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Prediction of EF-hand calcium-binding proteins and analysis of bacterial EF-hand

Renal replacement therapy (RRT) has become an established component of modern critical care. Approximately 60 - 70% of critically ill patients with severe acute kidney injury (AKI) are treated with RRT which represents ~5% of all intensive care unit (ICU) admissions (Ostermann & Chang, 2008; Uchino et al., 2005). Thirty years ago, intermittent haemodialysis for the critically ill patient with AKI was typically delivered three times weekly using dialysis machines without accurate volumetric control, acetate-based dialysate and unmodified cellulosic membrane dialysers. Peritoneal dialysis was performed with hard catheters and low dwell volumes. Since then, the types of RRT used in ICU and the available kits have advanced significantly.

Despite its worldwide use, the practice of RRT is variable. The main reasons are differences in expertise of nursing and medical staff, local availability of machines and lack of robust clinical data to support one technique over another (Pannu et al., 2008). Several important aspects related to the management of RRT, including mode, optimal indications and timing are the focus of ongoing discussion and opposing views.

#### **2. Aims of RRT**

AKI in critically ill patients manifests itself with varying degrees of uraemia, fluid accumulation, acid base disturbance and non-renal dysfunction. The clinical course can be very variable. RRT for AKI is predominantly supportive with the aim to maintain metabolic and volume haemostasis and to prevent uraemic complications and dysfunction of other organs during the critical illness until renal function recovers. It is important that these benefits of RRT are balanced by potential harm, including risks related to central venous access, infections and anticoagulation (Oudemans-van Straaten, 2007).

#### **3. Practice of RRT**

#### **3.1 Indications for RRT**

In the setting of chronic kidney disease, the European Best Practice Guidelines recommend starting chronic dialysis when a patient with an estimated glomerular filtration rate (GFR) of <15ml/min/1.73m2 has symptoms or signs of uraemia, fluid overload or malnutrition in spite of medical therapy or before estimated GFR has fallen to <6ml/min/1.73m2 in an asymptomatic patient (European Best Practice Guidelines, 2005). The overall aim is to replace renal function. The situation is very different in the acute setting where RRT for AKI is predominantly viewed as organ support until kidney function recovers. Although acute RRT should be started before the onset of any potentially life threatening complications of uraemia, the optimal time and indications remain controversial. Potential benefits of early initiation are more rapid metabolic/uraemic control and more effective prevention and management of fluid overload (Gibney et al., 2008). Some data also suggest that RRT before the onset of severe AKI may attenuate kidney-specific and non-kidney organ injury from acidemia, uremia, fluid overload, and systemic inflammation, and potentially translate into improved survival and earlier recovery of kidney function (Clark et al., 2006; Matson et al., 2004). The obvious counterargument is that early RRT might subject patients who would recover renal function with conservative treatment alone, to the potential risks associated with RRT (Vinsonneau & Monchi, 2011). Delay of RRT until AKI is severe avoids treatment in patients with potentially recoverable AKI but increases the risk of uraemic complications and fluid overload.

#### **3.1.1 Indicators for initiation of RRT**

Studies exploring the optimal indication for starting RRT have used different parameters, including arbitrary cut-offs for serum creatinine, serum urea or urine output, fluid balance, time from ICU admission or time after onset of AKI. Several retrospective studies have shown an association between lower serum urea levels at time of RRT and better outcomes (Gettings et al., 1999; Liu et al., 2006; Shiao et al., 2009). Liu et al reported a lower mortality in 122 patients in a mixed ICU who had serum urea levels ≤27 mmol/L (≤76 mg/dL) on the day when RRT was started compared to 121 patients with higher urea values (Liu et al., 2006). When adjusted for age, hepatic failure, sepsis, thrombocytopenia and serum creatinine, the relative risk of death with a higher urea level at time of RRT was 1.85 (95% CI 1.16 – 2.96). Improved mortality was also reported in other retrospective studies when RRT was instituted with serum urea <21 mmol/L (Gettings et al., 1999) or <23 mmol/L (Shiao et al., 2009) compared to higher levels. The authors made the conclusion that "early RRT may be better than late RRT". However, 2 larger studies did not find any correlation between serum urea at time of RRT and outcome (Bagshaw et al., 2009; Ostermann & Chang, 2009). Instead, they showed that patients who had a serum creatinine < 309 μmol/L at time of RRT had a greater risk of dying compared to those with higher serum creatinine levels. Other studies found a better outcome in patients with a shorter time from ICU admission (Payen et al., 2008; Piccinni et al., 2006), a higher urine output at time of RRT (Sughara & Suzuki, 2004), and a shorter time between onset of AKI and RRT (Ostermann & Chang, 2009).

Despite the perception that early RRT may be better, the data are conflicting (Bagshaw et al., 2009; Bouman et al., 2002; Demirkilic et al., 2004; Elahi et al., 2004; Gettings et al., 1999; Liu et al, 2006; Ostermann & Chang, 2009; Payen et al., 2008; Piccinni et al., 2006; Shiao et al., 2009; Sughara et al., 2004). There are only 2 randomized controlled trials (RCTs) exploring the impact of timing of RRT (Bouman et al., 2002; Sughara & Suzuki, 2004). The majority of data stem from retrospective analyses with different biochemical cut-offs to distinguish between early and late treatment. Therefore, it cannot be excluded that patients in the "early" RRT group simply had less severe AKI and that patients in the "late" group received RRT too late, ie. after the onset of uraemic complications. Finally, the interpretation of nonrandomized studies is limited by the exclusion of patients who met criteria for early RRT but never received it.

In the largest prospective RCT investigating the role of timing, 106 predominantly cardiac surgical patients with AKI were randomized to three groups: early high-volume continuous venovenous haemofiltration (CVVHF) (n=35), early low-volume CVVHF (n=35) and late low-volume CVVHF (n=36) (Bouman et al., 2002). There were no significant differences in 28 day mortality or duration of AKI between the groups. All hospital survivors recovered renal function except for one patient in the early low volume CVVH group. Of interest, 4 patients in the late arm recovered renal function spontaneously and 2 patients died before the criteria for CVVH were met. The authors came to the conclusion that there was no significant benefit with either early CVVH or high filtration rates for patients with oliguric AKI. A large retrospective analysis of 1,847 ICU patients treated with RRT for AKI demonstrated that the most important independent risk factors for ICU mortality were mechanical ventilation, associated organ failure, pre-existing chronic health problems, acidosis, oliguria and age (Ostermann & Chang, 2009). There was no association between serum urea and creatinine at time of RRT and outcome. The paper concluded that the decision to start RRT should depend less on classic renal parameters but more on the clinical status of the patient, degree of acidosis, risk of fluid overload and associated organ failure.

The negative impact of fluid overload is increasingly being recognised (Bouchard et al., 2009; Payen et al., 2008). In a retrospective analysis of 398 ICU patients, Bouchard et al found a significantly higher ICU mortality in patients who had gained 1-20% or more in body weight between ICU admission and day of RRT compared to patients without any weight gain (Bouchard et al., 2009). Oliguria and fluid overload in the context of AKI should be viewed as triggers for RRT independent of actual serum urea and creatinine results.

In summary, based on the existing data in the literature, the decision when to start RRT should take into account the patient's severity of illness and its trends, degree of fluid overload and number and types of associated organ failure. Individual serum creatinine or urea parameters are not adequate in identifying the optimal time for RRT. Obviously, in patients with a futile prognosis RRT may not be appropriate. In this case, withholding RRT constitutes good end-of life care (Gabbay & Meyer, 2009).

#### **3.2 Choice of RRT modality**

254 Hemodialysis - Different Aspects

<6ml/min/1.73m2 in an asymptomatic patient (European Best Practice Guidelines, 2005). The overall aim is to replace renal function. The situation is very different in the acute setting where RRT for AKI is predominantly viewed as organ support until kidney function recovers. Although acute RRT should be started before the onset of any potentially life threatening complications of uraemia, the optimal time and indications remain controversial. Potential benefits of early initiation are more rapid metabolic/uraemic control and more effective prevention and management of fluid overload (Gibney et al., 2008). Some data also suggest that RRT before the onset of severe AKI may attenuate kidney-specific and non-kidney organ injury from acidemia, uremia, fluid overload, and systemic inflammation, and potentially translate into improved survival and earlier recovery of kidney function (Clark et al., 2006; Matson et al., 2004). The obvious counterargument is that early RRT might subject patients who would recover renal function with conservative treatment alone, to the potential risks associated with RRT (Vinsonneau & Monchi, 2011). Delay of RRT until AKI is severe avoids treatment in patients with potentially recoverable AKI but increases the risk of uraemic complications

Studies exploring the optimal indication for starting RRT have used different parameters, including arbitrary cut-offs for serum creatinine, serum urea or urine output, fluid balance, time from ICU admission or time after onset of AKI. Several retrospective studies have shown an association between lower serum urea levels at time of RRT and better outcomes (Gettings et al., 1999; Liu et al., 2006; Shiao et al., 2009). Liu et al reported a lower mortality in 122 patients in a mixed ICU who had serum urea levels ≤27 mmol/L (≤76 mg/dL) on the day when RRT was started compared to 121 patients with higher urea values (Liu et al., 2006). When adjusted for age, hepatic failure, sepsis, thrombocytopenia and serum creatinine, the relative risk of death with a higher urea level at time of RRT was 1.85 (95% CI 1.16 – 2.96). Improved mortality was also reported in other retrospective studies when RRT was instituted with serum urea <21 mmol/L (Gettings et al., 1999) or <23 mmol/L (Shiao et al., 2009) compared to higher levels. The authors made the conclusion that "early RRT may be better than late RRT". However, 2 larger studies did not find any correlation between serum urea at time of RRT and outcome (Bagshaw et al., 2009; Ostermann & Chang, 2009). Instead, they showed that patients who had a serum creatinine < 309 μmol/L at time of RRT had a greater risk of dying compared to those with higher serum creatinine levels. Other studies found a better outcome in patients with a shorter time from ICU admission (Payen et al., 2008; Piccinni et al., 2006), a higher urine output at time of RRT (Sughara & Suzuki, 2004), and a shorter time between onset of AKI and RRT (Ostermann & Chang, 2009). Despite the perception that early RRT may be better, the data are conflicting (Bagshaw et al., 2009; Bouman et al., 2002; Demirkilic et al., 2004; Elahi et al., 2004; Gettings et al., 1999; Liu et al, 2006; Ostermann & Chang, 2009; Payen et al., 2008; Piccinni et al., 2006; Shiao et al., 2009; Sughara et al., 2004). There are only 2 randomized controlled trials (RCTs) exploring the impact of timing of RRT (Bouman et al., 2002; Sughara & Suzuki, 2004). The majority of data stem from retrospective analyses with different biochemical cut-offs to distinguish between early and late treatment. Therefore, it cannot be excluded that patients in the "early" RRT group simply had less severe AKI and that patients in the "late" group received RRT too late, ie. after the onset of uraemic complications. Finally, the interpretation of non-

and fluid overload.

**3.1.1 Indicators for initiation of RRT**

Current RRT options for ICU patients with AKI are continuous modes [continuous haemofiltration (CVVHF), continuous haemodialysis (CVVHD) and continuous haemodiafiltration (CVVHDF)], intermittent haemodialysis (HD), hybrid techniques like slow extended haemodialysis (SLED) or prolonged intermittent renal replacement therapy (PIRRT) and acute peritoneal dialysis. Some characteristics of the different modalities are listed in Table 1.

Continuous RRT is often perceived to offer greater cardiovascular stability compared to traditional intermittent HD. However, intermittent techniques have evolved over the last 20 years. HD machines now have accurate fluid balance control modules with real-time indirect assessment of relative changes in blood volume which allow rapid fluid removal with less haemodynamic instability. A switch towards bicarbonate-based dialysate and less bioincompatible membranes, together with a recognition of the importance of higher dialysate sodium concentrations and cooled dialysate have also led to a reduced the risk of intradialytic hypotension. Advantages of intermittent HD are the reduced need for anticoagulation, lower financial costs and greater flexibility which ultimately allows more time for investigations and therapies, including active rehabilitation. Small solutes such as potassium are removed more efficiently with HD which may be particularly beneficial in the setting of acute life threatening hyperkalaemia.

Table 1. Comparison between different modes of RRT (adapted from Mehta et al., 1993)

In addition to potentially better haemodynamic stability, continuous RRT offers the advantage of more sustained fluid removal and less fluctuations in fluid status and metabolic control. Obvious disadvantages are the need for continuous anticoagulation and less flexibility, including less time for the patient to participate in active rehabilitation. The rate of solute removal is lower than with intermittent HD. Over the last few years, there has been much debate whether haemofiltration offers additional benefits for patients with AKI and severe sepsis / septic shock beyond solute clearance (Peng Z et al., 2010). Proponents argue that RRT in the context of severe sepsis contributes to removal of soluble inflammatory mediators of sepsis and restores immune function through improved antigenpresenting capability and leukocyte responsiveness (Honoré et al., 2007). Although this concept of "blood purification" is conceptually appealing, the evidence is limited to data from animal models and small human studies (Bouman et al., 2007).

