Improving home haemodialysis: Stability evaluation of routine clinical chemistry analytes in blood samples of haemodialysis patients

Introduction: A growing number of dialysis patients is treated with home haemodialysis. Our current pre-analytical protocols require patients to centrifuge the blood sample and transfer the plasma into a new tube at home. This procedure is prone to errors and precludes accurate bicarbonate measurement, required for determining dialysate bicarbonate concentration and maintaining acid-base status. We therefore evaluated whether cooled overnight storage of gel separated plasma is an acceptable alternative. Materials and methods: Venous blood of 34 haemodialysis patients was collected in 2 lithium heparin blood collection tubes with gel separator (LH PSTTM II, REF 367374; Becton Dickinson, New Jersey, USA). One tube was analysed directly for measurement of bicarbonate, potassium, calcium, phosphate, glucose, urea, lactate, aspartate aminotransferase (AST), and lactate dehydrogenase (LD); whereas the other was centrifuged and stored unopened at 4 °C and analysed 24 h later. To measure analyte stability after 24 h of storage, the mean difference was calculated and compared to the total allowable error (TEa) which was used as acceptance limit. Results: Potassium (Z = - 4.28, P < 0.001), phosphate (Z = - 3.26, P = 0.001), lactate (Z = - 5.11, P < 0.001) and AST (Z = - 2.71, P = 0.007) concentrations were higher, whereas glucose (Z = 4.00, P < 0.001) and LD (Z = 3.13, P = 0.002) showed a reduction. All mean differences were smaller than the TEa and thus not clinically relevant. Bicarbonate (Z = 0.69, P = 0.491), calcium (Z = - 0.23, P = 0.815) and urea (Z = 0.81, P =0.415) concentrations were stable. Conclusions: Our less complex, user-friendly pre-analytical procedure resulted in at least 24 h stability of analytes relevant for monitoring haemodialysis, including bicarbonate. This allows shipment and analysis the next day

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

SIMPLE SUMMARY: To improve the treatment of patients with kidney disease, new therapies are being developed. Before being used on humans, such therapies need to be tested on animals with kidney disease because reduced kidney function may influence the safety and efficacy of the treatment. Using large animals for this purpose is important because they tolerate frequent blood sampling, which allows for repeated monitoring. Goats seem particularly suitable for the evaluation of novel hemodialysis therapies since they are docile, have easily accessible neck veins to obtain blood access and body weights comparable with humans. Currently, no simple method is available to measure kidney function in goats (with or without impaired kidney function). Therefore, we developed a simple method to measure the kidney function in goats and pigs, which is based on a single injection of iohexol and requires three blood samples. Subsequently, kidney function can be calculated using a formula derived from pharmacokinetic modelling. The measurement of kidney function using our simplified method is relatively easy to perform, reduces total blood sampling and eliminates the need for an indwelling bladder catheter as compared to existing methods that require continuous infusion of a substance and timed urine collection. ABSTRACT: 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 (CL(NLME)) and by a one-compartmental pharmacokinetic disposition model using iohexol plasma concentrations during the terminal elimination phase (CL(1CMT)). A simple method (CL(SM)) for the calculation of plasma clearance was developed based on the most appropriate relationship between CL(NLME) and CL(1CMT). CL(SM) and CL(NLME) showed good agreement (CL(NLME)/CL(SM) ratio: 1.00 ± 0.07; bias: 0.03 ± 1.64 mL/min; precision CL(SM) and CL(NLME): 80.9% and 80.7%, respectively; the percentage of CL(SM) estimates falling within ±30% (P30) or ±10% (P10) of CL(NLME): 53% and 12%, respectively). For mGFR(NLME) vs. mGFR(SM), bias was −0.25 ± 2.24 and precision was 49.2% and 53.6%, respectively, P30 and P10 for mGFR based on CL(SM) 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

UHPLC-MS/MS method for iohexol determination in human EDTA and lithium-heparin plasma, human urine and in goat- and pig EDTA plasma

Aim: Iohexol plasma clearance is used as an indicator of kidney function in clinical and preclinical settings. To investigate the pharmacokinetic profile of iohexol, a rapid, simple method for measurement of iohexol in different matrices and species was needed. Materials & methods: Iohexol was separated on an Accucore C18 column (Thermo Fisher Scientific, CA, USA). Detection was performed on a Thermo Scientific Quantiva tandem quadrupole mass spectrometer. The method was validated according to the requirements for bioanalytical methods issued by the US FDA and European Medicines Agency. Conclusion: We developed and validated a fast and efficient analytical method, suitable for analyzing iohexol in human EDTA plasma, human lithium-heparin plasma, human urine and goat- and pig EDTA plasma, using only one calibration line prepared in human EDTA plasma

