by Nicholas Hoenich

Introduction

Newcastle was one of the early adopters of haemodialysis for the treatment of renal failure, and David Kerr  became a recognised leader in the field. Much has been written about the contribution made by David and others in the field of renal bone disease, but   less well known is the dialyser evaluation programme undertaken at Newcastle in which different dialyser variants were evaluated and their performance characteristics described via the Department of Health Scientific and Technical Branch in reports circulated to each renal unit in the United Kingdom.

The evaluation ran from 1969-1996, a period during which the technology associated with the treatment of renal failure was rapidly  evolving.

The context

In the late 1960s, driven by technological advances (the parallel plate dialyser, the single patient proportionating system and the arteriovenous shunt) the focus of  treatment  by dialysis shifted from acute to chronic renal failure. By 1969, 32 renal units had been set up throughout the UK provided treatment for renal failure by dialysis.  The units ( generally 10 beds or less) were largely using single patient proportionating systems and non-disposable parallel plate dialysers, catering  for  hospital-based outpatient treatment as well as training patients for home haemodialysis. There were some variations in this approach in that some units used central dialysis fluid supply systems and individual bedside monitors whilst others used coil dialysers. Acute renal failure was still treated by the Travenol ( later Baxter) twin coil dialyser.

With the increase in the number of units and patients being treated, the equipment was supplied centrally by the newly created Department of Health and Social Security (DHSS) which replaced the earlier Ministry of Health and Ministry of Social Security in 1968.  The origins for this centralized approach lay in the recommendation of the working party on intermittent dialysis for chronic renal failure set up in 1965 under the chairmanship of Hugh de Wardener to advise the Minister of Health on clinical policy and on the development of equipment. There was concern from clinicians that the equipment supplied centrally would not perform correctly, and the working party requested that the Ministry of Health (MoH) carry out independent trials of all equipment before being placed on the central supply list.

Establishing the dialyser evaluation programme

Testing became the responsibility of The Scientific and Technical Branch of the DHSS upon its formation who set up and oversaw two separate evaluation programmes, one for  proportionating systems the other with dialysers.

Proportionating system evaluation

Proportionating systems (as well as early PD cyclers) were assessed  at the Atomic Weapons Research Establishment (AWRE) (Aldermaston, Berkshire) as it had a team of government scientists who were considered to have the relevant expertise. By the 1980’s this element of the evaluation programme  had moved from Aldermaston to Sheffield where it was carried out at the Institute for Biomedical Equipment Evaluation and Services (IBEES). Although initially the two elements of the evaluation programme were separate, in later years, the proximity of Sheffield to Newcastle led to collaboration between the two groups, whereby proportionating systems undergoing evaluation at Sheffield underwent a clinical user assessment at Newcastle upon Tyne which was undertaken by a designated nurse within the Renal Unit at the Royal Victoria Infirmary (RVI).

Dialyser evaluation

The evaluation of dialysers at Newcastle upon Tyne began in 1969 and was funded on a three year rolling budget.  Newcastle was selected, due to the presence of David Kerr, and an  established academic and clinical interest in the fluid dynamics and mass transfer of the dialysis process. Nicholas Hoenich ,a physicist, was appointed as a Scientific Officer in the Department of Medicine, RVI and was responsible for the day to day management of the evaluation programme.

Development of the dialyser evaluation programme in Newcastle

The initial studies were undertaken in the  Department of Mechanical Engineering using methods adapted from those described in an early issue of the Proceedings of the European Dialysis and Transplant association ( EDTA) to generate consistent and reproducible results (pdf). [Kerr DNS: Editorial-Testing new dialysers. Proc Eur Dial Transpl Assoc  1969: 6:319—322]. By 1971 the laboratory studies were undertaken in the  RVI using a modified  Lucas ( initially a Mk1 and later a Mk II ) single patient proportionating system. As accurate pressure measurements were the key to many of the parameters studied, and a greater accuracy than that displayed on the proportionating system was required, pressures were measured   initially using spill free mercury manometers and later using transducers. Flow rates were measured using timed volumetric collections.  These two elements continued to be used to generate laboratory data until the programme was discontinued, although by this time the Althin/Baxter 1000  was used as the proportionating system.

