Prescribing and assessing adequate hemodialysis

INTRODUCTION — Survival in patients with end-stage kidney disease (ESKD) is made possible by removal of uremic solutes by dialysis. The amount of dialysis that a patient receives and the amount of uremic toxin removal can impact morbidity and mortality [1,2]. Uremic toxins include small, water-soluble compounds such as urea, protein-bound solutes such as indoles and phenols, or larger middle molecules such as beta2-microglobulin. Although assessment of solute removal during dialysis has always been based on urea removal, evidence from experimental and clinical studies points to an adverse effect of middle molecules and protein-bound solutes on patient survival [3,4].

Two central issues in the management of patients undergoing maintenance hemodialysis include determining the optimal amount of dialysis that should be prescribed and quantifying the amount of dialysis that is actually delivered to individual patients. Improvement in patients' symptoms and the blood urea nitrogen (BUN) concentration are not accurate measures of dialysis adequacy for two reasons:

●The dialysis dose that reduces uremic symptoms is lower than the dose shown to increase survival. This is especially true when erythropoietin is started concurrently with dialysis for anemia since many symptoms attributed to uremia are actually related to anemia. (See "Treatment of anemia in nondialysis chronic kidney disease" and "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease".)

●The BUN depends on factors that are independent of the dialysis dose, such as protein intake, protein catabolic rate, and residual kidney function. A low BUN may reflect inadequate nutrition rather than sufficient dialytic urea removal.

Methods currently used to measure dialysis dose are based upon urea clearance. Although the best method is not known, the Kt/V is used by most nephrologists. This topic reviews the Kt/V and other methods that are used to measure the amount of dialysis delivered to individual patients. We also discuss dialysis dose recommendations for patients on hemodialysis. Assessing the adequacy of peritoneal dialysis and patient outcomes related to dialysis are discussed elsewhere:

●(See "Prescribing peritoneal dialysis".)

●(See "Measurement of solute clearance in continuous peritoneal dialysis: Kt/V and creatinine clearance".)

●(See "Inadequate solute clearance in peritoneal dialysis".)

●(See "Patient survival and maintenance dialysis".)

●(See "Dialysis modality and patient outcome".)

Kt/V

Definition and calculation — Kt/V is the preferred method for measuring the dialysis dose [5]. Kt/V is defined as the dialyzer clearance of urea (K) multiplied by the duration of the dialysis treatment (t, in minutes) divided by the volume of distribution of urea in the body (V, in mL), which is approximately equal to the total body water, corrected for volume lost during ultrafiltration [5]. The correction of total urea removal (Kt) for volume of distribution is important since the rate of urea removal depends on the total body burden of urea; in a large patient, a given degree of urea loss represents a lower rate of removal of the total body burden of urea (and presumably of other small uremic toxins).

Equation 1 shows the calculation for Kt/V. This formula and the accompanying nomogram have little systematic error for Kt/V values between 0.7 and 2.0, a range that covers the currently recommended Kt/V goals (figure 1) [6,7]:

 (Eq. 1)  Kt/V  =  -ln(R - 0.03) + [(4 - 3.5R)  x  (UF  ÷  W)] [6,7]

where R is the ratio of the postdialysis to predialysis blood urea nitrogen (BUN), UF is the ultrafiltration volume in liters, and W is the postdialysis weight in kg. A calculator capable of performing natural logarithms (ln) is generally used to determine the Kt/V. The formula for the Kt/V in the following calculator also takes the length of the dialysis session into consideration (calculator 1).

Single-pool versus double-pool — Unless otherwise stated, the Kt/V referred to in this topic review is the nonequilibrated, single-pool value. Single-pool Kt/V and equilibrated, double-pool Kt/V differ according to the timing and method of obtaining the postdialysis BUN. The timing of postdialysis BUN affects the Kt/V because the concentration of urea in blood samples drawn from the arterial access (ie, where blood leaves the patient and enters the dialyzer (figure 2)) increases for approximately 30 minutes after dialysis ends. The increase in BUN is caused by the following [8]:

●Dissipation of hemodialysis access recirculation and cardiopulmonary recirculation

●Equilibration of urea from the extravascular compartment into the vascular compartment, which can take up to 30 minutes after dialysis ends