Although there are differences in capillary fibre structure and design, most ICUs use the same dialysers for CRRT, PIRRT and IHD. The resurgence of batch dialysis systems (for instance, Genius® , NxStage®) and the use of individual water purification systems (microfilters, water softeners, multiple pass reverse osmosis) coupled with endotoxin filters has made it possible to provide haemodialysis even without access to ultrapure water supply as in chronic haemodialysis units.

#### **3.2.1 Continuous versus intermittent RRT**

It is widely perceived that continuous modes may be better for critically ill patients with AKI. However, prospective randomised clinical trials have failed to confirm this. Based on 4 different systematic reviews, there is no convincing evidence that continuous RRT is superior to intermittent HD in terms of mortality or renal recovery (Bagshaw et al., 2008; Kellum et al., 2002; Rabindranath et al., 2007; Tonelli et al., 2002). Although these analyses included different studies of varying methodological quality and size, the authors came to

intradialytic hypotension. Advantages of intermittent HD are the reduced need for anticoagulation, lower financial costs and greater flexibility which ultimately allows more time for investigations and therapies, including active rehabilitation. Small solutes such as potassium are removed more efficiently with HD which may be particularly beneficial in the

CVVH CVVHD CVVHDF Intermittent

Yes Yes Yes Not

Table 1. Comparison between different modes of RRT (adapted from Mehta et al., 1993)

from animal models and small human studies (Bouman et al., 2007).

supply as in chronic haemodialysis units.

**3.2.1 Continuous versus intermittent RRT**

In addition to potentially better haemodynamic stability, continuous RRT offers the advantage of more sustained fluid removal and less fluctuations in fluid status and metabolic control. Obvious disadvantages are the need for continuous anticoagulation and less flexibility, including less time for the patient to participate in active rehabilitation. The rate of solute removal is lower than with intermittent HD. Over the last few years, there has been much debate whether haemofiltration offers additional benefits for patients with AKI and severe sepsis / septic shock beyond solute clearance (Peng Z et al., 2010). Proponents argue that RRT in the context of severe sepsis contributes to removal of soluble inflammatory mediators of sepsis and restores immune function through improved antigenpresenting capability and leukocyte responsiveness (Honoré et al., 2007). Although this concept of "blood purification" is conceptually appealing, the evidence is limited to data

Although there are differences in capillary fibre structure and design, most ICUs use the same dialysers for CRRT, PIRRT and IHD. The resurgence of batch dialysis systems (for instance, Genius® , NxStage®) and the use of individual water purification systems (microfilters, water softeners, multiple pass reverse osmosis) coupled with endotoxin filters has made it possible to provide haemodialysis even without access to ultrapure water

It is widely perceived that continuous modes may be better for critically ill patients with AKI. However, prospective randomised clinical trials have failed to confirm this. Based on 4 different systematic reviews, there is no convincing evidence that continuous RRT is superior to intermittent HD in terms of mortality or renal recovery (Bagshaw et al., 2008; Kellum et al., 2002; Rabindranath et al., 2007; Tonelli et al., 2002). Although these analyses included different studies of varying methodological quality and size, the authors came to

+ diffusion

24 hours 24 hours variable 4 – 6 hours 6 – 12

100 - 250 100 - 250 100 - 250 200 - 350 100 - 300 none

20- 40 25 – 45 25 – 45 150 – 180 90 – 140 15 - 35

HD

absolutely

SLED /

Diffusion Diffusion Diffusion

hours

Not absolutely

PIRRT PD

24 hours

No

setting of acute life threatening hyperkalaemia.

Therapy time/day

Blood flow (ml/min)

Need for Anticoagulation

Urea clearance (ml/min)

Solute transport Convection Diffusion Convection

similar conclusions. The Hemodiafe Study, a multicenter RCT comparing intermittent HD versus CVVHDF in patients with AKI and multiple-organ dysfunction syndrome (MODS), showed that it is possible to treat almost all critically ill patients with AKI with intermittent HD, provided strict guidelines to improve tolerance and metabolic control are adhered to (Vinsonneau et al., 2006). In the intermittent HD group, haemodynamic stability was maintained by using a high dialysate sodium concentration and dialysate cooled to 350C. There was no difference in outcome between both groups.

Despite the lack of data that continuous RRT is superior to intermittent HD with regards to mortality or renal recovery, there is some evidence that fluid overload may be easier to control with continuous RRT compared to intermittent modalities. Retrospective analysis of data collected as part of the Program to improve Care in Acute Renal Disease (PICARD) study showed that patients treated with intermittent RRT continued to gain fluid in the subsequent days in contrast to patients on continuous RRT in whom the fluid balance was significantly better controlled (Bouchard et al., 2009). This observation makes intermittent HD less suitable for patients with major fluid overload and supports the recommendation to use continuous RRT for this patient group (Vanholder et al., 2011).

 In a small trial, 39 patients were randomised to either CVVHF or 12-hour SLED (Kielstein et al., 2004). Cardiovascular tolerability and urea clearances were equivalent. However, less heparin was needed and acidosis was corrected faster in patients treated with SLED. In another randomised trial in 60 patients, CVVHDF was compared to 6 – 8 hours of SLED (Abe et al., 2010). There was no difference in ICU or 30 day mortality but survivors in the SLED group had higher renal recovery rates and a shorter length of stay in ICU.

#### **3.2.2 Peritoneal dialysis versus continuous RRT**

Acute peritoneal dialysis in the ICU is possible but requires the insertion of a peritoneal dialysis catheter and relies on an intact peritoneum and adequate bowel movement. It is contraindicated in patients with abdominal pathology. Solute clearance and fluid removal are generally less predictable and controllable and may be reduced in patients with impaired mesenteric blood flow. Removal of large volumes of fluid may not be possible with small dwell volumes, especially in the first 2 weeks after insertion of the peritoneal catheter.

There are only limited data comparing peritoneal dialysis to continuous RRT in adults (Gangji et al., 2005; Swartz et al., 2005). In a Vietnamese study in patients with infection associated AKI, CVVHF was superior but the applied peritoneal dialysis strategies were different from current practice (Phu et al., 2002). Another study showed not difference but the clearance delivered by peritoneal dialysis was low (Gabriel et al., 2008).

In summary, analysis of the currently published studies shows no clear advantage of one modality over the other in terms of mortality or renal recovery. The decision regarding type of RRT should take into account the individual patient's clinical condition, medical and nursing expertise, and the availability of RRT machines. Regular education and training of those who provide RRT is essential with emphasis on the characteristics and values of each RRT technique. During the dynamic course of critical illness the type of RRT modality may have to change in response to the varying needs of the patient. Most clinicians choose continuous RRT for patients with cardiovascular compromise, significant fluid overload and multi-organ failure, and an intermittent mode for cardiovascularly stable patients (Kanagasundaram, 2007; VA NIH Acute Renal Failure Trial Network et al., 2008) Although the risk of hypotension is increased during intermittent HD, the Hemodiafe study showed that the introduction of a relatively simple treatment algorithm including use of a high dialysate sodium concentration of 145 mmol/L in combination with cooled dialysate and stopping vasodilator infusions, markedly reduced the risk of intradialytic hypotension (Vinsonneau et al., 2006). Hybrid techniques like SLED / PIRRT offer the advantages of both CRRT and intermittent HD, including haemodynamic stability, increased patient mobility and reduced financial costs.

#### **3.3 General care**

Severe AKI results in hypercatabolism and altered drug metabolism. Provision of adequate nutrition and attention to drug dosing are essential when looking after patients on RRT. While no particular mode or filter is recommended, it is important to understand the characteristics of these different RRT techniques and potential differences in drug removal. Both, under-treatment and drug toxicity have been reported in patients on RRT.

#### **4. Conclusions**

RRT is a form of organ support for critically ill patients with AKI. The most commonly used modalities are continuous haemo(dia)filtration and intermittent modes. There is no evidence that one mode is superior to another in terms of mortality or renal recovery. Except for a few specific indications, each modality can be considered a valid RRT option for critically ill patients with AKI. The choice should depend on the patient's clinical condition, medical and nursing expertise and local availability of machines. Intermittent HD is an acceptable option for critically ill patients with AKI, including patients with MODS provided clear guidelines are adhered to in order to prevent haemodynamic instability. For patients with significant fluid overload, continuous RRT appears more appropriate.

It is widely acknowledged that the way RRT is delivered has an impact on quality and outcome of patients with severe AKI. The value of regular education and training of those who deliver RRT, and attention to concurrent interventions (drug dosing, nutrition, fluid management) cannot be emphasized enough. There is a clear role for each different modality in the management of AKI in ICU. RRT should be individualised depending on the patient's varying needs during the critical illness.

#### **5. References**

(Kanagasundaram, 2007; VA NIH Acute Renal Failure Trial Network et al., 2008) Although the risk of hypotension is increased during intermittent HD, the Hemodiafe study showed that the introduction of a relatively simple treatment algorithm including use of a high dialysate sodium concentration of 145 mmol/L in combination with cooled dialysate and stopping vasodilator infusions, markedly reduced the risk of intradialytic hypotension (Vinsonneau et al., 2006). Hybrid techniques like SLED / PIRRT offer the advantages of both CRRT and intermittent HD, including haemodynamic stability, increased patient mobility

Severe AKI results in hypercatabolism and altered drug metabolism. Provision of adequate nutrition and attention to drug dosing are essential when looking after patients on RRT. While no particular mode or filter is recommended, it is important to understand the characteristics of these different RRT techniques and potential differences in drug removal.

RRT is a form of organ support for critically ill patients with AKI. The most commonly used modalities are continuous haemo(dia)filtration and intermittent modes. There is no evidence that one mode is superior to another in terms of mortality or renal recovery. Except for a few specific indications, each modality can be considered a valid RRT option for critically ill patients with AKI. The choice should depend on the patient's clinical condition, medical and nursing expertise and local availability of machines. Intermittent HD is an acceptable option for critically ill patients with AKI, including patients with MODS provided clear guidelines are adhered to in order to prevent haemodynamic instability. For patients with significant

It is widely acknowledged that the way RRT is delivered has an impact on quality and outcome of patients with severe AKI. The value of regular education and training of those who deliver RRT, and attention to concurrent interventions (drug dosing, nutrition, fluid management) cannot be emphasized enough. There is a clear role for each different modality in the management of AKI in ICU. RRT should be individualised depending on

Abe, M., Okada, K., Suzuki, M., Nagura, C., Ishihara, Y., Fujii, Y., Ikeda, K., Kaizu, K. &

Bagshaw, S.M., Berthiaume, L.R., Delaney, A. & Bellomo, R. (2008). Continuous versus

Bagshaw, S.M., Uchino, S., Bellomo, R., Morimatsu, H., Morgera, S., Schetz, M., Tan, I.,

injury: a meta-analysis. *Critical Care Medicine, Vol.* 36, pp. 610-617

Matsumoto, K. (2010). Comparison of sustained hemodiafiltration with continuous venovenous hemodiafiltration for the treatment of critically ill patients with acute

intermittent renal replacement therapy for critically ill patients with acute kidney

Bouman, C., Macedo, E., Gibney, N., Tolwani, A., Oudemans-van Straaten, H.M., Ronco, C., Kellum, J.A. & Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators (2009). Timing of renal replacement therapy

Both, under-treatment and drug toxicity have been reported in patients on RRT.

fluid overload, continuous RRT appears more appropriate.

the patient's varying needs during the critical illness.

kidney injury. *Artificial Organs,* Vol, 34, pp. 331-338

and reduced financial costs.

**3.3 General care**

**4. Conclusions**

**5. References**

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Honoré, P., Joannes-Bovau, O. & Gressens, B. (2007). Blood and plasma treatments: high-

Kanagasundaram, N.S. (2007). Renal replacement therapy in acute kidney injury: An

Kellum, J.A.,Angus, D.C., Johnson, J.P., Leblanc, M., Griffin, M., Ramakrishnan, N. & Linde-

Kielstein, J.T., Kretschmer, U., Ernst, T., Hafer, C., Bahr, M.J., Haller, H. & Fliser, D. (2004).

