, there is no randomized controlled trial to support the minimum targets of CrCl in patients on APD or in patients with a slow transport-type peritoneal membrane. For this reason, it is acceptable to use the same targets as for CAPD in these patients.
Target values of small solute clearance
Kt/V urea (per week)
CrCl (L/week per 1.73 m2)
> 45 L/week/1.73 m2 for APD patients with slow transport
> 60 L/week in H and HA transporters
>50 L/week in LA and L transporters
> 45 L/week/1.73 m2 for APD patients with slow transport
≥ 50 L/week/1.73 m2
(A) for Kt/V
(C) for CrCl
(A) for Kt/V
(C) for CrCl
15.2.1 Frequency of Measurement
Many guidelines suggest measurement of Kt/V urea and CrCl within the first month of dialysis initiation. These are typically done together with peritoneal equilibration test. As seen in Sect. 15.1, total Kt/V and CrCl are a sum of peritoneal and renal clearance . Thus, dialysis adequacy assessed by small solute clearance significantly relies on RRF during the initial period of PD. Because RRF gradually declines over time, it should be regularly monitored. It is generally recommended that a 24-h urine collection for urine volume and solute clearance measurement should be performed at a minimum of every 1–2 months for patients who have a significant residual urine volume. These can be monitored at longer intervals, for example, every 4–6 months if RRF is lost and patients do well without any significant deterioration in physical health. For patients without RRF, peritoneal Kt/V should be targeted to at least >1.7 by increasing frequency of exchanges or dialysis solution volume.
15.2.2 Kt/V Urea vs. CrCl
There is lack of evidence as to which parameter is superior in predicting adverse outcome. An early observation showed more experience and fewer methodological problems with Kt/V (Twardowski 1998). In addition, Kt/V urea is exclusively used for measurement of hemodialysis adequacy. In this regard, many physicians are more familiar with Kt/V urea than CrCl, and the former is more commonly used in clinical practice. As aforementioned, renal creatinine clearance overestimates true clearance and generally exceeds urea clearance. In contrast, creatinine slowly diffuses into the peritoneum due to higher molecular weight than urea; peritoneal CrCl is lower than urea clearance (Fig. 15.2). Therefore, CrCl should be interpreted with caution depending on PD modality and membrane types. Nevertheless, these two measures are small solute clearance and do not reflect middle molecule clearance. Given a variety of uremic toxins beyond small solute and disappointing results of the ADEMEX and the Hong Kong study, the targets for small solute clearance proposed by many guidelines should be understood as the minimum level to accomplish dialysis adequacy (Fig. 15.3).
Relationship between dialysis adequacy and survival. Once the minimum target of small solute clearance is achieved, survival rate does not increase. Beyond this point, other factors can play an important role in improving patient outcomes (see Sect. 15.4)
15.3 Factors Affecting Peritoneal Clearance
There are number of factors that determine peritoneal small solute clearance. As presented in Table 15.4, these can be classified into inherent and modifiable factors. Factors such as RRF, body size, and peritoneal membrane characteristics are inherent in individual patient, thus not easily modifiable. In contrast, we can adjust dwell volume, frequency of PD solution exchange, and use of high glucose concentration PD solution depending on patient’s inherent factors. Strategies for increasing small solute clearance are summarized in Fig. 15.4.
Strategies for improving small solute clearance
Factors affecting peritoneal clearance
Peritoneal membrane transport type
Dwell duration and exchange frequency
The use of high glucose concentration PD solutions
15.3.1 Inherent Factors
As noted above, total Kt/V urea and CrCl are largely dependent on RRF, while urine volume is maintained. It can contribute approximately up to 50% of total clearance during the initial period of dialysis. Accordingly, physicians should be alert on decline of RRF and consider increasing peritoneal clearance targeted to Kt/V of at least >1.7 when patients become anuric (Fig. 15.4 and Fig. 15.5). The importance of RRF has recently been highlighted in many aspects. It has been well demonstrated that RRF is more important than small solute clearance in determining clinical outcomes in dialysis patients. Therefore, much effort should be made to preserve RRF. This is discussed in detail in Sect. 15.5.
