**4.8 Factors affecting delivered Kt/V**

Factors that influences delivery of Kt/V is multifactorial: hematocrit, the effective dialyzer urea clearance *Kd* depends on blood and dialysate flow rates, dialyzer *K*o*A,* effective dialyzer surface area, anticoagulation, and recirculation. (60) Dialysis session time (*t*) is critical for reaching the *Kt/V* goal. Prescribe treatment time (PTT) and effective treatment time (ETT) may not always correlate, EET may be significantly less secondary to patient demand, clotting of dialyser, or intermittent pump stops. *V* does not substantially change during a single HD session but may change over time. Dialysis dose needs to be adjusted for an increase in *V*. However, if there is a loss in body mass (weight loss, amputation of limb), is associated with a decrease in *V, Kt/V* should not be reduced but rather adjusted to the higher, ideal patient *V* or BSA.

If faced with an inadequate delivered *Kt/V,* first check if that session was representative of an average session and no unusual problems may have occurred (e.g., shortened time because of patient request, needle difficulty, leaks, alarm triggering). (60) The use of commercial technologies that measure ionic dialysance can be implemented to monitor each dialysis. A frequent cause of low *Kt/V* is fistula integrity that causes a vascular access problem leading to recirculation. Blood sampling errors should be considered because delayed post-HD sampling will reduce *Kt/V*. Standardized blood sampling procedures should be implemented in each center. If, despite these checks, a low *Kt/V* remains unexplained, treatment time should be increased to 4.5 or 5 hours. Prescription of a more efficient dialyzer and higher blood and dialysate flow rates should also be considered. However, increasing treatment time, rather than increasing dialysate flow, or using two

Quantifying removal of toxic uremic solutes is important to assess the adequacy of HD. The delivered dialysis dose is a function of length of the session (*t*), dialysate and blood flow rates, volume of distribution (V) of the uremic toxin studied, and the dialyzer efficiency (*K*o*A*). Volume of distribution is very different for urea (total body water volume), than other small-molecular-weight. The minimum frequency and dosage of dialysis is three times per week, for a minimum treatment time of 3 to 4 hours, a blood flow rate of at least 250 ml/min, and a dialysate flow rate of 500 to 800 ml/min. Patients that are initiated on HD, *V* is unknown and has to be estimated (men, 58% of body weight; women, 55% of body weight). After obtaining measured *Kt/V* the dialysis prescription can be adjusted to meet the *Kt/V* goals. For patients with severe and long-standing uremia, it's recommended to provide several sessions in achieving target dose to avoid the dialysis disequilibrium syndrome.




Factors that influences delivery of Kt/V is multifactorial: hematocrit, the effective dialyzer urea clearance *Kd* depends on blood and dialysate flow rates, dialyzer *K*o*A,* effective dialyzer surface area, anticoagulation, and recirculation. (60) Dialysis session time (*t*) is critical for reaching the *Kt/V* goal. Prescribe treatment time (PTT) and effective treatment time (ETT) may not always correlate, EET may be significantly less secondary to patient demand, clotting of dialyser, or intermittent pump stops. *V* does not substantially change during a single HD session but may change over time. Dialysis dose needs to be adjusted for an increase in *V*. However, if there is a loss in body mass (weight loss, amputation of limb), is associated with a decrease in *V, Kt/V* should not be reduced but rather adjusted to the

If faced with an inadequate delivered *Kt/V,* first check if that session was representative of an average session and no unusual problems may have occurred (e.g., shortened time because of patient request, needle difficulty, leaks, alarm triggering). (60) The use of commercial technologies that measure ionic dialysance can be implemented to monitor each dialysis. A frequent cause of low *Kt/V* is fistula integrity that causes a vascular access problem leading to recirculation. Blood sampling errors should be considered because delayed post-HD sampling will reduce *Kt/V*. Standardized blood sampling procedures should be implemented in each center. If, despite these checks, a low *Kt/V* remains unexplained, treatment time should be increased to 4.5 or 5 hours. Prescription of a more efficient dialyzer and higher blood and dialysate flow rates should also be considered. However, increasing treatment time, rather than increasing dialysate flow, or using two

**4.6 Hemodialysis dose** 

of 65%.

average URR of 70%.

pediatric HD patients.

higher, ideal patient *V* or BSA.

**4.8 Factors affecting delivered Kt/V** 

**4.7 Recommendations for dialysis dose adequacy** 

Current recommendations in the United States are as follows (KDOQI) (64):

dialysers, would be more beneficial and practical to improve adequacy. Muscle exercise before or during dialysis improves *Kt/V* by increasing blood supply to poorly perfused urea rich muscle tissue and thus facilitates urea equilibration. Delivered *Kt/V* should be checked whenever the dialysis prescription has been modified substantially. Online clearance monitoring allows assessment of *Kt/V* during each single session without blood sampling.

#### **4.9 Should volume (V) be included in Kt/V to assess target clearance?**

In an attempt to address the question of optimal dialysis dose, several clinical trial have proposed that patients with small urea *V,* such as women, do worst compared to larger people. This is secondary to the notion that muscle mass closely correlate to total body water than to body weight. Thus, small urea *V* is a good indicator for low muscle mass. The Hemodialysis Study (HEMO) was performed in which 1846 patients were randomly assigned to a standard or high dose of dialysis and a low- or high-flux dialyzer (based on clearance of beta-2-microglobulin) which revealed a beneficial effect of higher *Kt/V* for women but not for men. (65) This suggests that individuals with low muscle mass may require a higher clearance in relation to *V* and therefore raises the question of whether *V* is the appropriate denominator for dialysis dose. (60) Native renal clearances, in contrast, are commonly related to body surface area (BSA), not to total body water. (60) It has been suggested to relate BSA to dialysis clearances. The ratio of BSA to urea *V* is generally higher in women than in men and decreases with an increment in *V*. Prescribing dialysis dose in relation to BSA (*K* × *t*/BSA) would result in more dialysis for smaller patients of either gender and for women of any size. (57,60) More work need to be done to validate this novel idea.