Kumar, V.A., Craig, M., Depner, T.A. & Yeun, J.Y. (2000). Extended daily dialysis: a new

Kumar, V.A., Yeun, J.Y., Depner, T.A. & Don, B.R. (2004). Extended daily dialysis vs

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Marshall, M.R., Ma, T., Galler, D., Rankin, A.P. & Williams, A.B. (2004). Sustained low-

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Ostermann, M., Chang, R. & Riyadh ICU Program Users Group (2008). Correlation between

Ostermann, M. & Chang, R.W.S. (2009). Correlation between parameters at initiation of

Oudemans-van Straaten, H.M. (2007). Primum non nocere, safety of continuous renal replacement therapy. *Current Opinion in Critical Care,* Vol. 13, pp. 635-637 Pannu, N., Klarenbach, S., Wiebe, N., Manns, B., Tonelli, M. & Alberta Kidney Disease

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### **Dry Weight and Measurements Methods**

Fansan Zhu and Nathan W. Levin

*Renal Research Institute, New York USA*

#### **1. Introduction**

262 Hemodialysis - Different Aspects

Vinsonneau, C. & Monchi, M. (2011). Too early initiation of renal replacement therapy may

be harmful. *Critical Care*, Vol. 15, pp. 11

intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial. *Lancet*, Vol. 368, pp. 379-385

#### **1.1 Why do we need dry weight for our patients?**

The need for a concept of dry weight derives from an awareness of the dangers of being overhydrated or as better expressed, being fluid overloaded. These dangers in the hemodialysis patient are reflected by strain on the heart indicated by left and eventually right ventricular hypertrophy and dilatation, with gradual reduction in the efficiency of the heart. Eventually, heart failure occurs with increased hospitalization and mortality rates. More recently interest in attaining dry weight has been stimulated by awareness that an abnormally low fluid load is also harmful in that it might be associated with unacceptable degrees of low blood pressure and consequently of ischemia of vital organs such as the brain, gut and liver. A working definition of dry weight is required before further discussion. Charra modified earlier thoughts on this as follows: the post dialysis weight at which the patient is and remains normotensive until the next dialysis in spite of interdialytic fluid retention (without ant-hypertensive drugs) (Charra, 2007; Charra *et al.*, 1996). This weight might be compared to the usual range of weights in a person with normal kidney function whose consumption of water in food or as liquids is balanced by loss of fluids through the skin lungs, gut and urine. However, there is always a range of fluid volumes within a liter or two around the true dry weight in patients with clinical dry weight assessment (Jaeger and Mehta, 1999).

Other definitions in dialysis patients have included the weight at which hypotension and symptoms such as muscle cramps, nausea and vomiting occurs (Agarwal and Weir, 2010; Leypoldt *et al.*, 2002). Clinical judgment of dry weight is often based on an educated guess since the one to three liters fluid overload characteristic of many dialysis patients cannot be detected by current routine physical examination (Sinha *et al.*, 2010; Zucchelli and Santoro, 2001). A more sensitive physical sign, which requires training and practice but is not widely taught, is the measurement of internal jugular vein pressure. This clinical sign faithfully represents right atrial pressure which is often increased with fluid overload, The equilibrium blood and interstitial fluid volumes is dependent on the differences between the interstitial and blood oncotic pressures, with accumulation of edema fluid, and increase of compliance (largely due to the normal gel structure being dissipated) As a result large volumes of fluid can accumulate with little increase in hydrostatic pressure. The effect of ultrafiltration (UF) is dependent on the degree of fluid overload in that the blood volume will decrease far more when the patient is close to dry weight (Merouani *et al. 2011*). Further, the blood volume change for the same volume of ultrafiltration is highly dependent on the ultrafiltration rate.

#### **1.2 Blood pressure and hydration**

The relationship of blood pressure level, which is a physical sign comparatively easy to measure with accuracy, to over hydration, is frequently discussed in the care of the dialysis patient. From work performed by many authors (Ok and Mees, 2010) (Charra and Chazot, 2003a), reduction in dietary sodium and in sodium loading during dialysis is associated with decrease of blood pressure to close to normotensive levels. While volume increase is associated with predominantly systolic pressure, diastolic pressure is also increased. It is not rare in older patients for the pulse pressure to be increased with low diastolic pressures associated with poorly compliant major blood vessels. This increased rigidity of the aorta and other large blood vessels occurs due to fibrosis with calcification possibly playing a major role. One confounding influence on the blood pressure and fluid overload relationship is a degree of cardiac damage over years so severe that blood pressure might be normal or even below normal (Charra and Chazot, 2003b). Reduction in fluid overload can actually increase blood pressure in such patients. Echocardiography is very useful in distinguishing patients with large failing hearts from those with normal blood pressure following adequate treatment with antihypertensive drugs or salt restriction (Santos and Peixoto, 2010).

#### **1.3 Sodium and fluid overload**

Sodium, in the form of salt, plays a major role in the fluid and electrolyte problems of the dialysis patient, to a large extent because the regulation of salt is almost completely absent once the kidneys are not functioning. The dialysis patient is at risk to the same extent as a healthy patient to increased dietary intake of sodium but in addition sodium is often added during the actual dialysis treatment (Matsuoka *et al.*, 1990; Schmieder, 1997). In health the balance of sodium is determined predominantly by renal regulation of tubular re-absorption as influenced directly or indirectly by plasma and extracellular volume. These functions are not present in the dialysis patients, and therefore expansion is obviously accompanied by relative inability to excrete water. Blood pressure increase occurs in most patients as the result of sodium and fluid retention and is considered to be a prime factor in the pathogenesis of the cardiac disease which is the major cause of hospitalization and mortality in dialysis patients, Left ventricular hypertrophy leads to ventricular dilatation and leftsided cardiac failure with pulmonary edema, and pulmonary hypertension. The right ventricle then also hypertrophies and fails with this being the basis for the congestive heart failure seen so often in dialysis patients (Fiaccadori *et al.2011*). Peripheral edema is obvious, especially in the legs but congestion of visceral organs may be of greater pathognomonic significance. An example is the gut where increased permeability to luminal endotoxin could promote the inflammation characteristic of most dialysis patients. While anti hypertensive drugs are successful in reducing blood pressure, control of salt and water may be more effective. Normal or low blood pressure in the absence of such treatment can be misleading since this can be due to the result of progressive cardiomyopathy and represents a poor prognosis. Recent research suggests that declines in blood pressure occurring in the absence of treatment are associated with poor outcomes (Silver *et al.*, 2008).

#### **1.4 Sodium control**

Control of salt intake becomes one of the most relevant aspects of the dialysis treatment; current recommendations are for less than six grams of salt to be ingested daily. Patient education concerning sodium content of individual items has variable effects but is often

The relationship of blood pressure level, which is a physical sign comparatively easy to measure with accuracy, to over hydration, is frequently discussed in the care of the dialysis patient. From work performed by many authors (Ok and Mees, 2010) (Charra and Chazot, 2003a), reduction in dietary sodium and in sodium loading during dialysis is associated with decrease of blood pressure to close to normotensive levels. While volume increase is associated with predominantly systolic pressure, diastolic pressure is also increased. It is not rare in older patients for the pulse pressure to be increased with low diastolic pressures associated with poorly compliant major blood vessels. This increased rigidity of the aorta and other large blood vessels occurs due to fibrosis with calcification possibly playing a major role. One confounding influence on the blood pressure and fluid overload relationship is a degree of cardiac damage over years so severe that blood pressure might be normal or even below normal (Charra and Chazot, 2003b). Reduction in fluid overload can actually increase blood pressure in such patients. Echocardiography is very useful in distinguishing patients with large failing hearts from those with normal blood pressure following adequate treatment with antihypertensive drugs or salt restriction (Santos and

Sodium, in the form of salt, plays a major role in the fluid and electrolyte problems of the dialysis patient, to a large extent because the regulation of salt is almost completely absent once the kidneys are not functioning. The dialysis patient is at risk to the same extent as a healthy patient to increased dietary intake of sodium but in addition sodium is often added during the actual dialysis treatment (Matsuoka *et al.*, 1990; Schmieder, 1997). In health the balance of sodium is determined predominantly by renal regulation of tubular re-absorption as influenced directly or indirectly by plasma and extracellular volume. These functions are not present in the dialysis patients, and therefore expansion is obviously accompanied by relative inability to excrete water. Blood pressure increase occurs in most patients as the result of sodium and fluid retention and is considered to be a prime factor in the pathogenesis of the cardiac disease which is the major cause of hospitalization and mortality in dialysis patients, Left ventricular hypertrophy leads to ventricular dilatation and leftsided cardiac failure with pulmonary edema, and pulmonary hypertension. The right ventricle then also hypertrophies and fails with this being the basis for the congestive heart failure seen so often in dialysis patients (Fiaccadori *et al.2011*). Peripheral edema is obvious, especially in the legs but congestion of visceral organs may be of greater pathognomonic significance. An example is the gut where increased permeability to luminal endotoxin could promote the inflammation characteristic of most dialysis patients. While anti hypertensive drugs are successful in reducing blood pressure, control of salt and water may be more effective. Normal or low blood pressure in the absence of such treatment can be misleading since this can be due to the result of progressive cardiomyopathy and represents a poor prognosis. Recent research suggests that declines in blood pressure occurring in the

absence of treatment are associated with poor outcomes (Silver *et al.*, 2008).

Control of salt intake becomes one of the most relevant aspects of the dialysis treatment; current recommendations are for less than six grams of salt to be ingested daily. Patient education concerning sodium content of individual items has variable effects but is often

**1.2 Blood pressure and hydration**

Peixoto, 2010).

**1.4 Sodium control**

**1.3 Sodium and fluid overload**

swamped by the easy availability of fast foods. However, notable examples exist of the success of this approach particularly in Tassin in France (Charra *et al.*, 2004) where the combination of compliance with a low salt diet, and relatively longer dialysis time has been associated over decades with well controlled blood pressure levels and low mortality (Chazot and Jean, 2008). Asking patients to reduce their fluid intake voluntarily is rarely successful because of the powerful effect of thirst and appeals to limit salt are far more likely to be successful.

Extra sodium may be administered in three ways during dialysis. The first is the use of dialysate sodium concentrations higher than the patient's level (Odudu *et al.2011*). As much as 3 to 5 g of sodium may be administered during a dialysis (Tetta *et al.2011*). This attribute of the dialysis treatment has been through a number of cycles. In the early days of dialysis sodium concentrations were low commensurate with long dialysis times and therefore low ultrafiltration rates (Silverstein *et al.*, 1974). As dialysis times were reduced, dialysate sodium concentrations increased but currently are decreasing again with more awareness of the effects of excess sodium. One potentially more precise solution to obtain balance has been the alignment of the dialysate and serum sodium levels which is approximately possible because of the opposite effects of the Gibbs-Donnan equilibrium and the fact that the plasma water concentration is about 7% higher than that of plasma sodium. The second is during priming of the dialysis circuit when the volume of saline administered is variable, depending on the degree of care, but is often 100 to 500 ml per treatment. Adding this volume to the ultrafiltration requirements deals with the problem in part but cannot be relied on to occur due to homodynamic instability. In addition the sodium content of the ultrafiltrate is lower than that of isotonic saline. The third is the use of saline for the management of hypotensive episodes when reductions in ultrafiltration rate are unsuccessful (Santos and Peixoto, 2010 ). Since the quantities given can be substantial, replacing saline with hypertonic glucose is an acceptable replacement, perhaps with reservations in some diabetic patients.

#### **2. Fluid volume measurements**

#### **2.1 Body fluid compartments**

Total body water (TBW) can be divided into two compartments: extracellular fluid volume (ECV) and intracellular fluid volume (ICV). Further, the extracellular compartment is divided into interstitial fluid and blood plasma volume (Fig.1).

Accuracy of measurement of extracellular fluid volume (ECV) is an important issue in research and clinical practice. Currently, the standard reference for body fluid measurements are dilution method using deuterated water (D2O) for total body water and NaBr for ECV measurements (Riek and Gerken, Pierson *et al.*, 1978; Kim *et al.*, 1999). However, with dilution method patients have to wait about 3 hours in order to obtain equilibrium of the diluting substances in the body. In addition, the accuracy of this method has been questioned for example, NaBr might overestimate the ECV(Thomas *et al.*, 1991).

Bioimpedance analysis (BIA) techniques have been used as noninvasive and simple methods to measure body fluid volume. The principle of BIA methodology is based on the physical principle that fluid volume is negative related to electrical resistance, and therefore, ECV and ICV can be calculated as

$$ECV \equiv \mathfrak{p}\_{ECV} \* \mathrm{L}^2/\mathrm{R}\_E \tag{1}$$

#### *ICV=* ρ*ICV \*L2/RI* (2)

where RE and RI are the extracellular and intracellular resistances calculated with the Cole model using multifrequency spectroscopy (BIS), L is the length of the measuring segment and ρECV and ρICV are resistivity in extracellular and intracellular fluid considered as constant. TBW can be calculated by sum of ECV and ICV. Current accuracy of estimation of ECV is about 1.0-1.5 L by advanced bioimpedance method (Moissl *et al.*, 2006; Zhu *et al.*, 2006a; Ellis, 2000). Main factors affecting accuracy of BIA or BIS to estimate fluid volume includes 1) error from measurement and 2) error of calculation from inaccurate assumptions. For example, the current standard method is the wrist to ankle (so called "whole body") bioimpedance measurement (De Lorenzo *et al.*, 1997). This method assumes that arm, trunk and leg can be modeled as a cylinder with uniform conductivity when electrical current is injected from hand to foot and voltage is measured between wrist and ankle. Since the different cross sectional areas between trunk and limbs, limbs' resistance (the arm and leg) contribute about 90 % of whole body resistance but the limbs' volume is less than 30 % of total body volume (Zhu *et al.*, 1998a; Zhu *et al.*, 1998b; Bracco *et al.*, 1996). This inhomogeneous distribution between resistance and volume in segments leads to different degrees of error which are associated with variation in body composition and in degrees of body hydration (Thomas *et al.*, 1998). As a result, estimation of fluid volume with whole body bioimpedance methods does not provide accurate information (Cox-Reijven *et al.*, 2001; Earthman *et al.*, 2007).

