This thesis has studied several modalities how to increase the organ utilisation rate. The results in this thesis indicate that the acceptance of kidneys with acute kidney injury stage 1 or 2 will... Show moreThis thesis has studied several modalities how to increase the organ utilisation rate. The results in this thesis indicate that the acceptance of kidneys with acute kidney injury stage 1 or 2 will significantly contribute to the donor pool as AKI kidneys have comparable outcomes and should therefore not be discarded. Clinically relevant biomarkers such as cell-free unmethylated-INS DNA, FMN, GSN, IGFBP3 and IGF2R were identified or explored in the first part of this thesis and may, if analysed and/or validated thoroughly, contribute to a better assessment of organ viability supporting the justified decision whether to accept or decline the donor organ.The second part of this thesis describes different aspects of the organ preservation technique of abdominal normothermic regional perfusion (aNRP). This relatively new machine perfusion technique has been shown to be feasible and safe, however, consensus regarding assessment parameters during perfusion, protocols and outcome measurements is still lacking. Despite of an inspiring surgical enthusiasm and keeninterest to accept this modality as a new standard, a randomised clinical trial is still required and entirely ethically justifiable in order to scientifically demonstrate superiority of this method for each individual abdominal organ comparing it to other successful (ex-situ) preservation and perfusion strategies. If aNRP can be shown to obtain better post transplantation outcomes whilst increasing organ utilisation, it may be the least complex and most cost-effective strategy in organ preservation. On the other hand, aNRP will only be used in DCD donors. As such, uncertainty regarding the quality of higher risk organs from DBD donors will still be evaluated ex-situ during cold and/or warm machine perfusion with the potential to repair or even regenerate injured organs and making them ‘transplantable’ again. Show less
Acute kidney injury (AKI) is a global public health concern with high mortality and morbidity. In ischemic-reperfusion injury (IRI), a main cause of AKI, the brush border membrane of S3 proximal... Show moreAcute kidney injury (AKI) is a global public health concern with high mortality and morbidity. In ischemic-reperfusion injury (IRI), a main cause of AKI, the brush border membrane of S3 proximal tubules (PT) is lost to the tubular lumen. How injured tubules reconstitute lost membrane lipids during renal recovery is not known. Here, we identified Mfsd2a, a sodium-dependent lysophosphatidylcholine (LPC) transporter, to be expressed specifically in the basolateral membrane of S3 PT. Using an in vivo activity probe for Mfsd2a, transport activity was found to be specific to the S3 PT. Mice with haploinsufficiency of Mfsd2a exhibited delayed recovery of renal function after acute IRI, with depressed urine osmolality and elevated levels of histological markers of damage, fibrosis, and inflammation, findings corroborated by transcriptomic analysis. Lipidomics revealed a deficiency in docosahexaenoic acid (DHA) containing phospholipids in Mfsd2ahaploinsufficiency. Treatment of Mfsd2ahaploinsufficient mice with LPC-DHA improved renal function and reduced markers of injury, fibrosis, and inflammation. Additionally, LPC-DHA treatment restored S3 brush border membrane architecture and normalized DHA-containing phospholipid content. These findings indicate that Mfsd2a-mediated trans-port of LPC-DHA is limiting for renal recovery after AKI and suggest that LPC-DHA could be a promising dietary supplement for improving recovery following AKI. Show less
Smeets, N.J.L.; Teunissen, E.M.M.; Velden, K. van der; Burgh, M.J.P. van der; Linders, D.E.; Teesselink, E.; ... ; Wildt, S.N. de 2022
Background: Acute kidney injury (AKI) and augmented renal clearance (ARC), both alterations of the glomerular filtration rate (GFR), are prevalent in critically ill children and neonates. AKI and... Show moreBackground: Acute kidney injury (AKI) and augmented renal clearance (ARC), both alterations of the glomerular filtration rate (GFR), are prevalent in critically ill children and neonates. AKI and ARC prevalence estimates are based on estimation of GFR (eGFR) using serum creatinine (SCr), which is known to be inaccurate. We aimed to test our hypothesis that AKI prevalence will be higher and ARC prevalence will be lower in critically ill children when using iohexol-based measured GFR (mGFR), rather than using eGFR. Additionally, we aimed to investigate the performance of different SCr-based eGFR methods. Methods In this single-center prospective study, critically ill term-born neonates and children were included. mGFR was calculated using a plasma disappearance curve after parenteral administration of iohexol. AKI diagnosis was based on the KDIGO criteria, SCr-based eGFR, and creatinine clearance (CrCL). Differences between eGFR and mGFR were determined using Wilcoxon signed-rank tests and by calculating bias and accuracy (percentage of eGFR values within 30% of mGFR values). Results: One hundred five children, including 43 neonates, were included. AKI prevalence was higher based on mGFR (48%), than with KDIGO or eGFR (11-40%). ARC prevalence was lower with mGFR (24%) compared to eGFR (38-51%). eGFR equations significantly overestimated mGFR (60-71 versus 41 ml/min/1.73 m(2), p<0.001-0.002). Accuracy was highest with eGFR equations based on age- and sex-dependent equations (up to 59%). Conclusion: Iohexol-based AKI prevalence was higher and ARC prevalence lower compared to standard SCr-based eGFR methods. Age- and sex-dependent equations for eGFR (eGFR-Smeets for neonates and eGFR-Pierce for children) best approached measured GFR and should preferably be used to optimize diagnosis of AKI and ARC in this population. Show less
Smeets, N.J.L.; Teunissen, E.M.M.; Velden, K. van der; Burgh, M.J.P. van der; Linders, D.E.; Teesselink, E.; ... ; Wildt, S.N. de 2022
Background Acute kidney injury (AKI) and augmented renal clearance (ARC), both alterations of the glomerular filtration rate (GFR), are prevalent in critically ill children and neonates. AKI and... Show moreBackground Acute kidney injury (AKI) and augmented renal clearance (ARC), both alterations of the glomerular filtration rate (GFR), are prevalent in critically ill children and neonates. AKI and ARC prevalence estimates are based on estimation of GFR (eGFR) using serum creatinine (SCr), which is known to be inaccurate. We aimed to test our hypothesis that AKI prevalence will be higher and ARC prevalence will be lower in critically ill children when using iohexol-based measured GFR (mGFR), rather than using eGFR. Additionally, we aimed to investigate the performance of different SCr-based eGFR methods.Methods In this single-center prospective study, critically ill term-born neonates and children were included. mGFR was calculated using a plasma disappearance curve after parenteral administration of iohexol. AKI diagnosis was based on the KDIGO criteria, SCr-based eGFR, and creatinine clearance (CrCL). Differences between eGFR and mGFR were determined using Wilcoxon signed-rank tests and by calculating bias and accuracy (percentage of eGFR values within 30% of mGFR values).Results One hundred five children, including 43 neonates, were included. AKI prevalence was higher based on mGFR (48%), than with KDIGO or eGFR (11-40%). ARC prevalence was lower with mGFR (24%) compared to eGFR (38-51%). eGFR equations significantly overestimated mGFR (60-71 versus 41 ml/min/1.73 m(2), p<0.001-0.002). Accuracy was highest with eGFR equations based on age- and sex-dependent equations (up to 59%).Conclusion Iohexol-based AKI prevalence was higher and ARC prevalence lower compared to standard SCr-based eGFR methods. Age- and sex-dependent equations for eGFR (eGFR-Smeets for neonates and eGFR-Pierce for children) best approached measured GFR and should preferably be used to optimize diagnosis of AKI and ARC in this population. Show less
Molen, A.J. van der; Dekkers, I.A.; Bedioune, I.; Darmon-Kern, E. 2022
Objectives To evaluate the incidence of adverse drug reactions (ADRs), including hypersensitivity reactions (HSRs) and post-contrast acute kidney injury (PC-AKI), after intra-arterial (IA)... Show moreObjectives To evaluate the incidence of adverse drug reactions (ADRs), including hypersensitivity reactions (HSRs) and post-contrast acute kidney injury (PC-AKI), after intra-arterial (IA) administration of ioversol. Methods and materials A systematic literature search was performed (1980-2021) and studies documenting IA use of ioversol, and reporting safety outcomes were selected. Key information on study design, patients' characteristics, indication, dose, and type of safety outcome were extracted. Results Twenty-eight studies (including two pediatric studies) with 8373 patients exposed to IA ioversol were selected. Studies were highly heterogenous in terms of design, PC-AKI definition, and studied population. PC-AKI incidence after coronary angiography was 7.5-21.9% in a