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.

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A systematic evaluation on reporting quality of modern studies on pulmonary heart valve implantation in large animals

Interactive CardioVascular and Thoracic Surgery ◽

10.1093/icvts/ivaa132 ◽

2020 ◽

Vol 31 (4) ◽

pp. 437-445

Author(s):

Marcelle Uiterwijk ◽

Annemijn Vis ◽

Iris de Brouwer ◽

Debora van Urk ◽

Jolanda Kluin

Keyword(s):

Heart Valve ◽

Heart Valves ◽

Animal Experiments ◽

Reporting Quality ◽

Systematic Evaluation ◽

Large Animal Model ◽

Large Animal ◽

Before And After ◽

Large Animals

Abstract OBJECTIVES Before new heart valves can be implanted safely in humans, animal experiments have to be performed. These animal experiments have to be clearly designed, analysed and reported to assess the accuracy and importance of the findings. We aimed to provide an overview of the reporting and methodological quality of preclinical heart valve research. METHODS We conducted a systematic literature search on biological and mechanical pulmonary valve implantations in large animals. We used the Animals in Research: Reporting In Vivo Experiments (ARRIVE) guidelines to score the quality of reporting in each article. We compared the scores before and after the introduction of the ARRIVE guidelines (2010). RESULTS We screened 348 articles, of which 31 articles were included. The included articles reported a mean of 54.7% adequately scored ARRIVE items (95% confidence interval 52.2–57.3%). We did not identify a difference in reporting quality (54.7% vs 54.8%) between articles published before and after 2010. We found an unclear (lack of description) risk of selection bias, performance bias and detection bias. CONCLUSIONS The reporting quality of studies that implanted bioprosthetic or mechanical valves in the pulmonary position in the large animal model is not on the desired level. The introduction of the ARRIVE guidelines in 2010 did not improve the reporting quality in this field of research. Hereby, we want to emphasize the importance of clearly describing the methods and transparently reporting the results in animal experiments. This is of great importance for the safe translation of new heart valves to the clinic. Clinical trial registration number PROSPERO (CRD42019147895).

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Plasma Phenylalanine and Tyrosine Responses to Different Nutritional Conditions (Fasting/Postprandial) in Patients With Phenylketonuria: Effect of Sample Timing

PEDIATRICS ◽

10.1542/peds.92.4.570 ◽

1993 ◽

Vol 92 (4) ◽

pp. 570-573

Author(s):

F. J. van Spronsen ◽

M. van Rijn ◽

T. van Dijk ◽

G. P.A. Smit ◽

D. J. Reijngoud ◽

...

Keyword(s):

Blood Sample ◽

Plasma Concentrations ◽

Dietary Treatment ◽

Nutritional Condition ◽

Blood Sampling ◽

Plasma Phenylalanine ◽

Nutritional Conditions ◽

Large Fluctuations ◽

Before And After ◽

Small Rise

Objective. To evaluate the adequacy of dietary treatment in patients with phenylketonuria, the monitoring of plasma phenylalanine and tyrosine concentrations is of great importance. The preferable time of blood sampling in relation to the nutritional condition during the day, however, is not known. It was the aim of this study to define guidelines for the timing of blood sampling with a minimal burden for the patient. Design. Plasma concentrations of phenylalanine and tyrosine were measured in nine patients with phenylketonuria who had no clinical evidence of tyrosine deficiency. These values were measured during the day both after a prolonged overnight fast, and before and after breakfast. Results. Phenylalanine showed a small rise during prolonged fasting, while tyrosine decreased slightly. After an individually tailored breakfast, phenylalanine remained stable, while tyrosine showed large fluctuations. Conclusion. It is concluded that the patient's nutritional condition (fasting/postprandial) is not important in the evaluation of the phenylalanine intake. To detect a possible tyrosine deficiency, however, a single blood sample is not sufficient and a combination of a preprandial and postprandial blood sample on the same day is advocated.

