Animal Models for Studying Protein-Bound Uremic Toxin Removal-A Systematic Review.

Protein-bound uremic toxins (PBUTs) are associated with the progression of chronic kidney disease (CKD) and its associated morbidity and mortality. The conventional dialysis techniques are unable to efficiently remove PBUTs due to their plasma protein binding. Therefore, novel approaches are being developed, but these require validation in animals before clinical trials can begin. We conducted a systematic review to document PBUT concentrations in various models and species. The search strategy returned 1163 results for which abstracts were screened, resulting in 65 full-text papers for data extraction (rats (n = 41), mice (n = 17), dogs (n = 3), cats (n = 4), goats (n = 1), and pigs (n = 1)). We performed descriptive and comparative analyses on indoxyl sulfate (IS) concentrations in rats and mice. The data on large animals and on other PBUTs were too heterogeneous for pooled analysis. Most rodent studies reported mean uremic concentrations of plasma IS close to or within the range of those during kidney failure in humans, with the highest in tubular injury models in rats. Compared to nephron loss models in rats, a greater rise in plasma IS compared to creatinine was found in tubular injury models, suggesting tubular secretion was more affected than glomerular filtration. In summary, tubular injury rat models may be most relevant for the in vivo validation of novel PBUT-lowering strategies for kidney failure in humans.

Bioengineered Kidney Tubules Efficiently Clear Uremic Toxins in Experimental Dialysis Conditions.

Patients with end-stage kidney disease (ESKD) suffer from high levels of protein-bound uremic toxins (PBUTs) that contribute to various comorbidities. Conventional dialysis methods are ineffective in removing these PBUTs. A potential solution could be offered by a bioartificial kidney (BAK) composed of porous membranes covered by proximal tubule epithelial cells (PTECs) that actively secrete PBUTs. However, BAK development is currently being hampered by a lack of knowledge regarding the cytocompatibility of the dialysis fluid (DF) that comes in contact with the PTECs. Here, we conducted a comprehensive functional assessment of the DF on human conditionally immortalized PTECs (ciPTECs) cultured as monolayers in well plates, on Transwell® inserts, or on hollow fiber membranes (HFMs) that form functional units of a BAK. We evaluated cell viability markers, monolayer integrity, and PBUT clearance. Our results show that exposure to DF did not affect ciPTECs' viability, membrane integrity, or function. Seven anionic PBUTs were efficiently cleared from the perfusion fluid containing a PBUTs cocktail or uremic plasma, an effect which was enhanced in the presence of albumin. Overall, our findings support that the DF is cytocompatible and does not compromise ciPTECs function, paving the way for further advancements in BAK development and its potential clinical application.

The European Green Deal and nephrology: a call for action by the European Kidney Health Alliance.

The world faces a dramatic man-made ecologic disaster and healthcare is a crucial part of this problem. Compared with other therapeutic areas, nephrology care, and especially dialysis, creates an excessive burden via water consumption, greenhouse gas emission and waste production. In this advocacy article from the European Kidney Health Alliance we describe the mutual impact of climate change on kidney health and kidney care on ecology. We propose an array of measures as potential solutions related to the prevention of kidney disease, kidney transplantation and green dialysis. For dialysis, several proactive suggestions are made, especially by lowering water consumption, implementing energy-neutral policies, waste triage and recycling of materials. These include original proposals such as dialysate regeneration, dialysate flow reduction, water distillation systems for dialysate production, heat pumps for unit climatization, heat exchangers for dialysate warming, biodegradable and bio-based polymers, alternative power sources, repurposing of plastic waste (e.g. incorporation in concrete), registration systems of ecologic burden and platforms to exchange ecologic best practices. We also discuss how the European Green Deal offers real potential for supporting and galvanizing these urgent environmental changes. Finally, we formulate recommendations to professionals, manufacturers, providers and policymakers on how this correction can be achieved.

A Uremic Pig Model for Peritoneal Dialysis.

