Immune dysfunction in uremia

Among uremic patients on hemodialysis and continuous ambulatory peritoneal dialysis treatment infectious complications leading to a high incidence of morbidity and mortality are a well documented problem. Polymorphonuclear leukocytes (PMNLs) are the main cells of the unspecific defence system during bacterial infections. There is a number of partly interdependent factors responsible for the diminished PMNL functions (chemotaxis, phagocytosis, intracellular killing by proteolytic enzymes and toxic oxygen radicals) found in uremia: iron overload, elevated levels of intracellular calcium and hemodialysis treatment per se has been shown to be involved in altered PMNL functions. Uremic toxins are circulating plasma factors accumulating in the serum of uremic patients. They are thought to play a crucial role in inhibiting the unspecific immune defence. A number of uremic toxins has already been purified and characterized. In our laboratory, a granulocyte inhibiting protein (GIP) with homology to immunoglobulin light chains has been isolated. We could show that free immunoglobulin light chains per se are able to interfere with essential PMNL functions. A GIP with homology to beta 2-microglobulin was also isolated from dialysis patients. Angiogenin was purified from uremic patients as a PMNL degranulation inhibiting protein and complement factor D was shown to adversely affect PMNL functions. A modified form of ubiquitin isolated from peritoneal dialysis patients interferes with PMNL chemotaxis. Furthermore, p-cresol was identified as a uremic solute that impairs the respiratory burst activity of PMNL. There is also increased clinical evidence for profound defects in the specific immune defence in uremia, such as the high susceptibility to viral infections in uremic patients, the deficient responses of their T lymphocytes, and the significantly depressed specific antibody responses.