Interaction of Human Serum Albumin with Uremic Toxins: The Need of New Strategies Aiming at Uremic Toxins Removal

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Abstract

Chronic kidney disease (CKD) is acknowledged worldwide to be a grave threat to public health, with the number of US end-stage kidney disease (ESKD) patients increasing steeply from 10,000 in 1973 to 703,243 in 2015. Protein-bound uremic toxins (PBUTs) are excreted by renal tubular secretion in healthy humans, but hardly removed by traditional haemodialysis (HD) in ESKD patients. The accumulation of these toxins is a major contributor to these sufferers’ morbidity and mortality. As a result, some improvements to dialytic removal have been proposed, each with their own upsides and drawbacks. Longer dialysis sessions and hemodiafiltration, though, have not performed especially well, while larger dialyzers, coupled with a higher dialysate flow, proved to have some efficiency in indoxyl sulfate (IS) clearance, but with reduced impact on patients’ quality of life. More efficient in removing PBUTs was fractionated plasma separation and adsorption, but the risk of occlusive thrombosis was worryingly high. A promising technique for the removal of PBUTs is binding competition, which holds great hopes for future HD. This short review starts by presenting the PBUTs chemistry with emphasis on the chemical interactions with the transport protein, human serum albumin (HSA). Recent membrane-based strategies targeting PBUTs removal are also presented, and their efficiency is discussed.

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Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients.

Fellype C. Barreto, Daniela Barreto, Sophie Liabeuf … (2009)

As a major component of uremic syndrome, cardiovascular disease is largely responsible for the high mortality observed in chronic kidney disease (CKD). Preclinical studies have evidenced an association between serum levels of indoxyl sulfate (IS, a protein-bound uremic toxin) and vascular alterations. The aim of this study is to investigate the association between serum IS, vascular calcification, vascular stiffness, and mortality in a cohort of CKD patients. One-hundred and thirty-nine patients (mean +/- SD age: 67 +/- 12; 60% male) at different stages of CKD (8% at stage 2, 26.5% at stage 3, 26.5% at stage 4, 7% at stage 5, and 32% at stage 5D) were enrolled. Baseline IS levels presented an inverse relationship with renal function and a direct relationship with aortic calcification and pulse wave velocity. During the follow-up period (605 +/- 217 d), 25 patients died, mostly because of cardiovascular events (n = 18). In crude survival analyses, the highest IS tertile was a powerful predictor of overall and cardiovascular mortality (P = 0.001 and 0.012, respectively). The predictive power of IS for death was maintained after adjustment for age, gender, diabetes, albumin, hemoglobin, phosphate, and aortic calcification. The study presented here indicates that IS may have a significant role in the vascular disease and higher mortality observed in CKD patients.

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Acute kidney injury increases risk of ESRD among elderly.

Areef Ishani, Jay L Xue, Jonathan Himmelfarb … (2009)

Risk for ESRD among elderly patients with acute kidney injury (AKI) has not been studied in a large, representative sample. This study aimed to determine incidence rates and hazard ratios for developing ESRD in elderly individuals, with and without chronic kidney disease (CKD), who had AKI. In the 2000 5% random sample of Medicare beneficiaries, clinical conditions were identified using Medicare claims; ESRD treatment information was obtained from ESRD registration during 2 yr of follow-up. Our cohort of 233,803 patients were hospitalized in 2000, were aged > or = 67 yr on discharge, did not have previous ESRD or AKI, and were Medicare-entitled for > or = 2 yr before discharge. In this cohort, 3.1% survived to discharge with a diagnosis of AKI, and 5.3 per 1000 developed ESRD. Among patients who received treatment for ESRD, 25.2% had a previous history of AKI. After adjustment for age, gender, race, diabetes, and hypertension, the hazard ratio for developing ESRD was 41.2 (95% confidence interval [CI] 34.6 to 49.1) for patients with AKI and CKD relative to those without kidney disease, 13.0 (95% CI 10.6 to 16.0) for patients with AKI and without previous CKD, and 8.4 (95% CI 7.4 to 9.6) for patients with CKD and without AKI. In summary, elderly individuals with AKI, particularly those with previously diagnosed CKD, are at significantly increased risk for ESRD, suggesting that episodes of AKI may accelerate progression of renal disease.

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Structural basis of the drug-binding specificity of human serum albumin.

Jamie Ghuman, Patricia A Zunszain, Isabelle Petitpas … (2005)

Human serum albumin (HSA) is an abundant plasma protein that binds a remarkably wide range of drugs, thereby restricting their free, active concentrations. The problem of overcoming the binding affinity of lead compounds for HSA represents a major challenge in drug development. Crystallographic analysis of 17 different complexes of HSA with a wide variety of drugs and small-molecule toxins reveals the precise architecture of the two primary drug-binding sites on the protein, identifying residues that are key determinants of binding specificity and illuminating the capacity of both pockets for flexible accommodation. Numerous secondary binding sites for drugs distributed across the protein have also been identified. The binding of fatty acids, the primary physiological ligand for the protein, is shown to alter the polarity and increase the volume of drug site 1. These results clarify the interpretation of accumulated drug binding data and provide a valuable template for design efforts to modulate the interaction with HSA.