Fig. 1. Body fluid compartments, extracellular fluid volume (ECV) consist of plasma and interstitial fluid volume.

As an example, the problem of inhomogeneous distribution in fluid volume and crosssectional area of body segments can be observed from an experiment of change in body position (Zhu *et al.*, 1998a).

where RE and RI are the extracellular and intracellular resistances calculated with the Cole model using multifrequency spectroscopy (BIS), L is the length of the measuring segment and ρECV and ρICV are resistivity in extracellular and intracellular fluid considered as constant. TBW can be calculated by sum of ECV and ICV. Current accuracy of estimation of ECV is about 1.0-1.5 L by advanced bioimpedance method (Moissl *et al.*, 2006; Zhu *et al.*, 2006a; Ellis, 2000). Main factors affecting accuracy of BIA or BIS to estimate fluid volume includes 1) error from measurement and 2) error of calculation from inaccurate assumptions. For example, the current standard method is the wrist to ankle (so called "whole body") bioimpedance measurement (De Lorenzo *et al.*, 1997). This method assumes that arm, trunk and leg can be modeled as a cylinder with uniform conductivity when electrical current is injected from hand to foot and voltage is measured between wrist and ankle. Since the different cross sectional areas between trunk and limbs, limbs' resistance (the arm and leg) contribute about 90 % of whole body resistance but the limbs' volume is less than 30 % of total body volume (Zhu *et al.*, 1998a; Zhu *et al.*, 1998b; Bracco *et al.*, 1996). This inhomogeneous distribution between resistance and volume in segments leads to different degrees of error which are associated with variation in body composition and in degrees of body hydration (Thomas *et al.*, 1998). As a result, estimation of fluid volume with whole body bioimpedance methods does not provide accurate information (Cox-Reijven *et*

Fig. 1. Body fluid compartments, extracellular fluid volume (ECV) consist of plasma and

As an example, the problem of inhomogeneous distribution in fluid volume and crosssectional area of body segments can be observed from an experiment of change in body

Intracellular fluid (35~40 %)

Cell membrane

Interstitial fluid (11~15 %)

Capillary

Plasma (4~5 %)

Intake

*ICV \*L2/RI* (2)

Lymphatics

*ICV=* ρ

*al.*, 2001; Earthman *et al.*, 2007).

Output

interstitial fluid volume.

position (Zhu *et al.*, 1998a).

Fig. 2. Change in segmental ECV during change in body position (Modified from Zhu et, al., J Appl Physol 85:497-504, 1998)

Fig.2 shows segmental ECVs changes during 30 minutes standing and then immediately after 30 minutes supine. As shown in Fig.2, the ECV in the leg increased and the trunk decreased about 3 % during the standing position due to the fluid volume accumulating in the leg by gravitational force. After assuming the supine position, ECV shifted back from the leg to the trunk. Although total ECV in the body did not change during the position changes, difference in ECV measured by wrist to ankle increased about 2 % in standing and decreased more than 6 % after being supine. This example clearly demonstrates that change in distribution of fluid volume can make a disproportional change in resistance in the segments because of their different geometric sizes, and therefore, ECV calculated from the sum of the resistances cannot be correct. It has to be noticed that change in fluid redistribution can be made not only by change in body position but also by change in fluid overload (Zhu *et al.*, 2008b).

#### **2.2 Measurement of fluid overload**

Fluid overload can be generally defined as the ECV accumulated in the body of greater than a normal degree. Although the measurement of the normal range of ECV (normal hydration, NH) is difficult; degrees of fluid overload estimated by clinical practice have widely been used in clinical practice. Excess fluid volume can be roughly estimated through clinical sign such as hypertension and by a physician's assessment such as increased jugular vein pressure. Accurate assessment of fluid overload or quantitative calculation of excess fluid volume is a challenge due to: 1) lack of a reliable techniques to measure ECV and 2) the normal range of ECV is unknown because of the variability of excess fluid in individuals not only derived from differences in intake of salt but also by variability due to the age or gender in the healthy population (Silva *et al*., 2008). Body fluid status is a dynamic equilibrium or steady state condition controlled by physiologic functions. But in dialysis patients this function is lost. From engineering point of view, estimation of fluid status in normal level (dry weight) can be generally divided into two aspects of methods: static and dynamic approaches.

#### **3. Static methods for estimating dry weight**

The principle of the static method is based on the degree of fluid overload can be assessed by comparison of a parameter using healthy subjects as reference.

#### **3.1 Bioimpedance vector analysis (RXc graph)**

Resistance (R) and reactance (Xc) graph shows relationship of change in impedance vector at 50 kHz in R-Xc plane to estimate degree of hydration or nutrition with the range of tolerance ellipses from healthy subjects (Fig 3) (Piccoli, 2005). This method was suggested by Piccoli et al to identify dry weight in hemodialysis patients according to 50th, 75th and 95th % of vector in healthy population (Piccoli, 1998). The advantage of this method is that the state of tissue hydration and nutrition can be reflected by the length and angle of a vector which consist of resistance and reactance at 50 kHz in R-Xc plan. Since 50 kHz current is applied, the impedance can be affected by electrical properties in both the extracellular and parts of the intracellular fluid compartments.

The major disadvantage with this method is that the state of hydration cannot be separately obtained due to the vector being determined by resistance and reactance. Therefore, this method is useful to generally compare the status of hydration or nutrition in populations but it cannot provide quantitative information about degree of fluid overload.

Fig. 3. Principle of phase ankle method (Modified from Piccoli, Contrib Nephrol. Basel, Karger, 2005, vol 149: pp 150–161)

#### **3.2 The ratios of fluid volume**

Ratios or percentage of ECV to body mass or one of components, for example ECV/TBW, ECV/ICV or ECV/body mass (BM) should be maintained in an approximately constant level controlled by normal physiologic function. Logically, these parameters should be able to

condition controlled by physiologic functions. But in dialysis patients this function is lost. From engineering point of view, estimation of fluid status in normal level (dry weight) can be

The principle of the static method is based on the degree of fluid overload can be assessed

Resistance (R) and reactance (Xc) graph shows relationship of change in impedance vector at 50 kHz in R-Xc plane to estimate degree of hydration or nutrition with the range of tolerance ellipses from healthy subjects (Fig 3) (Piccoli, 2005). This method was suggested by Piccoli et al to identify dry weight in hemodialysis patients according to 50th, 75th and 95th % of vector in healthy population (Piccoli, 1998). The advantage of this method is that the state of tissue hydration and nutrition can be reflected by the length and angle of a vector which consist of resistance and reactance at 50 kHz in R-Xc plan. Since 50 kHz current is applied, the impedance can be affected by electrical properties in both the extracellular and parts of the

The major disadvantage with this method is that the state of hydration cannot be separately obtained due to the vector being determined by resistance and reactance. Therefore, this method is useful to generally compare the status of hydration or nutrition in populations

but it cannot provide quantitative information about degree of fluid overload.

Fig. 3. Principle of phase ankle method (Modified from Piccoli, Contrib Nephrol. Basel,

Ratios or percentage of ECV to body mass or one of components, for example ECV/TBW, ECV/ICV or ECV/body mass (BM) should be maintained in an approximately constant level controlled by normal physiologic function. Logically, these parameters should be able to

generally divided into two aspects of methods: static and dynamic approaches.

**3. Static methods for estimating dry weight**

**3.1 Bioimpedance vector analysis (RXc graph)**

intracellular fluid compartments.

Karger, 2005, vol 149: pp 150–161)

**3.2 The ratios of fluid volume**

by comparison of a parameter using healthy subjects as reference.

identify the body hydration state (Lopot *et al.*, 2002; Farnetti *et al.*, 2004; Park *et al.*, 2009; Koziolek *et al.*, 2006; Booth *et al 2011.*). However, in practice, there are two issues as mentioned above:1) accuracy of ECV measurement and 2) the normal range in healthy population limits its usefulness in clinical practice. The normal range has been reported as from 0.37 to 0.46 in ECV/TBW and from 0.22 to 0.24 in ECV/BM (Katzarski *et al.*, 1996; Woodrow *et al.*, 2005; Zhu *et al.*, 2011; Chen *et al.*, 2002). The problems of the methods using the ratio of resistance with different frequencies such as ratio of extracellular resistance to intracellular resistance (Re/Ri) or resistance at 5 kHz to resistance at 200 kHz (R5/R200) are similar problem to the volume ratios (Spiegel *et al.*, 2000; Zhou *et al.2010*). A comparison of the ECV/TBW or ECV/BM in HD patients with healthy subjects is showing in Fig 4 (a) and (b). In that study a bioimpedance spectrum analyzer system (Hydra 4200, Xitron Technologies, CA) was used to measure whole body BIS (wBIS) in NS and in (HD) patients to obtain ECV and ICV (Zhu *et al.,* 2011). There was no significant difference in wECV/TBW between BL and DWcBIS in male patients although the patients had lost body fluid. The lack of sensitivity with this method limits the clinical application of wECV/TBW for individual patients (Fig. 4 (a)). The poor sensitivity of wECV/TBW can be explained that 1) since TBW is the sum of ECV and ICV, decrease in ECV produces the similar changes in the numerator and denominator of the ratio of ECV/TBW; 2) the accuracy of ICV measurements by wBIS is still not good enough for clinical use.

Fig. 4. Comparison of results in patient to NS with ECV/TBW (a) and with ECV/BM (b) (Modified from Zhu et al., Physiol Meas. 32:887-902, 2011)

In addition, accuracy of wrist to ankle (wBIS) measurements is affected by body composition and degree of hydration. (Sung *et al.*, 2001) (Bracco *et al.*, 1996) (Zhu *et al.*, 1998b). No difference in wECV/BM between NS and the patients at BL pre-HD might be explained that the ratios of ECV/BM depends on the body composition, such as more or less fat mass in the NS. (Fig.4 (b)).

#### **3.3 Body composition model**

Recently a whole body bioimpedance model (WBM) based on functions of body weight, ECV and ICV with wBIS has been developed to calculate degree of excess fluid volume (EFV) with the equation as following (Chamney *et al.*, 2007).

$$EFV = 1.136 \cdot ECV - 0.43 \cdot ICV - 0.114 \cdot BM \tag{3}$$

Fig. 5. Principle of whole body model (WBM) (Modified from Chamney et al *Am J Clin Nutr*  2007, 85:80 –9)

The weight at normal hydration (NHWWBM) with whole body model can be calculated by the difference between pre HD BM and excess fluid volume (EFV).

$$\text{NHWM}\_{\text{WBM}} = \text{Pre-HD BM} \cdot \text{EFV} \tag{4}$$

The principle of this method is based on the assumption that ECV is proportionally distributed in fat and other body components in healthy subjects (Fig.5). The main advantage with this method is that the model introduces relationships between fluid volume and fat mass which might reduce the error from variability of body composition. However, since this method is using whole body bioimpedance spectroscopy (wBIS) technique for collecting raw data, the problems with wBIS are inherent in the measurement so that accuracy of this method is reduced in subjects with great fluid overload.

#### **3.4 Calf resistivity method**

Calf bioimpedance measurement in dialysis patients was reported by Kouw et al to evaluate calf conductance between patients and NS (Kouw *et al.*, 1993). Recently, it was found that the value of calf conductance or resistivity (1/conductance) correlated with BMI (Zhu *et al, 2011*). To reduce the error, calf resistivity was normalized by BMI (resistivity/BMI) to reflect degree of body hydration. Generally, an assumption is correct that the calf is more hydrated than other segments of the body due to effect of gravity. Moreover, the calf has uniform structure of body composition so that it can reduce the error from bioimpedance measurement. Calf electrodes placement and measurements show in Fig.6.

Calf resistivity (ρ5) was calculated from resistance (R5) at 5 kHz and where *A* and *L* are the cross sectional areas of the calf and the distance (10 cm) between the sensing electrodes, respectively.

$$
\rho\_{\mathbb{S}} = \mathbb{R} \mathbb{s} \times \text{A} / \text{L} \text{ (}\Omega\text{-cm)}\tag{5}
$$

(a) (b) Fig. 5. Principle of whole body model (WBM) (Modified from Chamney et al *Am J Clin Nutr*

The weight at normal hydration (NHWWBM) with whole body model can be calculated by

 NHWWBM =Pre-HD BM - EFV (4) The principle of this method is based on the assumption that ECV is proportionally distributed in fat and other body components in healthy subjects (Fig.5). The main advantage with this method is that the model introduces relationships between fluid volume and fat mass which might reduce the error from variability of body composition. However, since this method is using whole body bioimpedance spectroscopy (wBIS) technique for collecting raw data, the problems with wBIS are inherent in the measurement

Calf bioimpedance measurement in dialysis patients was reported by Kouw et al to evaluate calf conductance between patients and NS (Kouw *et al.*, 1993). Recently, it was found that the value of calf conductance or resistivity (1/conductance) correlated with BMI (Zhu *et al, 2011*). To reduce the error, calf resistivity was normalized by BMI (resistivity/BMI) to reflect degree of body hydration. Generally, an assumption is correct that the calf is more hydrated than other segments of the body due to effect of gravity. Moreover, the calf has uniform structure of body composition so that it can reduce the error from bioimpedance

Calf resistivity (ρ5) was calculated from resistance (R5) at 5 kHz and where *A* and *L* are the cross sectional areas of the calf and the distance (10 cm) between the sensing electrodes,

ρ5 = R5×A/L (Ω⋅cm) (5)

the difference between pre HD BM and excess fluid volume (EFV).