Relationship between total Kt/V, peritoneal clearance, and residual renalfunction over time. (a) Total clearance decreases without increasing peritoneal clearance as residual renal function declines. (b) Total clearance remains unchanged if peritoneal clearance increases corresponding to a decrease in residual renal function
126.96.36.199 Body Size
Body size can also affect total clearance because Kt and CrCl are normalized to volume of distribution of urea, which is equal to total body water, and BSA, respectively. Theoretically, patients with extremely large body size may not adequately maintain PD in terms of small solute clearance. If a patient undergoes four exchanges of 2.0 L PD solutions per day to meet the target of Kt/V of >1.7 and net ultrafiltration is 1.0 L, then V = D/P urea ratio × (7 days × 9.0 L)/1.7. Assuming a D/P urea ratio of 0.9, then V is 40.6 L, which approximately fits to a man with a standard body size, 170 cm in height, and 70 kg in weight. Thus, obese patients have extremely high V, it is difficult to achieve a Kt/V urea target of >1.7 when typical peritoneal dialysis prescription is given. Conversely, Kt/V can be interpreted with caution in patients with very low V. Because these patients are more likely malnourished and deprived of muscle, it is not fair to say they do well on dialysis even though Kt/V is >1.7.
188.8.131.52 Peritoneal Membrane Characteristics
Peritoneal membrane transport types can be determined by peritoneal equilibration test. It is important to define membrane transport status in dialysis prescription. As seen in Fig. 15.2, equilibration of creatinine or larger molecules is slower and lower than that of urea. This can raise a problem regarding dialysis adequacy in patients on APD. These patients use a cycler and typically do 4–5 exchanges during 8–10 h. This inevitably requires short and frequent exchanges, resulting in lack of enough time for larger molecules to equilibrate. Urea clearance is acceptable because urea rapidly equilibrates within several hours. However, larger molecules than urea are not adequately removed due to the slower diffusion. This becomes more pronounced in slow transporters (previously known as low transport). These patients exhibit much slower equilibration of solutes than fast transporters. For this reason, dialysis prescription can be tailored depending on transport types. In general, high-volume exchanges and long-duration dwells are recommended in slow transporters, whereas short-duration dwell is more effective in fast transporters.
15.3.2 Modifiable Factors
These factors are related to dialysis prescription. When the target of Kt/V or CrCl is not achieved, we can adjust dialysis prescription by increasing dwell volume, increasing exchange frequency, and using hypertonic PD solutions. This adjustment is largely dependent on inherent factors, particularly such as transport types.
184.108.40.206 Dwell Volume
As explained above, increasing the dwell volumes is commonly used to achieve the target of Kt/V > 1.7, particularly in slow transporters. This strategy is also more effective in patients with large body size than in those with small body size. By doing this, peritoneal clearance can be increased because total drained volume is increased, while urea and creatinine equilibration are slightly decreased, giving a small dip in D/P urea or creatinine. As a result, total Kt calculated as total drained volume multiplied by D/P urea is increased. In patients with small body size, clearance is unlikely to increase by increasing dwell volume because of the greater decrease in equilibration. It is generally known that, assuming four exchanges given, increasing volume from 2.0 to 2.5 L can induce an approximately 20% increase in peritoneal clearance. However, patients may feel uncomfortable with larger instilled volume and may complain of back pain, abdominal discomfort, or shortness of breath. In addition, inguinal, ventral, or diaphragm hernia can develop due to an increase in intra-abdominal pressure. This complication can cause peritoneal fluid leak into soft tissue, thus leading to localized edema.
220.127.116.11 Adjusting Dwell Duration and Frequency of Exchanges
In typical patients on CAPD with average peritoneal transport types, increasing frequency from four to five exchanges per day accompanied by shortened dwell time does not hamper urea equilibration, which remains at 85–90% as long as patients ensure adequate dwell time of at least 4 h. In slow transporters, increasing clearance can be achieved by increasing dwell duration because creatinine equilibration still rises 4 h after the initiation of the dwell. On the other hand, in fast transporters, osmotic gradient is dissipated soon after the dwell, thus increasing frequency of daily exchanges can be an option to increase peritoneal clearance in these patients. However, one more exchange can be burdensome and limit daily activities in patients who have active lifestyle. They do not want to be tied up with PD exchange procedure. In this regard, increasing dwell volume is more effective and preferred to enhance clearance.
