Robert Tigerstedt and the Discovery of Renin.

The year 2022 marks the 125th anniversary of the discovery of the first element of the renin-angiotensin-aldosterone system. The importance of this event on the further development of nephrology, cardiology, and endocrinology left us compelled to reminisce about it and its main author, Robert Tigerstedt (1853-1923), who was one of Scandinavia's most famous scientists. He studied medicine at the University of Helsinki, Finland. His doctoral dissertation On the Mechanical Stimulation of the Nervous System and 10 other original publications made him famous among the neurophysiological community. From 1881, he worked in the Physiology Department at Karolinska Institute, Stockholm, where he created a modern laboratory and became a professor at age 33 years. After meeting Carl Ludwig in Leipzig, he became interested in central blood circulation. In 1886, with Per Bergman, he started a series meticulously performed experiments with extracts of the rabbit kidney cortex, which, when injected into other rabbits, increased their blood pressure. The hypothetical responsible substance was called renin. The results were presented at the International Congress of Medicine in Moscow in 1887. Forty years later, Harry Goldblatt confirmed Tigerstedt's theory that "the substance which comes from kidneys increases the blood pressure." After he returned to Finland in 1901, Tigerstedt headed the Physiology Institute in Helsinki. His further activities included scientific work, teaching, and socially oriented issues like healthy nutrition and conditions in prison camps. He was also interested in the history of medicine and was a member of the Nobel Committee. His Textbook of Human Physiology was published in numerous editions in many languages. He also authored the renowned Textbook of Physiological Methodology and Physiology of Circulation. Tigerstedt published over 200 scientific papers and was an honorary doctor at many universities. He was known for his strong personality, critical judgment, idealism, humor, and warm heart.

Low plasma activated protein C-protein C inhibitor complex concentration is associated with vascular access failure in hemodialysis patients.

BACKGROUND: Vascular access failure is a common cause of morbidity in patients with end-stage renal failure on hemodialysis (HD). Activation of the coagulation system and formation of a thrombus play important roles in recurrent arteriovenous fistula/graft (AVFG) failure. Thrombin in complex with thrombomodulin (TM) activates the anticoagulant protein C and creates activated protein C (APC), which is subsequently inactivated by the protein C inhibitor (PCI). The plasma concentration of the complex between APC and PCI (P-APC-PCI complex) is increased in hypercoagulable states and is therefore a sensitive indicator of the degree of activation of blood coagulation. METHODS: Thirty-five HD patients dialyzed through a functioning AVFG were studied. The period of patency of AVFGs was recorded. Blood was drawn before and after the HD session for the analysis of the APC-PCI complex, soluble TM concentration and activity, von Willebrand factor antigen and homocysteine. RESULTS: Patients with frequent AVFG failures (n = 8) had a significantly lower level of P-APC-PCI complex (median 0.09 microg/l) than those with less frequent AVFG failures (median 0.18 microg/l; n = 27; p = 0.04). No other significant differences were found between the groups. CONCLUSION: Thus, a low level of P-APC-PCI complex may be associated with an increased risk of AVFG failure in HD patients. Further prospective studies are needed to confirm these results and to evaluate the possibility of prophylactic measures.

Biocompatibility of a novel avidin-agarose adsorbent for extracorporeal removal of redundant radiopharmaceutical from the blood.

The use of monoclonal antibodies (MAbs) in cytotoxic conjugates (radionuclides, toxins, or drugs) for targeting tumor cells is restricted due to toxicity in vital organs. Through improved tumor targeting, it is possible to administer larger amounts of such labeled MAbs, thus improving the ability to eradicate tumor cells without increased normal organ toxicity. Extracorporeal affinity adsorption treatment (ECAT) has therefore been developed using an avidin-agarose (AA) adsorbent with high binding affinity for the biotinylated radiolabeled MAb, rituximab. During ECAT, excess radioimmunoconjugates, not bound to the tumor cells, can be removed improving tumor targeting. The present study was performed to estimate the biocompatibility of the AA adsorber. Seven patients with B-cell lymphoma not responding to conventional treatment were studied. During the ECAT procedure, blood (B) components, plasma (P) complement fragments C3a, C5a, and P-bradykinin were analyzed, and other laboratory tests were carried out. Slight decreases in B-hemoglobin (8.3%), B-thrombocytes (11.4%), and P-albumin (14.3%) were observed, and could be explained by the dilution of the blood with normal saline and acid citrate dextrose. The AA adsorbent had no effect on the blood cells, immunological status or P-bradykinin level. The AA adsorber demonstrated good hemocompatibility and biocompatibility, without any side effects in the patients.

