Incorporating residual kidney function into the dosing of intermittent hemodialysis

INTRODUCTION — Most patients with end-stage kidney disease have some level of native kidney function remaining when they initiate hemodialysis. For selected patients who have significant residual kidney function, some expert clinicians advocate that, under certain circumstances, the hemodialysis dose can be adjusted for the clearance provided by native kidney function. In such patients, the target clearance (ie, Kt/V) is the sum of clearances provided by hemodialysis and native kidney function [1-3]. As a result, the hemodialysis dose is lower than that which is typically prescribed. This method of prescribing a lower hemodialysis dose depending on the clearance provided by residual kidney function is called incremental hemodialysis [4].

The amount of prescribed hemodialysis can be decreased by reducing the hemodialysis time (for example, by time per session or by number of sessions) or by altering operating conditions such as dialyzer size and type, dialysate flow rate, or blood flow rate. The dose of hemodialysis must then be increased over time as residual kidney function declines in order to meet established dosing targets.

This topic review provides detailed information on providing incremental hemodialysis, including methods of estimating the hemodialysis dose based upon residual kidney function clearance.

Calculation of the standard hemodialysis dose is discussed elsewhere. (See "Prescribing and assessing adequate hemodialysis".)

BACKGROUND — Adjustment of the hemodialysis dose by including residual kidney function is not new. Historically, clinicians have always incorporated residual kidney function into the peritoneal dialysis prescription [5].

However, the practice has not been widely used for hemodialysis dosing, since the intermittent nature of hemodialysis makes incorporation of residual kidney function difficult [6]. Historically, it was considered impractical to adjust the hemodialysis dose for residual kidney function, as it was believed that residual kidney function declined rapidly with hemodialysis as compared with peritoneal dialysis [7]. However, subsequent studies, using contemporary hemodialysis techniques such as ultrapure water, volumetric control, and synthetic membranes, suggest that loss of kidney function is similar between hemodialysis and peritoneal dialysis [8]. (See "Residual kidney function in kidney failure".)

Furthermore, many patients on hemodialysis started on incremental hemodialysis are subsequently averse to increasing dialysis time. To convince these patients to increase time or frequency requires significant persuasion skills and effort [9], and, for many nephrologists, this is a reason to not offer incremental hemodialysis in the first place. As a consequence, many clinicians initiate dialysis at full dose duration and frequency simply to avoid future confrontations regarding dialysis dose intensity.

As a result, while there are extensive practical experience and outcomes data regarding incremental dosing of peritoneal dialysis, there are little experience and little published data on incremental dosing of hemodialysis. Many clinical trials that have examined peritoneal dialysis dosing incorporated residual kidney function [10,11]. In contrast, major clinical trials of hemodialysis dosing, such as the Hemodialysis (HEMO) Study, did not incorporate residual kidney function into hemodialysis dosing [12].

Several studies have examined the effect of incremental hemodialysis on patient outcomes, with varying results [13-20]. In a three-year prospective observational study that compared patients with residual kidney function undergoing twice-weekly hemodialysis to patients with lower residual kidney function on thrice-weekly hemodialysis, those undergoing twice-weekly dialysis had an increased risk of mortality [15]. Significantly more patients in the twice-weekly hemodialysis group used vascular catheters, although the increased mortality risk persisted after adjustment for catheter use.

However, several other studies reported that patients with residual kidney function starting dialysis on a twice-weekly basis have similar survival to patients starting thrice-weekly dialysis [16,17,21]. It is important to note that these studies did not compare twice-weekly hemodialysis patients with residual kidney function and thrice-weekly hemodialysis patients with residual kidney function, as did the study cited above [15].

A meta-analysis of 22 observational studies including 75,292 participants suggested that incremental hemodialysis does not decrease survival and postpones the time to full-dose dialysis by 12.1 months (95% CI 9.8-14.3) [18]. Another meta-analysis included 24 observational studies plus two small feasibility trials and totaled 101,476 participants [20,22,23]. The observational data suggested no mortality or hospitalization rate differences, but the feasibility trials suggested lower hospitalization rates. Observational but not trial data suggested a reduced loss of residual kidney function.

We believe clinicians should discuss the results of these studies with their patients. We generally start thrice-weekly hemodialysis in patients with more comorbid conditions and poorer nutritional status.

The major potential benefit of twice-weekly dialysis versus thrice-weekly dialysis is one of quality of life for patients. The improved quality of life is commented on by almost all patients receiving twice-weekly dialysis and is highly appreciated. However, a feasibility trial did not demonstrate an improved quality of life with incremental hemodialysis [23]. Another potential benefit to incorporating residual kidney function into dialysis dose is better preservation of residual kidney function [2,14,24-28].