In 1984 the evaluation laboratory moved to the new Medical School of the University of Newcastle at which point a second member of the evaluation team Celia Woffindin, newly graduated in Biochemistry from Edinburgh University,   was appointed enabling both routine evaluations and academic research to be undertaken. The evaluation programme had no other dedicated staff members.  Technical support was provided by the renal technicians, the Department of Medical Physics and the Department of Clinical Biochemistry at  the RVI. Administrative support came via David Kerr’s research secretary.  Within the programme some funding was available that permitted temporary technical support to be employed. This generally employed school leavers  waiting to take up places at university to study either medicine or natural sciences.  When clinical studies began, there was oversight from the nephrologists, as well as participation from overseas research fellows.

Laboratory evaluation procedures

Laboratory or in vitro studies focused on clearance and its variation with blood flow, the blood compartment volume and its variation with blood flow, the fluid removal (ultrafiltration) characteristics and the blood and dialysis fluid pathway pressure drops. Later additional studies to characterize   middle molecular removal characteristics of the devices were added to the studies. These initially used radioisotopically labelled compounds, but with the increased complexity associated with this approach, later studies were carried out using unlabelled Vitamin B₁₂ which could be easily measured in the laboratory.

Parallel flow and hollow fiber dialysers operated in a counter current flow configuration, and could be used with ease with a single patient proportionating system. Coil dialysers in contrast operated at a high dialysis fluid flow rate with the dialyser partially immersed in a tank containing dialysis fluid with the dialysis fluid being pumped at a high rate through the coil assembly at right angles to the direction of the blood flow rate. This meant  that the performance could not be directly compared with dialysers using a counter current flow configuration. To permit comparison,  a recirculating single pass system (RSP) was used which provided steady state condition for the measurement of solute transport. The RSP system was simply a small tank which contained the dialyser lined to a recirculating pump, with the dialysis fluid being continuously added by and removed with the conventional single patient system. This technical complexity was later dispensed with as variants of coil dialysers began to be produced which could be used directly with a single patient system.

Clinical evaluation procedures

In the course of the evaluation programme a standard clinical evaluation procedure was used. The clinical evaluation followed on after the completion of the  laboratory characterization of performance which enabled the behaviour of the device to be established and the generated data compared with that provided by the manufacturer.

Clinical evaluations began in 1970 on patients undergoing regular dialysis treatment initially at the RVI  and later also at Sunderland Royal Infirmary. The evaluation programme took a selection of the most important characteristics regarded as the minimum basis for clinical comparison and provided this information to the user via the reports permitting a rational choice. As with laboratory studies, the methodology was standardised, meaning that devices could be compared easily.  Clinical studies focused on establishing data most useful to the clinician namely clearance of small molecules ( urea, creatinine and later phosphate) measured during the second hour of dialysis, when conditions were considered stable. Devices under test were set up and prepared in accordance with manufacturers instructions. Flow rates were measured volumetrically for the dialysis fluid and by a calibrated 2 metre arterial race track  into which a small bubble of air was injected and its passage timed between two marks was used to determine the blood flow rate. Sampling from the arterial, venous and dialysis fluid segments of the circuit was  simultaneous and unlike for routine clinical measurements the sampling volume was much reduced ( around 1ml of blood for each sample). This reduction in volume compared to routine clinical samples was important, since early studies predated the availability of recombinant erythropoietin, and patients generally participated in multiple evaluations.  Generally ten devices were studied at six to eight different blood flow rates  to confirm data established in the laboratory. Data analysis for the studies was supported by the Department of Medical Statistics at the University of Newcastle, but for the early laboratory analysis methods commonly used in engineering were used.

As the single patient proportionating systems offered only a rudimentary control of fluid removal rate during treatment, fluid loss or ultrafiltration over short periods during treatment under controlled conditions  was also determined using a pad based weighing system in which pads linked to a monitor and recorder were used. The other clinical parameter studied was the volume of blood retained in the device ( and blood tubing set) following a standard rinse back volume. Patients participating in the clinical studies were recruited with informed consent following Ethics Committee approval and generally those patients who did not have dialysis-related complications such as hypotension or cramps during treatment were used. All had been receiving treatment for a minimum of three months.

