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Renal stimulation tests document the dynamic response of the glomerular filtration rate (GFR) after a single or a combination of stimuli, such as an intravenous infusion of dopamine or amino acids or an oral protein meal. The increment of the GFR above the unstimulated state has formerly been called the renal functional reserve (RFR). Although the concept of a renal reserve capacity has not withstood scientific scrutiny, the literature documenting renal stimulation merits renewed interest. An absent or a blunted response of the GFR after a stimulus indicates lost or diseased nephrons. This information is valuable in preventing, diagnosing and prognosticating acute kidney injury and pregnancy-related renal events as well as chronic kidney disease. However, before renal function testing is universally practiced, some shortcomings must be addressed. First, a common nomenclature should be decided upon. The expression of RFR should be replaced by renal functional response. Second, a simple protocol must be developed and propagated. Third, we suggest designing prospective studies linking a defective stimulatory response to emergence of renal injury biomarkers, to histological or morphological renal abnormalities and to adverse renal outcomes in different renal syndromes.

Aims. AKI is common after cardiac surgery involving CPB. S-cystatin C is a novel early biomarker for AKI awaiting validation in this setting. Goal was to develop a clinical predictive model for AKI and test the added value of s-cystatin C within the first 24 hrs post-op. Methods. 259 patients were enrolled. Patients with severe pre-existing renal insufficiency were excluded (eGFR

This review discusses renal sodium handling in heart failure. Increased sodium avidity and tendency to extracellular volume overload, i.e. congestion, are hallmark features of the heart failure syndrome. Particularly in the case of concomitant renal dysfunction, the kidneys often fail to elicit potent natriuresis. Yet, assessment of renal function is generally performed by measuring serum creatinine, which has inherent limitations as a biomarker for the glomerular filtration rate (GFR). Moreover, glomerular filtration only represents part of the nephron's function. Alterations in the fractional reabsorptive rate of sodium are at least equally important in emerging therapy-refractory congestion. Indeed, renal blood flow decreases before the GFR is affected in congestive heart failure. The resulting increased filtration fraction changes Starling forces in peritubular capillaries, which drive sodium reabsorption in the proximal tubules. Congestion further stimulates this process by augmenting renal lymph flow. Consequently, fractional sodium reabsorption in the proximal tubules is significantly increased, limiting sodium delivery to the distal nephron. Orthosympathetic activation probably plays a pivotal role in those deranged intrarenal haemodynamics, which ultimately enhance diuretic resistance, stimulate neurohumoral activation with aldosterone breakthrough, and compromise the counter-regulatory function of natriuretic peptides. Recent evidence even suggests that intrinsic renal derangements might impair natriuresis early on, before clinical congestion or neurohumoral activation are evident. This represents a paradigm shift in heart failure pathophysiology, as it suggests that renal dysfunction-although not by conventional GFR measurements-is driving disease progression. In this respect, a better understanding of renal sodium handling in congestive heart failure is crucial to achieve more tailored decongestive therapy, while preserving renal function.

Background and purpose: The physiological involvement of endogenous cholecystokinin (CCK) in the termination of feeding has been challenged by evidence of aversive effects of exogenous CCK8. We previously prolonged the anorectic effect of CCK by conjugation to polyethylene glycol (PEGylation) to produce PEG-CCK9. In this study, we investigated the ability of different doses of PEG-CCK9 to induce conditioned taste aversion (CTA) and satiety and identified the receptors involved in CTA induction. ispartof: British Journal of Pharmacology vol:155 issue:3 pages:417-423 ispartof: location:England status: published