With increasing interest in home dialysis, there is a need for a translational uremic large animal model to evaluate technical innovations in peritoneal dialysis (PD). To this end, we developed a porcine model with kidney failure. Stable chronic kidney injury was induced by bilateral subtotal renal artery embolization. Before applying PD, temporary aggravation of uremia was induced by administration of gentamicin (10 mg/kg i.v. twice daily for 7 days), to obtain uremic solute levels within the range of those of dialysis patients. Peritoneal transport was assessed using a standard peritoneal permeability assessment (SPA). After embolization, urea and creatinine concentrations transiently increased from 1.6 ± 0.3 to 7.5 ± 1.2 mM and from 103 ± 14 to 338 ± 67 µM, respectively, followed by stabilization within 1-2 weeks to 2.5 ± 1.1 mM and 174 ± 28 µM, respectively. Gentamicin induced temporary acute-on-chronic kidney injury with peak urea and creatinine concentrations of 16.7 ± 5.3 mM and 932 ± 470 µM respectively. PD was successfully applied, although frequently complicated by peritonitis. SPA showed a low transport status (D/P creatinine at 4 h of 0.41 (0.36-0.53)) with a mass transfer area coefficient of 9.6 ± 3.1, 4.6 ± 2.6, 3.4 ± 2.3 mL/min for urea, creatinine, and phosphate respectively. In conclusion, this porcine model with on-demand aggravation of uremia is suitable for PD albeit with peritoneal transport characterized by a low transport status.

Evidence on continuous flow peritoneal dialysis: A review.

Clinical application of continuous flow peritoneal dialysis (CFPD) has been explored since the 1960s, but despite anticipated clinical benefits, CFPD has failed to gain a foothold in clinical practice, among others due to the typical use of two catheters (or a dual-lumen catheter) and large dialysate volumes required per treatment. Novel systems applying CFPD via the existing single-lumen catheter using rapid dialysate cycling may solve one of these hurdles. Novel on-demand peritoneal dialysate generation systems and sorbent-based peritoneal dialysate regeneration systems may considerably reduce the storage space for peritoneal dialysate and/or the required dialysate volume. This review provides an overview of current evidence on CFPD in vivo. The available (pre)clinical evidence on CFPD is limited to case reports/series with inherently nonuniform study procedures, or studies with a small sample size, short follow-up, and no hard endpoints. Small solute clearance appears to be higher in CFPD compared to conventional PD, in particular at dialysate flows ≥100 mL/min using two single-lumen catheters or a double-lumen catheter. Results of CFPD using rapid cycling via a single-lumen catheter are too preliminary to draw any conclusions. Continuous addition of glucose to dialysate with CFPD appears to be effective in reducing the maximum intraperitoneal glucose concentration while increasing ultrafiltration efficiency (mL/g absorbed glucose). Patient tolerance may be an issue since abdominal discomfort and sterile peritonitis were reported with continuous circulation of the peritoneal dialysate. Thus, well-designed clinical trials of longer duration and larger sample size, in particular applying CFPD via the existing catheter, are urgently required.

A robust, accurate, sensitive LC-MS/MS method to measure indoxyl sulfate, validated for plasma and kidney cells.

Proximal tubular damage is an important prognostic determinant in various chronic kidney diseases (CKDs). Currently available diagnostic methods do not allow for early disease detection and are neither efficient. Indoxyl sulfate (IS) is an endogenous metabolite and protein-bound uremic toxin that is eliminated via renal secretion, but accumulates in plasma during tubular dysfunction. Therefore, it may be suitable as a tubular function marker. To evaluate this, a fast bioanalytical method was developed and validated for IS in various species and a kidney cell line using LC-MS/MS. An isotope-labeled IS potassium salt as an internal standard and acetonitrile (ACN) as a protein precipitant were used for sample pretreatment. The analyte was separated on a Polaris 3 C18-A column by gradient elution using 0.1% formic acid in water and ACN, and detected by negative electrospray ionization in selected reaction monitoring mode. The within-day (≤ 4.0%) and between-day (≤ 4.3%) precisions and accuracies (97.7 to 107.3%) were within the acceptable range. The analyte showed sufficient stability at all conditions investigated. Finally, applying this assay, significantly higher plasma and lower urine concentrations of IS were observed in mice with diabetic nephropathy with tubular damage, which encourages validation toward its use as a biomarker.

Correction to "Reactivity of (Vicinal) Carbonyl Compounds with Urea".

[This corrects the article DOI: 10.1021/acsomega.9b01177.].

Safety of electrooxidation for urea removal in a wearable artificial kidney is compromised by formation of glucose degradation products.