general population, 4.0-26.4% in diabetic patients, and 5.5-28.9% in patients with chronic kidney disease (CKD). PC-AKI requiring dialysis was rare and reported mainly in patients with severe CKD. No significant differences in PC-AKI rates were shown in studies comparing different iodinated contrast media (ICM). Based on seven studies of ioversol clinical development, the overall ADR incidence was 1.6%, comparable to that reported with other non-ionic ICM. Pediatric data were scarce with only one study reporting on PC-AKI incidence (12%), and one reporting on ADR incidence (0.09%), both after coronary angiography. Conclusions After ioversol IA administration, PC-AKI incidence was highly variable between studies, likely reflecting the heterogeneity of the included study populations, and appeared comparable to that reported with other ICM. The rate of other ADRs appears to be low. Well-designed studies are needed for a better comparison with other ICM. Show less
Molen, A.J. van der; Dekkers, I.A.; Bedioune, I.; Darmon-Kern, E. 2022
Objectives To evaluate the incidence of adverse drug reactions (ADRs), including hypersensitivity reactions (HSRs) and post-contrast acute kidney injury (PC-AKI), after intravenous (IV)... Show moreObjectives To evaluate the incidence of adverse drug reactions (ADRs), including hypersensitivity reactions (HSRs) and post-contrast acute kidney injury (PC-AKI), after intravenous (IV) administration of ioversol. Materials and methods A systematic literature search (1980-2021) of studies documenting IV use of ioversol and presence or absence of ADRs, HSRs, or PC-AKI was performed. Key information including patients' characteristics, indication and dose of ioversol, safety outcome incidence, intensity and seriousness were extracted. Results Thirty-one studies (> 57,000 patients) were selected, including 4 pediatric studies. The incidence of ADRs in adults was reported in 12 studies from ioversol clinical development with a median (range) of 1.65% (0-33.3%), and 3 other studies with an incidence between 0.13 and 0.28%. The incidence of HSRs (reported in 2 studies) ranged from 0.20 to 0.66%, and acute events (4 studies) from 0.23 to 1.80%. Severe reactions were rare with a median (range) of 0 (0-4%), and none were reported among pediatric patients. The incidence of ADRs and HSRs with ioversol, especially those of severe intensity, was among the lowest in studies comparing different iodinated contrast media (ICM) of the same class. PC-AKI incidence was variable (1-42% in 5 studies); however, ioversol exposure per se did not increase the incidence. Conclusions When administered by the IV route, ioversol has a good safety profile comparable to that of other ICM within the same class, with a low incidence of severe/serious ADRs overall, and particularly HSRs. PC-AKI incidence does not seem to be increased compared to patients who did not receive ioversol. Further well-designed studies are warranted to confirm these results. Show less
Acute kidney injury (AKI) is a frequent complication in patients with Staphylococcus aureus bacteremia (SAB), with a significant impact on patient management and outcome. This study aimed to... Show moreAcute kidney injury (AKI) is a frequent complication in patients with Staphylococcus aureus bacteremia (SAB), with a significant impact on patient management and outcome. This study aimed to provide insight in the proportion of patients with SAB that develop AKI, the risk factors for developing AKI in this population, and its reversibility. In this retrospective, multicenter cohort study, adult patients with SAB were eligible for inclusion. Patient characteristics, clinical variables, and laboratory results were retrieved from the electronic patient files. Primary outcome was development of AKI, defined as 1.5 times baseline creatinine. Secondary outcomes were reversibility of AKI and risk factors for AKI. A total of 315 patients with SAB were included, of whom 115/315 (37%) developed acute kidney injury. In 68/115 (59%), the AKI was reversible. If kidney function recovered, this occurred within 7 days in 56/68 (82%) of patients. In multivariable logistic regression analyses, independent risk factors for AKI were as follows: complicated SAB, use of diuretics, and hemodynamic instability. Development of AKI was associated with 30-day mortality (OR 3.9; CI 2.2-6.9; p < 0.01). Acute kidney injury is a frequent complication in patients with Staphylococcus aureus bacteremia. Considering the irreversibility in a relevant proportion of patients, future research into the underlying pathophysiology and potential interventions is warranted. Show less