### **4.10 Other dialysis factors related to outcomes**

There are many other factors that play a role in the outcome of dialysis adequacy. Such factor includes but is not restricted to middle molecule removal, hyperphosphatemia, preservation of RRF, vascular access, QOL and treatment time. In general, middle molecule removal is determined by the dialyser permeability, the presence of convection, protein binding, and dialysis duration. Given that daily dialysis results in more frequent solute level equilibration with less rebound, this technique provides higher middle molecule removal than with conventional hemodialysis. The retention of solutes of middle molecular size is proposed to play an important role in the pathogenesis of the uremic state and contribute significantly to the high mortality of dialysis patients. (60) High-flux dialyzers have the propensity to remove larger amounts of middle molecules than low-flux dialyzers due to higher membrane porosity, and this may even be further increased by the use of convective dialysis strategies, such as hemodiafiltration. Serum β2-microglobulin, is a surrogate for other uremic middle molecules, is effectively removed by high-flux than by low-flux dialysis, and predialysis β2-microglobulin levels were found to be related to mortality in patients treated randomly with high-flux or low-flux dialyzers. (70) Patient who has diabetes on HD, or on dialysis for longer than 3.7 years, and those with serum albumin levels below 40 g/l, may benefit most from high-flux dialysis. (69,71) The European Best Practice Guidelines have recommended maximizing the removal of middle molecules in all dialysis patients. (60,72)

Hyperphosphatemia is a major problem in HD and is managed by phosphate removal via dialysis, use of phosphate binder medication to prevent intestinal phosphate absorption

Hemodialysis Principles and Controversies 239

after 6 months. (75) Nocturnal dialysis is also associated with beneficial effects on vascular smooth muscle which restore the proliferation of the apoptosis ratio, which directly associated to serum phosphorus. However, there are no published randomized trials of nocturnal hemodialysis compared to other modalities. Thus studies comparing nocturnal hemodialysis to conventional hemodialysis should be performed to better understand the

Due to the nightly schedule with nocturnal hemodialysis, the cost of consumables is higher than conventional hemodialysis and is similar to the cost of short daily hemodialysis. However, the personnel cost of nocturnal hemodialysis is lower than that with in-center

Depending upon the consumable/personnel cost ratio in different countries, nocturnal hemodialysis can be less or more expensive than in-center conventional hemodialysis. In addition, the cost of medications, including EPO, antihypertensive agents, and phosphate

Performing hemodialysis requires the ability to access and return a patient's blood at a high rate. The optimal access would allow a high rate of blood flow, with no recirculation of dialyzed blood into the pre-dialysis blood, with maximal durability, minimal complications, and minimal gap from creation to use. Currently, no hemodialysis access approaches this

The preferred access currently is the arteriovenous fistula (AVF). The AVF is created surgically by connecting an artery to a vein, with the subsequent increased flow and pressure causing the vein to "arterialize," with thickened wall and increased size. This arterialized vein can then be accessed for hemodialysis. The advantages to the AVF are a high rate of blood flow with minimal recirculation, minimal complications because of the absence of foreign material, and an extended functional life. The primary shortcoming of the AVF is the significant time from initial placement to maturation for use, which ranges from 25 to 98 days (81). Typically AVF is not used until 3 months after placement. However, a recent study of the practice patterns at dialysis facilities in DOPPS suggests that earlier cannulation of AVFs (even prior to 4 weeks) was not associated with increased risk of access failure (81). Other issues include a significant rate of primary failure of AVFs (82), vascular steal syndrome, inability to create AVFs because of lack of suitable vessels (82-84), and

Given the significant time for their maturation, AVFs must be placed well before initiation of hemodialysis to avoid use of other accesses, such as tunneled catheters. Currently, only 15 percent of patients starting on hemodialysis use an AVF, and only 24 percent have a maturing AVF (85). One cause is late referral to nephrologists, but even with a timely referral to nephrologists, 46% of the patients did not have a permanent access placed prior to starting HD (85). Some barriers leading to this problem include patient resistance to creation of AVFs, poor access to surgeons, and decreased rate of primary patency of AVFs (85). Possible solutions include improved patient education, often through patient support groups in CKD clinics and referral to nephrologist at earlier stage of chronic kidney disease

Where creation of an AVF is impossible, insertion of an arteriovenous graft (AVG) may be feasible. The advantage of an AVG is the high primary patency rate and minimal gap

binders, is lower with nocturnal hemodialysis as well as cost of hospitalization.

development of stenoses leading to AVF thrombosis and AVF failure (82-84).

benefits with nocturnal hemodialysis.

goal; each available access has shortcomings.

hemodialysis regimens. (76)

**5.1 Vascular access** 

(85).

from dietary phosphate and dietary restriction. With the use of larger dialyzer surface area, hemodiafiltration, high-flux HD, removal of phosphate is significantly removal. Must monitor for hypophosphatemia with long frequent dialysis

End stage renal patients initiated on dialysis initially posess considerable residual renal function (RRF). However, most of these patients lose their RRF by the end of the first year on dialysis. By year three only 10% to 20% of patients retain their RRF. RRF of 2 to 3 ml/min urea clearance contributes significantly to the elimination of uremic toxins. (73) The retention of RRF results in lower serum β2-microglobulin, phosphate, potassium, urea, creatinine, and uric acid levels; higher hemoglobin concentration; enhanced nutritional status; better quality of life scores; and a reduced need for dietary and fluid restrictions. (60) Left ventricular hypertrophy is associated with loss of RRF. Patient with an estimated TBW of 40 liters, a residual urea clearance of 2 to 3 ml/min is equivalent to a *std-Kt/V* of 0.5 to 0.75/week. Dialysate water impurities, nephrotoxic agents such as radiocontrast, nonsteroidal anti-inflammatory drugs, aminoglycosides and activation of the immune system by bioincompatible membranes, intradialytic hypotension are risk factors for the loss of RRF. Patients who retain urine output may enhance survival augment with the regulation of fluid and electrolyte balance.

