Clinical evaluation of a newly developed automated hemodialysis system as a clinical trial
© The Author(s) 2018
Received: 5 January 2017
Accepted: 25 January 2018
Published: 9 February 2018
To cope with the increasing number of patients on long-term hemodialysis (HD), especially those with diabetic nephropathy, we designed a fully automated HD system to decrease staff workload and hence human errors related to HD treatment. In this study, we evaluated this new system as a clinical trial.
Based on a dialysis machine combined with a central dialysate delivery system (CDDS), the new system is characterized by the use of back ultrafiltrated dialysate (BUD) as a substitute fluid for priming, bonus shot and blood return, and the attachment of double endotoxin retentive filters (ETRFs).
The subjects comprised 61 patients from five HD facilities enrolled in a randomized, open-labeled crossover study after giving written informed consent.
A total of 348 HD treatments for 58 of the 61 patients were studied under a protocol designed in accordance with good clinical practice (GCP) guidelines and approved by the respective institutional review boards. No severe adverse effects were observed with either the test or control systems. The incidence of clinical events, including blood pressure decline, residual blood, and error in fluid removal, was not statistically significant in either group. Neither endotoxins nor bacteria were detected in the dialysate passing through the double filters.
This study confirmed the safety and effectiveness of an automated HD system based on CDDS.
(This Clinical Trial No. is 21500BZZ00045000)
The proportion of dialysis patients with diabetic nephropathy has been increasing steadily, reaching nearly 45% of patients commencing dialysis and 36.6% of existing patients.
The population of dialysis patients is aging rapidly. For both men and women, many patients commencing dialysis are between 80 and 84 years old, representing more than 15 and 17% of those commencing dialysis, respectively, with the median age at commencement of initiating dialysis now 69.1 years [1, 2].
Although those trends seen in Japan are also observed worldwide, the following problems such as an increase in the number of patients requiring various medical cares including considerable extra support from the staffs have become more prominent in the current setting of maintenance HD in Japan.
Thus, in Japan, the dialysis staffs’ shortages have become evident. The advantage of the central dialysate delivery system (CDDS) is its ability to deliver dialysis fluid to multiple patients at the same time, but full automation of the device has been required in order to decrease the number of operations, especially during the beginning and end of dialysis when multiple tasks converge.
Hemodialysis treatment is especially suitable for full automation because it involves multiple repetitions of similar operations. By implementing full automation with safety devices and fail-safe systems in place, we can achieve both the pursuit of a decrease in operational burden and an increase in efficiency, as well as safety from human error.
With the purification of dialysis fluid , fully automated devices actively utilizing back ultrafiltration dialysate (BUD) came into use . Blood return to the arterial side is usually performed by reversing the rotation of the blood pump in a similar manner to automatic devices using physiological saline.
We developed a dialysis console using BUD, and special features of this device are that rotation of the blood pump is not reversed during blood return to the arterial side and the blood return speed can be controlled while blood return pressure is monitored. We evaluated the safety and effectiveness of this novel fully automatic dialysis machine in a clinical trial, and present the results here.
Newly developed machine
Non-reversed rotation of blood pump during blood return to the patient
Assurance of quality of back ultrafiltrated dialysate (BUD). Contrasting strikingly with the preceding machine , non-reversed rotation of blood pump was materialized by the device shown in Fig. 2, where blood return speed is controlled based upon the blood return pressure monitored. To control the quality of BUD, a double endotoxin (ET) retentive filter (ETRF) was placed immediately before the dialyzer on the dialysis unit side, and furthermore, the following were devised: (1) auto-flushing of the ETRF, (2) leakage test of ETRF, (3) countermeasure to failure of a single ETRF, and (4) monitoring of ETRF use duration.
Prior to the clinical trial, the study plan including the inclusion and exclusion criteria of patients as shown below was reviewed by the institutional review board of each participating institution.
