Fluid balance-adjusted creatinine at initiation of continuous venovenous hemofiltration and mortality. A post-hoc analysis of a multicenter randomized controlled trial.

INTRODUCTION: Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is associated with high mortality. The creatinine-based stage of AKI is considered when deciding to start or delay RRT. However, creatinine is not only determined by renal function (excretion), but also by dilution (fluid balance) and creatinine generation (muscle mass). The aim of this study was to explore whether fluid balance-adjusted creatinine at initiation of RRT is related to 28-day mortality independent of other markers of AKI, surrogates of muscle mass and severity of disease. METHODS: We performed a post-hoc analysis on data from the multicentre CASH trial comparing citrate to heparin anticoagulation during continuous venovenous hemofiltration (CVVH). To determine whether fluid balance-adjusted creatinine was associated with 28-day mortality, we performed a logistic regression analysis adjusting for confounders of creatinine generation (age, gender, body weight), other markers of AKI (creatinine, urine output) and severity of disease. RESULTS: Of the 139 patients, 32 patients were excluded. Of the 107 included patients, 36 died at 28 days (34%). Non-survivors were older, had higher APACHE II and inclusion SOFA scores, lower pH and bicarbonate, lower creatinine and fluid balance-adjusted creatinine at CVVH initiation. In multivariate analysis lower fluid balance-adjusted creatinine (OR 0.996, 95% CI 0.993-0.999, p = 0.019), but not unadjusted creatinine, remained associated with 28-day mortality together with bicarbonate (OR 0.869, 95% CI 0.769-0.982, P = 0.024), while the APACHE II score non-significantly contributed to the model. CONCLUSION: In this post-hoc analysis of a multicentre trial, low fluid balance-adjusted creatinine at CVVH initiation was associated with 28-day mortality, independent of other markers of AKI, organ failure, and surrogates of muscle mass, while unadjusted creatinine was not. More tools are needed for better understanding of the complex determinants of "AKI classification", "CVVH initiation" and their relation with mortality, fluid balance is only one.

Towards a standardised informed consent procedure for live donor nephrectomy: the PRINCE (Process of Informed Consent Evaluation) project-study protocol for a nationwide prospective cohort study.

INTRODUCTION: Informed consent is mandatory for all (surgical) procedures, but it is even more important when it comes to living kidney donors undergoing surgery for the benefit of others. Donor education, leading to informed consent, needs to be carried out according to certain standards. Informed consent procedures for live donor nephrectomy vary per centre, and even per individual healthcare professional. The basis for a standardised, uniform surgical informed consent procedure for live donor nephrectomy can be created by assessing what information donors need to hear to prepare them for the operation and convalescence. METHODS AND ANALYSIS: The PRINCE (Process of Informed Consent Evaluation) project is a prospective, multicentre cohort study, to be carried out in all eight Dutch kidney transplant centres. Donor knowledge of the procedure and postoperative course will be evaluated by means of pop quizzes. A baseline cohort (prior to receiving any information from a member of the transplant team in one of the transplant centres) will be compared with a control group, the members of which receive the pop quiz on the day of admission for donor nephrectomy. Donor satisfaction will be evaluated for all donors who completed the admission pop-quiz. The primary end point is donor knowledge. In addition, those elements that have to be included in the standardised format informed consent procedure will be identified. Secondary end points are donor satisfaction, current informed consent practices in the different centres (eg, how many visits, which personnel, what kind of information is disclosed, in which format, etc) and correlation of donor knowledge with surgeons' estimation thereof. ETHICS AND DISSEMINATION: Approval for this study was obtained from the medical ethical committee of the Erasmus MC, University Medical Center, Rotterdam, on 18 February 2015. Secondary approval has been obtained from the local ethics committees in six participating centres. Approval in the last centre has been sought. RESULTS: Outcome will be published in a scientific journal. TRIAL REGISTRATION NUMBER: NTR5374; Pre-results.

Putative novel mediators of acute kidney injury in critically ill patients: handling by continuous venovenous hemofiltration and effect of anticoagulation modalities.

BACKGROUND: Novel putative mediators of acute kidney injury (AKI) include immune-cell derived tumour necrosis factor-like weak inducer of apoptosis (TWEAK), angiopoietin-2 (Ang-2) and protein pentraxin-3 (PTX3). The effect of continuous venovenous hemofiltration (CVVH) and different anticoagulation regimens on plasma levels were studied. METHODS: At 0, 10, 60, 180 and 720 min of CVVH, samples were collected from pre- and postfilter blood and ultrafiltrate. No anticoagulation (n = 13), unfractionated heparin (n = 8) or trisodium citrate (n = 21) were compared. RESULTS: Concentrations of TWEAK, Ang-2 and PTX3 were hardly affected by CVVH since the mediators were not (TWEAK, PTX3) or hardly (Ang-2) detectable in ultrafiltrate, indicating negligible clearance by the filter in spite of molecular sizes (TWEAK, PTX3) at or below the cutoff of the membrane. Heparin use, however, was associated with an increase in in- and outlet plasma TWEAK. CONCLUSION: Novel AKI mediators are not cleared nor produced by CVVH. However, heparin anticoagulation increased TWEAK levels in patient's plasma whereas citrate did not, favouring the latter as anticoagulant in CVVH for AKI.