Hemodialysis access recirculation occurs when dialyzed blood returning through the venous needle re-enters the extracorporeal circuit through the arterial needle, rather than returning to the systemic circulation. Significant hemodialysis access recirculation is abnormal and is usually due to venous stenosis, which obstructs venous outflow, resulting in increased pressure and backflow into the arterial needle (see "Arteriovenous fistula recirculation in hemodialysis", section on 'Definition and mechanism'). Cardiopulmonary recirculation is a result of dialyzed blood being sent directly to the heart and lungs from the dialyzer and returning to the arterial needle, bypassing the systemic circulation. The degree to which cardiopulmonary bypass occurs depends on the rate of blood flow in the dialyzer and the cardiac output. Cardiopulmonary bypass is most severe among patients with low cardiac output who are undergoing high-efficiency dialysis. The result of both hemodialysis access recirculation and cardiopulmonary recirculation is that the BUN sampled from arterial blood flowing into the dialyzer tends to be lower than from venous blood. Both hemodialysis access recirculation and cardiopulmonary recirculation dissipate within minutes after stopping dialysis (figure 3) [9].

To achieve the most accurate measure of the Kt/V (referred to as the equilibrated or double-pool Kt/V), it is necessary to use an equilibrated BUN measured from a sample obtained 30 minutes after dialysis has ended [10-12]. However, the 30-minute equilibrated BUN is difficult to perform in the outpatient clinical setting since most patients do not wish to add additional waiting time to the overall dialysis time.

To circumvent this inconvenience for patients, we and most other clinicians use a nonequilibrated BUN. We slow the blood pump to 100 mL/min for 15 seconds and then stop the pump before the blood sample for BUN is obtained. Slowing blood flow to 100 mL/min reduces the entry of cleared (ie, dialyzed) blood into the access and stops cardiopulmonary and hemodialysis access recirculation. This procedure is consistent with the 2006 National Kidney Foundation Dialysis Outcomes Quality Initiative (KDOQI) and the European and Canadian hemodialysis guidelines [5,13,14]. The Kt/V calculated from this sample is called the nonequilibrated or single-pool Kt/V.

The equilibrated, double-pool Kt/V is lower than the nonequilibrated, single-pool Kt/V since the urea concentration measured with the equilibrated sample is higher than that observed in the nonequilibrated sample. This difference is approximately 0.21 for the usual range of delivered doses of hemodialysis [15] and decreases with longer hemodialysis treatment times [10,11,15,16].

However, between individual patients, there may be variability in the required time for complete equilibration. As an example, some patients have diminished blood flow to specific tissue beds (ie, in the setting of low cardiac function or peripheral vascular disease, for example), which causes delayed equilibration. This variability is difficult to predict [17]. Incorrect sampling of postdialysis BUN is common and may cause erroneous conclusions concerning the correlation between patient outcomes and the presumed delivery of a specific amount of dialysis [18].

At the very least, it is important that, within facilities, the same procedure is consistently followed in order to ensure, as much as possible, reliable estimates of the Kt/V.

Limitations — Kt/V helped to improve dialysis efficiency and to standardize the dialysis procedure. Observational studies showed an inverse relationship between Kt/V and mortality [19,20]. However, despite its value as a practical guide to dialysis treatment, Kt/V suffers from important shortcomings as a sole indicator of the dialysis adequacy [10,21]. Limitations to the Kt/V include the following:

●Kt/V was developed in a younger dialysis population with fewer comorbidities compared with the contemporary dialysis population. In addition, Kt/V was developed in an era when dialysis utilized cellulosic dialyzers with a small surface area and pores. Dialysis is now more commonly performed with large-pore high-flux dialysis membranes, which remove more molecules with proven biological impact, and this may result in better outcomes [22].

●Kt/V is based on the kinetic patterns of one single solute, urea. Evidence of toxicity of urea is limited, and its impact on patients' outcomes has not been documented. Moreover, urea clearance determined by any method may not represent the kinetic behavior of other potentially toxic molecules (other small solutes, middle molecules, protein-bound solutes, phosphate, etc). As an example, the volume of distribution of urea is much smaller than similarly small-molecular-weight solutes such as the guanidine compounds, which have a well-documented toxic effect [23].

●Kt/V measures urea clearance in a single session, with the implicit assumption that the session is representative of all other sessions. Thus, the Kt/V does not account for missed treatments or shortened dialysis that may occur during other sessions.

●As noted above, errors in timing of postdialysis BUN determination may affect Kt/V determination because of variability in equilibration of urea in individual patients. (See 'Definition and calculation' above.)

●Kt/V tends to overestimate delivered dialysis among small-sized or malnourished patients. A high Kt/V may indicate either high Kt (clearance x time) or low V (volume). Low volume may reflect reduced skeletal muscle mass and malnutrition. Such patients may be under-dialyzed if their dialysis time is shortened because of high Kt/V [11,12].