A major challenge for the development of a wearable artificial kidney (WAK) is the removal of urea from the spent dialysate, as urea is the waste solute with the highest daily molar production and is difficult to adsorb. Here we present results on glucose degradation products (GDPs) formed during electrooxidation (EO), a technique that applies a current to the dialysate to convert urea into nitrogen, carbon dioxide, and hydrogen gas. Uremic plasma and peritoneal effluent were dialyzed for 8 hours with a WAK with and without EO-based dialysate regeneration. Samples were taken regularly during treatment. GDPs (glyoxal, methylglyoxal, and 3-deoxyglucosone) were measured in EO- and non-EO-treated fluids. Glyoxal and methylglyoxal concentrations increased 26- and 11-fold, respectively, in uremic plasma (at [glucose] 7 mmol/L) and 209- and 353-fold, respectively, in peritoneal effluent (at [glucose] 100 mmol/L) during treatment with EO, whereas no change was observed in GDP concentrations during dialysate regeneration without EO. EO for dialysate regeneration in a WAK is currently not safe due to the generation of GDPs which are not biocompatible.

Diabetic proximal tubulopathy: Can we mimic the disease for in vitro screening of SGLT inhibitors?

Diabetic kidney disease (DKD) is the foremost cause of renal failure. While the glomeruli are severely affected in the course of the disease, the main determinant for disease progression is the tubulointerstitial compartment. DKD does not develop in the absence of hyperglycemia. Since the proximal tubule is the major player in glucose reabsorption, it has been widely studied as a therapeutic target for the development of new therapies. Currently, there are several proximal tubule cell lines available, being the human kidney-2 (HK-2) and human kidney clone-8 (HKC-8) cell lines the ones widely used for studying mechanisms of DKD. Studies in these models have pushed forward the understanding on how DKD unravels, however, these cell culture models possess limitations that hamper research, including lack of transporters and dedifferentiation. The sodium-glucose cotransporters (SGLT) are identified as key players in glucose reabsorption and pharmacological inhibitors have shown to be beneficial for the long-term clinical outcome in DKD. However, their mechanism of action has, as of yet, not been fully elucidated. To comprehend the protective effects of SGLT inhibitors, it is essential to understand the complete functional, structural, and molecular features of the disease, which until now have been difficult to recapitulate. This review addresses the molecular events of diabetic proximal tubulopathy. In addition, we evaluate the protective role of SGLT inhibitors in cardiovascular and renal outcomes, and provide an overview of various in vitro models mimicking diabetic proximal tubulopathy used so far. Finally, new insights on advanced in vitro systems to surpass past limitations are postulated.

Simplified Iohexol-Based Method for Measurement of Glomerular Filtration Rate in Goats and Pigs.

The preclinical evaluation of novel therapies for chronic kidney disease requires a simple method for the assessment of kidney function in a uremic large animal model. An intravenous bolus of iohexol was administered to goats (13 measurements in n = 3 goats) and pigs (23 measurements in n = 5 pigs) before and after induction of kidney failure, followed by frequent blood sampling up to 1440 min. Plasma clearance (CL) was estimated by a nonlinear mixed-effects model (CLNLME) and by a one-compartmental pharmacokinetic disposition model using iohexol plasma concentrations during the terminal elimination phase (CL1CMT). A simple method (CLSM) for the calculation of plasma clearance was developed based on the most appropriate relationship between CLNLME and CL1CMT. CLSM and CLNLME showed good agreement (CLNLME/CLSM ratio: 1.00 ± 0.07; bias: 0.03 ± 1.64 mL/min; precision CLSM and CLNLME: 80.9% and 80.7%, respectively; the percentage of CLSM estimates falling within ±30% (P30) or ±10% (P10) of CLNLME: 53% and 12%, respectively). For mGFRNLME vs. mGFRSM, bias was -0.25 ± 2.24 and precision was 49.2% and 53.6%, respectively, P30 and P10 for mGFR based on CLSM were 71% and 24%, respectively. A simple method for measurement of GFR in healthy and uremic goats and pigs was successfully developed, which eliminates the need for continuous infusion of an exogenous marker, urine collection and frequent blood sampling.

A Uremic Goat Model Created by Subtotal Renal Artery Embolization and Gentamicin.