### **5. Frequency of dialysis**

DePalma first reported in 1969 the successful use of short daily or "quotidian" hemodialysis. (35) Short daily dialysis (SDD) was based upon the premise that patient outcomes would improved, compared with conventional three times per week hemodialysis. SDD would occur with a dialysis schedule that consisted of the same number of hours of dialysis per week but delivered over twice as many sessions. More specifically, this schedule consists of daily hemodialysis (five to seven days per week) provided for a duration of 1.5 to 3 or more hours per session. Initial attempts to popularize daily dialysis in the United States were suppressed by financial and logistical issues. This led to a decline in its use both in the home and in-center settings. However, over the last decade there has been resurgence in the use of daily dialysis, with several studies emerging from the United States and Europe showing improvements in various intermediate outcomes. Most recently, in the wake of the HEMO study, attention has turned from increasing the per-session dialytic dose, to altering variables such as treatment frequency or duration to improve outcomes (75-76) Daily dialysis has also been proposed as a rescue therapy and in the intensive care unit setting.

The mortality rate of patients undergoing maintenance hemodialysis is unacceptably high. An extremely high morbidity, relatively low quality of life (due in part to a high level of dependence and unemployment), and high cost have also been observed. Contrast this with frequent dialysis which provides a more physiological renal replacement, because it allows more gentle volume removal, reduction of hemodynamic stress and better blood pressure control. More frequent dialysis and prolonged-duration HD have the greatest effect on middle molecule clearance. (74) In addition, phosphorus removal is increased secondarily to its predominant intracellular distribution. Protein bound solutes like p-cresol are not changed, because these solutes depend on RRF. The benefits of more frequent dialysis improve BP, thus decreasing anti-hypertensive medications, decreasing intradialytic hypotension, lowering serum phosphate, raising albumin and hemoglobin with lower requirements for erythropoiesis stimulating agents. HD patients switch to nocturnal dialysis improved sleep efficiency especially in stage 3 and 4 sleep with decreased in daytime fatigue

from dietary phosphate and dietary restriction. With the use of larger dialyzer surface area, hemodiafiltration, high-flux HD, removal of phosphate is significantly removal. Must

End stage renal patients initiated on dialysis initially posess considerable residual renal function (RRF). However, most of these patients lose their RRF by the end of the first year on dialysis. By year three only 10% to 20% of patients retain their RRF. RRF of 2 to 3 ml/min urea clearance contributes significantly to the elimination of uremic toxins. (73) The retention of RRF results in lower serum β2-microglobulin, phosphate, potassium, urea, creatinine, and uric acid levels; higher hemoglobin concentration; enhanced nutritional status; better quality of life scores; and a reduced need for dietary and fluid restrictions. (60) Left ventricular hypertrophy is associated with loss of RRF. Patient with an estimated TBW of 40 liters, a residual urea clearance of 2 to 3 ml/min is equivalent to a *std-Kt/V* of 0.5 to 0.75/week. Dialysate water impurities, nephrotoxic agents such as radiocontrast, nonsteroidal anti-inflammatory drugs, aminoglycosides and activation of the immune system by bioincompatible membranes, intradialytic hypotension are risk factors for the loss of RRF. Patients who retain urine output may enhance survival augment with the regulation

DePalma first reported in 1969 the successful use of short daily or "quotidian" hemodialysis. (35) Short daily dialysis (SDD) was based upon the premise that patient outcomes would improved, compared with conventional three times per week hemodialysis. SDD would occur with a dialysis schedule that consisted of the same number of hours of dialysis per week but delivered over twice as many sessions. More specifically, this schedule consists of daily hemodialysis (five to seven days per week) provided for a duration of 1.5 to 3 or more hours per session. Initial attempts to popularize daily dialysis in the United States were suppressed by financial and logistical issues. This led to a decline in its use both in the home and in-center settings. However, over the last decade there has been resurgence in the use of daily dialysis, with several studies emerging from the United States and Europe showing improvements in various intermediate outcomes. Most recently, in the wake of the HEMO study, attention has turned from increasing the per-session dialytic dose, to altering variables such as treatment frequency or duration to improve outcomes (75-76) Daily dialysis has also been proposed as a rescue therapy and in the intensive care unit setting. The mortality rate of patients undergoing maintenance hemodialysis is unacceptably high. An extremely high morbidity, relatively low quality of life (due in part to a high level of dependence and unemployment), and high cost have also been observed. Contrast this with frequent dialysis which provides a more physiological renal replacement, because it allows more gentle volume removal, reduction of hemodynamic stress and better blood pressure control. More frequent dialysis and prolonged-duration HD have the greatest effect on middle molecule clearance. (74) In addition, phosphorus removal is increased secondarily to its predominant intracellular distribution. Protein bound solutes like p-cresol are not changed, because these solutes depend on RRF. The benefits of more frequent dialysis improve BP, thus decreasing anti-hypertensive medications, decreasing intradialytic hypotension, lowering serum phosphate, raising albumin and hemoglobin with lower requirements for erythropoiesis stimulating agents. HD patients switch to nocturnal dialysis improved sleep efficiency especially in stage 3 and 4 sleep with decreased in daytime fatigue

monitor for hypophosphatemia with long frequent dialysis

of fluid and electrolyte balance.

**5. Frequency of dialysis** 

after 6 months. (75) Nocturnal dialysis is also associated with beneficial effects on vascular smooth muscle which restore the proliferation of the apoptosis ratio, which directly associated to serum phosphorus. However, there are no published randomized trials of nocturnal hemodialysis compared to other modalities. Thus studies comparing nocturnal hemodialysis to conventional hemodialysis should be performed to better understand the benefits with nocturnal hemodialysis.

Due to the nightly schedule with nocturnal hemodialysis, the cost of consumables is higher than conventional hemodialysis and is similar to the cost of short daily hemodialysis. However, the personnel cost of nocturnal hemodialysis is lower than that with in-center hemodialysis regimens. (76)

Depending upon the consumable/personnel cost ratio in different countries, nocturnal hemodialysis can be less or more expensive than in-center conventional hemodialysis. In addition, the cost of medications, including EPO, antihypertensive agents, and phosphate binders, is lower with nocturnal hemodialysis as well as cost of hospitalization.

### **5.1 Vascular access**

Performing hemodialysis requires the ability to access and return a patient's blood at a high rate. The optimal access would allow a high rate of blood flow, with no recirculation of dialyzed blood into the pre-dialysis blood, with maximal durability, minimal complications, and minimal gap from creation to use. Currently, no hemodialysis access approaches this goal; each available access has shortcomings.