As examples:

●In a large, retrospective, cohort study, patients undergoing twice-weekly hemodialysis had a slower rate of kidney function decline compared with a matched cohort with comparable baseline residual kidney function [14].

●A study from Spain compared the change in residual kidney function between 61 patients on twice-weekly hemodialysis, 83 patients on peritoneal dialysis, and 49 patients on thrice-weekly hemodialysis [7]. Patients in each group had similar baseline estimated glomerular filtration rate (eGFR). Patients who had twice-weekly hemodialysis or were on peritoneal dialysis had a smaller median loss of eGFR compared with those who were hemodialyzed thrice weekly (-0.18 mL/min/month versus -0.33 mL/min/month, respectively).

The maintenance of residual kidney function is associated with improved survival and quality of life for patients. (See "Residual kidney function in kidney failure", section on 'Clinical importance of residual kidney function'.)

Because of the lack of clinical experience and clinical trials examining outcomes, the Kidney Disease Outcomes Quality Initiative (KDOQI) 2015 guidelines provide an ungraded recommendation that the dose of hemodialysis may be reduced in patients with significant residual native kidney function (Kr), provided Kr is measured periodically [29]. The KDOQI guidelines recommended that, for hemodialysis schedules other than thrice weekly, there should be a target standard Kt/V of 2.3 per week, with a minimum delivered weekly Kt/V dose of 2.1 using a method of calculation that includes the contributions of ultrafiltration and residual kidney function. This guideline is based on expert opinion only and places an equal value on residual kidney function and dose delivered by hemodialysis.

WHICH PATIENTS MAY BE CANDIDATES FOR INCREMENTAL HEMODIALYSIS? — We do not believe that there are sufficient data to recommend the use of incremental hemodialysis in all incident patients. As noted above, there are no high quality data demonstrating that starting hemodialysis with less than a full dose results in comparable survival to patients who have the same level of residual kidney function (calculator 1) and start dialysis with a full hemodialysis dose.

The decision whether to incorporate residual kidney function into the dialysis dose is best made between the patient and nephrologist, acknowledging that there are limited data to inform this decision [4].

For all patients on hemodialysis, many factors in addition to the Kt/V are considered in assessing hemodialysis adequacy. In all patients on hemodialysis, especially those patients receiving incremental hemodialysis, the dialysis prescription must be further modified in order to provide optimal fluid, electrolyte, and acid-base balance; to maintain hemodynamic stability during hemodialysis; and to address disorders of mineral metabolism. (See "Prescribing and assessing adequate hemodialysis".)

These factors must be considered in assessing candidates for incremental hemodialysis.

Candidates for incremental hemodialysis should meet the following criteria [1,9]:

●As a general rule, urine output at the initiation of hemodialysis must be sufficient (with or without diuretics) to keep interdialytic weight (fluid) gain to <2 kg. Ultrafiltration at hemodialysis to remove that volume should be well tolerated.

●Serum potassium and phosphorus should be well controlled with diet and phosphate binders before starting hemodialysis.

●Patients should not have a history of clinically significant heart failure or history of requiring ultrafiltration to maintain euvolemia.

●Patients should have good nutritional status based on numerous parameters. (See "Assessment of nutritional status in patients on hemodialysis", section on 'Our approach to the clinical assessment of nutritional status'.)

POTENTIAL RISKS — There are potential risks to incremental hemodialysis. These include:

●Under-dialysis due to unrecognized loss of kidney function – Patients who have residual kidney function incorporated into their hemodialysis dose require close monitoring of native kidney function.

●Reluctance among patients to increase to thrice-weekly hemodialysis or increase treatment duration – Patients must be made aware early on (before even embarking upon incremental hemodialysis) that they will have to increase the frequency of hemodialysis sessions or the duration of individual sessions within weeks to months after starting hemodialysis. There is only anecdotal information available on how difficult it is to have patients make this transition.

●Possible increased risk of heart failure, decline in nutritional status, hypertension, hyperphosphatemia, acidemia, and hyperkalemia – Patients need to be carefully selected and followed closely for the development of these conditions.

●Possible increased risk of mortality based on one multicenter observational study [15]. (See 'Background' above.)

POTENTIAL BENEFITS — There may be benefits associated with incremental hemodialysis. Putative benefits include:

●Decreased length or frequency of hemodialysis sessions – Length and frequency of hemodialysis are common patient complaints. If it can be done safely, decreasing the length or frequency of sessions will substantially improve quality of life.

●Fewer hemodialysis access complications – Less frequent access to fistulas, grafts, and catheters may decrease access complications. While there are no published data to suggest that access complications are less frequent with incremental hemodialysis, more frequent hemodialysis has been associated with increased access complications. (See "Short daily hemodialysis", section on 'Vascular access'.)