BACKGROUND: The objective of this study was to evaluate the usefulness of pre-operative visceral (VAT) and subcutaneous adipose tissue (SAT) evaluation in the prediction of acute kidney injury (AKI... Show moreBACKGROUND: The objective of this study was to evaluate the usefulness of pre-operative visceral (VAT) and subcutaneous adipose tissue (SAT) evaluation in the prediction of acute kidney injury (AKI) and decrease of eGFR at 12 months after radical nephrectomy (RN).METHODS: We relied on 112 patients who underwent RN between January 2010 and March 2017 at a single institution. Images from the pre-operatory CT scan were analyzed and both SAT and VAT assessments were carried out on a cross-sectional plane. eGFR was measured before surgery, at 7 days, and 12 months after surgery. ROC analysis was used to compare the diagnostic value of BMI, VAT ratio, and abdominal circumference in predicting AKI. Logistic regression models were fitted to predict the new onset of AKI, and the progression from chronic kidney disease (CKD) stage 1-3a to CKD stage 3b or from 3b to 4 at 12 months follow-up. Two logistic regression models were also performed to assess the predictors for AKI and CKD stage progression. The predictive accuracy was quantified using the receiver operating characteristic-derived area under the curve.RESULTS: Sixty-six patients (58.9%) had AKI after RN. Thirty-five (31.3%) patients were upgraded to CKD IIIb or from CKD stage IIIb to CKD IV. In the ROC analysis, VAT% performed better than the BMI and abdominal circumference (AUC=0.66 vs. 0.49 and 0.54, respectively). At multivariable analyses, VAT reached an independent predictor status for AKI (OR: 1.03) and for CKD stage at 12-month follow-up (OR: 1.05). Inclusion of VAT% into the multivariable models was associated with the highest accuracy both for AKI (AUC=0.700 vs. 0.570) and CKD stage progression (AUC=0.848 vs. 0.800).CONCLUSIONS: In patients undergoing RN, preoperative visceral adipose tissue ratio significantly predicts AKI incidence and is significantly predictive of 12-month CKD stage worsening. Show less
Pharmaceutical companies, governments and the general public have become increasingly aware that animal models used in drug testing lack vital aspects to serve as an accurate representation of... Show morePharmaceutical companies, governments and the general public have become increasingly aware that animal models used in drug testing lack vital aspects to serve as an accurate representation of human biology. As models of the human body should become more physiologically relevant, animal models no longer suffice because responses of animal cells often differ from human cells. Instead, in vitro cell culture models with 3D architecture, microfluidics and high throughput capabilities are a promising technology. These 3D models can be developed in ways that they will likely surpass animal models on important aspects like resemblance to a human body, predicting compound safety and efficacy, high throughput testing capabilities, ethical aspects, and costs.To demonstrate the feasibility of an advanced 3D in vitro model, we used a microfluidic in vitro platform to develop a kidney-on-a-chip platform which possess the ability to reproduce the tubular response to known and unknown nephrotoxicants and compounds as seen in in vitro and in clinical studies. Furthermore, we assessed the response of the model to renal ischemia/reperfusion injury and could measure the prevention of tubular damage when adding protective compounds.These findings show that 3D tissue models can compete with alternatives like animal models and 2D models. Show less
Background: The aim of this retrospective cohort study was to determine the incidence, potential risk factors, characteristics, and outcomes of acute kidney injury in children following the... Show moreBackground: The aim of this retrospective cohort study was to determine the incidence, potential risk factors, characteristics, and outcomes of acute kidney injury in children following the arterial switch operation for transposition of the great arteries. Methods: Retrospective review of children who underwent ASO between 2000 and 2020 in our tertiary children's hospital in the Netherlands. Pre-and post-ASO serum creatinine levels were collected. Severe AKI was defined as 100% serum creatinine rise or estimated creatinine clearance Results: A total of 242 children were included. Fifty-seven (24%) children developed severe AKI after ASO. Four patients with severe AKI were treated with