Nils Alwall and his artificial kidneys: Seventieth anniversary of the start of serial production

by | Sep 6, 2021 | Pioneer Editorials

Originally published in Volume 43 Issue 8 of Artificial Organs, 07 August 2019

In 1943, Willem Kolff (1911-2009) initiated hemodialysis in patients in The Netherlands and is considered a pioneer of dialysis treatment. However, Nils Alwall (1904-1986) of Lund, Sweden, built a dialysis apparatus a few years before Kolff, and greatly contributed to understanding the clinical aspects of dialysis therapy. His first experiments with laboratory animals (rabbits) date to the end of 1941. Alwall made a series of improvements to his original model of artificial kidney (“dialyzer-ultrafilter”) and the result was in fact the first serially produced apparatus in the world, with a wide therapeutic application. Seventy years have just passed since this dialyzer was introduced to clinical use in 1949. Before, Alwall performed numerous experiments with various apparatuses, whose structure evolved from a plate-type to a cylindrical apparatus with a spirally wound cellophane tube (semipermeable membrane). No sooner than 15 years later, in the mid-1960s, came the era of disposable dialysis filters (Figure 1).

Figure 1

Nils Alwall, 1965. Picture taken by the authors from the source; Ref. 2
The first cardboard-and-string model of a dialyzer, about 17 cm in height, was built by Alwall 1941. It is currently displayed at the Museum of Medicine in Lund (Figure 2A). In his first experimental dialyses in rabbits (1941-1942) he used a dialyzer resembling later plate apparatuses (Figure 2B). Two cellophane sheets placed between the Plexiglas frames constituted 1 unit. He usually used from 4 to 8 such units, fastened with screws (to get the system tight), and immersed them in the dialysis fluid (dialysate). Blood flowed in the spaces between the cellophane sheets.1

Figure 2

A, The first model of the dialyzer, 17 cm in height, 1941. (with permission from the source; Ref. 7); B, The plate dialyzer used in experiments with rabbits 1941/42. (with permission from the source; Ref. 1) [Color figure can be viewed at wileyonlinelibrary.com]
However, Alwall admitted that this model was impractical and returned to his initial idea of a dialyzer in the form of a standing cylinder (Figure 3A). A cylinder of stainless steel with spirally wound cellophane tubing produced at The Visking Corporation, Chicago, IL, USA (used in making sausage), was compressed with an adjustable cuff and immersed in the dialysate filling 2 L glass jam jars. The length of the cellophane tube was 0.6-1.3 m, and the dialysis surface did not exceed 0.1 m2, the dialysate had to be changed several times during one dialysis. On the Ebonite cover of the jars a disk recorder (gramophone) motor was mounted to enable mixing of the dialysate. The rabbits were connected with the dialyzer using glass cannulas that provided access to the vessels and the blood passed along the connected bicycle valve rubber tubes, with the flow supported by a roller pump, if needed. This apparatus had been used since 1942 and enabled also ultrafiltration: a clamp placed on the blood tube draining blood from the apparatus increased pressure inside the cellophane tube. The compression cuff caused flattening of the cellophane tube and thinning of the blood layer in contact with the wall of cellophane membrane, which made the dialysis process more efficient. In addition, the compression cuff prevented the increase in blood volume inside the cellophane tube while the inside pressure was increased during ultrafiltration. The influence of dialysis and ultrafiltration on the state of uremia, on the removal of toxins, the possibility to repeat the dialysis (up to 7 procedures in the same rabbit) as well as the methods of access to the vascular system (Alwall was the first to develop the arteriovenous shunt, in 1948) were first tested in rabbits. During dialysis in anephric rabbits, blood urea levels decreased by 20-30% and ultrafiltration of 0.1 L fluid per hour could be obtained. By 1953 more than 2000 rabbits had been used in these experiments.2 The use of ultrafiltration, beginning from 1942, was a pioneering solution to the treatment of overhydrated animals and later, humans.

Figure 3

Dialyzers in the form of a vertical cylinder, with wound cellophane tubing, used in experiments with rabbits; A, The first model, height 20.5 cm, built by Alwall in 1942; B, One of the Ebonite models, 18 cm in height, Trelleborg 1947; C, The stainless steel model, 15 cm in height, Avesta Jernverk 1949 (pictures a, and b with permission from Ref. 7 and picture c Ref. 1) [Color figure can be viewed at wileyonlinelibrary.com]
Greater in size dialyzers of the same design were built according to Alwall’s drawings and instructions by Bengt Clementz, a technician in the workshop of the Department of Physiology at the University of Lund. The glass jam jars were replaced with glass cylinders custom made in the Måleras glass factory (Figure 4A), and an electric heater and a thermostat were added to keep the dialysate temperature constant at 37°C. Such apparatuses, with the cellophane tube’s length of about 10 m, the dialysis surface of 0.65 m2, and a glass cylinder with capacity of 25 L were used in dog experiments, and one of them was used in the first human treatment procedure in Lund on 3-4 September 1946. Altogether, about 20 patients were treated with this dialyzer in the years 1946-1948.2 In January 1947, the first in the world dialysis ward was established in Lund.