●Better preservation of residual kidney function – Limited data suggest that less frequent hemodialysis may preserve residual kidney function [2,4,24-28]. (See 'Background' above.)

●Discontinuation of dialysis – There is another surprising benefit of prescribing incremental dialysis: It is not uncommon to find that patients may have regained kidney function to the point of being able to stop dialysis. Monthly monitoring of urea clearance can help identify patients who were thought to require dialysis but may not. Based on results from the Initiating Dialysis Early and Late (IDEAL) study, hemodialysis does not provide a survival benefit for patients with an estimated glomerular filtration rate (eGFR) >10 mL/min/1.73 m². For these patients, nephrologists should ascertain if the patient has uremic symptoms that improved with dialysis and whether to continue with dialysis [30]. (See "Indications for initiation of dialysis in chronic kidney disease".)

INFLUENCE ON QUALITY MEASURES — In the United States, quality measures must be met in order to be compensated by Medicare for providing hemodialysis (including the target Kt/V for patients undergoing thrice-weekly hemodialysis). The presence of residual kidney function is not recognized in quality measures reporting for patients on hemodialysis. Thus, if one takes into account residual kidney function by lowering the Kt/V obtained with a thrice-weekly dialysis schedule, the center could potentially be penalized for not meeting quality measures. However, if one instead decreases the number of sessions to two treatments per week, it will not affect quality measures, because Kt/V on twice-weekly hemodialysis is not reported as a quality measure. Indeed, most patients are more interested in decreasing the number of treatments rather than the duration.

THE PRESCRIPTION OF INCREMENTAL HEMODIALYSIS — There is no standard method for calculating the incremental hemodialysis dose, and no method has been linked to improved patient outcomes. The calculation is theoretical and requires an understanding of the rates at which urea (as a marker of solute) is cleared by the kidney and by intermittent hemodialysis [6]. Intermittent hemodialysis results in a marked decline in blood urea nitrogen (BUN) over the duration of the treatment, followed by a steady postdialysis increase in BUN. In contrast, residual kidney function provides continuous urea removal. Thus, one must combine the intermittent hemodialysis dose with the continuous urea removal from residual kidney function. In 1998, theoretical calculations were published that allow one to combine clearances from residual kidney function and hemodialysis [31].

There are four reported methods to incorporate residual kidney function into the dialysis dose. Method 1 is the simplest but is extremely conservative and will result in almost all patients requiring thrice-weekly dialysis. Method 2 is used by the authors and requires some easy calculations to perform. Methods 3 and 4 are more complex and involve computer programs in which data must be entered. There is no empirical evidence that any one of these methods is superior to the alternatives in terms of outcomes.

●Method 1 – Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines suggest that, if residual kidney function (calculator 1) is >2 mL/min/1.73 m², one could consider twice-weekly hemodialysis with a Kt/V goal of 2 or a goal of 0.9 for thrice-weekly hemodialysis [29]. This is an extremely cautious inclusion of estimated glomerular filtration rate (eGFR) into the overall hemodialysis prescription and practically excludes twice-weekly hemodialysis in the vast majority of patients.

●Method 2 – In this method, residual Kt/V is calculated and plotted on a graph that takes into account residual kidney function and Kt/V for one, two, or three hemodialysis sessions per week.

•Residual kidney function (calculator 1) is first measured as the urea clearance. Using urea clearance to measure kidney function conforms to the standard practice of using the BUN concentrations and urea removal rates to measure peritoneal dialysis and hemodialysis dose. Urea clearance generally underestimates the true glomerular filtration rate (GFR) and thus provides an appropriately conservative estimate of the contribution of residual kidney function.

There are several methods to measure urea clearance [32]. One method is to obtain a postdialysis BUN measurement and predialysis BUN measurement of two consecutive hemodialysis treatments and measure a 24-hour urine volume and urine urea concentration during the interdialytic interval. Urea clearance is calculated using the mean of the postdialysis and predialysis BUN as the plasma urea concentration, the urine volume, and urine urea concentration:

Urea clearance (in mL/min) = [[Urine urea (mg/dL) x urine volume (mL/24 hours)] x 24 hours/1440 minutes]/plasma urea (mg/dL)

An alternative method to measure urea clearance in hemodialysis patients is to obtain a 24-hour urine collection at the end of the weekend hemodialysis interval and use a BUN that is obtained at the start of the next hemodialysis treatment. However, this method tends to underestimate the actual clearance since the post-weekend BUN is likely the highest of the week and is in the denominator of the equation.