A large animal model of (end-stage) kidney disease (ESKD) is needed for the preclinical testing of novel renal replacement therapies. This study aimed to create stable uremia via subtotal renal artery embolization in goats and induce a temporary further decline in kidney function by administration of gentamicin. Renal artery embolization was performed in five Dutch white goats by infusing polyvinyl alcohol particles in branches of the renal artery, aiming for the embolization of ~80% of one kidney and complete embolization of the contralateral kidney. Gentamicin was administered to temporarily further increase the plasma concentrations of uremic toxins. After initial acute kidney injury, urea and creatinine plasma concentrations stabilized 1.5 ± 0.7 months post-embolization and remained elevated (12 ± 1.4 vs. 5.6 ± 0.8 mmol/L and 174 ± 45 vs. 65 ± 5.6 µmol/L, resp.) during follow-up (16 ± 6 months). Gentamicin induced temporary acute-on-chronic kidney injury with a variable increase in plasma concentrations of small solutes (urea 29 ± 15 mmol/L, creatinine 841 ± 584 µmol/L, phosphate 2.2 ± 0.3 mmol/L and potassium 5.0 ± 0.6 mmol/L) and protein-bound uremic toxins representative of patients with ESKD. A uremic goat model characterized by stable moderate uremia was established via subtotal renal artery embolization with the induction of temporary severe acute-on-chronic kidney injury by the administration of gentamicin, allowing preclinical in vivo validation of novel renal replacement technologies.

Evaluation of a system for sorbent-assisted peritoneal dialysis in a uremic pig model.

A system for sorbent-assisted peritoneal dialysis (SAPD) has been developed that continuously recirculates dialysate via a tidal mode using a single-lumen peritoneal catheter with the regeneration of spent dialysate by means of sorbents. SAPD treatment may improve plasma clearance by the maintenance of a high plasma-to-dialysate concentration gradient and by increasing the mass transfer area coefficient (MTAC) of solutes. The system is designed for daily 8-hr treatment (12 kg, nighttime system). A wearable system (2.3 kg, daytime system) may further enhance the clearance of phosphate and organic waste solutes during the day. Uremic pigs (n = 3) were treated with the day- (n = 3) and nighttime system (n = 15) for 4-8 hr per treatment. Plasma clearance (Cl), MTAC, and total mass transport (MT) of urea, creatinine, phosphate, and potassium were compared with a static dwell (n = 28). Cl, MTAC, and MT of urea, creatinine, phosphate, and potassium were low in the pig as compared to humans due to the pig's low peritoneal transport status and could be enhanced only to a limited extent by SAPD treatment compared with a static dwell (nighttime system: Cl urea: ×1.5 (p = .029), Cl creatinine: ×1.7 (p = .054), Cl phosphate: ×1.5 (p = .158), Cl potassium: ×1.6 (p = .011); daytime system: Cl creatinine: ×2.7 (p = .040), Cl phosphate: ×2.2 (p = .039)). Sorbent-assisted peritoneal dialysis treatment in a uremic pig model is safe and enhances small solute clearance as compared to a static dwell. Future studies in humans or animal species with higher peritoneal transport should elucidate whether our SAPD system enhances clearance to a clinically relevant extent as compared to conventional PD.

Drugs Commonly Applied to Kidney Patients May Compromise Renal Tubular Uremic Toxins Excretion.

In chronic kidney disease (CKD), the secretion of uremic toxins is compromised leading to their accumulation in blood, which contributes to uremic complications, in particular cardiovascular disease. Organic anion transporters (OATs) are involved in the tubular secretion of protein-bound uremic toxins (PBUTs). However, OATs also handle a wide range of drugs, including those used for treatment of cardiovascular complications and their interaction with PBUTs is unknown. The aim of this study was to investigate the interaction between commonly prescribed drugs in CKD and endogenous PBUTs with respect to OAT1-mediated uptake. We exposed a unique conditionally immortalized proximal tubule cell line (ciPTEC) equipped with OAT1 to a panel of selected drugs, including angiotensin-converting enzyme inhibitors (ACEIs: captopril, enalaprilate, lisinopril), angiotensin receptor blockers (ARBs: losartan and valsartan), furosemide and statins (pravastatin and simvastatin), and evaluated the drug-interactions using an OAT1-mediated fluorescein assay. We show that selected ARBs and furosemide significantly reduced fluorescein uptake, with the highest potency for ARBs. This was exaggerated in presence of some PBUTs. Selected ACEIs and statins had either no or a slight effect at supratherapeutic concentrations on OAT1-mediated fluorescein uptake. In conclusion, we demonstrate that PBUTs may compete with co-administrated drugs commonly used in CKD management for renal OAT1 mediated secretion, thus potentially compromising the residual renal function.

In vitro efficacy and safety of a system for sorbent-assisted peritoneal dialysis.

