An updated review of the existing knowledge regarding uremic toxins facilitates the design of experimental studies. We performed a literature search and found 621 articles about uremic toxicity published after a 2003 review of this topic. Eighty-seven records provided serum or blood measurements of one or more solutes in patients with CKD. These records described 32 previously known uremic toxins and 56 newly reported solutes. The articles most frequently reported concentrations of β2-microglobulin, indoxyl sulfate, homocysteine, uric acid, and parathyroid hormone. We found most solutes (59%) in only one report. Compared with previous results, more recent articles reported higher uremic concentrations of many solutes, including carboxymethyllysine, cystatin C, and parathyroid hormone. However, five solutes had uremic concentrations less than 10% of the originally reported values. Furthermore, the uremic concentrations of four solutes did not exceed their respective normal concentrations, although they had been previously described as uremic retention solutes. In summary, this review extends the classification of uremic retention solutes and their normal and uremic concentrations, and it should aid the design of experiments to study the biologic effects of these solutes in CKD.

Normal and Pathologic Concentrations of Uremic Toxins

To make an evidence-based evaluation of the relationship between kidney failure and cardiovascular risk, we reviewed the literature obtained from a PubMed search using pre-defined keywords related to both conditions and covering 18 years (1986 until end 2003). Eighty-five publications, covering 552 258 subjects, are summarized. All but three studies support a link between kidney dysfunction and cardiovascular risk. More importantly, the association is observed very early during the evolution of renal failure: an accelerated cardiovascular risk appears at varying glomerular filtration rate (GFR) cut-off values, which were >/=60 ml/min in at least 20 studies. Many studies lacked a clear definition of cardiovascular disease and/or used a single determination of serum creatinine or GFR as an index of kidney function, which is not necessarily corresponding to well-defined chronic kidney disease. In six studies, however, chronic kidney dysfunction and cardiovascular disease were well defined and the results of these confirm the impact of kidney dysfunction. It is concluded that there is an undeniable link between kidney dysfunction and cardiovascular risk and that the presence of even subtle kidney dysfunction should be considered as one of the conditions necessitating intensive prevention of this cardiovascular risk.

Chronic kidney disease as cause of cardiovascular morbidity and mortality.

Oxidative stress and inflammation, a link between chronic kidney disease and cardiovascular disease.

The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification.

A growing number of publications supports a biologic effect of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate. However, the use of unrealistically high free concentrations of these compounds and/or inappropriately low albumin concentrations may blur the interpretation of these results. Here, we performed a systematic review, selecting only studies in which, depending on the albumin concentration, real or extrapolated free concentrations of indoxyl sulfate and p-cresyl sulfate remained in the uremic range. The 27 studies retrieved comprised in vitro and animal studies. A quality score was developed, giving 1 point for each of the following criteria: six or more experiments, confirmation by more than one experimental approach, neutralization of the biologic effect by counteractive reagents or antibodies, use of a real-life model, and use of dose-response analyses in vitro and/or animal studies. The overall average score was 3 of 5 points, with five studies scoring 5 of 5 points and six studies scoring 4 of 5 points, highlighting the superior quality of a substantial number of the retrieved studies. In the 11 highest scoring studies, most functional deteriorations were related to uremic cardiovascular disease and kidney damage. We conclude that our systematic approach allowed the retrieval of methodologically correct studies unbiased by erroneous conditions related to albumin binding. Our data seem to confirm the toxicity of indoxyl sulfate and p-cresyl sulfate and support their roles in vascular and renal disease progression.

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate: A Systematic Review

Review on uremic toxins: Classification, concentration, and interindividual variability

Background: Uremic solute concentration increases as Glomerular Filtration Rate (GFR) declines. Weak associations were demonstrated between estimated GFR (eGFR) and the concentrations of several small water-soluble and protein-bound uremic solutes (MW 500Da). 
Materials and Methods: In 95 CKD-patients (CKD-stage 2-5 not on dialysis), associations between different eGFR-formulae (creatinine, CystatinC-based or both) and the natural logarithm of the concentration of several LMWP's were analyzed: i.e. parathyroid hormone (PTH), Cystatin C (CystC), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), leptin, retinol binding protein (RbP), immunoglobin light chains kappa and lambda (Ig-kappa and Ig-lambda), beta-2-microglobulin (beta M-2), myoglobin and fibroblast growth factor-23 (FGF-23)). 
Results: The regression coefficients (R-2) between eGFR, based on the CKD-EPI-Crea-CystC-formula as reference, and the examined LMWP's could be divided into three groups. Most of the LMWP's associated weakly (R-2 0.7). Almost identical R-2-values were found per LMWP for all eGFR-formulae, with exception of CystC and beta M-2 which showed weaker associations with creatinine-based than with CystC-based eGFR. 
Conclusion: The association between eGFR and the concentration of several LMWP's is inconsistent, with in general low R-2-values. Thus, the use of eGFR to evaluate kidney function does not reflect the concentration of several LMWP's with proven toxic impact in CKD.