●Kt/V cannot be used to compare treatments among patients when dialysis frequency is delivered more than three times weekly. For such patients, a modified method (called the standard Kt/V [stdKt/V]) is used to determine dialysis adequacy [24]. (See "Short daily hemodialysis", section on 'Measures of adequacy'.)

●Kt/V does not take into account contribution of residual kidney function to clearance of uremic toxins. A study of 32,251 patients on incident hemodialysis in a large United States dialysis organization found that the mortality risk associated with low single-pool Kt/V (ie, <1.2 versus >1.2) was linearly attenuated with greater residual kidney function [25].

●Kt/V does not take into account the intestinal generation of important uremic toxins such as indoxyl sulfate and p-cresyl sulfate given their limited clearance by hemodialysis [26].

In addition to the limitations listed above, other variables, such as the frequency of dialysis or treatment time, which are not factored into the Kt/V, may affect morbidity and mortality. Some studies have suggested that increasing the frequency of dialysis or treatment time, independent of Kt/V delivered, may result in significant clinical benefits. This issue is discussed below. (See 'Minimum dialysis frequency and time' below.)

The Kt/V also disregards a possible effect of total body water on patient outcomes independent of its effect on urea [11,12,16-18,27-30]. This issue is discussed below. (See 'Non-normalized dialysis dose (Kt) and the effect of volume as an independent variable' below.)

Kt/V does not also account for other patient-specific variables such as volume control, hemodynamic instability, clinical symptoms, and changes in biochemical parameters, which have been associated with patient outcome.

●(See "Patient survival and maintenance dialysis", section on 'Control of fluid balance and hypertension'.)

●(See "Patient survival and maintenance dialysis", section on 'Malnutrition'.)

●(See "Patient survival and maintenance dialysis", section on 'Disorders of mineral metabolism'.)

●(See "Patient survival and maintenance dialysis".)

●(See "Intradialytic hypotension in an otherwise stable patient", section on 'Outcomes'.)

As a result of these limitations, some investigators have questioned the value of Kt/V as the optimal method for assessing the adequacy of hemodialysis [23].

Non-normalized dialysis dose (Kt) and the effect of volume as an independent variable — As previously mentioned, the correction of total urea removal (Kt) for the volume of distribution (V) to result in the Kt/V is considered important because a given degree of urea loss represents a lower rate of removal of the total body burden of urea in a larger patient as compared with a smaller individual. However, this formula is a mathematical construct that assumes that V does not alter patient outcome independent of its effect upon the clearance of urea.

This is an important issue since some studies suggest that volume itself may affect outcome, independent of urea [11,12,16-18,27-30]:

●There is an increased relative risk of death among patients with extremely high values for Kt/V (>1.6), which could reflect high Kt (ie, dialysis) or low V [11,16,29]. In one study that included over 3000 patients on dialysis, patients with a very high Kt/V, but not those with high Kt, had an increased relative risk of death [11]. This observation was confirmed in a second study of over 37,000 patients on dialysis [29]. The increased mortality associated with very high Kt/V may reflect poor nutrition. In the first study, patients in the highest Kt/V quintile suffered from more severe protein-calorie malnutrition, but a higher Kt correlated with better nutritional status [11].

●A mathematical analysis of data relating to body size, dialysis dose, and mortality among over 40,000 patients found that improved survival was associated with both Kt and with increased body size [12].

●In a study that used direct online technology, increasing values for small molecular clearance, Kt, and body size were all associated with decreased mortality [30].

●One study reported that 25.8 percent of patients did not reach the minimum Kt while achieving target Kt/V [31]. The same group reported that prescribing an additional 3 liters or more above the minimum Kt dose adjusted for body surface area could potentially reduce mortality risk [32].

Some have suggested that Kt may provide a better measure of dialysis dose, but further studies are required to confirm this observation [11,33].

ALTERNATIVES TO Kt/V

Urea reduction ratio — The urea reduction ratio (URR) is closely related to Kt/V. The URR is the fractional reduction of urea (blood urea nitrogen [BUN]) during a single dialysis. It is simple to calculate (equation 2 below) but less accurate than Kt/V since it assumes that urea volume of distribution remains constant during dialysis (ie, no ultrafiltration).

Thus, the URR is 0.6 if the postdialysis BUN is 40 percent that of the predialysis value. Other investigators have used the percent reduction in urea (PRU), which involves the same calculation as the URR except that the result is multiplied by 100 to be expressed as a percentage.

Several different equations have been proposed to estimate the Kt/V from the PRU [34,35].

Because of its ease of calculation, the URR and Kt/V estimated from the URR are frequently used in epidemiologic studies [36-38].