renal replacement therapy. Children with severe AKI had a longer duration of mechanical ventilation 4.5 (1.0-29) versus 3 (1.0-12) days (p = 0.001), longer PICU stay 7 (2-76) versus 5 (1-70) days, (p = 0.001), higher rate of myocardial infarction 5% versus 0.5% (p = 0.001), sepsis 24% versus 9% (p = 0.002), post-operative pulmonary hypertension 19% versus 6% (p = 0.002), post-operative bleeding 9% versus 3% (p = 0.044), longer time to sternal closure 3 (1-19) versus 2 (1-6) days, (p = 0.009), and a higher mortality rate 9.0% versus 0.5% (p = 0.001) compared to children without severe AKI. Sepsis was a risk factor for developing severe AKI. Conclusions: In this single-centre cohort, 24% of our patients developed severe AKI after ASO, which is associated with increased morbidity, longer PICU stay, and higher mortality. Show less
The pipeline of biomarker translation from bench to bedside is challenging and limited biomarkers have been adopted to routine clinical care. Ideally, biomarker research and development should be... Show moreThe pipeline of biomarker translation from bench to bedside is challenging and limited biomarkers have been adopted to routine clinical care. Ideally, biomarker research and development should be driven by unmet clinical needs in health care. To guide researchers, clinical chemists and clinicians in their biomarker research, the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) has developed a structured questionnaire in which the clinical gaps in current clinical pathways are identified and desirable performance specifications are predefined. In kidney injury, the high prevalence of the syndrome acute kidney injury (AKI) in the hospital setting has a significant impact on morbidity, patient survival and health care costs, but the use of biomarkers indicating early kidney injury in daily patient care remains limited. Routinely, medical labs measure serum creatinine, which is a functional biomarker, insensitive for detecting early kidney damage and cannot distinguish between renal and prerenal AKI. The perceived unmet clinical needs in kidney injury were identified through the EFLM questionnaire. Nephrologists within our tertiary care hospital emphasized that biomarkers are needed for (1) early diagnosis of in-hospital AKI after a medical insult and in critically ill patients, (2) risk stratification for kidney injury prior to a scheduled (elective) intervention, (3) kidney injury monitoring in patients scheduled to receive nephrotoxic medication and after kidney transplantation and (4) differentiation between prerenal AKI and structural kidney damage. The biomarker search and selection strategy resulted in a rational selection of an eleven-protein urinary panel for kidney injury that target these clinical needs. To assess the clinical utility of the proposed biomarker panel in kidney injury, a multiplexed LC-MS test is now in development for the intended translational research. Show less
Background The safety of restarting angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) after acute kidney injury (AKI) is unclear. There is concern that... Show moreBackground The safety of restarting angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) after acute kidney injury (AKI) is unclear. There is concern that previous users do not restart ACEI/ARB despite ongoing indications. We sought to determine the risk of adverse events after an episode of AKI, comparing prior ACEI/ARB users who stop treatment to those who continue. Methods We conducted two parallel cohort studies in English and Swedish primary and secondary care, 2006-2016. We used multivariable Cox regression to estimate hazard ratios (HR) for hospital admission with heart failure (primary analysis), AKI, stroke, or death within 2 years after hospital discharge following a first AKI episode. We compared risks of admission between people who stopped ACEI/ARB treatment to those who were prescribed ACEI/ARB within 30 days of AKI discharge. We undertook sensitivity analyses, including propensity score-matched samples, to explore the robustness of our results. Results In England, we included 7303 people with AKI hospitalisation following recent ACEI/ARB therapy for the primary analysis. Four thousand three (55%) were classified as stopping ACEI/ARB based on no prescription within 30 days of discharge. In Sweden, we included 1790 people, of whom 1235 (69%) stopped treatment. In England, no differences were seen in subsequent risk of heart failure (HR 1.10; 95% confidence intervals (CI) 0.93-1.30), AKI (HR 0.90; 95% CI 0.77-1.05), or stroke (HR 