Duration of HD—more than 6 months
Age—more than 20 and less than 75
Treatment schedule—basically 3 to 5 h per treatment and three times a week
Physical condition—stable outpatient receiving HD as scheduled
Patients to whom kidney transplantation is planned
Patients to whom the shift from HD to other modalities such as HDF, CAPD, and so on is investigated
Patients who suffer from acute myocardial infarction, unstable angina, and cardiac insufficiency (NYHA; more than III)
Patients whose values of hepatic markers (AST, ALT) are higher than normal more than by two times
Patients who suffer from severe anemia (hematocrit; less than 20%)
Patients who suffer from malignant tumors
Patients who suffer from uncontrollable hypertension or hypotension
Patients who are pregnant or are suspected to be pregnant
Patients from whom more than 150 mL/min of extracorporeal blood volume cannot be obtained
Subjects were given an explanation of the clinical trial using the informed consent form and written information, and informed consent was given in writing by each subject. The clinical trial was conducted with due ethical considerations, such as maintaining subject confidentiality.
Basic frame of protocol
Assessment of the safety and the effectiveness
The safety (i.e., of devices/machine and of entry of BUD into the body) and effectiveness (i.e., performance of auxiliary functions as intended) of the study test machine were assessed in comparison with a control one (TR-3000M) in stable-phase chronic dialysis patients for the purpose of confirming its acceptability for a plurality of operators at multiple institutions.
Safety endpoints comprised (1) occurrence of adverse events, (2) failure of the study machine, and (3) comparison of high-sensitivity C-reactive protein (CRP) values pre- and post-dialysis as a bioreactive marker to the quality of BUD infused into patients.
Decrease in blood pressure—fall in systolic blood pressure by ≥ 20%
Residual blood corresponding in volume to approximately two thirds of the hollow fibers
Water removal error ≤ 400 g
Failure of the study machine denoted either premature discontinuation of dialysis or completion of dialysis delayed by 1 h or longer related to the machine, as agreed upon at the clinical trial research meeting.
An effectiveness endpoint consisted of checking and evaluating whether the test machine had performed auxiliary functions as intended. The evaluation was made not for each patient but for each session of dialysis.
Background characteristics of the hemodialysis patients
Dialysis duration (years)
Dry weight (kg)
Of the 61 patients who gave informed consent, there were 3 who withdrew consent before pre-testing, and there was a protocol deviation in one session of dialysis in group B (control machine). Consequently, 58 treated patients were subjected to the safety evaluation. For the effectiveness evaluation, 174 dialyses with the test machine in group A and 174 dialyses with the control one in group B were subjected to the assessment.
Hematological and laboratory results of hemodialysis patients
Control machine (C)*1
Test machine (T)*1
Significant difference (paired t test)
Leucocyte count (WBC)
6048.3 ± 1950.10
5974.1 ± 1931.60
6051.7 ± 2070.96
72.3 ± 14.01
70.7 ± 14.50
71.2 ± 14.49
11.6 ± 2.46
11.5 ± 2.43
11.5 ± 2.41
2114.8 ± 3817.68
2312.7 ± 4485.56
1360.1 ± 1810.18
2453.9 ± 4815.46
2415.4 ± 4807.21
1533.0 ± 2115.53
Results of the safety evaluation (test and control machines)
No. of adverse events
Adverse event occurrence
Study machine failure status
Highly sensitive CRP
Occurrence of adverse events (AE) agreed upon at the clinical trial research meeting and results of statistical analysis
No. of events
No. patients with AE
Decrease in blood pressure
χ2 = 0.165
P = 0.684
χ2 = 3.004
P = 0.125
Water removal error
χ2 = 2.295
P = 0.130
Decrease in blood pressure
A fall in blood pressure occurred during 24 dialyses with the test machine in 12 patients and during 26 dialyses with the control one in 14 patients. Of these patients, eight were common to both test and control machines. As for the circumstances in which a fall in blood pressure occurred, the event was peculiar to the study subjects, and it was found that the event occurred concomitantly with changes in water removal volume and dry weight on the day, according to the case report forms and findings by the responsible investigator. Therefore, we judged that there was no causal relationship of a decrease in blood pressure with the study machine.
There were three events of residual blood occurring in one patient on the test machine and no event with the control one. The events were confined to this one patient and were judged to be peculiar to this subject.