Figure 4

A, The dialyzer produced in the Institute of Physiology in Lund, 1943, 51 cm in height, used in the first dialysis in a patient on 3 September 1946 and in experiment with dogs (from Ref. 7); B, The dialyzer built of Ebonite, Trelleborg, 54 cm in height, used in the treatment of patients in 1948/1949 (from Ref. 2) [Color figure can be viewed at wileyonlinelibrary.com]

Only a few dialyzers of this type were made for the dialysis ward in Lund, its cost ($120) was equivalent to Alwall’s monthly scholarship. Due to the growing interest in other countries in 1947-1948, Alwall was asked about a possible availability of the dialyzers. One was loaned to a hospital in Copenhagen and another one was sent to Krakow, Poland. The diagrams and guidelines for use were sent to several other countries where copies of the dialyzer were built. In Israel a modified model was built and used in patients with acute renal failure.1

The design of Alwall’s dialyzer was simple, but the manufacturing required qualified workmanship. Each part of the dialyzer in contact with the cellophane membrane had to be perfectly smooth to prevent puncturing. The precision of performance was crucial because Alwall planned to carry out ultrafiltration with a negative pressure in the dialysate, which he thought was less harmful to blood cells. In this process, the cover of the cylinder with the wound cellophane membrane had to be tightly fitted. Alwall was looking for a manufacturer but in 1947 the demand for dialyzers was limited. In the end, Hilding Ståhlbrandt, the director of the Rubber Manufacturers in Trelleborg, agreed to build several models for research in rabbits. These apparatuses, made of hardened rubber (Ebonite) were used in Lund in 1947 and were evaluated positively regarding the effectiveness of dialysis, and ultrafiltration with a negative pressure in the dialysate compartment (Figure 3B). This prompted the development of a larger apparatus for use in patients (Figure 4B). The negative pressure up to 1 atmosphere in a closed, external cylinder with a dialysate was obtained initially by exposing a draining tube with the dialysate from the upper floor window (siphon mechanism); later a vacuum pump was applied. In this apparatus 3 segments of cellophane tubes of different length could be used, depending on the patient’s weight. The manufacturer was generous and Alwall was covering only 20% of the of prototype cost. This model was used in 59 patients in the years 1948-1949.2

A steam chamber was used for sterilization of the apparatus. Unfortunately, exposure to hot steam eventually deformed the dialyzer, so in 1948 Alwall managed to come in contact with Axel Axelson Johnson, chairman of the Johnson Metal Group, and production of a stainless steel dialyzer was started at the Swedish Metal Plant Avesta Jernverk AB. Axel Johnson was enthusiastic about “this significant medical activity.” The basic design was first that of the Ebonite dialyzer from Trelleborg. The first stainless steel models for rabbit experiments (Figure 3C) were provided in February 1949. Then, a larger dialyzer was developed for treatment of patients (Figure 5A). It consisted of 2 perforated cylinders. A cellophane tube, 20-21 m in length (dialysis surface of 1.6 m2) was wound on the smaller one, and the larger cylinder compressed the cellophane tube. The dialysate was mixed by an electric motor placed on a tight Plexiglass cover. The construction was gradually improved and after 1952 the models became bigger. An illumination of the inter-cylinder space was provided to detect possible leaking of the blood into the dialysate in case of perforation of the cellophane tube. After 1957 a cellophane tube of 30-40 m in length (dialysis surface up to 2.7 m2) could be wound (Figure 5B); however, 20-m tubes were commonly used.3 Ultrafiltration could remove about 1 L fluid per hour from the circulating blood. The dialysate in the outer cylinder (volume of 130-140 L) was changed every 2 hours by a stainless steel pipe system connected to the main dialysate reservoir of 850 L. Tap water was treated in softening columns and pH 7.4 in the dialysate was maintained using the carbonic/bicarbonate buffer system. Four composition variants of the dialysate were used, as needed, eg, low-sodium dialysate could be prepared beginning in 1951. A peristaltic roller pump (“sigma pump”) was used to deliver blood. In the years 1949-1965, the Avesta dialyzer was used in over 3000 human treatments in Lund.1, 2