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Abdominal congestion may play an important role in the cardiorenal syndrome and has been demonstrated to drive disease progression. An animal model for abdominal congestion, without other culprit mechanisms that are often present in patients such as low cardiac output or chronic kidney disease, might be interesting to allow a better study of the pathophysiology of the cardiorenal syndrome. The objective of this study was to develop a clinically relevant and valid rat model with abdominal venous congestion and without pre-existing heart and/or kidney dysfunction. To do so, a permanent surgical constriction (20 Gauge) of the thoracic inferior vena cava (IVC) was applied in male Sprague Dawley rats (IVCc, n = 7), which were compared to sham-operated rats (SHAM, n = 6). Twelve weeks after surgery, abdominal venous pressure (mean: 13.8 vs 4.9 mmHg, p < 0.01), plasma creatinine (p < 0.05), plasma cystatin c (p < 0.01), urinary albumin (p < 0.05), glomerular surface area (p < 0.01) and width of Bowman's space (p < 0.05) of the IVCc group were significantly increased compared to the SHAM group for a comparable absolute body weight between groups (559 vs 530g, respectively, p = 0.73). Conventional cardiac echocardiographic and hemodynamic parameters did not differ significantly between both groups, indicating that cardiac function was not compromised by the surgery. In conclusion, we demonstrate that constriction of the thoracic IVC in adult rats is feasible and significantly increases the abdominal venous pressure to a clinically relevant level, thereby inducing abdominal venous congestion. J.C. is supported by BOF funding from UHasselt/BIOMED. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The cardio-renal syndrome (CRS) is an umbrella term for life-threatening diseases in which cardiac and renal dysfunction occur simultaneously. It has been shown that heart failure patients with an increase in intra-abdominal pressure and central venous pressure (CVP), indicating the presence of abdominal and venous congestion, have a higher risk to develop CRS due to worsening renal function. It is hypothesized that abdominal venous congestion impairs heart and kidney function by causing damage to the heart and kidneys. Abdominal venous congestion was induced via constriction of the thoracic vena cava inferior (VCI). The effect of this constriction on heart, kidney and liver function was followed-up for twelve weeks after surgery via different in vivo and in vitro experiments. It was shown that VCI constriction increased abdominal CVP, but that this increase had a limited effect on heart and kidney function. On the other hand, liver function deteriorated after VCI constriction. Therefore, it can be concluded that the rat model is validated as abdominal venous congestion was induced via constriction of the VCI. As the effect of VCI constriction on heart and kidney function was limited, the presence of abdominal venous congestion was insufficient to induce CRS. Consequently, in future CRS research, the role of abdominal venous congestion in CRS development and progression can be further explored by combining this rat model with other models of heart or kidney failure.

Diabetic cardiomyopathy (DCM) is a devastating disease of the heart, which increases the risk of heart failure in individuals with diabetes mellitus (DM). DCM is characterized by structural and functional changes of the myocardium, which are attributable only to the presence of DM and not to confounding factors or diseases. To date, little is known about the pathophysiology of this disease and there is no specific treatment available. Therefore, a clinically relevant animal model, in which DCM is developed after induction of DM, is warranted. This study showed that the combination of a high fat diet and a low dose of streptozotocin is efficient to induce type 2 diabetes, a deteriorated left ventricular relaxation and an increased left ventricular pressure in a rat model. Moreover, rats which are fed only a high fat diet, will develop the insulin resistance syndrome. This nongenetic rat model has the additional advantage of being easy to induce and can be used in the future to unravel the molecular mechanisms of DCM.

Acute kidney injury (AKI) remains a common complication after cardiopulmonary bypass (CPB) and can be diagnosed by serum creatinine. However, serum creatinine is an insensitive and nonspecific biomarker. This study was designed to investigate whether a correlation exists between urinary oxygen tension (UOT) and early markers of AKI. The aim was to evaluate whether UOT could provide warning signs of an insufficient renal oxygen supply, which can lead to postoperative AKI. Publication of this supplement has been supported by ISICEM.

In case of an interatrial conduction delay (IACD), the left ventricle will contract before the left atrial contraction has ended and the mitral valve will close prematurely. This leads to left atrioventricular dyssynchrony. An IACD is frequent in pacemaker patients, but often neglected during follow-up. Therefore, the atrioventricular delay (AVD) will be left at nominal values which are usually too short. Consequently, these patients develop left atrioventricular dyssynchrony, causing dizziness, fatigue and dyspnoea. This could be prevented by lengthening the AVD. Otherwise, some of the patients have a too long AVD, leading to a suboptimal diastolic filling time. In these patients, the optimal AVD could be achieved by shortening the delay. Previous studies showed beneficial hemodynamic effects after AVD optimisation in cardiac resynchronisation therapy, biatrial and dual chamber pacemaker patients. We hypothesised that AVD optimisation would result in a better clinical outcome and left atrial function in dual chamber pacemaker patients. We set up a randomised cross-over study in which we optimised the AVD via transthoracic echocardiography (TTE). The benefit of optimisation was evaluated through an ergospirometry, a 6 minute walk test, TTE, HeartQoL questionnaire, NYHA class and BNP. Our study showed that individualised AVD optimisation by TTE improved the functional capacity and thus should be considered in every dual chamber pacemaker patient.