0.99; 95% CI 0.71-1.38), but there was an increased risk of death (HR 1.27; 95% CI 1.15-1.41) in those who stopped ACEI/ARB compared to those who continued. Results were similar in Sweden: no differences were seen in risk of heart failure (HR 0.91; 95% CI 0.73-1.13) or AKI (HR 0.81; 95% CI 0.54-1.21). However, no increased risk of death was seen (HR 0.94; 95% CI 0.78-1.13) and stroke was less common in people who stopped ACEI/ARB (HR 0.56; 95% CI 0.34-0.93). Results were similar across all sensitivity analyses. Conclusions Previous ACEI/ARB users who continued treatment after an episode of AKI did not have an increased risk of heart failure or subsequent AKI compared to those who stopped the drugs. Show less
Objective Guidelines on safe use of iodinated contrast material recommend intravenous prophylactic hydration to prevent post-contrast adverse (renal) effects. Recently, guidelines have been updated... Show moreObjective Guidelines on safe use of iodinated contrast material recommend intravenous prophylactic hydration to prevent post-contrast adverse (renal) effects. Recently, guidelines have been updated and standard prophylaxis is no longer recommended for the majority of patients. The current study aims to evaluate the consequences for clinical practice of the updated guidelines in terms of complications, hospitalisations, and costs. Methods The Contrast-Induced Nephropathy After Reduction of the prophylaxis Threshold (CINART) project is a retrospective observational study. All elective procedures with intravascular iodinated contrast administration at Maastricht University Medical Centre (UMC+) in patients aged > 18 years, formerly eligible for prophylaxis (eGFR 30-44 ml/min/1.73 m(2) or eGFR 45-59 ml/min/1.73 m(2) in combination with diabetes or > 1 predefined risk factor), and currently eligible for prophylaxis (eGFR < 30 ml/min/1.73 m(2)) were included. Data were used to calculate relative reductions in complications, hospitalisations, and costs associated with standard prophylactic intravenous hydration. CINART is registered with : NCT03227835. Results Between July 1, 2017, and July 1, 2018, 1992 elective procedures with intravascular iodinated contrast in patients formerly and currently eligible for prophylaxis were identified: 1808 in patients formerly eligible for prophylaxis and 184 in patients currently eligible for prophylaxis. At Maastricht UMC+, guideline updates led to large relative reductions in numbers of complications of prophylaxis (e.g. symptomatic heart failure; - 89%), extra hospitalisations (- 93%), and costs (- 91%). Conclusion Guideline updates have had a demonstrable impact on daily clinical practice benefiting patient, hospital, and health care budgets. Clinical practice varies between institutions and countries; therefore, a local estimation model is provided with which local impact on costs, hospitalisations, and complications can be calculated. Show less
The most important risk factor for atherosclerotic cardiovascular disease is increased levels of LDL-C. Statins have long been the most potent LDL-C lowering drugs on the market. However,... Show moreThe most important risk factor for atherosclerotic cardiovascular disease is increased levels of LDL-C. Statins have long been the most potent LDL-C lowering drugs on the market. However, statin treatment is complicated by the fact that a considerable number of patients is unable to tolerate full therapeutic doses, or can be classified as statin low or non-responders. In >25% of patients at (very) high risk for cardiovascular disease, statin efficacy is too limited to achieve current guideline-mandated LDL-C target goals, and aggressive statin therapy decreases relative risk for ASCD by only 30-35%, leaving an unacceptable residual relative risk of 65-70% for life-threatening events. It is clear that on-treatment LDL-C levels and on-treatment measures of systemic inflammation are of equal importance in this residual risk. Both for residual cholesterol risk and residual inflammatory risk, effective drug therapy has been lacking for decades. In this thesis, we describe the first clinical studies with novel compounds based on increased LDL-C levels and inflammation (including the required methodology), and present the methodology that may be useful to develop future compounds based on dysfunctional endothelial barrier function resulting in subendothelial cholesterol accumulation and subsequent atheroma formation. Show less
Stacul, F.; Bertolotto, M.; Thomsen, H.S.; Pozzato, G.; Ugolini, D.; Bellin, M.F.; ... ; ESUR Contrast Media Safety Comm 2018