Figure 5

Dialyzers made of stainless steel used for treatment of patients, produced at Avesta Jernverk; A, The first 1949 model, the height of the internal cylinder 51 cm, (from Ref. 1); B, The last 1957 model, the internal cylinder 59 cm in height (from Ref. 7) [Color figure can be viewed at wileyonlinelibrary.com]

The original dialyzer built at the Institute of Physiology and at first used in Alwall’s dialysis ward in 1946 was later replaced with Ebonite dialyzer until in 1949 an Avesta dialyzer was installed, and another one was added in 1953. By 1957 three Avesta dialyzers were in use. In 1966, 2 dialysis monitors and coil filters were provided by Gambro for clinical testing. Between 1949 and 1966, the Avesta factory produced dialyzers at the initial cost of about $3500. The interest in the world was significant, the waiting time for delivery reached several months, and Alwall was asked to intervene at Avesta Jernverk. These dialyzers had been purchased by about 50 dialysis centers in over 20 countries on 5 continents; Egypt, Kuwait, Mexico, China, the Soviet Union, Cuba, South Africa, USA, India, Australia, Japan, and in many European countries. Five dialyzers were sold to Germany, and 3 to Poland, Switzerland and Denmark each. At the end of the 1960s, they were still in use in 40 dialysis centers.2 The results of acute renal failure treatment with dialysis were considered so effective that in 1956 a Swedish insurance company bought three Avesta dialyzers for a total sum of $20 000 and donated them to three hospitals in Sweden (Göteborg, Stockhom and Umeå). Apparently, the Avesta dialyzer was one of the most frequently bought in these early years of dialysis therapy of acute and later also of chronic renal failure, and it proved relatively efficient for dialysis and ultrafiltration: the disadvantages were that it was heavy, not suitable for treatment outside the dialysis center, required intensive work of the staff, moreover, the cellophane membrane was often perforated during the winding up and the process had to be repeated. The contact of the used materials with blood led to pyrogenic reactions. Despite the volume reduction of the cellophane tube, the apparatus still required about 1.5 L of preserved blood from many donors and post-transfusion reactions were not uncommon. In practice, it could be used only once in a day, because the preparation for the treatment (washing, winding up, folding, and sterilization) required about 4 hours compared to the treatment duration of 6-10 hours. It was still possible to carry out 2 treatments within 24-hours using the same dialyzer but the workload on the staff was heavy, especially at nights. Despite these drawbacks, the dialyzer had been in use until the mid-1960s (over 15 years), when new possibilities emerged. Nevertheless, owing to the availability of Avesta dialyzers at that time, in numerous countries generations of doctors and dialysis personnel had an opportunity of specialized training.

Alwall was aware of the inadequacy of this dialyzer, of the growing demand for dialysis treatment as well as of ongoing debates and attempts to construct a simple disposable dialysis filter. An optimal solution would be if such filters were delivered to the dialysis ward ready for use, in sealed packing, after sterilization. The chance arose in 1961 when Alwall met Holger Crafoord, the director and shareholder of Åkerlund & Rausing and later of the Tetra Pak Company in Lund, the one which introduced the famous packing for fluids into the world market. They debated at length the status of treatment using available dialyzers, the situation of patients with renal failure, and the need for adequate, simple, and safe equipment for dialysis. Crafoord was fascinated by Alwall’s enthusiasm and commitment to saving patients’ life and decided to finance the project. Obviously, Alwall, as an inspirer and proponent became the main designer and consultant. Initially, the construction work was focused on the coil dialysis filter, carried out at the cooperating A. B. ARJO Company, located in the town of Eslöv, near Lund. The initial prototypes dated to 1962 (Figure 6, upper panel) were not successful, but a new construction consisting usually of 4 coil units, with 5 m length of a cellophane tube each, and total dialysis surface of 1.0 m2 (filter weight: 10.2 kg)4 proved satisfactory when tested at Alwall’s Nephrology Department in August 1964 (Figure 6, lower panel). Two or 3 units could be put together when planning a dialysis procedure in a child. However, these filters were not disposable, they required priming with the donor blood and were expensive to use. After each dialysis procedure they were sent to ARJO for exchange of the cellophane membrane and sterilization, and then returned to the dialysis ward. In total, 20 of such filters were produced and were in continuous circulation; they were used in about 400 hemodialysis procedures in 1966. The total cost of creation of the prototype of this filter was about $9000.2

Figure 6

Coil dialysis filter developed by Gambro with Alwall’s cooperation. Upper panel: The belt of plastic material, a component of the 2 abandoned models of 1962 (from Ref. 2); Lower panel: Schematic drawing of the coil filter, developed 1964 and in clinical use in 1966 (from Refs. 1 and 4, respectively) [Color figure can be viewed at wileyonlinelibrary.com]