Of note, creatinine clearance is greater than urea clearance, and the average of the urea and creatinine clearance is a better estimate of GFR. Given this, for a urea clearance >5 mL/min, one may consider also obtaining a creatinine clearance to see if the average is >10 mL/min, in which instance one may consider stopping dialysis if the patient has no uremic symptoms and no issues with volume control. (See "Indications for initiation of dialysis in chronic kidney disease".)

•Calculation of residual Kt/V (K_rt/V) from the urea clearance.

An online calculator is available to calculate K_rt/V. To calculate residual kidney function on this website, one must set peritoneal dialysis clearance equal to 0. Below, we show how to perform these calculations manually.

To obtain K_rt/V, one must calculate K_r (urea clearance/week), t (time), and V.

V (total body water) can be calculated from the Watson formula [33] in the following manner:

For example: An 80-year-old male patient who is 5’7” (67 inches or 170 cm), weighs 60 kg, and has a urine output of 800 mL per day, urine urea of 300 mg/dL, and a BUN of 68 mg/dL.

•Calculation of Kt/V required per treatment. Once K_rt is determined, it is combined with the clearance provided by hemodialysis to achieve a target Kt/V.

To perform this calculation, we use a figure developed by Gotch (figure 1) [31]. Using this figure, the K_rt/V is subtracted from target standard Kt/V (two per week). Using the example above, for the patient with K_rt/V of 0.76, one should subtract 0.76 from 2 on the vertical axis on the left side (resulting in approximately 1.24). Find where 1.24 on the vertical axis intersects with the 2X curve (horizontal dashed line) for twice-weekly hemodialysis. Move down from that intersect to the horizontal intersect (vertical dashed line [ie, approximately 1.2]), which is the per-session Kt/V required to be added to the residual function to achieve a total weekly standardized Kt/V dose of 2.0.

●Method 3 – Theoretically, the most precise method for calculating the incremental hemodialysis dose incorporates clearance provided by residual kidney function and accounts for ultrafiltration (figure 2) [6].

●Method 4 – A user-friendly tool for incremental hemodialysis is based on the concept that the hemodialysis dose to be prescribed is solely dependent on the normalized residual kidney function of the patient for each frequency of treatment [34].

MONITORING RESIDUAL KIDNEY FUNCTION — Residual kidney function can decline rapidly, especially in patients on hemodialysis. Residual kidney function should be closely monitored and the hemodialysis dose increased as residual kidney function decreases. Patients must be aware from the outset that they will need an increase in hemodialysis frequency or time in the future.

We recommend measuring 24-hour urinary volume once a month. If there is a significant decline in urinary volume, the urea clearance should be measured. Otherwise, measure urea clearance as described above every two to three months. If there is a decline in urea clearance, one must calculate the effect on residual Kt/V and the required hemodialysis dose.

SUMMARY

●General principles – Incremental hemodialysis is a method of dosing hemodialysis by which residual kidney function (calculator 1) is incorporated into the calculation of hemodialysis dose. Including residual kidney function can lead to the need for less than three hemodialysis treatments per week, shorter treatments, or less intense treatments. (See 'Introduction' above and 'Background' above.)

●Limited data to support use – There are insufficient data to prefer the use of incremental hemodialysis, as there are no good outcome studies that have shown that starting hemodialysis with less than a full dose results in comparable survival to patients who have the same level of residual kidney function and start hemodialysis with a full hemodialysis dose. Observational studies of patients on twice-weekly hemodialysis have not shown increased mortality. (See 'Background' above and 'Which patients may be candidates for incremental hemodialysis?' above.)

●Potential benefits – Incremental hemodialysis provides increased quality of life and is likely to preserve hemodialysis access. In addition, several observational studies suggest that, compared with thrice-weekly hemodialysis, twice-weekly hemodialysis may preserve residual kidney function, but the evidence is not strong. (See 'Potential benefits' above.)

●Selecting patients for incremental hemodialysis – Patients must be carefully selected for incremental hemodialysis. Potential candidates should have limited interdialytic weight gain, easily controlled serum potassium and phosphorus, no cardiovascular or pulmonary disease that is exacerbated by interdialytic fluid gains, and good nutritional status. Patients must understand that hemodialysis dose will be increased over time and be willing to do so. (See 'Which patients may be candidates for incremental hemodialysis?' above.)

●Monitoring residual kidney function – When prescribing incremental hemodialysis, residual kidney function must be checked regularly. The residual kidney function generally declines over time on hemodialysis. In order to have adequate clearance, the hemodialysis dose must be increased as residual kidney function decreases. (See 'Monitoring residual kidney function' above.)

●Prescribing incremental hemodialysis – Several methods are available for combining residual kidney function and hemodialysis dose mathematically. These methods have been developed based on theory and have not been tested in a prospective, randomized clinical trial. We err on the side of increased hemodialysis when using these approaches. (See 'The prescription of incremental hemodialysis' above.)