The aim of this thesis was to contribute to the next step in the implementation of these new biomarkers for AKI. In chapter 2 and chapter 3, we focused on the determination of the most ideal collection and storage conditions prior to the biomarker measurements. In chapter 4 the goal was to establish reference values for these novel biomarkers for healthy subjects with special attention for age and gender. In the following chapters we investigated the utility of these biomarkers in different clinical settings. Chapter 5 was attributed to the research we conducted on the association between KIM-1 and urinary cadmium concentrations. Finally, in chapter 6 we investigated a panel of novel biomarkers in an attempt to detect AKI after cardiac surgery requiring a cardiopulmonary bypass. Momenteel is het vroegtijdig opsporen van acuut en chronisch nierfalen gebaseerd op de stijging van de creatinine concentratie in het serum in combinatie met een daling in urine volume. Deze detectiemethode heeft het nadeel dat de vermelde veranderingen pas enkele uren tot dagen na het eigenlijk ontstaan van het nierprobleem waargenomen kunnen worden. Er is dan ook nood aan nieuwe, snellere detectiemethoden of biomerkers. Via proteomische onderzoeksmethoden werden een aantal eiwitten in het bloed en de urine ontdekt, die mogelijkerwijze als biomerker voor nierschade kunnen dienen. Deze eiwitten blijken in experimenten bij dieren en mensen immers verhoogd tot expressie te komen in geval van nierschade. Deze nieuwe biomerkers dienen echter gevalideerd te worden: er moet nagegaan worden op welke wijze ze het best gemeten worden, wat normale waarden zijn bij gezonde mensen en bij welke pathologieën en in welke patiëntengroepen ze verhoogd zijn. In deze doctoraatsthesis hebben we ons gericht op het validatieproces van enkele nieuwe biomerkers voor nierschade, nl. KIM-1, NGAL, NAG en Cystatine C. We hebben vooreerst aangetoond dat KIM-1, gemeten in de urine, niet afhankelijk is van de pH van de urine, maar de commerciële kit die gebruikt wordt voor de meting wel. Het is dan ook van belang om urinestalen voor de meting van KIM-1 op een pH rond 7 te brengen (hoofdstuk 2). Enkele andere verzamel- en opslagspecificaties voor de urinestalen waarin de biomerkers gemeten worden (zoals het toevoegen van protease inhibitoren, centrifugatie, maximale duur voor invriezen en de invriestemperatuur en –periode) zijn vervolgens onder de loep genomen, en richtlijnen hieromtrent zijn uitgewerkt (hoofdstuk 3). In het volgende deel van ons onderzoeksproject, hebben we urinestalen van verondersteld gezonde proefpersonen van alle leeftijden verzameld om zo referentiewaarden voor KIM-1, NGAL, Cystatine C en NAG op te stellen (hoofdstuk 4). Uit dierproeven van andere onderzoeksgroepen werd een positieve associatie afgeleid tussen de blootstelling aan het zware metaal cadmium, waarvan geweten is dat het schadelijke effecten heeft op de nier enerzijds en verhoogde KIM-1 concentraties in de urine anderzijds. We onderzochten een proefgroep van oudere personen die wonen in de omgeving van een industrieterrein met gekende verhoogde cadmiumwaarden in de bodem en de lucht en dus gedurende een lange periode blootgesteld zijn aan cadmium. Eenzelfde associatie werd aangetoond tussen cadmium en KIM-1 in de urine van deze proefpersonen (hoofdstuk 5). In het laatste deel van dit doctoraat werd onderzocht of de nieuwe biomerkers een rol kunnen spelen in de vroege detectie van acuut nierfalen, na het ondergaan van cardiale chirurgie waarbij extracorporele circulatie noodzakelijk is. Hierbij werden de concentraties van de urinaire biomerkers voor en op verschillende tijdstippen na de operatie vergeleken tussen volwassen patiënten die acuut nierfalen hadden ontwikkeld of niet. Voor elke gemeten biomerker (urinair KIM-1, NGAL, cystatine C en serum cystatine C) kon een associatie met acuut nierfalen gevonden worden op tenminste één tijdstip. Alleen serum Cystatine C bleek echter een voorspellende meerwaarde te hebben bovenop een klinisch model, dat werd samengesteld uit klinische parameters die momenteel reeds gebruikt worden in de detectie van AKI in het ziekenhuis (hoofdstuk 6).