However, although the URR is useful as an epidemiologic tool, its efficacy in individual patients is more limited because of a relatively broad range of Kt/V that may be seen at a given URR. One study found that a median URR of 0.62 was associated with a median Kt/V of 1.12 [37]. However, Kt/V values <1.0 (indicating under-dialysis) and >1.30 (indicating adequate dialysis) were each seen in 10 percent of cases with this URR.

This variability is due in part to urea removal with ultrafiltration, which is not considered in the URR. A large ultrafiltration requirement alone can raise the Kt/V by 0.2 [37]. Formulas have been published that attempt to correct for this and other effects [39]. These and other similarly derived equations correlate reasonably well with the more rigorously calculated Kt/V when the Kt/V and PCR are in the normal or expected range [6]. They are most accurate when the Kt/V is between 0.7 and 1.3 (URR of approximately 40 to 65 percent), the dialysis time is three to five hours, and total body water is 50 to 60 percent of body weight.

Many of the limitations of the Kt/V apply to the URR, including the following:

●Urea clearance determined by any method may not represent the behavior of other potentially toxic molecules.

●URR reflects clearance during a single session and does not account for missed treatments or shortened dialysis that may occur during other sessions.

●Errors in timing of postdialysis BUN determination affect URR value.

●URR cannot be used to compare treatments among patients when dialysis frequency is delivered more than three times weekly.

●The effect of URR on survival is mitigated by the effect of serum albumin, a major marker of inflammation and protein energy wasting [27].

Solute removal index — The solute removal index (SRI) is a measure of the total amount of urea removed during dialysis and is determined by multiplying the urea concentration in the dialysate by the volume of spent dialysate [40]. Since the SRI does not rely upon changes in the BUN, it is unaffected by the timing of the postdialysis blood sample.

Limitations of the SRI include the following [41,42]:

●Few studies have correlated patient outcomes with the SRI.

●It is impractical to collect the total spent dialysate.

●The calculated hemodialysis dose obtained using SRIs is relatively inaccurate compared with that calculated from equilibrated BUN [42].

THE OPTIMAL AMOUNT OF DIALYSIS

Target Kt/V — Kt/V remains the preferred method for measurement of the dialysis dose by clinical practice guidelines [5,43]. These guidelines recommend a target single-pool Kt/V of 1.2 to 1.4 per session [5,44].

The following recommendations are from the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, which recommend a target single-pool Kt/V of 1.4 per hemodialysis session for patients treated three times weekly, with a minimum delivered single-pool Kt/V of 1.2 [5,43]:

●Minimally adequate dose should be a single-pool Kt/V of 1.2

●Target recommended dose should be a single-pool Kt/V of 1.4

The Centers for Medicare and Medicaid Services (CMS) conditions for coverage for end-stage kidney disease (ESKD) facilities state that dialysis facilities must achieve and sustain the prescribed dose of dialysis to meet a hemodialysis Kt/V of at least 1.2. In our dialysis program, we target a single-pool Kt/V of approximately 1.4 in order to ensure that a minimum Kt/V ≥1.2 is achieved.

Studies have shown that the delivered amount of dialysis is often less than the prescribed amount [45-47]. Thus, a Kt/V of 1.4 is targeted in order to ensure that the minimum Kt/V of 1.2 is achieved [14,48,49]. There are no randomized studies to support the minimum dialysis dose of Kt/V ≥1.2. However, analysis of retrospective studies has suggested that a Kt/V ≥1.2 is associated with better survival [19,50,51]. As an example, a retrospective analysis of data from several studies showed that an equilibrated Kt/V ≥1.05 was associated with improved mortality [51]. An equilibrated Kt/V of 1.05 is approximately equivalent to a nonequilibrated (or single-pool) Kt/V of 1.2 [52,53]. (See 'Kt/V' above.)

Targeting a Kt/V greater than 1.4 does not appear to improve survival or reduce hospitalization rates. This was shown in the Hemodialysis (HEMO) study [54]. Patients were randomly assigned to a standard dose (equilibrated Kt/V of 1.05, which is equivalent to a single-pool Kt/V of approximately 1.2) or high dose (equilibrated Kt/V of 1.45, which is equivalent to a single-pool Kt/V of 1.65) and a low- or high-flux dialyzer (based on clearance of beta-2 microglobulin) [54]. Achieved nonequilibrated, single-pool Kt/V in the standard- and high-dose groups were 1.32 and 1.71, respectively. At a mean follow-up time of 2.8 years, the risk of death from any cause was the same in the high- and standard-dose groups (relative risk [RR] of 0.96) (figure 4) and in the high- and low-flux groups (RR of 0.92) (figure 5). The rate of all hospitalizations (excluding those related to access) was also the same for both dialysis doses and both flux groups. These results were confirmed by The Membrane Permeability Outcome (MPO) trial [4] and the EGE trial [55].