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Studies in sheep examining plasma follistatin elevations due to frequent blood sampling or surgery

Reproduction Fertility and Development ◽

10.1071/rd9960273 ◽

1996 ◽

Vol 8 (2) ◽

pp. 273 ◽

Cited By ~ 7

Author(s):

R Klein ◽

DM Robertson ◽

IJ Clarke

Keyword(s):

Intravenous Injection ◽

Plasma Clearance ◽

Blood Sampling ◽

Induced Response ◽

Tetraacetic Acid ◽

Before And After ◽

Bolus Intravenous Injection ◽

Per Se ◽

Frequent Sampling ◽

Elevate Plasma

This study examined the effects of the anticoagulant heparin on plasma follistatin (FS) concentrations used during blood sampling in Corriedale ewes. Plasma FS concentrations increased acutely (P < 0.01) following a bolus intravenous injection of heparin (3200 U). To determine whether frequent sampling per se can also increase plasma FS concentrations, ewes were sampled using a substitute anticoagulant, ethylenediamine tetraacetic acid. Frequent sampling had no effect on plasma FS concentrations. alpha-2 Macroglobulin concentrations were measured before and after bilateral ovariectomy and sham ovariectomy to determine whether this agent causes an increase in plasma FS concentrations 10-12 h after laparotomy. No differences in plasma alpha-2 macroglobulin concentrations were observed at the time of the observed increase in plasma FS concentrations. In conclusion: (1) heparin caused acute elevations in plasma FS concentrations probably by binding to FS, thereby reducing its plasma clearance; (2) rapid blood sampling per se did not elevate plasma FS concentrations; (3) alpha-2 macroglobulin concentrations were not elevated at the same time as plasma FS concentrations 10-12 h after surgery; and (4) the small increase in alpha-2 macroglobulin concentrations before surgery was attributable to a stress-induced response as seen in other species.

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

Biology ◽

10.3390/biology10040292 ◽

2021 ◽

Vol 10 (4) ◽

pp. 292

Author(s):

Maaike K. van Gelder ◽

Joost C. de Vries ◽

Sabbir Ahmed ◽

Anneke S. Monninkhof ◽

Gérard A. P. de Kort ◽

...

Keyword(s):

Renal Artery ◽

Plasma Concentrations ◽

Kidney Injury ◽

Uremic Toxins ◽

Large Animal Model ◽

Large Animal ◽

Artery Embolization ◽

Contralateral Kidney ◽

Chronic Kidney Injury ◽

Renal Artery Embolization

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.

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Plasma Clearance of B-Type Natriuretic Peptide (BNP) before and after Bariatric Surgery for Morbid Obesity

Clinical Chemistry ◽

10.1093/clinchem/hvaa308 ◽

2020 ◽

Author(s):

Kian Keong Poh ◽

Asim Shabbir ◽

Jinghao Nicholas Ngiam ◽

Poay Sian Sabrina Lee ◽

Jimmy So ◽

...

Keyword(s):

Bariatric Surgery ◽

Morbid Obesity ◽

Natriuretic Peptide ◽

Plasma Clearance ◽

Sodium Intake ◽

Plasma Concentrations ◽

Wall Stress ◽

Before And After ◽

Cardiac Filling ◽

Lower Production

Abstract Background Obese patients have lower plasma concentrations of the cardiac natriuretic peptides (NPs) than their age- and sex-matched counterparts. This may reflect lower production and/or increased peptide clearance. It is unclear whether NP bioactivity is affected by obesity. Methods We studied the effects of obesity on B-type natriuretic peptide (BNP) clearance and bioactivity by comparing results from standardized intravenous infusions of BNP administered 2 weeks before and 6 months after bariatric surgery in 12 consecutive patients with morbid obesity (body mass index, BMI > 35 kg/m2). Anthropometric, clinical, neurohormonal, renal, and echocardiographic variables were obtained pre- and postsurgery. Pre- vs postsurgery calculated intrainfusion peptide clearances were compared. Results BMI (44.3 ± 5.0 vs 33.9 ± 5.2 kg/m2, P < 0.001) and waist circumference (130.3 ± 11.9 vs 107.5 ± 14.7 cm, P < 0.001) decreased substantially after bariatric surgery. Calculated plasma clearance of BNP was reduced (approximately 30%) after surgery. Though not controlled for, sodium intake was presumably lower after bariatric surgery. Despite this, preinfusion endogenous plasma NP concentrations did not significantly differ between pre- and postsurgery studies. The ratio of plasma N-terminal (NT)-proBNP to 24 h urine sodium excretion was higher postsurgery (P = 0.046; with similar nonsignificant findings for BNP, atrial NP (ANP) and NT-proANP), indicating increased circulating NPs for a given sodium status. Mean plasma NP concentrations for given calculated end-systolic wall stress and cardiac filling pressures (as assessed by echocardiographic E/e’) rose slightly, but not significantly postsurgery. Second messenger, hemodynamic, renal, and neurohormonal responses to BNP were not altered between studies. Conclusion Obesity is associated with increased clearance, but preserved bioactivity, of BNP.