**Excess fluid**

so that accuracy of this method is reduced in subjects with great fluid overload.

measurement. Calf electrodes placement and measurements show in Fig.6.

2007, 85:80 –9)

**3.4 Calf resistivity method**

respectively.

The cross sectional area was calculated by Eq 6, where Cave was the mean of the two measured calf circumferences (Cave = (CMax + CMin)/2).

$$\mathbf{A} = \mathbb{C}\_{\text{ave}}2 / (4\pi) \tag{6}$$

To reduce the effect of differences in body composition, resistivity ρ5 was normalized by the body mass index (BMI; calculated as BM [kg] divided by height2 [m]2), and reported as calf normalized resistivity (ρN,5) in units of Ωm3/kg (Eq 7).

$$
\mathfrak{p}\_{\mathsf{N}\mathsf{N}} = \mathfrak{p}\_{\mathsf{5}} / \text{BMI}.\tag{7}
$$

Fig. 6. Four electrodes are placed on the lateral side of calf to inject current (0.8 mA) and measure voltage. One sensing electrode (ES1) is placed on the point of maximal calf circumference (CMax); while the other sensing electrode (ES2) was placed 10 cm below the ES1 which was defined at the point as minimal circumference (CMin)

Fig.7 shows that the standard deviations in normalized resistivity (ρN,5) was significantly less than the non-normalized values (ρ5). The average of normalized resistivity in normal subjects (NS) was 20.5±1.99 \*10-2 (Ωm3/kg) in males and 21.7±2.6 \*10-2 (Ωm3/kg) in females respectively. It can be defined with the values of the mean minus the standard deviation as minimal levels of normal hydration males (18.5 \*10-2 Ωm3/kg) and in females (19.1 10-2 Ωm3/kg) respectively (Fig.7).

Fig. 7. Comparison of resistivity and normalized resistivity in NS

Normalized resistivity (ρN,5) in NS differed significantly between males and females, but there were no significant differences between the age groups (Fig. 8).

Fig. 8. Comparison of normalized resistivity in NS with different ages. (Modified from Zhu et al., Physiol Meas. 32:887-902, 2011)

Fig. 9 demonstrated the change in fluid volume in HD patients from BL with fluid overload to reaching the dry weight. There was no difference in normalized resistivity between NS and the patients who reached dry weight (DW).

Fig. 9. Comparison of normalized resistivity between HD patients and NS. (Modified from Zhu et al., Physiol Meas. 32:887-902, 2011)

The unit of measurement of ρN,5 in Ω∗[m3/kg], can be interpreted also for its physical meaning. Since m3/kg is equal to 1/kg/m3, which is the reciprocal of density, the parameter ρN,5 can be interpreted as ohm per density measured by bioimpedance, so that it does reflect the relationship of hydration to body density (Zhu *et al. 2011*).

#### **3.5 Vena cava diameter index**

272 Hemodialysis - Different Aspects

Normalized resistivity (ρN,5) in NS differed significantly between males and females, but

21.6±2.5

19.9±12.3

21.1±2.6

Fig. 8. Comparison of normalized resistivity in NS with different ages. (Modified from Zhu

**20-30 30-40 40-50 50-60**

**Age of normal subjects (years)**

p=ns p=ns p=ns

Fig. 9 demonstrated the change in fluid volume in HD patients from BL with fluid overload to reaching the dry weight. There was no difference in normalized resistivity between NS

Fig. 9. Comparison of normalized resistivity between HD patients and NS. (Modified from

**post-BL**

**DW**

p<0.05

**NS**

p=ns

**pre-DW**

p<0.05 p<0.05

The unit of measurement of ρN,5 in Ω∗[m3/kg], can be interpreted also for its physical meaning. Since m3/kg is equal to 1/kg/m3, which is the reciprocal of density, the parameter ρN,5 can be interpreted as ohm per density measured by bioimpedance, so that it

does reflect the relationship of hydration to body density (Zhu *et al. 2011*).

**pre-BL**

**0**

**10**

**[**Ω

**m3/kg]\*10-2**

**20**

**30**

there were no significant differences between the age groups (Fig. 8).

20.7±1.9

et al., Physiol Meas. 32:887-902, 2011)

 **Normalized resistivity**

**10-2**

Ω

**m3/kg**

and the patients who reached dry weight (DW).

**Normalized resistivity**

**10**

**15**

**20**

**25**

**30**

Zhu et al., Physiol Meas. 32:887-902, 2011)

Measurement of inferior vena cava diameter index (IVCD) has been used to indicate hydration by intravascular volume with ultrasound technique (Krause *et al.*, 2001). This is a noninvasive method for fluid volume in blood. However, it cannot indicate the state of interstitial fluid volume because the degree of hydration in intravascular space cannot proportionally reflect fluid overload in interstitial space (Katzarski *et al.*, 1997; Dietel *et al.*, 2000). In addition, variability of healthy subjects is so large that it cannot be applied in patients due to lack of precision of device (Bendjelid *et al.*, 2002; Agarwal *et al.2011*).

#### **3.6 Biochemical parameters**

Serum indicators Atrial Natriuretic Peptide (ANP), Brain Natriuretic Peptide (BNP), NT Pro BNP and Cyclic Guanidine Monophosphate (cGMP) have been suggested to indicate degrees of fluid volume expanded in dialysis patients (Ishibe and Peixoto, 2004; van de Pol *et al.*, 2007). The measurements might reflect the fluid status in the blood compartment but cannot be used to determine state of interstitial fluid because the relationship between plasma volume and interstitial fluid volume proportion is unknown for individual patient. As a result, the normal ranges of these parameters were reported with such large variability that they cannot be applied in clinical practice. Cardiac dysfunction and variable removal during dialysis are other problem for its application (Bargnoux *et al.*, 2008).

#### **4. Dynamic methods**

#### **4.1 Two compartments model**

Change in ECV during HD provides information about body hydration. Relative blood volume (RBV) has been used to monitor reduction of plasma in blood compartment during ultrafiltration (UF) (Leypoldt and Cheung, 1998; Chamney *et al.*, 1999). Since change in RBV reflects the state of vascular refilling, a number of authors have suggested that the curve of RBV either with the slope change or with maximum change in RBV value at the end of treatment might indicate degree of hydration based on change in the state of refilling rate (Sinha *et al.*, 2010; Agarwal *et al.*, 2008). Fig.10 shows the relationship between change in blood volume and interstitial volume (VIT) by UF.

Relationship can be described with a simple two compartments model (Fig.10) by differential equations as following.

$$\frac{dBV}{dt} = k\_{IB} \cdot V\_{IT} - k\_{BI} \cdot BV - \text{UFR} \tag{8}$$

$$\frac{dV\_{IT}}{dt} = -k\_{IB} \cdot V\_{IT} + k\_{BI} \cdot BV \tag{9}$$

where BV represents plasma volume in blood, kIB and kBI are transfer coefficients between two compartments; UFR is ultrafiltration rate which is the driving force in this dynamic system. From Eq.8 kIB times VIT represents refilling rate (RFR). Although we assume kIB is constant which is determined by pressure gradient between two compartments in the same treatment, kIB can be various in different hydration state. Since kBI times BV is much less than kIB times VIT, the model can be considered as a four parameters system. Then, the equations can be rewritten as following

$$\frac{dBV}{dt} = k\_{IB}^{\cdot} \cdot V\_{IT} - \text{LIFR} \tag{10}$$

$$\frac{dV\_{IT}}{dt} = -\boldsymbol{k\_{IB}^{\*}} \cdot \boldsymbol{V\_{IT}} \tag{11}$$

Fig. 10. Two compartment model: blood volume and interstitial fluid volume

#### **4.2 Blood volume monitor**

From Eq.10, the changes in RBV depend on the difference between UFR and refilling rate (RFR). RFR is determined by fluid status (VIT) and pressure gradient (kIB) which is associated with individual cardiac function and homodynamic parameters. In general, absolute or change in RBV have little relationship to body fluid status because RBV indicates the state of difference between UFR and refilling rate (Barth *et al.*, 2003). Even though constant UFR is used in the same patient, RFR is generally not associated with fluid status because the kIB is affected by body hydration, fluid status and cardiac function in individual treatments. A sample shows the relationship between change in RBV and calf normalized resistivity during HD (Fig. 11).

Fig. 11. Relationship between RBV and calf resistance ratio (RE0/RET) with different UFR in a same patient (From *Sipahioglu etal.,* Blood Purif 2010;29:230–242.)

274 Hemodialysis - Different Aspects

*IB IT dBV k V UFR*

*IB IT*

kBI

*dt* =⋅ − (10)

*dt* =− ⋅ (11)

UFR

'

*IT* '

Fig. 10. Two compartment model: blood volume and interstitial fluid volume

**4.2 Blood volume monitor**

resistivity during HD (Fig. 11).

*dV k V*

VIT BV

kIB

From Eq.10, the changes in RBV depend on the difference between UFR and refilling rate (RFR). RFR is determined by fluid status (VIT) and pressure gradient (kIB) which is associated with individual cardiac function and homodynamic parameters. In general, absolute or change in RBV have little relationship to body fluid status because RBV indicates the state of difference between UFR and refilling rate (Barth *et al.*, 2003). Even though constant UFR is used in the same patient, RFR is generally not associated with fluid status because the kIB is affected by body hydration, fluid status and cardiac function in individual treatments. A sample shows the relationship between change in RBV and calf normalized

+ 0.4334\*X + 1.56, R<sup>2</sup>

+ 0.4252\*X + 1.78, R<sup>2</sup>

= 0.9275

= 0.9724

= 0.9789

Fig. 11. Relationship between RBV and calf resistance ratio (RE0/RET) with different UFR in a

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 **X =** Η**R0/Rt, %**

same patient (From *Sipahioglu etal.,* Blood Purif 2010;29:230–242.)

**Y =**

Η**RBV, %**

YUFR=500 = 0.009\*X<sup>2</sup>

UFR=1100 ml/h UFR=850 ml/h UFR=500 ml/h (

YUFR=850 = 0.002\*X<sup>2</sup>

YUFR=1100 = 0.006\*X2

RBV method provides a simple way to monitor change in plasma volume which indicates change in RFR durring HD. Since the RBV shows a relative change, it cannot represent refilling rate from tissue so that it cannot reflect body hydration. Absolute refilling rate can only be calculated if we know the absolute blood volume or refilling volume. RBV can be useful to tell if UFR is correct in individual treatment. A recent study showed that neither in the slope nor maximal change of RBV was observed when patient reduction the post HD weight (Fig.12).

Fig. 12. RVB were compared between BL and dry weight in maximal change of RBV (RBVmin) and in RBV slope. No difference either in slope or in maximal change of RBV were obtained when body fluid reduced.

#### **4.3 Continuous measurement of calf bioimpedance spectroscopy (cBIS)**

Calf bioimpedance spectroscopy (cBIS) method provides a way to continuously measure calf ECV during HD. Relative change in ECV can be represented by RE0/REt where RE0 and REt are extracellular resistance at beginning and at any time until the end of HD. Since the plasma volume only take about ten percent of ECV in the calf, change in RE0/RET mainly indicate change in interstitial fluid volume. The ratio of RE0/REt indicates the ratio of extracellular fluid volume in any time (ECVt) to the volume at the beginning (ECV0). The relationship can be described as following (Zhu *et al.*, 2004).

$$\frac{ECV\_t}{ECV\_0} = \frac{\rho\_{ECV}\frac{L^2}{R\_{Et}}}{\rho\_{ECV}\frac{L^2}{R\_{E0}}} = \frac{\frac{1}{R\_{Et}}}{\frac{1}{R\_{E0}}} = \frac{R\_{E0}}{R\_{Et}}\tag{12}$$

where ρECV is the resistivity in extracellular fluid volume, *L* is the length of the measurement area of the calf and RE0 and REt are extracellular resistance at beginning and at any time during dialysis respectively. Since ρECV and *L* are constant in this equation, they are canceled in the ratio of volume so that RE0/REt is equal to ECVt/ECV0. This is the principle why decrease in calf RE0/REt represents the reduction of extracellular fluid volume. In our previously study, when the curve of RE0/REt is flattening, it indicates a limitation of excess fluid in interstitial space so that the state of this hydration can be defined as normal hydration state. Fig.13 show the principle of the continuous monitoring RE0/REt until reach the flattening in last 20 minutes.