Each of these three trials also showed benefits of high-flux dialyzers on all-cause mortality for certain prespecified conditions (serum albumin ≤4 g/dL, undergoing maintenance hemodialysis for ≥3.7 years) or post-hoc subgroups (patients with diabetes mellitus or arteriovenous fistulas). High-flux membranes provide higher clearance of larger solutes, removal of which might improve cardiovascular outcomes. Indeed, a meta-analysis of the above three trials showed that the use of high-flux dialyzers was associated with a decrease in cardiovascular mortality compared with low-flux membranes (hazard ratio [HR] 0.82, 95% CI 0.70-0.96) [56]. Based on these findings, the KDOQI Adequacy Work group recommends that high-flux dialyzers should be used provided proper water treatment is available [5].

Concerns that have been raised regarding the HEMO study include the relative exclusion of larger-sized patients, disproportionate representation of African Americans, and enrollment of prevalent patients [57]. However, these concerns are largely unfounded [48]. As an example, given that larger-sized patients have a lower mortality, the relatively increased number of smaller-size patients increased the power of the HEMO study. In addition, the finding of a high degree of correlation between mortality and dialysis dose in the as-treated analysis is unlikely to represent an effect of dose on mortality but rather a bias underlying the effect of mortality on the achieved Kt/V [58].

A potential explanation for the lack of impact of increasing Kt/V on patients' outcomes was provided by a post-hoc analysis of the data and samples from the HEMO study [59]. This analysis found no clear relationship between Kt/V and serum concentrations of the small solutes studied such as p-cresyl sulfate, indoxyl sulfate, hippurate, and methylguanidine. Relatively large increases in Kt/V failed to greatly reduce the levels of these uremic solutes. Increasing Kt/V by approximately 30 percent reduced predialysis serum concentrations of these solutes by <10 percent and even smaller for other small solutes, indicating that Kt/V is not a good metric for the effects of changes in dialysis prescriptions on serum concentrations of individual solutes [59]. However, one study suggested that urea itself may be toxic, lending some support for the continued usefulness of Kt/V urea [60].

Minimum dialysis frequency and time — At our institution, we routinely prescribe dialysis treatment times of at least four hours per session for a minimum of three sessions per week for our patients, irrespective of their Kt/V. The 2015 National Kidney Foundation's KDOQI clinical practice guideline recommends that patients with little or no residual kidney function (ie, <2 mL/min) who are undergoing three-times-weekly dialysis undergo a minimum dialysis time of three hours per session [43]. However, we believe that longer dialysis sessions are better tolerated, since shorter sessions more commonly precipitate muscle cramps, fatigue, and intradialytic hypotension as more fluid is removed in a shorter period of time.

Increasing time on hemodialysis can be attained by increasing session length, increasing frequency, or both. Data from randomized trials and observational studies, testing different strategies of increasing dialysis time (longer session or higher frequency), suggest that more time on hemodialysis may improve outcomes:

●In a trial conducted by the Frequent Hemodialysis Network (FHN), patients were randomly assigned to receive in-center hemodialysis six times per week (frequent) or three times per week (conventional) for one year [61,62]. The group assigned more frequent hemodialysis received approximately two additional hours per week compared with the conventional group. At 3.6 years, frequent hemodialysis reduced mortality (16 versus 28 percent). Other benefits of more frequent hemodialysis included better control of hypertension and serum phosphate, reduced increase in left ventricular mass, and improved quality of life.

●Several observational studies of patients with adequate clearances (ie, Kt/V) have reported lower mortality rate in patients who had dialysis session lengths greater than four hours compared with those with less than four hours per session [63-66]. One study, for example, compared mortality rates among 39,172 patients in 852 facilities who initiated treatment for ≥4 hours and 47,721 patients in 631 facilities who initiated treatment for three hours [66]. Mortality within two years was significantly lower among patients treated in facilities that prescribed ≥4 hours of hemodialysis compared with those treated in facilities that prescribed three hours of hemodialysis (adjusted HR 0.79, 95% CI 0.73-0.86). In another study, patients dialyzed for more than four hours per session had lower pre- and postdialysis systolic blood pressure, greater intradialytic weight loss, higher hemoglobin and serum albumin, and lower serum phosphorus and white blood cell counts, all of which may have contributed to better survival [64].