Thirty-five years of hemodialysis: two case reports as a tribute to Nils Alwall.

Two patients with long-term (35 years) survival on hemodialysis are described. Kidney replacement therapy for these patients was initiated by a pioneer in hemodialysis, Nils Alwall, in 1968 and 1971, respectively. Kidney transplantation was attempted twice in both patients; however, the dialysis-free interval was less than 18 months in both patients. These patients represent two of the longest known survivors on hemodialysis worldwide. Factors that may have influenced their survival are discussed, and the complications that have occurred over the years are presented.

Heart transplantation across the antibodies against HLA and ABO.

We have intentionally performed heart transplantation in a 5-year-old child, despite the most unfavourable risk factors for patient survival; the presence of high level of antibodies against donor's human leucocyte antigen (HLA) class I/II and blood group antigens. Pretransplant treatment by mycophenolate mofetil, prednisolone, tacrolimus, intravenous immunoglobulin, rituximab, protein-A immunoadsorption (IA) and plasma exchange reduced antibody titres against the donor's lymphocytes from 128 to 16 and against the donor's blood group antigen from 256 to 0. The patient was urgently transplanted with a heart from an ABO incompatible donor (A(1) to O). A standard triple-drug immunosuppressive protocol was used. No hyperacute rejection was seen. Antibodies against the donor's HLA antigens remained at a low level despite three acute rejections. Rising anti-A(1) blood group antibodies preceded the second rejection and were reduced by two blood group-specific IAs and remained at a low level. The patient is doing well despite the persistence of donor-reactive antibodies.

A novel platform for radioimmunotherapy: extracorporeal depletion of biotinylated and 90Y-labeled rituximab in patients with refractory B-cell lymphoma.

Radioimmunotherapy is limited by the absorbed dose to radiosensitive organs. Removal of circulating radiolabeled MAbs after tumor tissue has been optimally targeted and should permit the administration of higher radioactivity to patients, resulting in a higher absorbed tumor dose. A novel "extracorporeal affinity adsorption treatment" (ECAT) device (MitraDep)was tested, with which biotinylated and radiolabeled MAbs can be removed from the circulation by passing whole blood over a filter coated with avidin. The antibodies were simultaneously radiolabeled and biotinylated using a trifunctional moiety comprising DOTA and biotin. Eight patients--all but 1 of whom with aggressive or mantle cell B-cell lymphoma-- who had failed to respond to standard therapies received infusions of 250 mg/m(2) cold rituximab and 150 MBq (111)In-rituximab-biotin for immunoscintigraphy. A week later, the patients were treated with another 250 mg/m(2) rituximab followed by (111)In/-(90)Y-rituximab-biotin (11 or 15 (90)Y MBq/kg). ECAT was performed 48 hours later. All 8 patients receiving (111)In-rituximab-biotin showed tumor uptake. Seven patients received radioimmunotherapy and subsequent ECAT. The mean depletion of (90)Y-rituximab-biotin in whole blood after ECAT was 96%, in the whole body 49%, in the lungs 62%, and in the liver and kidneys 40%. No effects on patients' vital signs and no adverse effects on hematological or coagulation parameters was observed during the ECAT procedure. A dose-escalation study is initiated.

Rapid resolution of EPO-induced pure red cell aplasia after a course of immunoadsorption therapy using protein A columns.

Pure red cell aplasia (PRCA) is a rare, but important, complication of erythropoietin (EPO) replacement therapy in patients with renal disease. There is no consensus about the best way to treat this condition; however, recent reports indicated that immunosuppressive therapy is beneficial. We report a patient with EPO-induced PRCA treated with a regimen initially designed for antifactor VIII antibodies in patients with hemophilia. This regimen consists of immunoadsorption therapy using protein A columns, followed by oral prednisolone and single bolus infusions of intravenous immunoglobulin G and cyclophosphamide. Shortly after the course, a swift and rapid increase in reticulocyte count was evident; the patient became transfusion independent and has remained so during 2 years of follow-up. By means of this report, we wish to encourage others to consider this option when first-line treatments fail.