Evaluation of the Kiil dialyser

The first evaluation undertaken at Newcastle upon Tyne was  of a Kiil type dialyser manufactured in the UK that was to be placed on the central supply list. The Kiil dialyser designed by a Norwegian urologist Fredrik Kiil owed its orgins to the earlier Skeggs-Leonard kidney but was manufactured from polypropylene and was unusual in that Kiil did not patent the design. This meant that others could copy or adapt the design.

There were two candidate devices, one manufactured by Watson Marlow ( Falmouth) Ltd and the other by Heppell Engineering (Templefield, Harlow) ( developed by the husband of an early dialysis patient; a short British Pathe film showing Olga Heppell dialysing at home in 1964 can be seen at https://www.youtube.com/watch?v=s8gqp09DRAY) . Based on the findings at Newcastle the one manufactured by Watson Marlow was selected.  By 1972 the widely used Kiil was being replaced by the Meltec Multipoint manufactured by Meltec Ltd (Bourne End) which was  identical in assembly to the Kiil type device but which offered a different internal structure to support the membranes and was made of Perspex ( the British equivalent of Plexiglass).  Dialysers like the Kiil used sheet membranes that were stretched over the grooved boards in pairs to form envelopes through which blood flowed via blood ports placed between the membrane sheets. The board assembly  was mounted on an aluminium frame and clamped together prior to pressure testing and sterilization with formaldehyde. The building and assembly of these non disposable devices involved a steep learning curve to ensure that failure ( either in preparation or during use) was minimised.

Figure: Assembling the Kiil dialyser

With practice, nursing staff ensured that the failure rate was around 5%, however, in the home where patients and spouse built the dialysers it was generally higher as the  boards were heavy and required two persons to assemble the dialyser.  The 0.6m² Meltec Multipoint offered the advantage  that  it delivered the same performance as the larger 1m² Watson Marlow Kiil  but its  assembly proved easier for patients.

The role of industry in dialyser development

Between 1969 and 1971 the growth in the number of patients being dialysed was mirrored by increasing involvement by industry. This surge being attributed to a desire to “obtain a slice of the cake” in what was seen as a growth market,   and also the absence of regulations.  Frequently the companies were set up by engineers working in collaboration with either a physician or a pharmacist, or by an entrepreneur.  A notable example of the former is Ab Gambro in Sweden now part of Baxter, , which grew out of the  collaboration between the Swedish nephrologist Nils Alwall, one of the early exponents of dialysis treatment for acute renal failure, and  Holger Crafoord, a Swedish industrialist. In Italy, the entrepreneurship displayed by Mario Veronesi resulted in the formation of two companies involved in haemodialysis  – Dasco and Bellco.

Although the manufacture of non-disposable flat plate devices was well established in the UK, only Avon Medicals, a division of the Capon Heaton Company based in Stritchley, Birmingham produced coil type dialysers as well as blood tubing sets for use in haemodialysis.

This rapid growth in device technology meant that by 1969 there were  sixty seven different designs or design modifications in use in Europe. The early disposable devices were expensive and this precluded their routine use, however they were used to provide backup for both hospital and home patients in the event of a blood leak. For example at  Newcastle the Gambro Alwall, a multilayer single use parallel plate device. that used a metal frame to hold the multiple layers in place and weighed around 8 kg, was used to provide the backup both in the hospital and the home.  In parallel with the disposable plate dialysers , disposable hollow fibre dialysers were also developed, the earliest being the  the Cordis Dow CDAK which utilized hollow fibres developed and manufactured by the parent company of Cordis Dow , the Dow Chemical Company.   In 1969 Enka Ag ( now Membrana) began the production of cellulose based membranes in a hollow fibre format and this further increased the diversity of products available as major manufacturers expanded their product portfolio.

Coil dialysers also continued to be used.