Coagulation, Fibrinolysis and Inhibitors in Failing Filters during Continuous Venovenous Hemofiltration in Critically Ill Patients with Acute Kidney Injury: Effect of Anticoagulation Modalities.

INTRODUCTION: The mechanisms of early filter failure and clotting with different anticoagulation modalities during continuous venovenous hemofiltration (CVVH) are largely unknown. METHODS: Citrate, heparin and no anticoagulation were compared. Blood was drawn pre- and post filter up to 720 min. Concentrations of the thrombin-antithrombin (TAT), activated protein C-protein C inhibitor (APC-PCI), and type I plasminogen activator inhibitor (PAI-1) were determined. RESULTS: In case of early filter failure (<24 h), inlet concentrations of TAT and APC-PCI were higher over time, irrespective of anticoagulation. There was more production of APC-PCI and platelet-derived PAI-1 in the filter after 10 min in the heparin group than in other groups. In clotting filters, production of APC-PCI and PAI was also higher with heparin than citrate. CONCLUSION: Coagulation activation in plasma and inhibition of anticoagulation in plasma and filter may partly determine early CVVH filter failure due to clotting, particularly when heparin is used. Regional anticoagulation by citrate circumvents the inhibition of anticoagulation and fibrinolysis by platelet activation following heparin.

The effects of kidney transplantation on sleep, melatonin, circadian rhythm and quality of life in kidney transplant recipients and living donors.

BACKGROUND: Sleep disturbance is an important medical problem in patients with end-stage renal disease. It might be related to the disruption of the body's circadian clock since nocturnal levels of its key biomarker melatonin are markedly reduced. We aimed at investigating whether a change in renal function due to kidney transplantation or donation would modify sleep, melatonin levels, circadian rhythmicity, and quality of life in kidney transplant recipients (KTR) and living donors (LD). METHODS: In KTR, we assessed saliva melatonin concentrations, sleep quality and daytime sleepiness prior to and at 2 weeks and 3 months after transplantation. In LD, we assessed these parameters prior to and at 3 months after donation. We additionally assessed 24-hour core body temperature (cBT), 24-hour blood pressure profile, and quality of life (QoL) prior to and 3 months after transplantation. RESULTS: Twenty-three KTR and 23 LD completed the study. Regarding sleep, the amount of nighttime awake minutes tended to be reduced in recipients after transplantation (p = 0.05). Nocturnal melatonin concentrations did not change with transplantation or donation. Blood pressure dipping profile and the two circadian markers dim-light melatonin onset and time of core body temperature minimum did not change. Nevertheless, KTR reported that daytime sleepiness and QoL had improved. CONCLUSION: Objectively nocturnal sleep quality marginally improved after transplantation. Subjectively patients reported improved QoL and daytime sleepiness scores. Changes in renal function were not associated with modified melatonin secretion or circadian rhythmicity.

Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill patients with acute kidney injury: a multi-center randomized clinical trial.

INTRODUCTION: Because of ongoing controversy, renal and vital outcomes are compared between systemically administered unfractionated heparin and regional anticoagulation with citrate-buffered replacement solution in predilution mode, during continuous venovenous hemofiltration (CVVH) in critically ill patients with acute kidney injury (AKI). METHODS: In this multi-center randomized controlled trial, patients admitted to the intensive care unit requiring CVVH and meeting inclusion criteria, were randomly assigned to citrate or heparin. Primary endpoints were mortality and renal outcome in intention-to-treat analysis. Secondary endpoints were safety and efficacy. Safety was defined as absence of any adverse event necessitating discontinuation of the assigned anticoagulant. For efficacy, among other parameters, survival times of the first hemofilter were studied. RESULTS: Of the 139 patients enrolled, 66 were randomized to citrate and 73 to heparin. Mortality rates at 28 and 90 days did not differ between groups: 22/66 (33%) of citrate-treated patients died versus 25/72 (35%) of heparin-treated patients at 28 days, and 27/65 (42%) of citrate-treated patients died versus 29/69 (42%) of heparin-treated patients at 90 days (P = 1.00 for both). Renal outcome, i.e. independency of renal replacement therapy 28 days after initiation of CVVH in surviving patients, did not differ between groups: 29/43 (67%) in the citrate-treated patients versus 33/47 (70%) in heparin-treated patients (P = 0.82). Heparin was discontinued in 24/73 (33%) of patients whereas citrate was discontinued in 5/66 (8%) of patients (P < 0.001). Filter survival times were superior for citrate (median 46 versus 32 hours, P = 0.02), as were the number of filters used (P = 0.002) and the off time within 72 hours (P = 0.002). The costs during the first 72 hours of prescribed CVVH were lower in citrate-based CVVH. CONCLUSIONS: Renal outcome and patient mortality were similar for citrate and heparin anticoagulation during CVVH in the critically ill patient with AKI. However, citrate was superior in terms of safety, efficacy and costs. TRIAL REGISTRATION: Clinicaltrials.gov NCT00209378. Registered 13th September 2005.