The preferred access currently is the arteriovenous fistula (AVF). The AVF is created surgically by connecting an artery to a vein, with the subsequent increased flow and pressure causing the vein to "arterialize," with thickened wall and increased size. This arterialized vein can then be accessed for hemodialysis. The advantages to the AVF are a high rate of blood flow with minimal recirculation, minimal complications because of the absence of foreign material, and an extended functional life. The primary shortcoming of the AVF is the significant time from initial placement to maturation for use, which ranges from 25 to 98 days (81). Typically AVF is not used until 3 months after placement. However, a recent study of the practice patterns at dialysis facilities in DOPPS suggests that earlier cannulation of AVFs (even prior to 4 weeks) was not associated with increased risk of access failure (81). Other issues include a significant rate of primary failure of AVFs (82), vascular steal syndrome, inability to create AVFs because of lack of suitable vessels (82-84), and development of stenoses leading to AVF thrombosis and AVF failure (82-84).

Given the significant time for their maturation, AVFs must be placed well before initiation of hemodialysis to avoid use of other accesses, such as tunneled catheters. Currently, only 15 percent of patients starting on hemodialysis use an AVF, and only 24 percent have a maturing AVF (85). One cause is late referral to nephrologists, but even with a timely referral to nephrologists, 46% of the patients did not have a permanent access placed prior to starting HD (85). Some barriers leading to this problem include patient resistance to creation of AVFs, poor access to surgeons, and decreased rate of primary patency of AVFs (85). Possible solutions include improved patient education, often through patient support groups in CKD clinics and referral to nephrologist at earlier stage of chronic kidney disease (85).

Where creation of an AVF is impossible, insertion of an arteriovenous graft (AVG) may be feasible. The advantage of an AVG is the high primary patency rate and minimal gap

Hemodialysis Principles and Controversies 241

thrombosis (95). Treatment with anticoagulant or anti-platelet therapy, e.g. aspirin, ticlopidine or warfarin, has a modest effect on reducing stenosis and increasing patency of fistulas; however, this treatment is associated with increased risk of hemorrhage (96). Antiplatelet therapy should be a part of routine care in patient with graft but not AV fistula (97). Other pharmacological approaches for prevention of stenosis and patency of vascular access including calcium channel blocker, ACE-I and fish oil have been investigated, but further research is required to determine the role of these agents in maintaining fistula

Another complication of AVF and AVG is vascular access induced ischemia and is related to significant amounts of blood flow via AV fistulas. This diversion of blood via the fistula could cause decrease of blood flow to the distal tissue and cause ischemia (known as steal syndrome). It could rarely cause exacerbation of heart failure in paints with underlying disease. Elderly patients, patients with diabetics, peripheral vascular disease or coronary artery disease are at increase risk of ischemia. Pain during hemodialysis is a characteristic

Another vascular access complication is central venous obstruction occurring in patients with previously inserted venous catheter or pacemaker placement. The rate of central venous obstruction is higher in patients who had their brachial venous accessed prior to dialysis access placement compare to patient who had internal jugular vein accessed. The most common clinical presentation is pain and swelling of the ipsilateral arm usually accompanied with the superficial collateral vein around the shoulder. Other clue for diagnosis of central venous obstruction is finger ulceration, pain and inadequate dialysis. The first option for treatment is percutaneous transluminal angioplasty and stent placement (angioplasty alone has a high rate of restenosis). The second option is surgical revision with

One of the most common complications of hemodialysis catheters is decrease of flow or thrombosis. Catheter thrombosis prevention is generally achieved through instillation of heparin into the catheter ports after completion of dialysis; a recent study suggests that weekly instillation of recombinant tissue plasminogen activator (tPA) may prevent thrombosis more effectively (98). Catheter thrombosis can be treated effectively by instillation of tPA into the catheter lumens or with exchange of the catheter over a guidewire; however, thrombosis frequently recurs, necessitating further procedures. One cause of frequent catheter malfunction is the formation of a fibrin sheath around the tip of the catheter. This can be treated with a 3 hour infusion of low-dose tPA or with mechanical

The prevalence of central venous catheters in the United States is about 20-30% despite recommendations from major societies to increase the use of AV fistulas known as fistula first initiative. There is an increased risk of mortality with the use of catheters compared with the use of AV fistulas (100). This increased rate of mortality is likely related to infection. The rate of catheter related blood stream infection is 0.5 to 6.6 episodes per 1,000 catheter days (101). The source of this infection is bacterial seeding from biofilms that form on the inside and outside of the blood stream catheter. The rate of CRBSI is directly related

bypass grafting and placement of HERO catheter (as discussed above).

**6.2 Catheter thrombosis and fibrin sheath formation** 

stripping, although secondary patency rates remain low (99).

**6.3 Catheter related blood stream infection (CRBSI)** 

patency.

symptom.

between creation and first use (84,86). Because of the presence of foreign material, there is increased risk of access infection, although less than that with tunneled catheters, and there is an increased rate of stenosis, thrombosis, and graft failure compared with AVFs. One new technique in the creation of AVGs is the Hemodialysis Reliable Outflow (HeROTM) dialysis catheter, a new FDA approved device for catheter-dependent and significant vasculopathic patients. The HeRO device is an AVG that extends from the arm into the right ventricle. This may avoid problems with stenosis at the venous anastomosis leading to graft failure. The third means of chronic hemodialysis access is the tunneled catheter. This catheter, like the standard non-tunneled dialysis catheter used for acute hemodialysis access and nontunneled catheters used for venous access, is inserted into a central vein, usually the internal jugular vein, but the risk of infection is reduced by increasing the distance between the vein and skin entry by running the catheter through a subcutaneous tunnel. This access has the advantage of being usable immediately upon insertion, but it has the highest rate of infection, particularly catheter-related bacteremia, and is associated with higher costs, morbidity, and mortality, compared with other accesses (87-88). Other complications of the tunneled catheter include intraluminal thrombosis and fibrin sheath.