Fig. 13. Shows the principle of curve of RE0/REt during UF. The curve can be represented as exponential function of two variables and two constants (a and c)

The main advantage with curve of RE0/REt is the method does not require a normal range from a healthy population but utilizes its slope change as an indicator of tissue hydration. Flattening of the curve during 20 minutes has been defined as excess fluid volume being completely removed in the body when the patients reach dry weight.(Fig.14).

Fig. 14. Comparison of the curve of RE0/REt in group patients between BL and DW (Modified from Int J Artif Organs 27:104-9, 2004).

fluid in interstitial space so that the state of this hydration can be defined as normal hydration state. Fig.13 show the principle of the continuous monitoring RE0/REt until reach

Fig. 13. Shows the principle of curve of RE0/REt during UF. The curve can be represented as

The main advantage with curve of RE0/REt is the method does not require a normal range from a healthy population but utilizes its slope change as an indicator of tissue hydration. Flattening of the curve during 20 minutes has been defined as excess fluid volume being

exponential function of two variables and two constants (a and c)

completely removed in the body when the patients reach dry weight.(Fig.14).

Fig. 14. Comparison of the curve of RE0/REt in group patients between BL and DW

**0 50 100 150 200 250**

**Time [min]**

BL DW

(Modified from Int J Artif Organs 27:104-9, 2004).

**70**

**80**

**90**

**Change in RE0/REt [%]**

**100**

**110**

the flattening in last 20 minutes.

Fig 14 shows change in curve of RE0/REt in a group of patients with different hydration states. However, this method has a problem if the patients with deep vein thrombosis of the calf can stop or reduce the fluid volume from leg back to main circulation and this problem will cause less change in the curve RE0/REt during HD treatment. In this case, RE0/REt curve cannot indicate hydration change in the body.

#### **4.4 Combination of static and dynamic method**

Principle of the method using RE0/REt curve and normalized resistivity is shows in Fig.15. The slope of change in resistance represents the removal of excess fluid volume in the calf. The flattening of the resistance curve means that the fluid exchange between intravascular and interstitial compartments has reached an equilibrium state. We hypothesize that DW has been reached if the curve is flattening and the normalized resistivity is in the normal range (Fig. 15). Approaching normalized resistivity value in the calf provides a secondary indication of DW. The system used is a refinement of the Xitron Hydra multifrequency device which measures both extracellular resistance and resistivity (Zhu *et al.*, 2008a). The algorithm used to determine normal hydration state employs two criteria together: a) flattening of the change in resistance (RE0/REt) curve; and b) normalized resistivity in the range derived from healthy subjects.

Fig. 15. Determination of dry weight with calf bioimpedance spectroscopy (cBIS)

#### **4.4.1 Definition of flattening of the curve**

RE0 and REt represent ECV at different times with change in ECV during whole HD. Since the curve may be affected by a movement of the patient's body during HD, the noise might influence the measurement of RE. To reduce these interferences, a dynamic filter has been developed to reduce the error.

#### **4.4.2 Continuous curve of the slope of RE0/REt within specific time**

The ratio of RE,i/RE,i+1 is collected from any two successive series of data, where subscript *i* (*i*=1, 2, 3, …N) represent *i*th value of measurement from a series of N data. The RE at the start of HD is considered to be the reference of the initial hydration status (RE0).

We have defined that the curve of continuous measurement of the λ is flattening as

$$
\delta(\Delta \mathbf{t}) < \mathbf{C}\_1 \tag{13}
$$

where Δt =tm represents the time interval between t- tm minutes which can be present in more general form as follows:

$$
\Delta \mathbf{t} = t\_{i^\*} \mathbf{t}\_{i^\* \leftarrow m \nu} \tag{14}
$$

where *i* represents the number of *i-*th measurement and *i* = 0, 1, 2, … N-m, N is the total number of measurements; *m* represents the number of measurements and tm represents the time at *m* measurements. The flattening of the curve can be defined by Eq.13. At any specific time (*ti+m*), when the δ(Δt) < 0.01 the curve during this 20 minutes is considered as flatting.

#### **4.4.3 Continuous measurement of resistivity**

To continuously measure calf resistivity, calf circumference must be measured because at the same time the cross-sectional area is reducing during the treatment. The major issue of continuously calculate resistivity is how to measure the calf circumference during HD. The calf cross sectional area during HD can be calculated based on an assumption that change in circumference during dialysis is due to decrease in the fluid volume of the calf. Therefore, the value of circumference can be calculated by Eq.15

$$\mathcal{X}\_t = \sqrt{\mathcal{X}\_0^2 - \frac{4\pi p\_0 L}{R\_{E,0}} (1 - \frac{R\_{E,0}}{R\_{E,t}})} \tag{15}$$

where χ0 and RE,0 are measured at the start of dialysis. The ρ0 is a resistivity with constant value which is experimentally calibrated by actual measurements of circumference , L is 10 cm, RE0 and REt are resistance measured by the bioimpedance device at the initial time and by continuous measurement until the end of the treatment. With Eq.15, circumference can be accurately calculated (Zhu *et al.*, 2006b).

#### **4.4.4 Continuous calculation of resistivity change**

With Eq.5 to Eq.15, calf resistivity during HD treatment can be calculated in Eq.17.

*L R tt t* π χ ρ4 ,5 <sup>2</sup> <sup>⋅</sup> <sup>=</sup> <sup>Ω</sup>·cm (16)

To compare the resistivity and reduce the variation, normalized resistivity is defined as

$$
\rho\_N = \frac{\rho\_t}{BMI} \times 10^{\circ 2} \,\Omega \cdot \text{m}^3/\text{kg} \tag{17}
$$

where BMI is body mass index defined as body weight (Wt) divided by body height (H) squared. Since we know the range of normalized resistivity in NS, the patient's normal hydration level can be obtained by comparing the minimal level of normalized resistivity, which is given by

$$
\rho\_{\rm N,P} \ge \rho\_{\rm N,H} \qquad \Omega \cdot \text{m}^3/\text{kg} \tag{18}
$$

where Δt =tm represents the time interval between t- tm minutes which can be present in

 Δt = *ti* - *ti+m*, (14) where *i* represents the number of *i-*th measurement and *i* = 0, 1, 2, … N-m, N is the total number of measurements; *m* represents the number of measurements and tm represents the time at *m* measurements. The flattening of the curve can be defined by Eq.13. At any specific time (*ti+m*), when the δ(Δt) < 0.01 the curve during this 20 minutes is considered as flatting.

To continuously measure calf resistivity, calf circumference must be measured because at the same time the cross-sectional area is reducing during the treatment. The major issue of continuously calculate resistivity is how to measure the calf circumference during HD. The calf cross sectional area during HD can be calculated based on an assumption that change in circumference during dialysis is due to decrease in the fluid volume of the calf. Therefore,

2 0 ,0

πρ

where χ0 and RE,0 are measured at the start of dialysis. The ρ0 is a resistivity with constant value which is experimentally calibrated by actual measurements of circumference , L is 10 cm, RE0 and REt are resistance measured by the bioimpedance device at the initial time and by continuous measurement until the end of the treatment. With Eq.15, circumference can

> *L R tt*

,5

π

where BMI is body mass index defined as body weight (Wt) divided by body height (H) squared. Since we know the range of normalized resistivity in NS, the patient's normal hydration level can be obtained by comparing the minimal level of normalized resistivity,

4

To compare the resistivity and reduce the variation, normalized resistivity is defined as

,0 , <sup>4</sup> (1 ) *<sup>E</sup>*

=− − (15)

<sup>2</sup> <sup>⋅</sup> <sup>=</sup> <sup>Ω</sup>·cm (16)

= ×10-2 Ω·m3/kg (17)

*NP NH* , , ≥ Ω·m3/kg (18)

*E E t L R R R*

0

With Eq.5 to Eq.15, calf resistivity during HD treatment can be calculated in Eq.17.

χ

*t*

*<sup>t</sup> <sup>N</sup> BMI* ρ

> ρ

ρ

ρ

ρ

 χ

*t*

χ

1

( t) C Δ < (13)

We have defined that the curve of continuous measurement of the λ is flattening as

δ

more general form as follows:

**4.4.3 Continuous measurement of resistivity**

the value of circumference can be calculated by Eq.15

**4.4.4 Continuous calculation of resistivity change**

be accurately calculated (Zhu *et al.*, 2006b).

which is given by

where ρN,P represent the patient's value for normalized resistivity and ρN,H represents a minimal level of normalized resistivity in healthy subjects (18.3 \*10-2 Ωm3/kg for male and 20 \*10-2 Ωm3/kg for female respectively) from previous study.

#### **4.4.5 Continuous calculation of body weight**

Body weight (Wt) during HD treatment can also be continuously calculated by

$$\mathcal{W}\_t = \mathcal{W}\_{\text{Pr}} - \sum\_i \mathcal{L}IF \mathcal{R}\_i \times \Delta t\_i - \mathcal{W}\_V \tag{19}$$

where WPre is pre HD weight, UFR is ultrafiltration rate, Δt is the treatment time at *i*-th period of time with constant UFR (UFR>0), *WV* is any possible change in weight including use of intravenous or oral fluids. Final, dry weight (DWt) can be calculated in a general and continuous form as follows.

$$IDV\_t = \mathcal{W}\_{\text{Pr}\varepsilon} - \int\_{t\_0}^{t\_{DW}} \mathcal{U}FR(t) \cdot dt - \mathcal{W}\_V \tag{20}$$

where UFR(t) is a function of UFR with the time in case UFR is not constant. To obtain a numeric result it is assumed that the initial constant is zero. when the patient reaches dry weight, dry weight can be calculated by pre HD body weight minus ultrafiltration volumes during subsequent treatments (Zhu *et al.*, 2008a).

#### **5. Summary**

This chapter presents clinical issues and current new techniques to estimate fluid overload in dialysis patients. During the last decades, many technologies have substantially improved; these advanced tools provide the possibility to understand physiological mechanisms to control and adjust body fluid status in dialysis patients. Body fluid status can be explained with respect to terms such as dry weight, normal hydration and fluid overload.

Fluid overload can be specifically defined as extracellular fluid volume in dialysis patients greater than level of the normal ECV range. However, normal range of ECV must be clearly expressed and it must be a measurable value. Hydration is not the same as fluid overload. In chemistry, hydration is defined as a ratio of water to total mixed components of the system. In the body, hydration can be defined as the ratio of water to the mass of other body components. Since the water or ECV in healthy population is a range, normal hydration should be defined as a range and it is determined by 1) absolute ECV range; 2) total body mass and its components. The main challenge is to find the relationship between ECV and body mass components in a healthy population. The concept of dry weight in dialysis patient is defined as the patient having no excess fluid volume at post dialysis weight. However, body weight consists of different components, such as fat and muscle with variability of fluid content so that if body composition changes, the body hydration does not proportionally follow this change. The main question in the determination of dry weight is how to quantitate the degree of fluid overload.

Methodologies of measuring fluid overload can be generally divided into three techniques: static, dynamic and combination of both methods. With static methods, fluid status is measured in the intravascular compartment such as IVCD, peptides such as ANP, BNP and in both the intravascular and extravascular fluid compartment with methods such as such as the BIA vector, WBM and calf resistivity. With dynamic method, currently, two methods are reported: RBV monitor measures changes in plasma volume only while continuous measurement of calf RE0/REt provides information about change in plasma and interstitial fluid volume.

BIA phase angle bioimpedance at 50 kHz technique provides multi information about state of hydration and nutrition but it cannot produce quantitative value of fluid overload for individual. Whole body (Wrist to ankle) bioimpedance spectroscopy techniques have been largely improved to measure fluid volume, however, this method has the inherent problem of body composition influencing measurement of resistance so that its accuracy for measuring fluid overload cannot be further improved. Calf normalized resistivity provides a simple way to measure degree of fluid overload. Other measurements, such as biochemical or IVCD methods, cannot indicate the hydration of extravascular space directly so that they are not reliable in detecting degree of fluid overload. RBV measurement displays change in plasma volume but it cannot provide direct information about fluid overload in interstitial compartment. A general relationship exists between change in blood volume and refilling volume but this complicated by the effect of other factors on refilling such as autonomic tone, vascular tone, splanchnic vasoconstriction and temperature. Calf continuous measurement of RE0/REt monitors the ECV changes including plasma and interstitial fluid volume. The main advantage of this method is that it does not require a control parameter to estimate fluid overload. However, calf RE0/REt curve could be affected by lower limb venous thromboses. The combination of calf RE0/REt curve and normalized resistivity can provide the best information concerning dry weight estimation the individual patient but this method may take a long time because post dialysis weight has to be reduced gradually over a long period of time if the patient is greatly fluid overloaded.