A system for sorbent-assisted peritoneal dialysis (SAPD) was designed to continuously recirculate dialysate via a tidal mode using a single lumen peritoneal catheter with regeneration of spent dialysate by means of sorbent technology. We hypothesize that SAPD treatment will maintain a high plasma-to-dialysate concentration gradient and increase the mass transfer area coefficient of solutes. Thereby, the SAPD system may enhance clearance while reducing the number of exchanges. Application is envisaged at night as a bedside device (12 kg, nighttime system). A wearable system (2.0 kg, daytime system) may further enhance clearance during the day. Urea, creatinine, and phosphate removal were studied with the daytime and nighttime system (n = 3 per system) by recirculating 2 liters of spent peritoneal dialysate via a tidal mode (mean flow rate: 50 and 100 mL/min, respectively) for 8 h in vitro. Time-averaged plasma clearance over 24 h was modeled assuming one 2 liter exchange/day, an increase in mass transfer area coefficient, and 0.9 liters ultrafiltration/day. Urea, creatinine, and phosphate removal was 33.2 ± 4.1, 5.3 ± 0.5, and 6.2 ± 1.8 mmol, respectively, with the daytime system and 204 ± 28, 10.3 ± 2.4, and 11.4 ± 2.1 mmol, respectively, with the nighttime system. Time-averaged plasma clearances of urea, creatinine and phosphate were 9.6 ± 1.1, 9.6 ± 1.7, and 7.0 ± 0.9 mL/min, respectively, with the nighttime system and 10.8 ± 1.1, 13.4 ± 1.8, and 9.7 ± 1.6 mL/min, respectively, with the daytime and nighttime system. SAPD treatment may improve removal of uremic toxins compared with conventional peritoneal dialysis, provided that peritoneal mass transport will increase.

Protein-Bound Uremic Toxins in Hemodialysis Patients Relate to Residual Kidney Function, Are Not Influenced by Convective Transport, and Do Not Relate to Outcome.

Protein-bound uremic toxins (PBUTs) are predominantly excreted by renal tubular secretion and hardly removed by traditional hemodialysis (HD). Accumulation of PBUTs is proposed to contribute to the increased morbidity and mortality of patients with end-stage kidney disease (ESKD). Preserved PBUT excretion in patients with residual kidney function (RKF) and/or increased PBUT clearance with improved dialysis techniques might improve the prognosis of patients with ESKD. The aims of this study are to explore determinants of PBUTs in HD patients, and investigate whether hemodiafiltration (HDF) lowers PBUT plasma concentrations, and whether PBUTs are related to the outcome. Predialysis total plasma concentrations of kynurenine, kynurenic acid, indoxyl sulfate, indole-3-acetic acid, p-cresyl sulfate, p-cresyl glucuronide, and hippuric acid were measured by UHPLC-MS at baseline and after 6 months of follow-up in the first 80 patients participating in the CONvective TRAnsport Study (CONTRAST), a randomized controlled trial that compared the effects of online HDF versus low-flux HD on all-cause mortality and new cardiovascular events. RKF was inversely related to kynurenic acid (p < 0.001), indoxyl sulfate (p = 0.001), indole-3-acetic acid (p = 0.024), p-cresyl glucuronide (p = 0.004) and hippuric acid (p < 0.001) plasma concentrations. Only indoxyl sulfate decreased by 8.0% (-15.3 to 34.6) in patients treated with HDF and increased by 11.9% (-15.4 to 31.9) in HD patients after 6 months of follow-up (HDF vs. HD: p = 0.045). No independent associations were found between PBUT plasma concentrations and either risk of all-cause mortality or new cardiovascular events. In summary, in the current population, RKF is an important determinant of PBUT plasma concentrations in HD patients. The addition of convective transport did not consistently decrease PBUT plasma concentrations and no relation was found between PBUTs and cardiovascular endpoints.

Phenylglyoxaldehyde-Functionalized Polymeric Sorbents for Urea Removal from Aqueous Solutions.

For realization of a wearable artificial kidney based on regeneration of a small volume of dialysate, efficient urea removal from dialysate is a major challenge. Here a potentially suitable polymeric sorbent based on phenylglyoxaldehyde (PGA), able to covalently bind urea under physiological conditions, is described. Sorbent beads containing PGA groups were obtained by suspension polymerization of either styrene or vinylphenylethan-1-one (VPE), followed by modification of the aromatic groups of poly(styrene) and poly(VPE) into PGA. It was found that PGA-functionalized sorbent beads had maximum urea binding capacities of 1.4-2.2 mmol/g and removed ∼0.6 mmol urea/g in 8 h at 37 °C under static conditions from urea-enriched phosphate-buffered saline, conditions representative of dialysate regeneration. This means that the daily urea production of a dialysis patient can be removed with a few hundred grams of this sorbent which, is an important step forward in the development of a wearable artificial kidney.