The plasma level and biomarker value of neutrophil gelatinase-associated lipocalin in critically ill patients with acute kidney injury are not affected by continuous venovenous hemofiltration and anticoagulation applied.

INTRODUCTION: Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury (AKI), and levels reflect severity of disease in critically ill patients. However, continuous venovenous hemofiltration (CVVH) may affect plasma levels by clearance or release of NGAL by activated neutrophils in the filter, dependent on the anticoagulation regimen applied. We therefore studied handling of NGAL by CVVH in patients with AKI. METHODS: Immediately before initiation of CVVH, prefilter blood was drawn. After 10, 60, 180, and 720 minutes of CVVH, samples were collected from pre- and postfilter (in- and outlet) blood and ultrafiltrate. CVVH with the following anticoagulation regimens was studied: no anticoagulation in case of a high bleeding tendency (n = 13), unfractionated heparin (n = 8), or trisodium citrate (n = 21). NGAL levels were determined with enzyme-linked immunosorbent assay (ELISA). RESULTS: Concentrations of NGAL at inlet and outlet were similar, and concentrations did not change over time in any of the anticoagulation groups; thus no net removal or production of NGAL occurred. Concentrations of NGAL at inlet correlated with disease severity at initiation of CVVH and at the end of a CVVH run. Concentrations of NGAL in the ultrafiltrate were lower with citrate-based CVVH (P = 0.03) and decreased over time, irrespective of anticoagulation administered (P < 0.001). The sieving coefficient and clearance of NGAL were low and decreased over time (P < 0.001). CONCLUSIONS: The plasma level and biomarker value of NGAL in critically ill patients with AKI are not affected by CVVH, because clearance by the filter was low. Furthermore, no evidence exists for intrafilter release of NGAL by neutrophils, irrespective of the anticoagulation method applied.

Citrate confers less filter-induced complement activation and neutrophil degranulation than heparin when used for anticoagulation during continuous venovenous haemofiltration in critically ill patients.

BACKGROUND: During continuous venovenous haemofiltration (CVVH), regional anticoagulation with citrate may be superior to heparin in terms of biocompatibility, since heparin as opposed to citrate may activate complement (reflected by circulating C5a) and induce neutrophil degranulation in the filter and myeloperoxidase (MPO) release from endothelium. METHODS: No anticoagulation (n = 13), unfractionated heparin (n = 8) and trisodium citrate (n = 17) regimens during CVVH were compared. Blood samples were collected pre- and postfilter; C5a, elastase and MPO were determined by ELISA. Additionally, C5a was also measured in the ultrafiltrate. RESULTS: In the heparin group, there was C5a production across the filter which most decreased over time as compared to other groups (P = 0.007). There was also net production of elastase and MPO across the filter during heparin anticoagulation (P = 0.049 or lower), while production was minimal and absent in the no anticoagulation and citrate group, respectively. During heparin anticoagulation, plasma concentrations of MPO at the inlet increased in the first 10 minutes of CVVH (P = 0.024). CONCLUSION: Citrate confers less filter-induced, potentially harmful complement activation and neutrophil degranulation and less endothelial activation than heparin when used for anticoagulation during continuous venovenous haemofiltration in critically ill patients.

[Kolff and the artificial kidney]. / Kolff en de kunstnier.