●Another observational study compared all-cause mortality of 1206 patients who received nocturnal, in-center, extended-hours hemodialysis for at least 60 days with 111,707 patients who received conventional hemodialysis [67]. The average treatment times in the extended-hours hemodialysis sessions were 6.7 hours compared with 3.5 hours for conventional hemodialysis sessions, both administered three times weekly. Patients were followed for up to five years. In the primary analysis, patients treated with extended-hours hemodialysis had a 33 percent lower adjusted risk of death compared with those who were treated with conventional hemodialysis (95% CI 7-51 percent) [67].

●By contrast, another trial found that long-term mortality was higher in patients assigned to frequent, nocturnal hemodialysis performed at home, despite improvements in blood pressure and serum phosphate [68,69]. This was thought to result from an unexpectedly low mortality rate in patients receiving conventional hemodialysis (2 percent at one year), the loss of residual kidney function, and the high rates of dialysis modality switches in this study [69].

In practice, most patients resist spending more time receiving hemodialysis. This was demonstrated in the Time to Reduce Mortality in End-Stage Renal Disease (TiME) trial, a pragmatic, cluster-randomized trial, which sought to study the impact of longer dialysis sessions on mortality and rate of hospitalization among patients on incident hemodialysis [70]. Dialysis facilities randomly assigned to the intervention group were asked to prescribe their patients a session duration of ≥255 minutes; control facilities were given no advice about session length. If the treating nephrologist felt that the ≥255 minutes duration was not appropriate for an individual patient, then shorter treatments could be prescribed. The trial was terminated early at a median follow-up of 1.1 years due to an inadequate difference in the delivered dialysis time between the intervention (216, 95% CI 214-219 minutes) and the control group (207, 95% CI 206-211 minutes). Due to this lack of difference in dialysis time, there was no difference demonstrated in mortality or hospitalization rates between the two groups. Major reasons identified for poor adoption of longer session length were unwillingness by patients to have longer dialysis treatments, perception by the treating nephrologists that longer sessions were unnecessary due to adequate solute clearance, and perception by the nephrologists that longer session durations were not in the best interest of the patient due to older age or frailty.

Patient-specific parameters — The dialysis prescription is modified further for individual patients in order to provide optimal fluid, electrolyte, and acid-base balance; to maintain hemodynamic stability during dialysis; and to address disorders of mineral metabolism.

●Fluid status – We agree with the consensus opinion reported from the 2013 symposium of chief medical officers of dialysis providers in the United States that the normalization of the extracellular fluid volume should be a primary goal of dialysis [71]. However, some patients have large interdialytic fluid gains in between dialysis sessions. This leads to high fluid removal rates during dialysis that may result in poor outcomes, possibly mediated by intradialytic hemodynamic instability and/or myocardial stunning [72,73]. Evidence suggesting that more rapid ultrafiltration may be harmful includes the following:

•A retrospective analysis of over 15,000 patients from seven countries participating in DOPPS showed that an ultrafiltration rate >10 mL/hour/kg was associated with significantly increased risk of intradialytic hypotension and all-cause mortality [65].

•In a prospective study of nearly 300 patients on dialysis, each 1 mL/hour/kg increase in the ultrafiltration rate was associated with a 22 percent increase in mortality risk [74].

•An observational study including approximately 118,000 patients on hemodialysis reported incrementally greater harm and mortality associated with greater ultrafiltration rates, even at rates <10 mL/hour/kg [72].

To address concerns about higher ultrafiltration rates, the Centers for Medicaid and Medicare Services adopted a quality measure ultrafiltration rate threshold of 13 mL/hour/kg. However, as the studies above suggest, ultrafiltration rate–associated harm may occur at levels less than 13 mL/hour/kg. Moreover, observational data suggest that ultrafiltration rate thresholds scaled to weight may lead to worse outcomes in patients with higher body weight [75,76].

Therefore, for patients with large interdialytic weight gains, the dialysis time per session should be increased or more frequent dialysis should be considered to allow a lower ultrafiltration rate. This is consistent with the 2015 KDOQI guidelines [43].

Large interdialytic weight gain may also be mitigated by continuation of diuretics in those with residual kidney function and residual urine output [77]. We generally continue loop diuretics in patients on incident hemodialysis. We discontinue diuretics when the urine output becomes negligible.

●Electrolytes, acid-base balance, and bone mineral metabolism – Electrolytes, acid-base balance, and bone mineral metabolism are regularly assessed for individual patients. The individual dialysis prescription may be revised depending upon this assessment. Persistent hyponatremia suggests volume overload, which may be addressed by adjusting the ultrafiltration as described above. Persistent hyperkalemia usually reflects dietary noncompliance but may occasionally require adding an additional dialysis session per week or prescribing potassium binders on nondialysis days. However, persistent hyperkalemia may also reflect inadequate dialysis due to access recirculation, which will be reflected in the Kt/V. (See 'Causes of inadequate dialysis' below.)