#### **6. References**

the BIA vector, WBM and calf resistivity. With dynamic method, currently, two methods are reported: RBV monitor measures changes in plasma volume only while continuous measurement of calf RE0/REt provides information about change in plasma and interstitial

BIA phase angle bioimpedance at 50 kHz technique provides multi information about state of hydration and nutrition but it cannot produce quantitative value of fluid overload for individual. Whole body (Wrist to ankle) bioimpedance spectroscopy techniques have been largely improved to measure fluid volume, however, this method has the inherent problem of body composition influencing measurement of resistance so that its accuracy for measuring fluid overload cannot be further improved. Calf normalized resistivity provides a simple way to measure degree of fluid overload. Other measurements, such as biochemical or IVCD methods, cannot indicate the hydration of extravascular space directly so that they are not reliable in detecting degree of fluid overload. RBV measurement displays change in plasma volume but it cannot provide direct information about fluid overload in interstitial compartment. A general relationship exists between change in blood volume and refilling volume but this complicated by the effect of other factors on refilling such as autonomic tone, vascular tone, splanchnic vasoconstriction and temperature. Calf continuous measurement of RE0/REt monitors the ECV changes including plasma and interstitial fluid volume. The main advantage of this method is that it does not require a control parameter to estimate fluid overload. However, calf RE0/REt curve could be affected by lower limb venous thromboses. The combination of calf RE0/REt curve and normalized resistivity can provide the best information concerning dry weight estimation the individual patient but this method may take a long time because post dialysis weight has to be reduced

gradually over a long period of time if the patient is greatly fluid overloaded.

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### **Current Status of Synthetic and Biological Grafts for Hemodialysis**

Purav P. Patel1, Maria Altieri2, Tarun R. Jindal3, Steven R. Guy4, Edward M. Falta5, Eric A. Elster5, Frank P. Hurst5, Anton N. Sidawy2 and Rahul M. Jindal2,5 *1Medical University of Lublin 2George Washington School of Medicine 3Indiana University School of Medicine 4Department of Surgery, Drexel University, Philadelphia 5Walter Reed Army Medical Center, Washington DC 1Poland 2,3,4 5USA*

#### **1. Introduction**

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improves dry weight assessment and blood pressure control in hemodialysis

Leonard E F and Levin N W (2011) Estimation of normal hydration in dialysis patients using whole body and calf bioimpedance analysis *Physiol Meas* 32 887-902 Zhu F, Kuhlmann M K, Kaysen G A, Sarkar S, Kaitwatcharachai C, Khilnani R, Stevens L,

Leonard E F, Wang J, Heymsfield S and Levin N W (2006a) Segment-specific resistivity improves body fluid volume estimates from bioimpedance spectroscopy

for the estimation of hydration state during hemodialysis using a calf

R and Levin N W (2004) Adjustment of dry weight in hemodialysis patients using intradialytic continuous multifrequency bioimpedance of the calf *Int J Artif Organs*

resistivity in hemodialysis patients using bioimpedance analysis *Conf Proc IEEE*

volumes during changes in body position by bioimpedance analysis *J Appl Physiol*

changes in extracellular volume measured during hemodialysis using a segmental

Patients with chronic kidney disease (CKD) stage 4 or 5 have the option of kidney transplantation, hemodialysis (HD), peritoneal dialysis (PD), or conservative management.1 National Kidney and Urologic Disease Information Clearinghouse reported that in 2007, there were 368, 544 U.S. residents with ESRD who were receiving dialysis, of whom 341, 264 were undergoing HD.2 Quality of life and long-term survival of patients with CKD who are on HD depends on the successful placement of vascular access, as autogenous arteriovenous access, prosthetic arteriovenous access, or tunneled central venous catheter. DOQI guidelines are emphatic that autogenous arteriovenous access placement should be considered first, as it provides the optimal vascular access, followed by prosthetic grafts if autogenous arteriovenous access placement is not possible. There is a great deal of controversy regarding the choice of synthetic or biological material, as the guidelines suggest that it should be based on surgeon's experience and preference. The evidence to support the superiority of tapered versus uniform tubes, thick- versus thin- walled characteristics, elastic versus non-elastic arterial, stretch vs. standard PTFE, externally supported vs. unsupported grafts, is still evolving.

An ideal vascular graft would have the following characteristics: 1) appropriate size to match host vessels, 2) mechanical strength, 3) low thrombogenicity/complete endothelialization, 4) rapid/complete healing, 5) ease of handling, 6) resistance to infection, 7) structural durability in face of repeated needle puncture, 8) low incidence of hyperplastic intimal changes and 9) low cost.3

In this chapter, we will review the development of vascular grafts over the years and discuss the advantages of one over the other.

#### **2. Prosthetic grafts for hemodialysis**

Although the first synthetic graft used for HD access in the United States was made of Dacron dating back to the early 1970s, unfavorable results and the availability of better prosthetic materials like expanded PTFE (ePTFE) forced its abandonment. In 1976, Dr. Baker presented the first results of ePTFE grafts in 72 HD patients. Since then ePTFE remains the graft of choice for vascular access.4 ePTFE is considered the material of choice due to the fact that it is readily accessible, ease of implantation, good medium term patency, and relatively low complication rates compared to other synthetic and biological materials.5 The medical community has made strenuous efforts to increase the use of autogenous arterovenous access, prevalence has increased from 22% in 1995 to 57.7% in 2011. However, the use of synthetic grafts still remains significant (18.4% prevalence in 2011).6,7

#### **2.1 Indications for use of prosthetic grafts**

Autogenous arteriovenous access are clearly superior in terms of long term patency to grafts, but not feasible in many patients undergoing HD8. The indications for prosthetic grafts include: lack of suitable vessels particularly in elderly and diabetic patients, need for immediate cannulation and in children who cannot tolerate multiple painful venipunctures.5

#### **2.2 Complications associated with prosthetic grafts**

Graft failures are typically caused by stenosis (leading cause of graft failure) due to thrombosis and neointimal hyperplasia at site of anastamosis, as well as graft infection (contributes to 10- 15% of graft failure).9,10 Other less common complications of prosthetic accesses include; steal syndrome, seromas, aneurysm formation, central vein stenosis and bleeding.11 Thrombosis seems to occur soon after implantation due to technical problem, with a clot typically forming at the surface of the graft when it is rst exposed to blood. The clot is formed initially of platelet aggregates, and then fibrin and thrombin is laid down via activation of the coagulation cascade. Platelet activity is generally most intense during the rst 24 hours and subsides to a very low level after 1 week.9 Neointimal hyperplasia in prosthetic conduits can be attributed to upstream and downstream events. The upstream factors include; hemodynamic stress at the graft-vein anastamosis, compliance mismatch between the graft material and vein (more studies required to establish this factor), arterial injury at the time of graft placement, intrinsic properties of the synthetic graft itself (shown to attract macrophages which then secrete specific cytokines bFGF, PDGF, and VEGF), graft injury from dialysis needles, as well as the presence of uremia (causing endothelial dysfunction even prior to synthetic graft implant).12-14 The downhill events are essentially a consequence of the upstream events. Pro-inflammatory cells release cytokines promoting the migration of smooth muscle cells and myofibroblasts from the adventitia media into the intimal layer, where they proliferate and cause lesions of neointimal hyperplasia.13 These stenotic lesions are usually treated by percutaneous angioplasty (PTA) or open patch angioplasty, which unfortunately, predisposes the patient to restenotic lesions due to endothelial and smooth muscle cell injury.15

Infection is the second most common complication of synthetic grafts and can lead to further complications such subacute bacterial endocarditis, epidural or brain abscess.11 These complications can lead to graft failure in up to 35% of patients.16 Graft infections have an incidence rate as high as 2%, and are 4 times as prevalent in synthetic grafts when compared to autogenous veins.9 Common causative organisms are Staphylococcus aureus (26.32% of

Although the first synthetic graft used for HD access in the United States was made of Dacron dating back to the early 1970s, unfavorable results and the availability of better prosthetic materials like expanded PTFE (ePTFE) forced its abandonment. In 1976, Dr. Baker presented the first results of ePTFE grafts in 72 HD patients. Since then ePTFE remains the graft of choice for vascular access.4 ePTFE is considered the material of choice due to the fact that it is readily accessible, ease of implantation, good medium term patency, and relatively low complication rates compared to other synthetic and biological materials.5 The medical community has made strenuous efforts to increase the use of autogenous arterovenous access, prevalence has increased from 22% in 1995 to 57.7% in 2011. However, the use of

Autogenous arteriovenous access are clearly superior in terms of long term patency to grafts, but not feasible in many patients undergoing HD8. The indications for prosthetic grafts include: lack of suitable vessels particularly in elderly and diabetic patients, need for immediate cannulation and in children who cannot tolerate multiple painful venipunctures.5

Graft failures are typically caused by stenosis (leading cause of graft failure) due to thrombosis and neointimal hyperplasia at site of anastamosis, as well as graft infection (contributes to 10- 15% of graft failure).9,10 Other less common complications of prosthetic accesses include; steal syndrome, seromas, aneurysm formation, central vein stenosis and bleeding.11 Thrombosis seems to occur soon after implantation due to technical problem, with a clot typically forming at the surface of the graft when it is rst exposed to blood. The clot is formed initially of platelet aggregates, and then fibrin and thrombin is laid down via activation of the coagulation cascade. Platelet activity is generally most intense during the rst 24 hours and subsides to a very low level after 1 week.9 Neointimal hyperplasia in prosthetic conduits can be attributed to upstream and downstream events. The upstream factors include; hemodynamic stress at the graft-vein anastamosis, compliance mismatch between the graft material and vein (more studies required to establish this factor), arterial injury at the time of graft placement, intrinsic properties of the synthetic graft itself (shown to attract macrophages which then secrete specific cytokines bFGF, PDGF, and VEGF), graft injury from dialysis needles, as well as the presence of uremia (causing endothelial dysfunction even prior to synthetic graft implant).12-14 The downhill events are essentially a consequence of the upstream events. Pro-inflammatory cells release cytokines promoting the migration of smooth muscle cells and myofibroblasts from the adventitia media into the intimal layer, where they proliferate and cause lesions of neointimal hyperplasia.13 These stenotic lesions are usually treated by percutaneous angioplasty (PTA) or open patch angioplasty, which unfortunately, predisposes the patient to

Infection is the second most common complication of synthetic grafts and can lead to further complications such subacute bacterial endocarditis, epidural or brain abscess.11 These complications can lead to graft failure in up to 35% of patients.16 Graft infections have an incidence rate as high as 2%, and are 4 times as prevalent in synthetic grafts when compared to autogenous veins.9 Common causative organisms are Staphylococcus aureus (26.32% of

synthetic grafts still remains significant (18.4% prevalence in 2011).6,7

**2. Prosthetic grafts for hemodialysis**

**2.1 Indications for use of prosthetic grafts**

**2.2 Complications associated with prosthetic grafts**

restenotic lesions due to endothelial and smooth muscle cell injury.15

**Abbreviations**: polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), carbon lined (CL), graft platelet accumulation index (GPAI), high porous (HP), tridodecylmethylammonium chloride (TDMAC), polycarbonate polyurethane (PU), per patient year (PPY), polyurethaneurea (PUU), polyurethane vascular graft (PVG), transposed brachio-basilic fistula (TBB), clot free survival (CFS), autogenous brachial vein-brachial artery access (ABBA), brachio-basilic arteriovenous fistula (BBAVF), Not available (N/A)

Table 1. Clinical trials of prosthetic grafts for hemodialysis.

infections cultured), methacillin resistant Staphylococcus aureus (21.05%), followed by Pseudomonas aeruginosa (5.26%).11 The largest number of infections occur when patients are going under routine dialysis (more than 50% of patients) and as a complication of chronic cannulation, rather than postoperative complications.11 Reducing *Staphylococcus aureus* carrier state in patients undergoing HD and improving antiseptic technique may reduce the rate of infections in grafts.

#### **2.3 Characteristics of PTFE grafts**

294 Hemodialysis - Different Aspects

**Abbreviations**: polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), carbon lined (CL), graft platelet accumulation index (GPAI), high porous (HP), tridodecylmethylammonium chloride (TDMAC), polycarbonate polyurethane (PU), per patient year (PPY), polyurethaneurea (PUU), polyurethane vascular graft (PVG), transposed brachio-basilic fistula (TBB), clot free survival (CFS), autogenous brachial vein-brachial artery access (ABBA), brachio-basilic arteriovenous fistula (BBAVF),

Table 1. Clinical trials of prosthetic grafts for hemodialysis.