Water removal error
Water removal error occurred at 6 dialyses with the test machine in six patients and at 11 dialyses with the control one in seven patients. The results showed a significantly lower incidence for the test machine. However, the measurement of the UF pump capacity (i.e., determination of water removal precision) performed at the relevant institution on the occasion the error occurred showed no error in water removal volume, and the determination of water removal precision made after retrieval of the study machines also failed to demonstrate any error in water removal volume. As a result of the deliberation with the responsible investigators based on these considerations, the errors were thought to be attributable to errors in pre-dialysis measurement of body weight and subjects’ diet adjustment. The responsible investigators and the sponsor thus judged that there was no problem with the water removal precision of the study machine.
Results of the effectiveness evaluation
No. of completed operations/no. of operations
Operation completion rate (%)
As noted by the Japan Society for Dialysis Therapy , both the number of dialysis patients (304,592) and dialysis machines (121,835) showed a tendency to increase as of December 31, 2014. The status quo of the number of nurses is only being maintained. The increases in both the patient population and the patients requiring nursing care are likely to be related to the progressive increase in reported medical incidents in dialysis rooms [8, 9], with 2905 events in 2009 compared with 1946 events in 2005.
In view of the above factors, dialysis operations have been partially automated in order to prevent manipulative errors related to the increased burden on nurses, as well as to realize the practicability of concurrent care of several patients. With an automated machine, the nurse can concentrate on patient care because the dialysis machine should perform safety monitoring of the intra-circuit pressure, air bubbling, etc. after the nurse has programmed the machine.
The use of BUD instead of saline leads to cost reductions, as does automation of those operations that place an increased burden on staff—starting dialysis, when blood pressure falls in a patient and completion of dialysis. The lessening of workload is particularly conspicuous when CDDS is used because one staff member can prepare and initiate dialysis to several patients simultaneously. We also confirmed that the system readily fulfills the water quality control standards required for the use of BUD, and the CDDS has been judged a suitable system for producing sufficiently purified dialysate (Fig. 5).
By the way, the first clinical use of BUD was tried as “Pull and Push Therapy” by Drs. T. Shinzato and K. Maeda  in 1982. Although the filtration through not a dialyzer but a special filter was used, use of the filtered dialysate was approved as the substitution fluid for hemodiafiltration as Gambro’s AK-100Ultra machine in 1998 . As mentioned above, TR-3000MA machine was the first automated machine without the reversed rotation of blood pump during blood return, which is noted to decrease the operation risk as compared to the reversing rotation system of blood pump.
Through this clinical trial, the safety of this system was proved and later was approved by the Japanese Government. Since then, the quantitative effectiveness of this system including the labor-saving effect is being confirmed.
We confirmed the availability of fully automated dialysis machine by the clinical trial study.
Transparency declarations: none to declare.
I (TS) thank Ms. Yoko Doi and Midori Matsudaira for giving fine secretarial works.
This study was performed as the phase III clinical trial funded by Toray Medical Co. Ltd. Tokyo, Japan. The role of the funding body was a reward to the data collection of investigators in each chronic hemodialysis institution.
Availability of data and materials
Data are available on request to the authors.
The corresponding author (TS) planned the study, searched the literature, assessed the studies, extracted the data, analyzed the data, and prepared the article. JM, SF, JH, HY, and KI assisted in the data collection and article preparation. TB and TK gave the detail of the study protocol from phase III clinical trial detail. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The study protocol was approved by the ethical committee of the Wakayama Medical University, Wakayama, Japan. In addition, the clinical trial study protocol was also checked and approved by the institutional review board (IRB) of the Wakayama Medical University, Wakayama, Japan. Written informed consent was obtained from all subjects.
Consent for publication
All participant gave us to accept study protocol with informed consents.
The corresponding author (TS) has received an honorarium from Toray Medical Co. Ltd., Tokyo, Japan. TB is an employee of Toray Medical Co., Ltd., Japan. TK is a scientific advisory board in Toray Medical Co., Ltd., Japan. However, this involvement does not raise the question of bias in the work reported, or in the conclusions, implications, or opinions stated.
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