### **6. Management of access complications**

#### **6.1 Detection and treatment of stenosis and thrombosis of AVF and AVG**

Stenosis of AVF and AVG commonly develop over time, generally resulting from response to endothelial damage. This can occur at the anastamosis between native vessels or between a graft and a native vessel, with endothelial damage caused by surgical trauma, or distal to the venous anastamosis, with endothelial damage from rapid turbulent flow. If these stenoses are not recognized and corrected, increased access pressures and decreased flow can result in thrombosis of the access. Once an access has thrombosed, even if it can be salvaged, the duration of secondary patency is relatively short, with 62% one year patency average (89). Therefore, monitoring and subsequent treatment of stenosis in AVFs and AVGs is critical to prolonging the life of these hemodialysis accesses. For an excellent review of the various methods of monitoring accesses, see reference 90. There are several ways to monitor for stenosis. Physical exam, looking for abnormalities such as change in thrill, bruit or pulse, presence of arm swelling, or prolonged bleeding after dialysis, can be quite helpful in detecting access problems (91). Another common way to detect stenosis is with dynamic venous pressure monitoring. With this technique, the pressure at the venous needle is measured with low dialysis pump rate. If the pressure is over 80, or if there is significant increase from prior pressures, there is a high likelihood of outflow stenosis (92). Measuring static access pressures (with blood pump off) is more accurate, and can also detect arterial stenoses, but this technique requires additional equipment, and is therefore not common (93). Another monitoring method growing in use is Doppler flow measurement. If the flow decreases to less than 650 mL/minute, or if there has been significant interval decrease in flow, there is a high likelihood of stenosis (94). Stenoses can be detected by Doppler ultrasound, but the gold standard for detection and treatment of access stenosis is fistulogram, or the injection of contrast into the access to demonstrate visually the stenosis. When a fistulogram demonstrates stenosis, the stenosis can be repaired with angioplasty or surgical revision. While angioplasty has a shorter secondary patency than surgical revision, angioplasty is generally the first line treatment of stenosis and thrombosis of AVF and AVG, since surgical revision can be performed after angioplasty in case of recurrent stenosis or

between creation and first use (84,86). Because of the presence of foreign material, there is increased risk of access infection, although less than that with tunneled catheters, and there is an increased rate of stenosis, thrombosis, and graft failure compared with AVFs. One new technique in the creation of AVGs is the Hemodialysis Reliable Outflow (HeROTM) dialysis catheter, a new FDA approved device for catheter-dependent and significant vasculopathic patients. The HeRO device is an AVG that extends from the arm into the right ventricle. This may avoid problems with stenosis at the venous anastomosis leading to graft failure. The third means of chronic hemodialysis access is the tunneled catheter. This catheter, like the standard non-tunneled dialysis catheter used for acute hemodialysis access and nontunneled catheters used for venous access, is inserted into a central vein, usually the internal jugular vein, but the risk of infection is reduced by increasing the distance between the vein and skin entry by running the catheter through a subcutaneous tunnel. This access has the advantage of being usable immediately upon insertion, but it has the highest rate of infection, particularly catheter-related bacteremia, and is associated with higher costs, morbidity, and mortality, compared with other accesses (87-88). Other complications of the

tunneled catheter include intraluminal thrombosis and fibrin sheath.

**6.1 Detection and treatment of stenosis and thrombosis of AVF and AVG** 

Stenosis of AVF and AVG commonly develop over time, generally resulting from response to endothelial damage. This can occur at the anastamosis between native vessels or between a graft and a native vessel, with endothelial damage caused by surgical trauma, or distal to the venous anastamosis, with endothelial damage from rapid turbulent flow. If these stenoses are not recognized and corrected, increased access pressures and decreased flow can result in thrombosis of the access. Once an access has thrombosed, even if it can be salvaged, the duration of secondary patency is relatively short, with 62% one year patency average (89). Therefore, monitoring and subsequent treatment of stenosis in AVFs and AVGs is critical to prolonging the life of these hemodialysis accesses. For an excellent review of the various methods of monitoring accesses, see reference 90. There are several ways to monitor for stenosis. Physical exam, looking for abnormalities such as change in thrill, bruit or pulse, presence of arm swelling, or prolonged bleeding after dialysis, can be quite helpful in detecting access problems (91). Another common way to detect stenosis is with dynamic venous pressure monitoring. With this technique, the pressure at the venous needle is measured with low dialysis pump rate. If the pressure is over 80, or if there is significant increase from prior pressures, there is a high likelihood of outflow stenosis (92). Measuring static access pressures (with blood pump off) is more accurate, and can also detect arterial stenoses, but this technique requires additional equipment, and is therefore not common (93). Another monitoring method growing in use is Doppler flow measurement. If the flow decreases to less than 650 mL/minute, or if there has been significant interval decrease in flow, there is a high likelihood of stenosis (94). Stenoses can be detected by Doppler ultrasound, but the gold standard for detection and treatment of access stenosis is fistulogram, or the injection of contrast into the access to demonstrate visually the stenosis. When a fistulogram demonstrates stenosis, the stenosis can be repaired with angioplasty or surgical revision. While angioplasty has a shorter secondary patency than surgical revision, angioplasty is generally the first line treatment of stenosis and thrombosis of AVF and AVG, since surgical revision can be performed after angioplasty in case of recurrent stenosis or

**6. Management of access complications** 

thrombosis (95). Treatment with anticoagulant or anti-platelet therapy, e.g. aspirin, ticlopidine or warfarin, has a modest effect on reducing stenosis and increasing patency of fistulas; however, this treatment is associated with increased risk of hemorrhage (96). Antiplatelet therapy should be a part of routine care in patient with graft but not AV fistula (97). Other pharmacological approaches for prevention of stenosis and patency of vascular access including calcium channel blocker, ACE-I and fish oil have been investigated, but further research is required to determine the role of these agents in maintaining fistula patency.

Another complication of AVF and AVG is vascular access induced ischemia and is related to significant amounts of blood flow via AV fistulas. This diversion of blood via the fistula could cause decrease of blood flow to the distal tissue and cause ischemia (known as steal syndrome). It could rarely cause exacerbation of heart failure in paints with underlying disease. Elderly patients, patients with diabetics, peripheral vascular disease or coronary artery disease are at increase risk of ischemia. Pain during hemodialysis is a characteristic symptom.