Not available (N/A)

While PTFE is available in various configurations and is produced by various manufacturers, very few have proven to be more beneficial in improving patency in randomized clinical trials for long-term.1

#### **2.3.1 Effect of wall thickness**

In order to examine the effect of wall thickness on patency, Lenz et al.17 investigated both standard wall and thin wall configuration of PTFE. Although the incidence of complications and mortality did not statistically differ amongst the 2 groups, standard ePTFE had better patency rates. Studies comparing 2 manufacturers of ePTFE grafts: Gore-Tex**®** (W.L. Gore and Associates, Flagstaff, AZ) and Impra**®** (C. R. Bard Inc., Murray Hill, NJ) did not find any difference in the performance of 6-mm standard ePTFE grafts.18 19

#### **2.3.2 Effect of stretch characteristics**

In an attempt to reduce kinking of the graft in areas of angulation and to improve intraoperative handling, the graft was modified to stretch (Gore- Tex**®** Stretch). Tordoir et al. reported a cumulative primary patency rate of 59% in the stretch ePTFE group compared to 29% in standard ePTFE group at 1 year (p < 0.01). In addition, there were significantly fewer thrombotic events for the stretch ePTFE grafts as opposed to the standard ePTFE grafts (40%vs. 12%, p<0.001).20 Early cannulation of stretch ePTFE grafts was not found to increase peri-operative morbidity rates or decrease 12-month cumulative primary patency rates.21 In contrast, another study comparing the patency of early cannulation with late cannulation in Gore-Tex**®** stretch grafts showed that graft patency after thrombosis formation was significantly higher in the late cannulation group (p=0.0002).22

#### **2.3.3 Effect of ringed reinforcement**

Ring reinforced grafts were created to reduce kinking at the apex of loop grafts and decrease incidence of thrombosis associated with external compression. In a retrospective study in which 632 reinforced and non-reinforced PTFE grafts were compared for patency and complications, it was found that non-reinforced grafts had higher primary and secondary patency rates.23

#### **2.3.4 Effect of cuff or hood on venous ourflow**

One of the few modifications that improved patency rates in PTFE vascular grafts was placing a cuff or hood on the venous outflow. The main objective of placing a cuffed PTFE graft is to enlarge the outflow, and reduce mechanical sheer stress in order to reduce thrombotic occlusion caused by neointimal hyperplasia.1 In a computer simulated model, Venaflo**®** II (C. R. Bard Inc., Murray Hill, NJ), a flared-end ePTFE graft to simulate a vein

Table 2. Clinical trials of biological conduits for hemodialysis

cuff, showed measurable improvements in reducing wall shear stress gradient, wall shear stress angle gradient, and radial pressure gradient.25 Sorom et al.26found that Venaflo**®** II was associated with increased blood flow rates during HD and improved graft patency compared with ePTFE graft. Similarly, in a smaller study it was found that a flared-end ePTFE graft provided stable blood flow and satisfactory graft patency during 2 years of follow-up, even in high risk patients with a prior history of vascular access thrombosis.27 However, a European study did not show improvement in patency rate despite a reduction in thrombotic occlusion and stenosis.24

#### **2.3.5 Effect of coating PTFE**

Another technique meant to improve PTFE graft has been coating the PTFE vascular grafts with carbon or heparin to prevent early graft failure and improve overall patency rates.28 In a canine model, Tsuchida et al. showed that the graft platelet accumulation index (GPAI) was significantly (p<0.05) lower in the carbon lined PTFE group when compared to the control PTFE group.29 They concluded that carbon lining decreases platelet accumulation on PTFE grafts. Propaten**®**, ePTFE with bioactive heparin covalently bound to it (W.L. Gore and Associates) has also been shown to be effective in improving graft patency. It is the only vascular graft of its kind approved for HD access on the market. Davidson et al. 30 found 20% improved primary graft patency of about 80% at one year when comparing Propaten**®** to standard ePTFE. In order to diminish the risk of neointimal hyperplasia. Cagiannos et al.31 studied the effects of coating an ePTFE graft with rapamycin in a porcine model. They showed that the rapamycin coated grafts significantly (P <0.0001) lowered cross sectional narrowing in the outflow graft when compared to non-coated grafts; as well as no evidence of medial necrosis or aneurysmal degeneration. After a four week observation period, coated grafts showed features of diminished neointimal hyperplasia compared to untreated ePTFE grafts. Researchers have also analyzed the effect of a bioabsorbable vascular wrap mesh containing paclitaxel on neointimal hyperplasia in a sheep model. Paclitaxel coated mesh significantly reduced neointimal hyperplasia and neointimal capillary density without toxicity to adjacent vessels.32

#### **2.3.6 Self-sealing grafts**

K/DOQI recommends that PTFE grafts should not be routinely used until at least 2 weeks after placement and not until swelling has subsided so that palpation of the course of the graft can be performed. This time is needed for tissue-to-graft incorporation, reducing peri graft hematoma.1 Due to this complication, newer "self-sealing" grafts have been designed that can be cannulated sooner.11 Vectra**®** vascular grafts (C. R. Bard Inc., Murray Hill, NJ) made of a proprietary blend of segmented polyetherurethaneurea and a siloxane containing a surface-modifying additive (SMA), were designed to provide early cannulation, reducing the need for temporary central venous catheters to provide access until the graft matures. In a study of 76 patients, in which Vectra**®** grafts were compared to transposed brachio-basilic vein (TBB) autogenous access, Kakkos et al.33 found that aggressive graft surveillance and endovascular treatment methods resulted in equivalent long-term secondary patency rates. The advantage of earlier use of Vectra**®** graft must be balanced against the need for more frequent secondary interventions and the risk of graft infection. In a single center study, Jefic

cuff, showed measurable improvements in reducing wall shear stress gradient, wall shear stress angle gradient, and radial pressure gradient.25 Sorom et al.26found that Venaflo**®** II was associated with increased blood flow rates during HD and improved graft patency compared with ePTFE graft. Similarly, in a smaller study it was found that a flared-end ePTFE graft provided stable blood flow and satisfactory graft patency during 2 years of follow-up, even in high risk patients with a prior history of vascular access thrombosis.27 However, a European study did not show improvement in patency rate despite a reduction

Another technique meant to improve PTFE graft has been coating the PTFE vascular grafts with carbon or heparin to prevent early graft failure and improve overall patency rates.28 In a canine model, Tsuchida et al. showed that the graft platelet accumulation index (GPAI) was significantly (p<0.05) lower in the carbon lined PTFE group when compared to the control PTFE group.29 They concluded that carbon lining decreases platelet accumulation on PTFE grafts. Propaten**®**, ePTFE with bioactive heparin covalently bound to it (W.L. Gore and Associates) has also been shown to be effective in improving graft patency. It is the only vascular graft of its kind approved for HD access on the market. Davidson et al. 30 found 20% improved primary graft patency of about 80% at one year when comparing Propaten**®** to standard ePTFE. In order to diminish the risk of neointimal hyperplasia. Cagiannos et al.31 studied the effects of coating an ePTFE graft with rapamycin in a porcine model. They showed that the rapamycin coated grafts significantly (P <0.0001) lowered cross sectional narrowing in the outflow graft when compared to non-coated grafts; as well as no evidence of medial necrosis or aneurysmal degeneration. After a four week observation period, coated grafts showed features of diminished neointimal hyperplasia compared to untreated ePTFE grafts. Researchers have also analyzed the effect of a bioabsorbable vascular wrap mesh containing paclitaxel on neointimal hyperplasia in a sheep model. Paclitaxel coated mesh significantly reduced neointimal hyperplasia and neointimal capillary density without

K/DOQI recommends that PTFE grafts should not be routinely used until at least 2 weeks after placement and not until swelling has subsided so that palpation of the course of the graft can be performed. This time is needed for tissue-to-graft incorporation, reducing peri graft hematoma.1 Due to this complication, newer "self-sealing" grafts have been designed that can be cannulated sooner.11 Vectra**®** vascular grafts (C. R. Bard Inc., Murray Hill, NJ) made of a proprietary blend of segmented polyetherurethaneurea and a siloxane containing a surface-modifying additive (SMA), were designed to provide early cannulation, reducing the need for temporary central venous catheters to provide access until the graft matures. In a study of 76 patients, in which Vectra**®** grafts were compared to transposed brachio-basilic vein (TBB) autogenous access, Kakkos et al.33 found that aggressive graft surveillance and endovascular treatment methods resulted in equivalent long-term secondary patency rates. The advantage of earlier use of Vectra**®** graft must be balanced against the need for more frequent secondary interventions and the risk of graft infection. In a single center study, Jefic

in thrombotic occlusion and stenosis.24

**2.3.5 Effect of coating PTFE**

toxicity to adjacent vessels.32

**2.3.6 Self-sealing grafts**

et al. obtained 81% (108 of 133 grafts) cannulation rate within 4 days of Polyurethane (PU) [Thoratec**®** Vascular Access Graft] graft placement in which none of the recipients required a temporary catheter. A shorter mean bleeding time after withdrawal of dialysis needle was also acquired in the PU graft group (4.0 minutes vs. 9.2 minutes in ePTFE group).34 Similarly, Glickman et al. showed that PU grafts had achieved better hemostasis at cannulation sites compared to ePTFE sites when the two were compared at 5 minutes or less after dialysis (P<0.0001). Also, they showed that 53.9% of all PU grafts were cannulated before 9 days vs. none of the ePTFE grafts (P<0.001).35 In the HIV- positive ESRD patient population, reduction of temporary catheter use and prevention of infection is critical. A study of 30 consecutive HIV positive patients receiving Vectra**®** graft implantation showed a lower infection rate (10% vs. 45%) than published reports of infection in PTFE grafts. It was concluded that the unique self-sealing property of the Vectra**®** grafts reduced the development of perigraft hematoma and may have accounted for decreased infection.36

#### **3. Biological conduits for hemodialysis**

Biological graft materials tend to have less intimal hyperplasia at the venous anastamosis, reduced tendency to thrombose, and a lower risk of infection when compared to PTFE.11 Butler et al. compared bovine heterographs to PTFE and found that the synthetic graft had significantly fewer late thromboses, increased resistance to infection, easier to repair and had comparable longevity.37 Anderson et al. found that bovine heterographs required twice as many revisions per dialysis month to maintain patency.38

SynerGraft**®** 100 (SG100 [CryoLife Inc., Atlanta, GA]) is a modified bovine ureter graft with some similarities to synthetic graft (similar internal diameter and strong tissue matrix). This graft has been processed to remove xenograft cells while maintaining a collagen matrix that is not chemically cross-linked by aldehydes allowing re-population by autologous cells. Matsuura et al. reported a primary patency rate of 72.6% and 58.6% for SG 100 vs. 57.4% and 54.7% for the ePTFE grafts at 6 months and 12 months, respectively. SG 100 graft showed fibroblast cell migration and proliferation with incorporation into the surrounding subcutaneous tissue after 10 weeks, and procollagen synthesis demonstrated at 24 weeks; while the ePTFE graft had no evidence of cellular ingrowth.39 In a study of 23 patients receiving SG 100 grafts, Darby et al. found that the bovine ureter graft was a stable vascular access conduit, providing a suitable graft alternative when autologous vein was not available. Their study showed 29% primary, 45% primary assisted, and 81% secondary patency rates at 1 year, with only a 5% infection rate.40 On the other hand, Chemla et al. found that both grafts were adequate conduits for HD, the anticipated advantages for SG 100 were not seen in either patency or stability.41

#### **4. Future developments in prosthetic and biological conduits for hemodialysis**

The use of pharmacological agents may hold the promise of long-term graft patency. Treatment with 200 mg of dipyridamole and 25 mg of aspirin twice daily resulted in significant improvement of patency rates while adverse effects in both the treatment and placebo groups remained the same.45 Other agents, such as fish oil and anticoagulants have also been tried with limited success (table 4).

**Abbreviations:** expanded polytetrafluoroethylene (ePTFE), Not available (N/A)

Table 3. Clinical trials of experimental conduits for hemodialysis

**Abbreviations:** expanded polytetrafluoroethylene (ePTFE), Not available (N/A)

Table 3. Clinical trials of experimental conduits for hemodialysis

**Abbreviations**: expanded polytetrafluoroethylene (ePTFE), polytetrafluoroethylene (PTFE), Not available (N/A).

Table 4. Effects of various medications on vascular access grafts

In an approach of reducing neointimal hyperplasia by decreasing mechanical sheer stress, a new double channel (Bi-Flow) graft was designed. These grafts showed laminar flow and lower levels of turbulence, leading to lower risk of stenosis.46

#### **5. Conclusions**

Prosthetic grafts should be reserved for situations where autogenous vein is not available to perform an access. The most commonly used prosthetic graft is e-PTFE based. Newer advances in medication bonding to decrease thrombosis and formation of intimal hyperplasia may be promising. In addition, various graft characteristics such as flared-end and stretch may provide better patency. Biologic grafts are being tested; however, at this point data are lacking to show superiority over prosthetic grafts. This area is a fertile ground for randomized clinical trials in the search for a man made or biologic graft that would equal autogenous vein in patency and complication rates.

#### **6. Abbreviations**

Chronic kidney disease (CKD), hemodialysis (HD), peritoneal dialysis (PD), arteriovenous fistula (AVF), polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE), transposed brachialbasilic vein (TBB), percutaneous angioplasty (PTA)

#### **7. Definitions**

Primary Patency: Interval of time from access placement to any intervention necessary tomaintain patency of access. Assisted Primary Patency: Interval of time from access placement to time of intervention necessary to maintain the functionality of the access. Secondary Patency: Interval of time from access placement to access abandonment including intervening surgical or endovascular manipulations

### **8. Manufacturer and graft**

#### **9. Disclaimer**

306 Hemodialysis - Different Aspects

In an approach of reducing neointimal hyperplasia by decreasing mechanical sheer stress, a new double channel (Bi-Flow) graft was designed. These grafts showed laminar flow and