In October 1964, the company A.B. Gambro was established: The name Gambro came from the abbreviation of the Gamla Brogatan (Old Bridge) Street in Stockholm, where Crafoord’s “Old Bridge Street Medical Supplies Company A.B. was located. In 1965-1966, Crafoord sold his shares in Åkerlund & Rausing and in Tetra Pak and became exclusively involved in the development of Gambro which was extended by purchasing of A.B. Instrumenta in Lund, manufacturers of various medical devices, including respirators. This company took up the construction of AK (Artificial Kidney)—dialysis monitor, partially at the premises of ARJO. Also here, Alwall enforced the clinical need for these dialysis devices (monitoring 7 clinical and technical parameters of the procedure) and clinically tested 2 AK 1, using coil dialysis filters, in 1966. The market price of the AK 1 monitor was about $8000.2

The new ward of 14 bed sites, each equipped with AK 1 monitors opened in 1968; it was one of the most modern in the world.

In 1965, work was started to develop a disposable plate filter based on Kiil’s dialyzer used in the 1960s, the one which required the exchange of cellophane membrane before each treatment. The first prototype of the Gambro plate filter was considered unsuccessful (Figure 7A). The subsequent model consisting of metal and plastic parts with a dialysis membrane (Cuprophane) surface of 1.0 m2 proved satisfactory, and despite its considerable weight (7.5 kg), dimensions (590 × 165 × 110 mm), relatively high price ($100 each) entered serial production in 1967 under the name “Ad Modum Alwall” (Figure 7B).4 The advantage of this plate filter was a small blood volume of 200-300 mL and low resistance in the blood chamber so that the priming with donor’s blood before the start of dialysis was not necessary. The treatment within 7-8 hours gave similar dialysis results as a 12-13 hours’ treatment using Kiil’s dialyzer. It was the first model of a disposable plate dialysis filter in the world. Introduction of the “Ad Modum Alwall” filter gave rise to a spectacular development of Gambro, which obtained space in Lund for the construction of its own headquarters. The production of dialysis filters and monitors was transferred from ARJO in Eslöv to Gambro in Lund in 1970/1971, and the cooperation with ARJO was closed in the next year. Gambro was getting more consolidated and all the work on new models of dialysis filters and monitors was taken over by a team of engineers, technicians, medical, and administrative staff. A new model of a disposable plate filter, the first in the world made entirely of plastic materials but still based on the experience acquired with the filter “Ad Modum Alwall,” was developed by the Gambro team and was launched in 1972 as “Gambro Lundia” (Figure 7C); its membrane surface was 0.54-1.0 m2 and the weight 2.0-2.6 kg.4

Figure 7

Disposable plate dialysis filter from Gambro: A, Prototype built in 1965, but never in clinical use (from Ref. 2); B, Model of “Ad Modum Alwall,” in clinical use between 1967 and 1972 (from Ref. 4). These 2 models were built in cooperation with Alwall; C, Model “Gambro Lundia,” built exclusively of plastic material, in use since 1972 (from Ref. 4) [Color figure can be viewed at wileyonlinelibrary.com]

Alwall retired in 1971, but he remained a consultant at Gambro until 1984, and cooperation between Gambro and the Nephrology Department in Lund continued, and included clinical assessment of the produced dialysis filters and monitors. In January 1985, the new Gambro Research Center in Lund called “Alwall Laboratory” was opened in the presence of Alwall.

A more thorough presentation of Nils Alwall’s activity as a visionary, originator, designer, and researcher of the clinical aspects of hemodialysis was given recently.5 His persistent efforts and hard work on the development of this form of treatment of kidney failure helped a great number of patients to improve their fate and let them live longer. In Sweden, he got the nickname “Man of a Miracle.”6

Biographies

Jan Kurkus, MD, PhD graduated from the Warsaw Medical School 1962 and since 1964 was a staff member of the Department of Internal Medicine, Warsaw Medical School Hospital. He attained his PhD in 1972. He also studied at the Memorial Sloan-Kettering Cancer Center, New York, NY, USA in 1975/1976 (special fellow in medicine) and 1982 (visiting investigator). Since 1985, he was a staff member of the Department of Nephrology, University Hospital of Lund, Sweden. The last positions he held were Head of the Dialysis Ward, Senior Consultant, and Associate Professor. He is presently retired.

Janusz Ostrowski, MD, PhD is a nephrologist and PD Medical Director for Diaverum Poland, one of the world’s largest independent renal care providers. He is also a Professor at the Centre of Postgraduate Medical Education, Warsaw, Poland, Head of the Department of History of Medicine as well as President of the International Association for the History of Nephrology.