Cardiovascular disease and infections are major causes for the high incidence of morbidity and mortality of patients with chronic kidney disease. Both complications are directly or indirectly associated with disturbed functions or altered apoptotic rates of polymorphonuclear leukocytes, monocytes, lymphocytes, and dendritic cells. Normal responses of immune cells can be reduced, leading to infectious diseases or pre-activated/primed, giving rise to inflammation and subsequently to cardiovascular disease. This review summarizes the impact of kidney dysfunction on the immune system. Renal failure results in disturbed renal metabolic activities with reduced renin, erythropoietin, and vitamin D production, which adversely affects the immune system. Decreased kidney function also leads to reduced glomerular filtration and the retention of uremic toxins. A large number of uremic toxins with detrimental effects on immune cells have been identified. Besides small water-soluble and protein-bound compounds originating from the intestinal microbiome, several molecules in the middle molecular range, e.g., immunoglobulin light chains, retinol-binding protein, the neuropeptides Met-enkephalin and neuropeptide Y, endothelin-1, and the adipokines leptin and resistin, adversely affect immune cells. Posttranslational modifications such as carbamoylation, advanced glycation products, and oxidative modifications contribute to uremic toxicity. Furthermore, high-density lipoprotein from uremic patients has an altered protein profile and thereby loses its anti-inflammatory properties.

Kidney dysfunction leads to disturbed renal metabolic activities and to impaired glomerular filtration, resulting in the retention of toxic solutes affecting all organs of the body. Cardiovascular disease (CVD) and infections are the main causes for the increased occurrence of morbidity and mortality among patients with chronic kidney disease (CKD). Both complications are directly or indirectly linked to a compromised immune defense. The specific coordinated roles of polymorphonuclear leukocytes (PMNLs), monocytes/macrophages, lymphocytes and antigen-presenting cells (APCs) in maintaining an efficient immune response are affected. Their normal response can be impaired, giving rise to infectious diseases or pre-activated/primed, leading to inflammation and consequently to CVD. Whereas the coordinated removal via apoptosis of activated immune cells is crucial for the resolution of inflammation, inappropriately high apoptotic rates lead to a diminished immune response. In uremia, the balance between pro- and anti-inflammatory and between pro- and anti-apoptotic factors is disturbed. This review summarizes the interrelated parameters interfering with the immune response in uremia, with a special focus on the non-specific immune response and the role of uremic toxins.

The progression of chronic kidney disease (CKD) leads to the dysfunction of multiple organs with clinical features constituting the uraemic syndrome and is characterized by a variety of metabolic and enzymatic disturbances. Many different substances, which are normally secreted into the urine by the healthy kidneys, are retained in the body. Those uraemic retention solutes which are the main actors during the development and manifestation of the uraemic syndrome are called uraemic toxins [ 1 ]. The identification, characterization and analytical determination of toxins responsible for the adverse biological effects encountered in uraemia and the knowledge of their patho-physiological importance is crucial for future prevention and therapy in patients with CKD stage 5. The information obtained from these analyses will make it possible to evaluate existing therapeutic approaches and to define new prognostic markers for the removal of uraemic toxins and, more importantly, it will allow the design of new specific removal strategies or other interventions to decrease and even normalize the plasma levels of uraemic toxins.

The activation of polymorphonuclear leucocytes (PMNLs) causes inflammation and as a result cardiovascular disease, which is a main risk factor for increased morbidity and mortality in patients with chronic kidney disease. Toxins accumulating in uraemic patients play a major role in modulating essential PMNL functions and apoptosis, the latter being crucial for a coordinated resolution of inflammation. One uraemic toxin is phenylacetic acid (PAA). We therefore investigated whether PAA contributes to the deranged immune response in uraemia by modulating PMNL activities. PMNL oxidative burst, phagocytosis and surface expression of the activation markers CD11b and CD18 were measured by flow cytometry in whole blood from healthy subjects in the presence and absence of PAA. Spontaneous apoptosis of isolated PMNLs was assessed by evaluating morphological features under the fluorescence microscope and by measuring the DNA content by flow cytometry. PMNL chemotaxis was tested by the under-agarose method. PAA significantly enhanced the stimulation of PMNL oxidative burst by Escherichia coli, phagocytosis of E. coli by PMNLs and the expression of CD11b and CD18 at the PMNL surface. PAA significantly decreased PMNL apoptosis resulting in an increased percentage of viable cells. PAA affected neither the oxidative burst stimulated by phorbol-12-myristate-13-acetate nor PMNL chemotaxis. PAA increases the activation of various PMNL functions and the expression of surface activation markers, while it attenuates PMNL apoptotic cell death. Therefore, PAA may contribute to the inflammatory state and consequently to increased cardiovascular risk in uraemic patients.

Background. Disturbed polymorphonuclear leukocyte (PMNL) apoptosis contributes to the dysregulation of the non-specific immune system in uraemia. Intracellular Ca ²⁺ modulates PMNL apoptotic cell death. We investigated the effect of para -hydroxy-hippuric acid (PHA), an erythrocyte plasma membrane Ca ²⁺ -ATPase inhibitor accumulating in uraemic sera, and of cyclopiazonic acid (CPA), an inhibitor of the sarko/endoplasmatic Ca ²⁺ -ATPase, on PMNL apoptosis. Methods. Apoptosis of PMNLs from healthy subjects and from haemodialysis (HD) patients was assessed after incubation for 20 h by evaluating morphological features under the fluorescence microscope and by measuring the DNA content and caspase activities by flow cytometry. The intracellular calcium concentration ([Ca ²⁺ ] _i ) was determined by measurement of fura-2 fluorescence using the 340/ 380 nm dual wavelength excitation. Results. Spontaneous apoptosis of PMNLs from healthy subjects and from HD patients did not differ. PHA significantly attenuated, while CPA increased, the apoptotic cell death of PMNLs from healthy subjects. The PHA effect was not observed with PMNLs from HD patients, irrespective of whether the blood was drawn before or after HD treatment. Baseline [Ca ²⁺ ] _i was increased in PMNLs obtained from HD patients before dialysis but reversed after dialysis. The PHA effects were not mediated via [Ca ²⁺ ] _i . The chemotactic peptide N -formyl- l -methionyl- l -leucyl- l -phenylalanine (fMLP) induced a [Ca ²⁺ ] _i increase and reduced PMNL survival. Extracellular Ca ²⁺ did not affect CPA- and fMLP-induced apoptosis. Conclusions. PHA, without affecting [Ca ²⁺ ] _i , attenuates apoptosis of healthy but not of uraemic PMNLs. CPA and fMLP enhance PMNL apoptosis independently of Ca ²⁺ influx.