In patients on APD, this strategy of adjusting dwell time and frequency of exchanges can be also applied in clinical practice. These patients use a cycler during nighttime, thus problems of increasing frequency of exchanges can be resolved by the aid of the machine, which is particularly helpful in fast transporters. However, as aforementioned, shortened dwell time caused by frequent exchanges may result in insufficient solute clearance. Loss of RRF can worsen this problem. Moreover, middle molecule clearance is time dependent. Therefore, in this case, many patients require one or more exchanges of daytime dwell to increase clearance. Another way to increase clearance is to increase dwell volume as in CAPD. APD patients are unlikely to complain of abdominal discomfort because intra-abdominal pressure is not increased in supine position. How to prescribe dialysis in APD is described in detail in Chap. 4.
18.104.22.168 The Use of High Concentration Glucose Solution
Because ultrafiltration is mainly derived from osmotic gradient, the use of high concentration glucose solution can increase ultrafiltration volume by inducing higher osmotic gradient. Accordingly, peritoneal clearance can increase as total drained volume is a determinant of Kt. However, there is much concern about glucose toxicity to the peritoneal membrane damage. In addition, glucose can be absorbed via peritoneal capillary beds, leading to systemic harmful effects such as hyperglycemia, hypertriglyceridemia, weight gain, inflammation, etc. For this reason, it is generally recommended to limit the use of high concentration glucose solutions unless volume overload should be controlled. Moreover, glucose-sparing strategies have recently prevailed to preserve peritoneal membrane and to prevent glucose toxicity-associated complication.
15.4 Comprehensive Understanding of Dialysis Adequacy
As seen in the ADEMEX study and the Hong Kong study, further increase in small solute clearance beyond some point did not improve clinical outcomes. In fact, urea and creatinine may be merely markers of kidney function, and there are more uremic toxins besides small solutes. Less importance of small solute clearance was also observed in patients undergoing hemodialysis. The Hemodialysis Study Group conducted a randomized controlled trial in 1846 patients to evaluate whether high dose of dialysis could improve survival compared with standard dose (Eknoyan et al. 2002). They failed to demonstrate that increasing Kt/V urea up to 1.7 was beneficial in decreasing mortality and morbidity. The findings of the randomized controlled trials in dialysis patients suggest that there are more other factors that can determine clinical outcomes, and thus much attention should be paid to these factors after the minimum targets of Kt/V urea and CrCl are achieved. Therefore, we should comprehensively understand dialysis adequacy beyond small solute clearance. Dialysis adequacy cannot be determined by one biochemical marker. More importantly, it should encompass the management of fluid overload, blood pressure, acid-base disturbances, anemia, malnutrition, calcium-phosphorus mineral disturbances, inflammation, and middle molecule clearance (Fig. 15.6). To achieve these goals, RRF should be preserved because kidney is involved in all aspects of dialysis adequacy. It is no wonder why RRF is more associated with clinical outcomes than any other parameters. To corroborate this view, the current guidelines put much emphasis on the preservation of RRF and fluid overload management rather than small solute clearance. These are discussed in detail in Sects. 15. 5 and 15.6.
Comprehensive understanding of dialysis adequacy
15.5.1 Survival Benefit of RRF
Recently, the importance of RRF has been highlighted through a number of studies. Its significant impact on patient survival was first reported in 1995 by Maiorca et al. (1995). They observed 68 CAPD and 34 HD patients in a prospective observational study for 3 years and found that persistence of RRF was associated with improved survival. In the following year, the CANUSA study first demonstrated the survival benefit with an increase in small solute clearance assessed by Kt/V urea. Five years later, the group reanalyzed the CANUSA data to evaluate relative contribution of RRF and peritoneal clearance to dialysis adequacy (Bargman et al. 2001). The results showed that each 5 L/week per 1.73 m2 increment in GFR was associated with a 12% decrease in risk of death, but no association between peritoneal creatinine clearance and mortality was found. Furthermore, the original finding of the ADEMEX study indicated no improvement in patient survival by increasing small solute clearance. Interestingly, in the multivariable analysis, residual renal Kt/V urea and CrCl were significantly associated with a reduced risk of mortality, whereas peritoneal Kt/V urea and CrCl were not. Subsequently published studies from the European cohort and the Asian cohort consistently have shown the survival advantage of RRF compared with no effect of peritoneal clearance on survival. As in PD patients, loss of RRF was a significant predictor of death in HD patients (Shafi et al. 2010).