The handling of Kill boards, and blood leaks during the dialysers use meant that blood borne virus infection was a hazard for patients and staff in renal units. The availability of non- disposable dialysers, and the publication of the Rosenheim Report in 1972 providing recommendations for preventing blood-borne virus infection in dialysis units, meant that there was a switch from the rebuildable to the disposable dialyser. Due to the many different types now on the market their central supply was no longer practical and this  led to direct marketing to nephrologists by the manufacturers. Clinicians were inundated with literature/samples and calls from manufacturers urging them to use a particular device, and were lavishly entertained at dialysis meetings.  In persuading clinicians to use their product, manufacturers, typically focused on the good points of devices  with little mention of any disadvantages. As testing methods were not standardised,  it was difficult to make comparisons between different devices from different manufacturers. Furthermore, production techniques were evolving meaning that there was marked inter-batch variation in the performance and reliability of devices produced.

Within this environment, the DHSS continued  to support the evaluation programme  but played no role in the decisions that individual units made in selecting which dialyser to use. Decision makers found the   availability of data from a single source helpful, as did the manufacturers who frequently used the data produced at Newcastle as the basis for adjustment or modification of their manufacturing processes.

Travel aspects of the dialyser evaluation programme

In connection with the evaluation programme there was a steady stream  of visitors to Newcsatle and this provided opportunity to expose visitors to Newcastle nightlife, Newcastle Brown Ale, and the local dialect which many found incomprehensible; a copy of  “Larn yersel Geordie” helped them navigate and understand the language. On a personal level the evaluation programme provided the opportunity to meet and occasionally share a drink with many of the innovators and exponents of dialysis. It also gave rise to “nephrotravel” to  factories in Europe –  Lund ( Sweden), Sweinfurt, bad Homburg, Wuppertal  and Hechingen (Germany), and Mirandola (Italy),  the United States ( Lakewood Colorado, and Deerfield Illinois) as well as travel to international conferences in Europe and further  afield  to disseminate the findings of the studies carried out at Newcastle .

Nick Hoenich in the  dialysis unit in Reading, Pennsylvania 1969

A Dialysis meeting in Italy, 1977. L to R:  S Ringoir (nephrologist, Gent, Belgium), Nick Hoenich, L Luppi (Bellco SpA Mirandola), G Orlandini (nephrologist, Bergamo, Italy)

Achievements of the dialyser evaluation programme, and modern dialyser usage

Over its 27 year existence, the dialyser evaluation programme evaluated over three hundred different dialyser types drawn from the four basic categories:  non disposable parallel plate, disposable parallel plate, hollow fibre, and coil. Today hollow fibre dialysers are universally used,   cellulose based membranes are no longer used and have been replaced by membranes manufactured from synthetic polymers. Single patient proportionating systems have become more sophisticated,  have the  the ability to accurately control fluid removal during treatment, and to perform  on-line  treatments  such as haemodiafiltration.  Only a handful of companies remain and the dialysers they produce offer a consistent and reliable level of performance. Put simply the market has matured. The central supply approach remains,  albeit  in a modified form via the NHS Supply chain. Within this, there is no independent assessment of functional performance, with purchasers confident that performance data has been established in accordance with standardised methods. Unlike in the 1970s clinical performance data is not  given on the product specification but is available on request from the manufacturers.

It is easy to dismiss the Newcastle Evaluation programme as a historical foot note to the development of dialysis in the UK. However, it should be remembered that when the the programme began in the early 1970s dialysis was less established, and dialyser design was a growth industry with a ’wild west’ feel. Everyone involved – manufacturers, medical staff, nurses and technicians  – were all on learning curves, with little or no formal training.  Comparative performance data established under standardised conditions were non-existent.  Although the evaluation programme is long ended, elements of the  methodology developed and used at Newcastle upon Tyne have stood the test of time and today form part of the current International Standard test methods for haemodialysers, haemodiafilters, and haemofilters, universally used by  manufacturers worldwide, and ensures that measurement and representation of device performance is standardised.

 

 

 

 

 

 

 

 

Last Updated on April 29, 2024 by John Feehally