A Ninhydrin-Type Urea Sorbent for the Development of a Wearable Artificial Kidney.

The aim of this study is to develop polymeric chemisorbents with a high density of ninhydrin groups, able to covalently bind urea under physiological conditions and thus potentially suitable for use in a wearable artificial kidney. Macroporous beads are prepared by suspension polymerization of 5-vinyl-1-indanone (vinylindanone) using a 90:10 (v/v) mixture of toluene and nitrobenzene as a porogen. The indanone groups are subsequently oxidized in a one-step procedure into ninhydrin groups. Their urea absorption kinetics are evaluated under both static and dynamic conditions at 37 °C in simulated dialysate (urea in phosphate buffered saline). Under static conditions and at a 1:1 molar ratio of ninhydrin: urea the sorbent beads remove ≈0.6-0.7 mmol g-1 and under dynamic conditions and at a 2:1 molar excess of ninhydrin ≈0.6 mmol urea g-1 sorbent in 8 h at 37 °C, which is a step toward a wearable artificial kidney.

Urea removal strategies for dialysate regeneration in a wearable artificial kidney.

The availability of a wearable artificial kidney (WAK) that provides dialysis outside the hospital would be an important advancement for dialysis patients. The concept of a WAK is based on regeneration of a small volume of dialysate in a closed-loop. Removal of urea, the primary waste product of nitrogen metabolism, is the major challenge for the realization of a WAK since it is a molecule with low reactivity that is difficult to adsorb while it is the waste solute with the highest daily molar production. Currently, no efficient urea removal technology is available that allows for miniaturization of the WAK to a size and weight that is acceptable for patients to carry. Several urea removal strategies have been explored, including enzymatic hydrolysis by urease, electro-oxidation and sorbent systems. However, thus far, these methods have toxic side effects, limited removal capacity or slow removal kinetics. This review discusses different urea removal strategies for application in a wearable dialysis device, from both a chemical and a medical perspective.

Kidney-based in vitro models for drug-induced toxicity testing.

The kidney is frequently involved in adverse effects caused by exposure to foreign compounds, including drugs. An early prediction of those effects is crucial for allowing novel, safe drugs entering the market. Yet, in current pharmacotherapy, drug-induced nephrotoxicity accounts for up to 25% of the reported serious adverse effects, of which one-third is attributed to antimicrobials use. Adverse drug effects can be due to direct toxicity, for instance as a result of kidney-specific determinants, or indirectly by, e.g., vascular effects or crystals deposition. Currently used in vitro assays do not adequately predict in vivo observed effects, predominantly due to an inadequate preservation of the organs' microenvironment in the models applied. The kidney is highly complex, composed of a filter unit and a tubular segment, together containing over 20 different cell types. The tubular epithelium is highly polarized, and the maintenance of this polarity is critical for optimal functioning and response to environmental signals. Cell polarity is dependent on communication between cells, which includes paracrine and autocrine signals, as well as biomechanic and chemotactic processes. These processes all influence kidney cell proliferation, migration, and differentiation. For drug disposition studies, this microenvironment is essential for prediction of toxic responses. This review provides an overview of drug-induced injuries to the kidney, details on relevant and translational biomarkers, and advances in 3D cultures of human renal cells, including organoids and kidney-on-a-chip platforms.

Reactivity of (Vicinal) Carbonyl Compounds with Urea.

Urea removal from dialysate is the major obstacle in realization of a miniature dialysis device, based on continuous dialysate regeneration in a closed loop, used for the treatment of patients suffering from end-stage kidney disease. For the development of a polymeric urea sorbent, capable of removing urea from dialysate with high binding capacities and fast reaction kinetics, a systematic kinetic study was performed on the reactivity of urea with a library of low-molecular-weight carbonyl compounds in phosphate-buffered saline (pH 7.4) at 323 K. It was found that dialdehydes do not react with urea under these conditions but need to be activated under acidic conditions and require aldehyde groups in close proximity to each other to allow a reaction with urea. Among the 31 (hydrated) carbonyl compounds tested, triformylmethane, ninhydrin, and phenylglyoxaldehyde were the most reactive ones with urea. This is attributed to the low dehydration energies of these compounds, as calculated by Gibbs free energy differences between the hydrated and dehydrated carbonyl compounds, which are favorable for the reaction with urea. Therefore, future urea sorbents should contain such functional groups at the highest possible density.