15.5.2 Mechanistic Link Between RRF and Better Survival
22.214.171.124 Fluid Status, Blood Pressure, Cardiac Hypertrophy, and RRF
There have been a number of studies to explain mechanisms responsible for the improved survival conferred by RRF. As seen in Fig. 15.6, RRF plays an important role in the regulation of a variety of disturbances in dialysis patients. Fluid overload is a significant determinant of adverse outcomes and is highly associated with increased blood pressure, cardiac hypertrophy, and congestive heart failure in these patients. Ates et al. evaluated the effects of fluid and sodium removal on mortality in 125 PD patients (Ates et al. 2001). They observed an increased patient survival rate in proportion to the amount of sodium and fluid removal. In particular, a 3-year patient survival rate was highest in patients with fluid removal >2035 mL/24 h/1.73 m2, whereas it was lowest in those with fluid removal <1265 mL/24 h/1.73 m2. Their findings highlight the harmful effects of fluid retention on patient survival. Not surprisingly, fluid overload can be more easily controlled in patients with RRF than in anuric patients. In a cross-sectional study by Konings et al. (2003a, b), extracellular water content was significantly and inversely correlated with residual GFR. In addition, patients with residual GFR < 2 mL/min had higher extracellular water than those with residual GFR > 2 mL/min. This finding suggests that presence of RRF is advantageous for fluid management. Accordingly, blood pressure can be more controlled by maintaining fluid balance in patients with preserved RRF. Menon et al. performed a retrospective observational study to identify factors associated with uncontrolled blood pressure in 207 PD patients (Menon et al. 2001). In their study, declining RRF was significantly associated with high blood pressure. Moreover, fluid overload can contribute to the development of left ventricular hypertrophy. The prevalence of left ventricular hypertrophy is remarkably high, up to 75–90% in patients who initiate dialysis (Wang et al. 2002a, b, 2004a, b, c). It is well known that it is an independent predictor of cardiovascular events and death in dialysis patients (Silberberg et al. 1989). In a cross-sectional study by Wang et al., left ventricular hypertrophy index was significantly lower in patients with preserved RRF than anuric patients. However, this association was not observed for peritoneal clearance. Interestingly, sodium and fluid removal differ between the kidney and the peritoneum depending on presence or absence of RRF in patients undergoing PD. Cheng et al. evaluated fluid status by using bioimpedance analysis in 195 CAPD patients and found that sodium and fluid removal was greater by the kidney than by the peritoneum in patients with urine volume > 400 mL per day (Cheng et al. 2006). Conversely, peritoneal clearance in sodium and fluid removal became more important as RRF declined. Taken together, all these findings suggest that in the absence of RRF, patients are more likely to have fluid overload, high blood pressure, and cardiac dilatation, which ultimately result in the increased cardiovascular morbidity and mortality.
126.96.36.199 Middle Molecule and Phosphate Clearance and RRF
Middle molecule clearance has recently emerged as an important therapeutic target in dialysis patients. Among many middle molecules, β2-microglobulin (β2MG) has widely been investigated. Many studies have consistently shown that β2MG is a strong and independent predictor of mortality in ESRD patients. RRF is also associated with removal of middle molecules. Bammens et al. conducted a longitudinal observational study to evaluate relative contribution of the peritoneum and the kidney to the clearance of small solutes and β2MG (Bammens et al. 2005). Renal clearance of urea and creatinine declined over time, while peritoneal clearance of these molecules increased. Interestingly, there was also a decline in renal clearance of β2MG, but its peritoneal clearance remained stable throughout the study period. These findings suggest that, for small solutes, peritoneal clearance can increase in compensation for loss of RRF. However, the elimination of middle molecule, β2MG, is less likely to be counterbalanced by the peritoneum.