AGEs zijn eiwitten of vetten die in vivo versuikerd worden. Enerzijds is er steeds meer bewijs dat AGEs mogelijk ook betrokken zijn in de ontwikkeling en vooruitgang van hart- en nierfalen. Anderzijds is het bekend dat vrouwen over het algemeen minder gevoelig zijn aan cardiovasculaire aandoeningen. De huidige studie had als doel om het effect van AGEs op de hart- en nierfunctie en om de geslachtsverschillen in hart- en nierfunctie te bestuderen als gevolg van verhoogde AGEs in het lichaam. Mannelijke en vrouwelijke Sprague-Dawley ratten werden dagelijks i.p geïnjecteerd met AGEs (20 mg/kg) of BSA met eenzelfde concentratie gedurende 6 weken.Injecties van AGEs gedurende 6 weken leidden tot hart dysfunctie. Hypertrofie werd bevestigd met een verhoogd hart gewicht-tibia lengteverhouding in beide geslachten. Totaal collageen was hoger in AGE-BSA geïnjecteerde dieren, waarbij het totaal collageen hoger was bij mannen dan bij vrouwen. Urine analyse toonde veranderingen in elektrolyt concentraties van AGE-BSA behandelde mannelijke dieren en fibrose was uitgesproken in de cortex. Deze studie toont aan dat AGE-BSA injecties aanleiding geven tot fibrose in zowel het hartweefsel als nierweefsel. Mannelijke ratten vertonen meer uitgesproken fibrose dan de vrouwtjes wat de duidelijke verslechtering in hartfunctie in vivo deels verklaart.

HF is a complex clinical condition characterized by cardiac and non cardiac morbidity, with high morbidity and mortality and incremental costs for health care. The objective of this thesis was to investigate if optimal patient care through an individually tailored approach would lead to better outcomes. A first study was set up to assess the impact of RAS and ' blocker uptitration in HFrEF versus HFpEF patients after hospital admission; which concluded that uptitration of RAS blockers after a HF hospitalization is more feasible in younger patients with low co morbidity burden, and is an independent predictor of outcome in HFrEF but not HFpEF patients. Next to an optimal neurohumoral blocker therapy, elaborate HF care also comprises an extensive disease management program. A second study was set up to investigate the feasibility and impact of a hospital-wide, individually tailored and transmural disease management program in reducing ADHF and all-cause readmission rates and improving cl

Background: The novel urinary biomarkers for the early detection of kidney injury after ischemic or toxic insults have recently been well studied, including neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), cystatin C (Cys-C)and Nacetyl- β Dglucosaminidase (NAG). The lack of reference values have greatly impeded progress in the diagnosis and treatment of patients with AKI and have a detrimental effect on the possibly outcomes of clinical trials of cardiac surgery. Objective: The first objective of this study was to estimate the normal value of urinary NGAL, KIM-1, Cys-C and NAG in a healthy population. The second objective was to evaluate the diagnostic performance of urinary biomarkers in a prospective pilot study including adults after cardiopulmonary bypass (CPB) surgery. Methods: The age study population consist of 337 healthy non-smoking subjects (191 female, 146 male ranging from 4 months to 90 years). Urine samples were obtained at routine visit to the ZOL hospital. ELISA was used to measure urinary NGAL, KIM-1 and Cys-C. BIOQuant N-acetyl-B-D-Glucosaminidase (NAG) assay was used to measure NAG. The prospective pilot study consists of 25 adults (7 females, 18 males ranging from 51 to 84 years) who required CPB surgery. Urine and blood samples were obtained before and 3, 6, 12 and 24 hours after CPB surgery. Patients were divided into the AKI and non-AKI groups according to developed AKI after surgery, AKI was defined as a ≥ 0.3 mg/dl increase in sCr from the base line within 48h after the surgery. Urinary KIM-1 and NGAL were measured using ELISA assay. Results: Age study: significant age related differences were found for KIM-1, NGAL, Cys- C and NAG. In addition, significant differences between gender were found for KIM-1, NGAL and NAG. Cardiac study: 25 patients were enrolled, 20% developed AKI. Urinary KIM-1/Cr level was significantly increased 24h post surgery and was significantly associated with AKI within 24h ,while urinary NGAL level did not show such a performance. Conclusions: Based on our results, further study in larger population with biomarker panel is needed for the evaluation of normal values with variance factors as well as to establish the prediction value to diagnose AKI for long and short outcomes after cardiac surgery.