Another vascular access complication is central venous obstruction occurring in patients with previously inserted venous catheter or pacemaker placement. The rate of central venous obstruction is higher in patients who had their brachial venous accessed prior to dialysis access placement compare to patient who had internal jugular vein accessed. The most common clinical presentation is pain and swelling of the ipsilateral arm usually accompanied with the superficial collateral vein around the shoulder. Other clue for diagnosis of central venous obstruction is finger ulceration, pain and inadequate dialysis. The first option for treatment is percutaneous transluminal angioplasty and stent placement (angioplasty alone has a high rate of restenosis). The second option is surgical revision with bypass grafting and placement of HERO catheter (as discussed above).

### **6.2 Catheter thrombosis and fibrin sheath formation**

One of the most common complications of hemodialysis catheters is decrease of flow or thrombosis. Catheter thrombosis prevention is generally achieved through instillation of heparin into the catheter ports after completion of dialysis; a recent study suggests that weekly instillation of recombinant tissue plasminogen activator (tPA) may prevent thrombosis more effectively (98). Catheter thrombosis can be treated effectively by instillation of tPA into the catheter lumens or with exchange of the catheter over a guidewire; however, thrombosis frequently recurs, necessitating further procedures. One cause of frequent catheter malfunction is the formation of a fibrin sheath around the tip of the catheter. This can be treated with a 3 hour infusion of low-dose tPA or with mechanical stripping, although secondary patency rates remain low (99).

### **6.3 Catheter related blood stream infection (CRBSI)**

The prevalence of central venous catheters in the United States is about 20-30% despite recommendations from major societies to increase the use of AV fistulas known as fistula first initiative. There is an increased risk of mortality with the use of catheters compared with the use of AV fistulas (100). This increased rate of mortality is likely related to infection. The rate of catheter related blood stream infection is 0.5 to 6.6 episodes per 1,000 catheter days (101). The source of this infection is bacterial seeding from biofilms that form on the inside and outside of the blood stream catheter. The rate of CRBSI is directly related

Hemodialysis Principles and Controversies 243

a new long term catheter, exchange of the infected catheter with a new one over guidewire, or use of systemic antibiotics and an antibiotic lock in the existing catheter. Antibiotic therapy for catheter-related infection is often initiated empirically. The initial choice of antibiotics will depend on the severity of the patient's clinical disease, the risk factors for infection, and the likely pathogens associated with the specific intravascular device (109). Antibiotic therapy should be administered to patients with persistent fungemia or bacteremia after catheter removal (especially if the infection is caused by S. aureus). Longterm catheters should be removed from patients with CRBSI associated with any of the following conditions: severe sepsis; suppurative thrombophlebitis; endocarditis; bloodstream infection that continues despite antimicrobial therapy to which the infecting microbes are susceptible (110). In uncomplicated CRBSI involving long-term catheters due to pathogens other than S. aureus, P. aeruginosa, fungi, because of the limited access sites in many patients who require long-term intravascular access for survival in hemodialysis patients, treatment should be attempted without catheter removal, with use of both systemic and antimicrobial lock therapy for 14 days and cultures should be repeated one week after completion of antibiotics treatment. The rate of treatment failure, however, is higher for patient treated with antibiotics alone (111). If the symptoms resolve after 2–3 days of intravenous antibiotic therapy, guidewire exchange of the catheter is associated with cure rates that are comparable to those associated with immediate removal and delayed placement of a new catheter (110). Localized Cellulites (exit site infection) should be treated with systemic antibiotics and exit site care. Tunnel track infection, however, requires catheter removal since it involves space in an area with limited vascular supply (112).

A large diameter venous catheter (a dual lumen venous catheter) usually placed in the internal jugular or femoral vein, is needed for acute or urgent hemodialysis in the absence of permanent vascular access. This catheter is used in patients with acute kidney injury who need urgent hemodialysis, in patients who need removal of a toxic agent by means of dialysis, or with chronic dialysis patients with a temporary inability to use a permanent access, as with catheter-related bacteremia. Using this type of access, one lumen of the venous catheter is allocated to draw blood (arterial side) and the other lumen is allocated to return the blood. Separation of arterial from venous lumen minimized the recirculation of blood during hemodialysis. Because of high risk of infection, non-tunneled femoral catheter should be removed within a week, while non-tunneled internal jugular catheters can be used for about 2 weeks. Hemodialysis catheters placed in the subclavian veins have a significant risk of subclavian stenosis, which can cause the arm on that side to be unsuitable for AVF or AVG placement, and so catheters are generally not placed in the subclavian veins. An indwelling cuffed catheter is tunneled under the skin and placed in the internal jugular vein by an interventional nephrologist, interventional radiologist or surgeon. It is used when acute renal failure is expected to require hemodialysis for more than 2 weeks

**6.5 Extracorporeal therapies in the ICU setting - continuous renal replacement** 

Critically ill, hemodynamically unstable intensive care unit (ICU) patients are typically the most challenging to treat with conventional dialytic modalities as described above. The

**6.4 Acute vascular access** 

**therapy** 

because of the decreased rate of infection (1034).

to the species and level of virulence of the seeding bacteria. Meticulous catheter care and reeducation of personnel responsible for insertion of the catheters are the key elements in lowering the rate of catheter related infection (101). The catheter care includes but is not limited to sterile technique of catheter placement, exit –site care, sterile technique during initiation and termination of dialysis (including the use of a sterile barrier, sterile gloves, and antiseptic to clean the tubes) and the replacement of malfunctioning catheters over a guidewire (empirical administration of antibiotics does not reduce the incidence of catheter associated bacteremia) (102). Using standard antiseptic precautions the incidence of catheter related infection could drop to one episode per 1,000 catheter days which could be used to assess the quality of catheter care.

The current guidelines indicate the use of tunneled cuffed catheter for long term use (more than 3 weeks duration) in patients in need of hemodialysis based on pathophysiological considerations as well as a generally lower rate of infection of tunneled, cuffed catheters compared to nontunneled catheters (103). The location of catheters influences the risk of infection. The femoral lines carry a higher rate of infection compare with the subclavian or jugular lines. Subsequent studies, however, only confirm an increase risk of femoral catheter infection in the patients with a higher BMI (87-88,102).

