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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–D) Typical FITC-sinistrin kinetic curves (arbitrary units) in a control mouse at week zero (A), and four (B); and in an ADR-administered mouse prior to (C) and at four weeks post-adriamycin administration (D). (E) The mean half-life of FITC-sinistrin for the ADR-administered and control groups is shown weekly for four weeks. 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 ≤ 0.05 (*), p ≤ 0.01 (**), see also Table S3.
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f2: (A–D) Typical FITC-sinistrin kinetic curves (arbitrary units) in a control mouse at week zero (A), and four (B); and in an ADR-administered mouse prior to (C) and at four weeks post-adriamycin administration (D). (E) The mean half-life of FITC-sinistrin for the ADR-administered and control groups is shown weekly for four weeks. 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 ≤ 0.05 (*), p ≤ 0.01 (**), see also Table S3.

Mentions: To assess changes in glomerular filtration over time with the transcutaneous device, we undertook serial measurements of FITC-sinistrin half-life over 4 weeks. Representative examples of clearance curves from control and ADR animals are shown in Fig. 2A–D. The FITC-sinistrin half-life in the ADR group was increased with statistical significance from week 2 onwards (Fig. 2E, Table S1A, S3). Given that GFR is inversely correlated to the FITC-sinistrin half-life1018, these results suggest that GFR is slightly impaired 2 weeks after ADR administration and deteriorates further between weeks 3 and 4, reflecting the progressive nature of the nephropathy19. An LME model revealed statistically significant linear changes in the FITC-sinistrin half-life within the ADR group over time, with an average increment of 2.45 (=(0.02 + 0.33) × 7) minutes per week (p < 0.001). These changes were statistically different when compared with controls, in which no significant changes in half-life were detected (p = 0.76, Table 1). The levels of BUN and SCr as indicators of kidney function revealed no significant differences between the experimental control groups at week 5 (Figure S1D,E).


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–D) Typical FITC-sinistrin kinetic curves (arbitrary units) in a control mouse at week zero (A), and four (B); and in an ADR-administered mouse prior to (C) and at four weeks post-adriamycin administration (D). (E) The mean half-life of FITC-sinistrin for the ADR-administered and control groups is shown weekly for four weeks. 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 ≤ 0.05 (*), p ≤ 0.01 (**), see also Table S3.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: (A–D) Typical FITC-sinistrin kinetic curves (arbitrary units) in a control mouse at week zero (A), and four (B); and in an ADR-administered mouse prior to (C) and at four weeks post-adriamycin administration (D). (E) The mean half-life of FITC-sinistrin for the ADR-administered and control groups is shown weekly for four weeks. 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 ≤ 0.05 (*), p ≤ 0.01 (**), see also Table S3.
Mentions: To assess changes in glomerular filtration over time with the transcutaneous device, we undertook serial measurements of FITC-sinistrin half-life over 4 weeks. Representative examples of clearance curves from control and ADR animals are shown in Fig. 2A–D. The FITC-sinistrin half-life in the ADR group was increased with statistical significance from week 2 onwards (Fig. 2E, Table S1A, S3). Given that GFR is inversely correlated to the FITC-sinistrin half-life1018, these results suggest that GFR is slightly impaired 2 weeks after ADR administration and deteriorates further between weeks 3 and 4, reflecting the progressive nature of the nephropathy19. An LME model revealed statistically significant linear changes in the FITC-sinistrin half-life within the ADR group over time, with an average increment of 2.45 (=(0.02 + 0.33) × 7) minutes per week (p < 0.001). These changes were statistically different when compared with controls, in which no significant changes in half-life were detected (p = 0.76, Table 1). The levels of BUN and SCr as indicators of kidney function revealed no significant differences between the experimental control groups at week 5 (Figure S1D,E).

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