Willem Kolff (1911-2009), son of a physician, studied medicine in Leiden and specialised in internal medicine in Groningen. It was there that he started attempts to apply the phenomenon of dialysis in patients suffering from renal failure. He built the first prototypes of dialysis machines after his appointment as an internist in the municipal hospital in Kampen, during the Second World War. Indeed, in the first 15 patients he managed to decrease urea levels, resulting in temporary clinical improvement, but eventually they all died. It was not until after the war that dialysis helped a patient survive an episode of acute glomerulonephritis. After 1950 he continued his work on artificial organs in the United States (first in Cleveland and later, after 1967, in Salt Lake City). Although most of his work from then on revolved around the development of an artificial heart, he also contributed to the design of a compact, disposable apparatus for dialysis, the 'twin coil'. Haemodialysis also became feasible for patients with chronic renal failure after the 'Scribner shunt' (1960) provided easy access to the circulation. Peritoneal dialysis is another option. Excess mortality, mainly from cardiovascular disease, is still a largely unsolved problem.

Effect of anticoagulation regimens on handling of interleukin-6 and -8 during continuous venovenous hemofiltration in critically ill patients with acute kidney injury.

OBJECTIVE: During continuous venovenous hemofiltration (CVVH) to replace renal function in acute kidney injury (AKI), anticoagulation of the filter is routinely required. A survival benefit for citrate has been reported, possibly due to reduced proinflammatory effects of the filter (bioincompatibility). We hypothesized that the type of anticoagulation modulates the immune response to, and clearance by CVVH of interleukin-6 (IL-6) and -8 (IL-8). METHODS: Three anticoagulation regimens were compared: trisodium citrate (n=17), unfractionated heparin (n=8) and no anticoagulation in case of bleeding tendency (n=13). Immediately before initiation of CVVH (cellulose triacetate membrane) pre-filter blood was drawn. Thereafter, at 10, 60, 180 and 720 min, samples were collected from the pre- and postfilter blood and from ultrafiltrate. IL-6 and IL-8 were determined by ELISA. RESULTS: High inlet levels of IL-6 and IL-8, particularly in the no anticoagulation group, were associated with non-survival. The inlet concentrations and mass rates of IL-6 and IL-8 decreased during CVVH. The course of fluxes across the filter were similar for the groups, however. Although increasing in time for IL-6 in the no anticoagulation group, mass removal and adsorption of IL-6 and IL-8 were low and did not differ among the anticoagulation groups. CONCLUSIONS: Blood to membrane contact, adsorption/clearance and anticoagulation do not increase nor attenuate high circulating levels of IL-6 and IL-8 during CVVH for AKI. This renders the hypothesis that the reported survival benefit for citrate anticoagulation is based on a reduction of bioincompatibility unlikely.

Metabolic effects of citrate- vs bicarbonate-based substitution fluid in continuous venovenous hemofiltration: a prospective sequential cohort study.

BACKGROUND: Studies investigating the metabolic effects of citrate-based substitution fluids are lacking. This study aims to compare the effect of citrate- vs bicarbonate-based substitution fluid used during continuous venovenous hemofiltration (CVVH) for acute kidney injury on acid-base balance and electrolytes in critically ill patients. METHODS: This was a prospective sequential cohort study in patients with a contraindication for systemic anticoagulation. The first cohort was treated by bicarbonate-based CVVH (n = 10) and the second cohort was treated by CVVH with citrate-based substitution fluid (n = 19). Flow of the latter was coupled to blood flow, and ionized calcium concentrations were monitored and kept constant by calcium-glubionate infusion. RESULTS: No major differences between the 2 groups were found in baseline acid-base parameters. In both groups, arterial pH increased after initiation of treatment and normalized on the average within 18 hours in either group. No differences were found in bicarbonate concentrations. Electrolyte control was comparable for the groups. CONCLUSION: Citrate-based substitution fluid is comparable to bicarbonate-based substitution fluid during CVVH in critically ill patients with acute kidney injury, concerning acid-base balance and electrolyte control. This implies complete conversion of citrate to bicarbonate in the patients studied.

Continuous venovenous hemofiltration with or without predilution regional citrate anticoagulation: a prospective study.

BACKGROUND/AIMS: Continuous venovenous hemofiltration (CVVH) requires anticoagulation to prevent circuit clotting and its use is contraindicated in patients with high bleeding risk. The aim of this study was to compare CVVH with and without regional citrate anticoagulation (RCA) with respect to filter life, azotemic control and cost. METHODS: This was a prospective sequential cohort study. The first cohort of patients with a high bleeding risk and acute renal failure was treated by anticoagulant-free predilution CVVH (n = 31). In the second cohort, CVVH was applied with RCA (n = 20). RESULTS: The median filter life was 41 h (interquartile range 20-62) with RCA and 12 h (8-28) without RCA (p = 0.001). The azotemic control was better in the group with RCA. The hourly cost was comparable between the two groups. CONCLUSION: Regional anticoagulation with citrate-based replacement solution improved filter life compared to anticoagulant-free predilution CVVH. This regimen appeared safe, feasible and without metabolic complications or increased costs.