●Rehabilitation and quality of life – Important clinical outcomes that are less easily quantified, but may nevertheless reflect the adequacy of dialysis, are generally monitored for individual patients, including rehabilitation and quality of life. Within individual dialysis units, trends of morbidity and mortality rates over time should be examined as they reflect the impact of the overall quality of dialysis care on hard clinical outcomes.

The American Society of Nephrology Dialysis Advisory Group has proposed a multidimensional construct for the quantification and characterization of optimal dialysis delivery [78]. Although clearance of small and middle molecules characterizes dialysis delivery, sole reliance on small solute clearances as a measure of dialysis adequacy fails to fully capture the intended clinical effects of dialysis therapy. Thus, the group suggested that clinical physiologic parameters such as blood pressure, heart rate, cardiac geometry and function, and nutrition may be used as measures to quantify the results of dialysis therapy.

MONITORING — An assessment of the dialysis regimen in stable patients on hemodialysis is performed once per month by most clinicians. The assessment should include a review of the Kt/V, ultrafiltration requirement per session, hemodynamic stability during dialysis sessions, blood pressure control, a review of intradialytic or interdialytic symptoms, and laboratory monitoring for anemia, metabolic bone disease, and electrolyte disturbances.

However, there is a paucity of evidence to support such assessments at monthly intervals. As an example, in one study of patients on chronic hemodialysis in Canada, there was no difference in all-cause mortality, hospitalizations, cardiovascular events, or frequency of hyperkalemia between patients who underwent laboratory measurements at six-week rather than monthly intervals [79].

CAUSES OF INADEQUATE DIALYSIS

Low Kt/V — Various factors contribute to inadequate dialysis, as measured by Kt/V. These include low blood flows, short dialysis time, and access recirculation. Causes of low Kt/V were assessed in a study of 146 stable patients on dialysis in whom measurements of Kt/V and access recirculation were obtained every month for three successive months [45]. The following results were reported:

●Approximately 40 percent of low Kt/V values were due to a lower than prescribed blood flow or time of dialysis, which resulted largely from inadequate needle placement and patient-initiated time constraints, respectively.

●Twenty-five percent of abnormal values resulted from significant access recirculation.

●A cause was not uncovered in the remaining patients; however, subsequent Kt/V values rapidly returned to baseline values without any intervention.

Increased body mass, impaired sodium removal, poor dialysate flow rate, blood tubing effects, and needle gauge size may also be unrecognized causes of inadequate hemodialysis [46,80-85]. Dialysis using a central venous catheter is also associated with decreased dialysis delivery [86]. (See "Central venous catheters for acute and chronic hemodialysis access and their management".)

Patients who have a Kt/V that is below target should be carefully assessed. The initial assessment should include the following [87]:

●Fistula integrity – Access problems are common causes of inadequate dialysis. (See "Arteriovenous fistula recirculation in hemodialysis".)

●Treatment duration – The dialysis time may end up being less than prescribed. Causes include a late-arriving patient, the late initiation of dialysis by staff, early termination because of patient request, and events during the treatment that cause the temporary cessation of dialysis (such as hypotension, a blood leak, needle difficulties, excessive triggering of machine alarms related to high venous pressures).

●Method of obtaining blood urea nitrogen (BUN) samples – Technical errors resulting in an incorrectly low predialysis BUN or a high postdialysis BUN may cause a decreased Kt/V.

●Dialysis machine and patient-specific variables – Inadequate machine calibration, low blood flow rates, and overestimation of dialyzer clearance all may result in low Kt/V.

A secondary assessment should be performed if the initial analysis does not lead to the quick identification of the cause or correction of a low Kt/V. This may involve the incorporation of measures to improve effective hemodialysis treatment times, correct errors in blood sampling, or improve dialyzer clearance. Attempts to improve clearance may include an assessment of extracorporeal pressures, measures to decrease dialyzer clotting and fistula recirculation, and calibration of blood and dialysis flows. The use of two dialyzers in series or parallel may be another method to improve clearance in very large patients [88-90].

Occasionally, the primary problem may be a reduction in dialysis efficiency because of significant cardiopulmonary recirculation (which allows the entry of dialyzed blood to blood delivered to the dialyzer) or to delayed transfer of urea out of the cells (ie, prolonged equilibration). In such patients, the urea clearance of the blood delivered to the dialyzer is already at near maximal levels. As a result, increasing dialyzer size, blood flow, or dialysate flow will produce only a marginal improvement. The only way to compensate for the reduced efficiency of urea removal is to increase the time on dialysis. (See 'Definition and calculation' above.)

