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Measures of kidney function by minimally invasive techniques correlate with histological glomerular damage in SCID mice with adriamycin-induced nephropathy.

Scarfe L, Rak-Raszewska A, Geraci S, Darssan D, Sharkey J, Huang J, Burton NC, Mason D, Ranjzad P, Kenny S, Gretz N, Lévy R, Kevin Park B, García-Fiñana M, Woolf AS, Murray P, Wilm B - Sci Rep (2015)

Bottom Line: Maximising the use of preclinical murine models of progressive kidney disease as test beds for therapies ideally requires kidney function to be measured repeatedly in a safe, minimally invasive manner.Measurements with either technique showed a significant impairment of renal function in experimental animals versus controls, with significant correlations with the proportion of scarred glomeruli five weeks after induction of injury.Moreover, their use will also lead to a reduction in experimental animal numbers.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

ABSTRACT
Maximising the use of preclinical murine models of progressive kidney disease as test beds for therapies ideally requires kidney function to be measured repeatedly in a safe, minimally invasive manner. To date, most studies of murine nephropathy depend on unreliable markers of renal physiological function, exemplified by measuring blood levels of creatinine and urea, and on various end points necessitating sacrifice of experimental animals to assess histological damage, thus counteracting the principles of Replacement, Refinement and Reduction. Here, we applied two novel minimally invasive techniques to measure kidney function in SCID mice with adriamycin-induced nephropathy. We employed i) a transcutaneous device that measures the half-life of intravenously administered FITC-sinistrin, a molecule cleared by glomerular filtration; and ii) multispectral optoacoustic tomography, a photoacoustic imaging device that directly visualises the clearance of the near infrared dye, IRDye 800CW carboxylate. Measurements with either technique showed a significant impairment of renal function in experimental animals versus controls, with significant correlations with the proportion of scarred glomeruli five weeks after induction of injury. These technologies provide clinically relevant functional data and should be widely adopted for testing the efficacies of novel therapies. Moreover, their use will also lead to a reduction in experimental animal numbers.

No MeSH data available.


Related in: MedlinePlus

(A) Mean change in body weight of mice up to five weeks after adriamycin administration. Animals of the ADR group had a mean body weight loss of approximately 20% by week 1, while control animals had a mean body weight gain of 5%. (B) Mean albuminuria over 24 hours, measured weekly. ADR-administered animals had a mean maximum of albuminuria of approximately 90 mg/24 h at 3 weeks, while in control animals urinary albumin stayed constant throughout the study at around 0.03 mg/24 h. (C) Mean albumin:creatinine ratio (alb:cr) measured weekly, showing similar temporal dynamics to 24 h albuminuria. Data points (circles = control, n = 5; squares = ADR-administered, n = 6) and bars show mean ± standard error. Asterisks indicate significance of mixed-design ANOVA models: p ≤ 0.01 (**), p ≤ 0.001 (***), see also Table S3.
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f1: (A) Mean change in body weight of mice up to five weeks after adriamycin administration. Animals of the ADR group had a mean body weight loss of approximately 20% by week 1, while control animals had a mean body weight gain of 5%. (B) Mean albuminuria over 24 hours, measured weekly. ADR-administered animals had a mean maximum of albuminuria of approximately 90 mg/24 h at 3 weeks, while in control animals urinary albumin stayed constant throughout the study at around 0.03 mg/24 h. (C) Mean albumin:creatinine ratio (alb:cr) measured weekly, showing similar temporal dynamics to 24 h albuminuria. Data points (circles = control, n = 5; squares = ADR-administered, n = 6) and bars show mean ± standard error. Asterisks indicate significance of mixed-design ANOVA models: p ≤ 0.01 (**), p ≤ 0.001 (***), see also Table S3.

Mentions: Kidney injury was induced by intravenous (iv) ADR administration once in 6 SCID female mice while 5 control SCID females received saline injection. The weights of ADR-administered versus control mice reached their lowest point one week after nephrotoxin administration. Over the next four weeks, weights in the ADR group returned towards time-matched control values but did not attain them (Fig. 1A, S1A). To determine damage to the glomerular macromolecular barrier, we measured total 24-hour urinary excretion and the albumin:creatinine ratio on a weekly basis (Fig. 1B,C, S1B,C). Using either measure, albuminuria was significantly elevated in the ADR group at weeks 2 to 4, with attenuation at week 4 (Fig. 1B,C, Table S1A, S3). Similar effects have been previously reported in ADR-induced SCID mice4917. A linear mixed-effects (LME) model showed statistically significant linear and quadratic changes of albuminuria over time within the ADR group (p < 0.001 for both the linear and second degree terms, Table 1).


