Fluid Management: Past, Present, and Future

Sabrina Casper MSc • Lemuel Rivera Fuentes, MD • Peter Kotanko, MD, FASN

Physicians now have an assessment toolkit to help them manage fluid balance in dialysis patients.  Bioimpedance devices and relative blood volume (RBV) monitors are among the most noteworthy technical advances, but because attaining favorable RBV ranges requires constant adjustments to the ultrafiltration (UF) rate, these devices cannot do the job alone. To address this issue, Fresenius Medical Care developed its UF control algorithm. This innovation continuously compares the patient’s RBV profile to the target curve and makes UF rate adjustments, resulting in a final UF removal within the prescribed UF goal range. In recognition of its potential to improve long-term patient outcomes, the US Food and Drug Administration granted a rare 21st Century Breakthrough Device designation to the company’s UF controller.

Fluid balance is tightly regulated through a delicate and coordinated interplay of organs—most prominently the kidneys, but also the gastrointestinal tract, liver, skin, and nervous, circulatory, and endocrine systems. The intricate physiology responds in a highly coordinated way to changes in water, salt, and other nutrients to meet the body’s demands. In healthy adults, the total body water (TBW), as a fraction of body weight, is about 50 percent in females and 60 percent in males. This fraction decreases slightly with age. Broadly speaking, TBW can be separated into intracellular (about two-thirds of TBW) and extracellular (about one-third of TBW) water compartments. Blood volume contributes approximately 70-75 mL/kg body weight to TBW.

Dysfunction of the organs and systems that regulate fluid balance can result in disturbed fluid status. Both fluid depletion (FD) and fluid overload (FO) come with acute and long-term consequences. Kidneys are a marvel and have a tremendous capacity to control TBW through regulating urine volume and composition. Consequently, most patients with impaired kidney function or end-stage kidney disease experience at some point either FO or FD.

To quantitate fluid status and complement clinical judgment, several diagnostic tools have been developed. They can be broadly classified as either biochemical tests or technical devices. The former includes, for example, the measurement of natriuretic peptides—e.g., brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP)—which increase in response to several conditions such as heart failure, left ventricular hypertrophy, and FO. In individuals receiving dialysis, these conditions frequently coexist, rendering biochemical markers of fluid status unreliable.1 In contrast, technical devices to assess fluid status are widely used in dialysis. The two most noteworthy tools are bioimpedance devices and relative blood volume (RBV) monitors.

Collaborating with Nephrocare in Fresenius Medical Care’s Europe, Middle East, and Africa region, researchers studied the relationship of baseline and one-year cumulative FO exposure in 39,566 incident dialysis patients from 26 countries.2 The researchers used the company’s Body Composition Monitor, a whole-body multi-frequency bioimpedance spectroscopy device, to assess fluid status. Cumulative one-year FO exposure predicted a higher risk of death. In an international cohort study in 8,883 hemodialysis patients from the MONitoring Dialysis Outcomes (MONDO) initiative, both pre-dialysis FO and FD were associated with higher mortality.3

Less data exist regarding the association between RBV changes attained during hemodialysis (HD) and patient outcomes. In a study of 308 patients receiving hemodialysis and followed for a median of 30 months, FO was detected by relative plasma volume (RPV) monitoring.4 The researchers discovered that a shallow intradialytic slope of RPV with a decline of less than 1.39 percent per hour was associated with higher mortality. A study of 842 patients followed for a median of 30.8 months corroborated these results directionally.5 The authors identified what they termed “favorable” RBV ranges that were associated with improved survival (Figure 1). Approximately 32 percent of patients attained RBVs within the favorable ranges, while 65 percent had RBV trajectories above and 2.5 percent below. 

FIGURE 1  |  Relative blood volume ranges associated with significantly lower all-cause mortality. The hourly RBV ranges associated with improved survival: first hour, 93-96 percent [hazard ratio (HR) 0.58 (95 percent confidence interval (CI) 0.42-0.79)]; second hour, 89-94 percent [HR 0.54 (95 percent CI 0.39-0.75)]; third hour, 86-92 percent [HR 0.46 (95 percent CI 0.33-0.65)].

The Crit-Line® in a Clip (CLiC®) device allows real-time monitoring of a patient’s RBV during hemodialysis. While possible in theory, active attainment of the favorable RBV ranges would require frequent manual adjustments of the ultrafiltration (UF) rate, an intervention that may not be feasible in routine clinical practice. To address that problem, Fresenius Medical Care has developed the so-called Adaptive UF Feedback Control algorithm, which directs a patient’s RBV curve into the favorable ranges. The algorithm automatically raises and lowers the UF rate during HD in response to a patient’s treatment-specific RBV trajectory, measured with the CLiC®. The general closed-loop flow is shown in Figure 2.