Inadequate fluid removal — We agree with the consensus opinion of chief medical officers of dialysis providers in the United States that barriers to sufficient fluid removal may include the following [71]:

●Absence of widely available validated tools for dry weight assessment

●Requirement for longer treatment times

●Intradialytic hypotension and/or cramping associated with aggressive ultrafiltration

●Inconsistent reimbursement for additional treatments per week

●Patient reluctance to increase treatment time or frequency and to reduce sodium intake

●Clinician-related factors including the limited assessment of fluid status and provision of dietary counseling and delays in adjusting the dialysis prescription

Any evidence of fluid overload, including a blood pressure >150/90 mmHg prior to dialysis, should prompt a decrease in the target weight. The reduction in target weight should be gradual. Poorly controlled blood pressure is often evidence of inadequate ultrafiltration and may necessitate extending the time on dialysis or more frequent ultrafiltration (see 'Patient-specific parameters' above). For all patients, dietary counseling should be provided regarding sodium restriction [43].

OPTIONS FOR INCREASING REMOVAL OF UREMIC TOXINS — Options to increase the removal of uremic toxins include the following [91]:

●Increasing blood flow or dialysate flow rate

●Increasing dialyzer surface area

●Increasing dialysis time (by extending the time per session, increasing the number of sessions per week, or both)

In addition, residual kidney function contributes to the removal of toxins [92]. Efforts should be made to preserve residual kidney function. (See "Residual kidney function in kidney failure".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dialysis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Dialysis or kidney transplantation — which is right for me? (Beyond the Basics)" and "Patient education: Hemodialysis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Significance of dialysis adequacy – The amount of dialysis that a patient receives affects morbidity and mortality. Two central issues in the management of patients undergoing maintenance hemodialysis include determining the optimal amount of dialysis that should be prescribed and assessing the amount of delivered dialysis for individual patients. (See 'Introduction' above.)

●Kt/V – The preferred method of measuring delivered dialysis is the equilibrated or single-pool Kt/V, which is defined as the dialyzer clearance of urea (K, obtained from the manufacturer in mL/min and periodically measured and verified by the dialysis team), multiplied by the duration of the dialysis treatment (t, in minutes), divided by the volume of distribution of urea in the body (V, in mL), which is approximately equal to the total body water. (See 'Kt/V' above.)

●Limitations of Kt/V – The Kt/V has many limitations. In addition to technical difficulties related to timing of measurement of urea, limitations include an overestimate of delivered dialysis among patients who are small sized or malnourished; the assumption that urea clearance reflects other small solutes' clearances, which may not be correct; and the assumption that the Kt/V measured in a single session reflects delivered dialysis in all other sessions for individual patients. In addition, the Kt/V does not account for a possible independent effect of dialysis-session length or total body water on patient outcomes, nor does it factor in other patient-related variables such as volume control, hemodynamic instability, clinical symptoms, and changes in biochemical parameters, which have been associated with patient outcome. (See 'Limitations' above.)

●Target Kt/V – There is no universally accepted target value for the Kt/V. We use Kt/V as a marker of minimal dialysis adequacy. We suggest a minimum Kt/V ≥1.2, rather than lower values (Grade 2C). Some studies suggest that Kt/V ≥1.2 is associated with decreased mortality (see 'The optimal amount of dialysis' above). In order to achieve the suggested minimum Kt/V, we target a single-pool Kt/V of 1.4, which is consistent with the 2006 Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines. (See 'Target Kt/V' above.)

●Minimum dialysis time – Even if the minimum Kt/V is achieved with shorter times, we suggest a minimum dialysis session time of at least four hours, rather than a shorter time (Grade 2C). Dialysis session times less than four hours have been associated with increased mortality and morbidity. (See 'Minimum dialysis frequency and time' above.)

●Patient-specific parameters – The dialysis prescription may be modified for individual patients in order to provide optimal fluid, electrolyte, and acid-base balance; to maintain hemodynamic stability during dialysis; and to address disorders of mineral metabolism. Clinical outcomes should be monitored, including rehabilitation and quality of life. Trends of morbidity and mortality rates in individual dialysis facilities should be followed over time. (See 'Patient-specific parameters' above.)

●Monitoring dialysis adequacy – An assessment of the dialysis dose in stable patients on hemodialysis is performed once per month by most clinicians. Patients who have a Kt/V that is below target should be carefully assessed for fistula integrity and adequate treatment duration as prescribed. (See 'Monitoring' above and 'Causes of inadequate dialysis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Robert E Cronin, MD, and William L Henrich, MD, MACP, who contributed to earlier versions of this topic review.