Although the prophylactic use of systemic antibiotics at the time of insertion of a catheter is not currently recommended, the antimicrobial lock solutions for prevention of catheter related infection and bactremia are recommended (101). The ideal lock solution has anticoagulant and antimicrobial activity, is safe, and does not induce bacterial resistance. The antimicrobial solutions most frequently used are antibiotics or chemicals, citrate (30% concentrated since the lower concentration has little antimicrobial affect) (104). Antimicrobial lock solutions substantially reduce the risk of catheter related infection (102). The potential disadvantage of usage of antibiotics for antimicrobial lock solution is bacterial resistance and predisposition to highly resistance bacterial infection. There is also a potential adverse effect of these antibiotics including aminoglycoside-related ototoxicity. The disadvantage of usage of citrate is hypocalcemia and adverse cardiac event if the locking solution is pushed to the patient blood (105).

Application of topical antibiotics to the exit site may reduce the incidence of catheter related infection in patients on hemodialysis. The most recent CDC guideline recommends use of povidone iodine antiseptic ointment or bacitracin/gramicidin/polymyxin B at the hemodialysis catheter exit site after each dialysis session (101). A recent Cochrane review on this subject concluded that the current data support only the topical application of mupirocin alone (among antibacterial agents) for prevention of catheter related infection (106). The use of antibiotic coated catheter in hemodialysis patients has not been shown to reduce the incidence of catheter related infection (101,107).

Staphylococcus species in general and S. aureus in particular are among the most common cause of bacterial related infection. Mortality rate is high among the patient infected with S. aureus (8%). Morbidity related to S. aureus is secondary to its high propensity to colonize prosthetic materials, heart valves, bones and joints. Nasal carriage of S. aureus is common among patients on dialysis, in whom it is associated with an increased risk of S. aureus infection. Successful elimination of S. aureus nasal carriage can be achieved by a short (5 day) course of mupirocin applied daily to the anterior nares (108).

Treatment of CRBSI requires systemic antibiotics and frequently discontinuation of the catheter and placement of temporary catheter. There are four possible options for treatment of CRBSI. Intravenous antibiotics alone, prompt catheter removal with delayed placement of

to the species and level of virulence of the seeding bacteria. Meticulous catheter care and reeducation of personnel responsible for insertion of the catheters are the key elements in lowering the rate of catheter related infection (101). The catheter care includes but is not limited to sterile technique of catheter placement, exit –site care, sterile technique during initiation and termination of dialysis (including the use of a sterile barrier, sterile gloves, and antiseptic to clean the tubes) and the replacement of malfunctioning catheters over a guidewire (empirical administration of antibiotics does not reduce the incidence of catheter associated bacteremia) (102). Using standard antiseptic precautions the incidence of catheter related infection could drop to one episode per 1,000 catheter days which could be used to

The current guidelines indicate the use of tunneled cuffed catheter for long term use (more than 3 weeks duration) in patients in need of hemodialysis based on pathophysiological considerations as well as a generally lower rate of infection of tunneled, cuffed catheters compared to nontunneled catheters (103). The location of catheters influences the risk of infection. The femoral lines carry a higher rate of infection compare with the subclavian or jugular lines. Subsequent studies, however, only confirm an increase risk of femoral catheter

Although the prophylactic use of systemic antibiotics at the time of insertion of a catheter is not currently recommended, the antimicrobial lock solutions for prevention of catheter related infection and bactremia are recommended (101). The ideal lock solution has anticoagulant and antimicrobial activity, is safe, and does not induce bacterial resistance. The antimicrobial solutions most frequently used are antibiotics or chemicals, citrate (30% concentrated since the lower concentration has little antimicrobial affect) (104). Antimicrobial lock solutions substantially reduce the risk of catheter related infection (102). The potential disadvantage of usage of antibiotics for antimicrobial lock solution is bacterial resistance and predisposition to highly resistance bacterial infection. There is also a potential adverse effect of these antibiotics including aminoglycoside-related ototoxicity. The disadvantage of usage of citrate is hypocalcemia and adverse cardiac event if the locking

Application of topical antibiotics to the exit site may reduce the incidence of catheter related infection in patients on hemodialysis. The most recent CDC guideline recommends use of povidone iodine antiseptic ointment or bacitracin/gramicidin/polymyxin B at the hemodialysis catheter exit site after each dialysis session (101). A recent Cochrane review on this subject concluded that the current data support only the topical application of mupirocin alone (among antibacterial agents) for prevention of catheter related infection (106). The use of antibiotic coated catheter in hemodialysis patients has not been shown to

Staphylococcus species in general and S. aureus in particular are among the most common cause of bacterial related infection. Mortality rate is high among the patient infected with S. aureus (8%). Morbidity related to S. aureus is secondary to its high propensity to colonize prosthetic materials, heart valves, bones and joints. Nasal carriage of S. aureus is common among patients on dialysis, in whom it is associated with an increased risk of S. aureus infection. Successful elimination of S. aureus nasal carriage can be achieved by a short (5-

Treatment of CRBSI requires systemic antibiotics and frequently discontinuation of the catheter and placement of temporary catheter. There are four possible options for treatment of CRBSI. Intravenous antibiotics alone, prompt catheter removal with delayed placement of

assess the quality of catheter care.

infection in the patients with a higher BMI (87-88,102).

solution is pushed to the patient blood (105).

reduce the incidence of catheter related infection (101,107).

day) course of mupirocin applied daily to the anterior nares (108).

a new long term catheter, exchange of the infected catheter with a new one over guidewire, or use of systemic antibiotics and an antibiotic lock in the existing catheter. Antibiotic therapy for catheter-related infection is often initiated empirically. The initial choice of antibiotics will depend on the severity of the patient's clinical disease, the risk factors for infection, and the likely pathogens associated with the specific intravascular device (109). Antibiotic therapy should be administered to patients with persistent fungemia or bacteremia after catheter removal (especially if the infection is caused by S. aureus). Longterm catheters should be removed from patients with CRBSI associated with any of the following conditions: severe sepsis; suppurative thrombophlebitis; endocarditis; bloodstream infection that continues despite antimicrobial therapy to which the infecting microbes are susceptible (110). In uncomplicated CRBSI involving long-term catheters due to pathogens other than S. aureus, P. aeruginosa, fungi, because of the limited access sites in many patients who require long-term intravascular access for survival in hemodialysis patients, treatment should be attempted without catheter removal, with use of both systemic and antimicrobial lock therapy for 14 days and cultures should be repeated one week after completion of antibiotics treatment. The rate of treatment failure, however, is higher for patient treated with antibiotics alone (111). If the symptoms resolve after 2–3 days of intravenous antibiotic therapy, guidewire exchange of the catheter is associated with cure rates that are comparable to those associated with immediate removal and delayed placement of a new catheter (110). Localized Cellulites (exit site infection) should be treated with systemic antibiotics and exit site care. Tunnel track infection, however, requires catheter removal since it involves space in an area with limited vascular supply (112).