Measures of kidney function by minimally invasive techniques correlate with histological glomerular damage in SCID mice with adriamycin-induced nephropathy.

Scarfe L, Rak-Raszewska A, Geraci S, Darssan D, Sharkey J, Huang J, Burton NC, Mason D, Ranjzad P, Kenny S, Gretz N, Lévy R, Kevin Park B, García-Fiñana M, Woolf AS, Murray P, Wilm B - Sci Rep (2015)

(A) Mean change in body weight of mice up to five weeks after adriamycin administration. Animals of the ADR group had a mean body weight loss of approximately 20% by week 1, while control animals had a mean body weight gain of 5%. (B) Mean albuminuria over 24 hours, measured weekly. ADR-administered animals had a mean maximum of albuminuria of approximately 90 mg/24 h at 3 weeks, while in control animals urinary albumin stayed constant throughout the study at around 0.03 mg/24 h. (C) Mean albumin:creatinine ratio (alb:cr) measured weekly, showing similar temporal dynamics to 24 h albuminuria. Data points (circles = control, n = 5; squares = ADR-administered, n = 6) and bars show mean ± standard error. Asterisks indicate significance of mixed-design ANOVA models: p ≤ 0.01 (**), p ≤ 0.001 (***), see also Table S3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556979&req=5

f1: (A) Mean change in body weight of mice up to five weeks after adriamycin administration. Animals of the ADR group had a mean body weight loss of approximately 20% by week 1, while control animals had a mean body weight gain of 5%. (B) Mean albuminuria over 24 hours, measured weekly. ADR-administered animals had a mean maximum of albuminuria of approximately 90 mg/24 h at 3 weeks, while in control animals urinary albumin stayed constant throughout the study at around 0.03 mg/24 h. (C) Mean albumin:creatinine ratio (alb:cr) measured weekly, showing similar temporal dynamics to 24 h albuminuria. Data points (circles = control, n = 5; squares = ADR-administered, n = 6) and bars show mean ± standard error. Asterisks indicate significance of mixed-design ANOVA models: p ≤ 0.01 (**), p ≤ 0.001 (***), see also Table S3.
Mentions: Kidney injury was induced by intravenous (iv) ADR administration once in 6 SCID female mice while 5 control SCID females received saline injection. The weights of ADR-administered versus control mice reached their lowest point one week after nephrotoxin administration. Over the next four weeks, weights in the ADR group returned towards time-matched control values but did not attain them (Fig. 1A, S1A). To determine damage to the glomerular macromolecular barrier, we measured total 24-hour urinary excretion and the albumin:creatinine ratio on a weekly basis (Fig. 1B,C, S1B,C). Using either measure, albuminuria was significantly elevated in the ADR group at weeks 2 to 4, with attenuation at week 4 (Fig. 1B,C, Table S1A, S3). Similar effects have been previously reported in ADR-induced SCID mice4917. A linear mixed-effects (LME) model showed statistically significant linear and quadratic changes of albuminuria over time within the ADR group (p < 0.001 for both the linear and second degree terms, Table 1).

Bottom Line: Maximising the use of preclinical murine models of progressive kidney disease as test beds for therapies ideally requires kidney function to be measured repeatedly in a safe, minimally invasive manner.Measurements with either technique showed a significant impairment of renal function in experimental animals versus controls, with significant correlations with the proportion of scarred glomeruli five weeks after induction of injury.Moreover, their use will also lead to a reduction in experimental animal numbers.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

ABSTRACT
Maximising the use of preclinical murine models of progressive kidney disease as test beds for therapies ideally requires kidney function to be measured repeatedly in a safe, minimally invasive manner. To date, most studies of murine nephropathy depend on unreliable markers of renal physiological function, exemplified by measuring blood levels of creatinine and urea, and on various end points necessitating sacrifice of experimental animals to assess histological damage, thus counteracting the principles of Replacement, Refinement and Reduction. Here, we applied two novel minimally invasive techniques to measure kidney function in SCID mice with adriamycin-induced nephropathy. We employed i) a transcutaneous device that measures the half-life of intravenously administered FITC-sinistrin, a molecule cleared by glomerular filtration; and ii) multispectral optoacoustic tomography, a photoacoustic imaging device that directly visualises the clearance of the near infrared dye, IRDye 800CW carboxylate. Measurements with either technique showed a significant impairment of renal function in experimental animals versus controls, with significant correlations with the proportion of scarred glomeruli five weeks after induction of injury. These technologies provide clinically relevant functional data and should be widely adopted for testing the efficacies of novel therapies. Moreover, their use will also lead to a reduction in experimental animal numbers.

No MeSH data available.


Related in: MedlinePlus