https://biblio.ugent.be/publication/3096840/file/3096853.pdf

Estimated Glomerular Filtration Rate Is a Poor Predictor of the Concentration of Middle Molecular Weight Uremic Solutes in Chronic Kidney Disease

Current chemotherapy for multiple myeloma is based on bortezomib (BOR), dexamethasone (DEX), and thalidomide (THA). The purpose of the present study was to examine their clearance during high-cutoff (HCO) hemodialysis and to accordingly apply the results to the dialytic removal of protein-bound substances in general. During in vitro hemodialysis with human blood (blood, dialysate, and ultrafiltration flow rates 250, 500 and 5 mL/min, respectively) comparing a highly permeable HCO dialyzer (Theralite, 2.1 m(2) ) to a high-flux dialyzer (PFX; 2.1 m(2) ), ultrafiltered volume was replaced by saline containing 30 g/L urea. After recirculation for equilibration, BOR was injected, and arterial and venous samples were drawn after 10, 11, and 12 min to measure the plasma clearance (K) of both urea and BOR. The same procedure was performed with THA and DEX. By mathematical simulation, the influence of varying plasma albumin concentrations (CHSA ) on the protein-bound drug fraction (PBF) and K was assessed. Plasma K values of HCO and PFX for THA, BOR, and DEX were about 40% (80 ± 7 vs. 65 ± 6 mL/min; P < 0.05), 70% (40 ± 8 vs. 33 ± 4 mL/min; P < 0.05), and 65% (47 ± 11 vs. 38 ± 7 mL/min; P < 0.05), respectively-lower (P < 0.0001) compared with urea (125 ± 7 vs. 122 ± 5 mL/min). K was highest (P < 0.0001) for THA. K was negatively correlated with CHSA (THA, r(2)  = 0.58, P < 0.001; BOR, r(2)  = 0.24, P < 0.05; DEX, r(2)  = 0.22, P < 0.05). CHSA continually decreased (P < 0.05) over time only with HCO, resulting in lower calculated PBF. Compared with BOR and DEX (minimum 72 and 56%, respectively), the PBF of THA (37%) was significantly lower (P < 0.001). A mathematical simulation based on the K values of urea and the drugs reliably estimated PBF (r(2)  = 0.886, P < 0.001). Drugs for multiple myeloma therapy are significantly removed with both HCO and PFX, with important implications for the dosing and timing of administration, particularly in patients with cast nephropathy receiving extended dialysis. If the Kurea of a dialyzer and the PBF of any given drug are known, Kdrug can be reliably estimated by mathematical simulation.

Clearance of drugs for multiple myeloma therapy during in vitro high-cutoff hemodialysis

The invention relates to a blood treatment system comprising at least one first device and at least one second device. The first device is a membrane filter for removing toxic mediators from blood, and the second device is suitable for removing granulocytes and monocytes from blood. The first device has a first blood-side flow path for conducting blood, and the second device has a second blood-side flow path. The first and second device are connected serially one behind the other such that the first blood-side flow path is fluidically connected to the second blood-side flow path. The membrane filter has a filter interior in the housing of the membrane filter and a semi-permeable membrane arranged in the filter interior, said membrane separating the filter interior into a retentate area and a permeate area. The housing has a blood inlet device and a blood outlet device, which are fluidically connected to the retentate area, and a permeate outlet for discharging permeate from the permeate area. The blood inlet device, the retentate area, and the blood outlet device form the first blood-side flow path. The membrane filter has a separating characteristic such that the filter coefficient for albumin, SK Alb , ranges from 0.015 to 0.35.

System for removing pro-inflammatory mediators as well as granulocytes and monocytes from blood

The membrane has an interior filter space in its housing and a semipermeable membrane arranged in the interior filter space, which membrane divides the interior filter space into a retentate chamber and permeate chamber. The housing has a blood inlet device and a blood outlet device that are in fluid communication with the retentate chamber, as well as a permeate outlet for diverting permeate from the permeate chamber. The blood inlet device, the retentate chamber and the blood outlet device form the first blood flow path. The membrane filter has a separation characteristic such that the sieve coefficient for albumin, SKAlb, is within the range from 0.015 to 0.35.

Horst Dieter Lemke

Papers

Review on uremic toxins: Classification, concentration, and interindividual variability

Estimated Glomerular Filtration Rate Is a Poor Predictor of the Concentration of Middle Molecular Weight Uremic Solutes in Chronic Kidney Disease

Clearance of drugs for multiple myeloma therapy during in vitro high-cutoff hemodialysis

System for removing pro-inflammatory mediators as well as granulocytes and monocytes from blood

System for removal of pro-inflammatory mediators as well as granulocytes and monocytes from blood