FIGURE 2  |  Closed-loop flow of the Adaptive UF controller

Before the treatment, the physician prescribes a target UF volume together with a maximum- and minimum-allowed volume deviation tailored for each patient. The controller manages the UF rate adjustments, resulting in a final UF removal within the prescribed UF goal range. The controller not only aims at attaining favorable RBV ranges but also steers the entire RBV curve to abide by a population-validated ideal trajectory that passes through half-hourly RBV values associated with the best patient survival. By continuously comparing the patient’s treatment-specific RBV profile to the target curve, UF rate adjustments are made every 10 minutes to direct the patient’s RBV curve toward that trajectory while observing the prescribed UF goal range. At the end of 2018, Fresenius Medical Care submitted the UF controller concept to the US Food and Drug Administration and was granted 21st Century Breakthrough Device designation.

The UF controller was first tested through computer simulations (“in silico”), then in the laboratory setting using an analog model that allowed the adjustment of key components such as absolute blood volume, UF volume, plasma refill rate, and treatment time. After the successful bench testing, the first non-significant risk investigational device exemption clinical research study was initiated. In that study, the UF controller was carried out in an assisted setting (“nurse-in-the-loop”) where it could not change the UF rate automatically. In the assisted setting, the controller’s UF rate recommendations were evaluated by a dialysis nurse who either implemented or disregarded them. This “nurse-in-the-loop” setting was accomplished by connecting a 2008T machine’s CLiC to a laptop with the control algorithm embedded into a graphical user interface. This interface tracked the RBV curve in real time, UF volume, and UF rate, and displayed the favorable RBV ranges. 

Fifteen subjects (63 dialysis sessions) were analyzed. In the depicted dialysis session example, the UF rate changed around every 10 minutes, steering the patient’s RBV trajectory through the favorable RBV ranges. In this session, the prescribed UF goal was 3.5 L with an allowed deviation of ± 1 L (Figure 3).6 The final UF volume eventually removed was 4.1 L, showing that the controller was able to attain the favorable RBV ranges while staying within the prescribed UF volume limits.

FIGURE 3  |  Example of a “nurse-in-the-loop” study treatment. The UF rate was adjusted by a nurse based on the control algorithm recommendations during the treatment, successfully keeping the patient within the favorable RBV ranges.

Considering all studied sessions, 63 percent of 300 RBV target timepoints were within the favorable RBV ranges (Figure 4). Out of 1,038 controller UF recommendations, 926 (89.2 percent) were accepted by dialysis nurses. The UF rates suggested by the controller were neither excessively high nor low. The frequency of intradialytic hypotension and muscle cramps was not increased, and there was no indication of adverse events related to the use of the UF controller.

FIGURE 4  |  Proportion of RBV values below, within, and above the respective RBV target range for each of the RBV target timepoints. Underlying data: all subjects who contributed data (N=14), all RBV targets (N=300).

In summary, the UF controller steered patients’ RBV curves toward the predefined target ranges while strictly observing the prescribed UF goal range. Importantly, the authors who studied the 842 patients had reported that only about a third of them were able to achieve the favorable RBV ranges at three hours into a conventional HD treatment.7 In contrast, with the use of the UF controller, over 70 percent of subjects were within the desired three-hour RBV target. While it is posited that outcomes will improve in patients who are actively steered into the favorable RBV ranges by the UF controller, well-designed and rigorously executed outcome studies are warranted. The next phase of the UF controller studies is being planned and will include intradialytic BP monitoring and use of a fully automated adaptive UF feedback design.

Fluid management in individuals receiving maintenance dialysis has come a long way, from exclusive reliance on physical examination and history taking, to quantitative assessment by bioimpedance and RBV monitoring, to an Adaptive UF Feedback Control algorithm. While each of these is valuable, the future of fluid management still lies in the wise and collaborative application of all the available tools.

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References

1. Agarwal R. B-type natriuretic peptide is not a volume marker among patients on hemodialysis. Nephrol Dial Transplant 2013 Dec;28(12):3082-89. doi: 10.1093/ndt/gft054.
2. Zoccali C, Moissl U, Chazot C, et al. Chronic fluid overload and mortality in ESRD. J Am Soc Nephrol 2017 Aug;28(8):2491-97. doi:10.1681/ASN.2016121341. 
3. Dekker MJE, Marcelli D, Canaud BJ, et al. Impact of fluid status and inflammation and their interaction on survival: a study in an international hemodialysis patient cohort. Kidney Int 2017 May;91(5):1214-23. doi: 10.1016/j.kint.2016.12.008. 
4. Agarwal, R. Hypervolemia is associated with increased mortality among hemodialysis patients. Hypertension 2010 Sep;56(3):512-17. doi: 10.1161/HYPERTENSIONAHA.110.154815.
5. Preciado P, Zhang H, Thijssen S, et al. All-cause mortality in relation to changes in relative blood volume during hemodialysis. Nephrol Dial Transplant 2019 Aug 1;34(8):1401-08. doi: 10.1093/ndt/gfy286.
6. Ibid.
7. Ibid.