### **6.4 Acute vascular access**

A large diameter venous catheter (a dual lumen venous catheter) usually placed in the internal jugular or femoral vein, is needed for acute or urgent hemodialysis in the absence of permanent vascular access. This catheter is used in patients with acute kidney injury who need urgent hemodialysis, in patients who need removal of a toxic agent by means of dialysis, or with chronic dialysis patients with a temporary inability to use a permanent access, as with catheter-related bacteremia. Using this type of access, one lumen of the venous catheter is allocated to draw blood (arterial side) and the other lumen is allocated to return the blood. Separation of arterial from venous lumen minimized the recirculation of blood during hemodialysis. Because of high risk of infection, non-tunneled femoral catheter should be removed within a week, while non-tunneled internal jugular catheters can be used for about 2 weeks. Hemodialysis catheters placed in the subclavian veins have a significant risk of subclavian stenosis, which can cause the arm on that side to be unsuitable for AVF or AVG placement, and so catheters are generally not placed in the subclavian veins. An indwelling cuffed catheter is tunneled under the skin and placed in the internal jugular vein by an interventional nephrologist, interventional radiologist or surgeon. It is used when acute renal failure is expected to require hemodialysis for more than 2 weeks because of the decreased rate of infection (1034).

### **6.5 Extracorporeal therapies in the ICU setting - continuous renal replacement therapy**

Critically ill, hemodynamically unstable intensive care unit (ICU) patients are typically the most challenging to treat with conventional dialytic modalities as described above. The

Hemodialysis Principles and Controversies 245

with a standard thrice-weekly regimen (with a target Kt/V of 1.2 to 1.4 per treatment) or standard CRRT (with an effluent flow rate of 20 mL/kg per hour) does not improve clinical

In the RENAL study (a trial in Australia and New Zealand), 1508 patients with AKI were randomly assigned to CVVHDF at an effluent flow of either 25 or 40 mL/kg per hour (119). At 90 days, mortality was the same in each group (44.7 percent, odds ratio 1.00, 95% CI 0.31 to 1.23). In addition, the incidence of patients who continued to receive renal replacement therapy at 90 days was similar with both dialysis doses (6.8 and 4.4 percent of higher and

Two meta-analyses, one consisting of 3841 patients and 8 trials and the other 3999 patients and 12 trials, found that more intense therapy did not improve survival compared with less

[1] Grassmann A, Gioberge S, Moeller S, Brown G. ESRD patients in 2004: global overview

[2] United States Renal Data System. USRDS 2010 Annual Data Report: Atlas of End-Stage

[3] Alper B, Shenava, R, Young, B, et. al. Uremia. Medscape. Batuman V. Mar 17, 2010.

[4] Termorshuizen F, Dekker FW, van Manen JG et al., Relative contribution of residual

[5] Rosansky SJ, Clark WF, Eggers P, Glassock RJ. Initiation of dialysis at higher GFRs: is the

[6] Schrier R. Manual of Nephrology: Diagnosis and Therapy. Philadelphia: Lippincott

[7] Pendse, S, Singh, A, Zawada, E. Initiation of dialysis in Handbook of Dialysis, 4th ed,

[8] Rosansky SJ, Eggers P, Jackson K, Glassock R, Clark WF. Early Start of Hemodialysis

[9] NKF-KDOQI Clinical Practice Guidelines. Am J Kidney Dis 1997; 30(3 Suppl 2): S67–

[10] Obrador RT, Auora P, Kausz AT et al. Level of renal function at the initiation of

[11] National Kidney Foundation. KDOQI Clinical practice guidelines and clinical practice

adequacy and vascular access. Am J Kidney Dis 2006; 48(Suppl 1): S1–S322. [12] Tang, SC, Ho, YW, Tang, AW, et al. Delaying initiation of dialysis till symptomatic

uraemia--is it too late? Nephrol Dial Transplant 2007; 22:1926.

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Dialysis (NECOSAD)-2, J Am Soc Nephrol 2004; 15:1061-70

May Be Harmful. Arch Intern Med. 2011; 171(5):396-403)

of patient numbers, treatment modalities and associated trends. Nephrol. Dial.

Renal Disease in the United States 2010; Bethesda, MD, National Institute of Health,

renal function and different measures of adequacy to survival in hemodialysis patients: an analysis of the Netherlands Cooperative Study on the Adequacy of

apparent rising tide of early dialysis harmful or helpful? Kidney Int. 2009

Daugirdas, JT, Blake, PG, Ing, TS (Eds). Lippincott Williams & Wilkins,

dialysis in the US end-stage renal disease population. Kidney Int 1999; 5: 2227–

recommendations for 2006 updates: hemodialysis adequacy, peritoneal dialysis

lower-intensity groups, odds ratio 1.59, 95% CI 0.86 to 2.92).

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Philadelphia 2007.

S136.

2235.

Williams & Wilkins, 2009.

intensive regimens (118-119). There was significant trial heterogeneity.

outcomes.

**8. References** 

intermittent volume and solute fluxes may cause significant morbidity, which includes worsening of hypotension and arrhythmias. Multiple modalities of renal replacement therapy are currently available. These include intermittent hemodialysis (IHD), continuous renal replacement therapies (CRRTs), and hybrid therapies, such as sustained low-efficiency dialysis (SLED).



CRRTs involve either dialysis (diffusion-based solute removal) or filtration (convectionbased solute and water removal) treatments that operate in a continuous mode (114-117). The major advantage of continuous therapy is the slower rate of solute or fluid removal per unit of time. Thus, CRRT is generally better tolerated than conventional therapy, since many of the complications of intermittent hemodialysis are related to the rapid rate of solute and fluid loss. It must be emphasized, however, that the protection afforded by CRRT is relative, not absolute.