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&nbsp;kg, nighttime system). A wearable system (2.3&nbsp;kg, daytime system) may further enhance the clearance of phosphate and organic waste solutes during the day. Uremic pigs (n&nbsp;=&nbsp;3) were treated with the day- (n&nbsp;=&nbsp;3) and nighttime system (n&nbsp;=&nbsp;15) for 4-8&nbsp;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&nbsp;=&nbsp;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&nbsp;=&nbsp;.029), Cl creatinine: ×1.7 (p&nbsp;=&nbsp;.054), Cl phosphate: ×1.5 (p&nbsp;=&nbsp;.158), Cl potassium: ×1.6 (p&nbsp;=&nbsp;.011); daytime system: Cl creatinine: ×2.7 (p&nbsp;=&nbsp;.040), Cl phosphate: ×2.2 (p&nbsp;=&nbsp;.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

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

De draagbare kunstnier: hoe staan de zaken?

Draagbare dialyseapparaten geven dialysepatiënten de mogelijkheid om thuis te dialyseren en vergroten daarmee hun mobiliteit en autonomie. Centraal in de ontwikkeling van deze apparaten staat het ontwikkelen van een strategie om dialysaat te hergebruiken. Momenteel wordt in Nederland toegewerkt naar een klinische trial met een draagbaar hemodialyseapparaat van circa 10 kg en naar een klinische trial met een draagbaar systeem van circa 10 kg voor peritoneale dialyse met continue flow

From portable dialysis to a bioengineered kidney

Introduction: Since the advent of peritoneal dialysis (PD) in the 1970s, the principles of dialysis have changed little. In the coming decades, several major breakthroughs are expected. Areas covered: Novel wearable and portable dialysis devices for both hemodialysis (HD) and PD are expected first. The HD devices could facilitate more frequent and longer dialysis outside of the hospital, while improving patient’s mobility and autonomy. The PD devices could enhance blood purification and increase technique survival of PD. Further away from clinical application is the bioartificial kidney, containing renal cells. Initially, the bioartificial kidney could be applied for extracorporeal treatment, to partly replace renal tubular endocrine, metabolic, immunoregulatory and secretory functions. Subsequently, intracorporeal treatment may become possible. Expert commentary: Key factors for successful implementation of miniature dialysis devices are patient attitudes and cost-effectiveness. A well-functioning and safe extracorporeal blood circuit is required for HD. For PD, a double lumen PD catheter would optimize performance. Future research should focus on further miniaturization of the urea removal strategy. For the bio-artificial kidney (BAK), cost effectiveness should be determined and a general set of functional requirements should be defined for future studies. For intracorporeal application, water reabsorption will become a major challenge

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

Connective tissue growth factor is related to all-cause mortality in hemodialysis patients and is lowered by on-line hemodiafiltration : Results from the convective transport study

Connective tissue growth factor (CTGF) plays a key role in the pathogenesis of tissue fibrosis. The aminoterminal fragment of CTGF is a middle molecule that accumulates in chronic kidney disease. The aims of this study are to explore determinants of plasma CTGF in hemodialysis (HD) patients, investigate whether CTGF relates to all-cause mortality in HD patients, and investigate whether online-hemodiafiltration (HDF) lowers CTGF. Data from 404 patients participating in the CONvective TRAnsport STudy (CONTRAST) were analyzed. Patients were randomized to low-flux HD or HDF. Pre-dialysis CTGF was measured by sandwich ELISA at baseline, after six and 12 months. CTGF was inversely related in multivariable analysis to glomerular filtration rate (GFR) (p < 0.001) and positively to cardiovascular disease (CVD) (p = 0.006), dialysis vintage (p < 0.001), interleukin-6 (p < 0.001), beta-2-microglobulin (p = 0.045), polycystic kidney disease (p < 0.001), tubulointerstitial nephritis (p = 0.002), and renal vascular disease (p = 0.041). Patients in the highest quartile had a higher mortality risk compared to those in the lowest quartile (HR 1.7, 95% CI: 1.02–2.88, p = 0.043). HDF lowered CTGF with 4.8% between baseline and six months, whereas during HD, CTGF increased with 4.9% (p < 0.001). In conclusion, in HD patients, CTGF is related to GFR, CVD and underlying renal disease and increased the risk of all-cause mortality. HDF reduces CTGF