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Rate of disappearance of glycerol from plasma of fetal and newborn sheep

Journal of Applied Physiology ◽

10.1152/jappl.1990.68.1.271 ◽

1990 ◽

Vol 68 (1) ◽

pp. 271-274 ◽

Cited By ~ 1

Author(s):

G. G. Power ◽

K. T. Ball ◽

H. Asakura ◽

P. D. Gluckman

Keyword(s):

Clearance Rate ◽

Plasma Clearance ◽

Plasma Concentrations ◽

Exponential Model ◽

Volume Of Distribution ◽

Glycerol Concentration ◽

Fetal Sheep ◽

Double Exponential ◽

Before And After ◽

Double Exponential Model

The disappearance of glycerol from plasma was studied after a single intravenous injection to estimate its volume of distribution (Vdist), plasma clearance rate, and rate constant for irreversible loss (kd). Studies were repeated before and after birth of the lamb to test whether loss of the placenta could account for rapidly increasing plasma concentrations in the newborn. The disappearance of glycerol was closely described by a double-exponential model in each instance. In fetal sheep Vdist averaged 0.41 +/- 0.15 (SD) 1/kg fetal wt (n = 15). This volume decreased to 0.33 +/- 0.11 l/kg (n = 8) soon after functionally removing the placenta (by snaring the umbilical cord and maintaining the fetus with intrauterine ventilation), but the change was not significant. In newborn lambs 1-3 days of age, Vdist averaged 0.45 +/- 0.11 l/kg (n = 5, NS). Plasma clearance rate also did not change significantly, averaging 7.9 +/- 2.9, 7.9 +/- 3.8, and 9.0 +/- 5.9 ml.min-1.kg-1 in the fetus, after simulated birth, and in the newborn lamb, respectively, kd also was not altered measurably and averaged 0.020 +/- 0.006, 0.024 +/- 0.007, and 0.019 +/- 0.007 min-1 during the same time periods. Similar results were obtained by using three widely different amounts of infused glycerol. The results indicate that removal of glycerol does not depend on placental function to an appreciable extent. It is concluded that plasma glycerol concentration reflects principally glycerol turnover and, hence, lipolysis before and after birth.

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Exercise training-induced bradycardia: evidence for enhanced parasympathetic regulation without changes in intrinsic sinoatrial node function

Journal of Applied Physiology ◽

10.1152/japplphysiol.01111.2014 ◽

2015 ◽

Vol 118 (11) ◽

pp. 1344-1355 ◽

Cited By ~ 31

Author(s):

George E. Billman ◽

Kristen L. Cagnoli ◽

Thomas Csepe ◽

Ning Li ◽

Patrick Wright ◽

...

Keyword(s):

Heart Rate ◽

Exercise Training ◽

Large Animal Model ◽

Baseline Heart Rate ◽

Large Animal ◽

Atrial Pacing ◽

Before And After ◽

Model Training ◽

Exercise Induced ◽

Parasympathetic Regulation

The mechanisms responsible for exercise-induced reductions in baseline heart rate (HR), known as training bradycardia, remain controversial. Therefore, changes in cardiac autonomic regulation and intrinsic sinoatrial nodal (SAN) rate were evaluated using dogs randomly assigned to either a 10- to 12-wk exercise training ( Ex, n = 15) or an equivalent sedentary period ( Sed, n = 10). Intrinsic HR was revealed by combined autonomic nervous system (ANS) blockade (propranolol + atropine, iv) before and after completion of the study. At the end of the study, SAN function was further evaluated by examining the SAN recovery time (SNRT) following rapid atrial pacing and the response to adenosine in anesthetized animals. As expected, both the response to submaximal exercise and baseline HR significantly ( P < 0.01) decreased, and heart rate variability (HRV; e.g., high-frequency R-R interval variability) significantly ( P < 0.01) increased in the Ex group but did not change in the Sed group. Atropine also induced significantly ( P < 0.01) greater reductions in HRV in the Ex group compared with the Sed group; propranolol elicited similar HR and HRV changes in both groups. In contrast, neither intrinsic HR ( Ex before, 141.2 ± 6.7; Ex after, 146.0 ± 8.0 vs. Sed before, 143.3 ± 11.1; Sed after, 141.0 ± 11.3 beats per minute), the response to adenosine, corrected SNRT, nor atrial fibrosis and atrial fibrillation inducibility differed in the Ex group vs. the Sed group. These data suggest that in a large-animal model, training bradycardia results from an enhanced cardiac parasympathetic regulation and not from changes in intrinsic properties of the SAN.

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