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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

Correlation graphs showing the correlation of both control and ADR group data between the percentage of abnormal glomeruli and maximum observed albuminuria (A), FITC-Sinistrin half-life at week 4 (B), IRDye excretion half-life in the cortex at week 5 (C) and IRDye TMAX delay (D) at week 5.Data points represent individual animals (circles = control, n = 5; squares = ADR-administered, n = 6). Trendlines for control (dashed line) and ADR-administered (solid line) animals are displayed.
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f5: Correlation graphs showing the correlation of both control and ADR group data between the percentage of abnormal glomeruli and maximum observed albuminuria (A), FITC-Sinistrin half-life at week 4 (B), IRDye excretion half-life in the cortex at week 5 (C) and IRDye TMAX delay (D) at week 5.Data points represent individual animals (circles = control, n = 5; squares = ADR-administered, n = 6). Trendlines for control (dashed line) and ADR-administered (solid line) animals are displayed.

Mentions: Next, we evaluated whether the two novel minimally invasive dye clearance methods we have used here to detect kidney filtration function, are suitable for long-term regenerative medicine therapy studies through their statistical association with detected glomerular damage. Importantly, since we had observed a wide range in the proportions of scarred glomeruli (as assessed by the above criteria) in the ADR kidneys, we questioned whether specific glomerular damage in individual mice was associated with specific measures of kidney function. Therefore, we examined the relationship in individual animals between glomerular histological lesions and (i) albuminuria, (ii) FITC-sinistrin half-life and (iii) IRDye excretion kinetics in individual animals (Fig. 5). In ADR mice, there was no significant association between glomerular histological damage (week 5) and the amount of albuminuria measured at the maximum (weeks 2–3) or at the final point of urine collection in week 4 (Table 2). Therefore, albuminuria is not a reliable measure of glomerular histological damage in this model. By contrast, assessment of the relationship between FITC-sinistrin half-life and the proportion of histologically damaged glomeruli revealed a significant positive correlation between FITC-sinistrin half-life values at week 4 and glomerular damage at week 5 (coefficient = 0.94, p = 0.001; see Table 2).


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)

Correlation graphs showing the correlation of both control and ADR group data between the percentage of abnormal glomeruli and maximum observed albuminuria (A), FITC-Sinistrin half-life at week 4 (B), IRDye excretion half-life in the cortex at week 5 (C) and IRDye TMAX delay (D) at week 5.Data points represent individual animals (circles = control, n = 5; squares = ADR-administered, n = 6). Trendlines for control (dashed line) and ADR-administered (solid line) animals are displayed.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Correlation graphs showing the correlation of both control and ADR group data between the percentage of abnormal glomeruli and maximum observed albuminuria (A), FITC-Sinistrin half-life at week 4 (B), IRDye excretion half-life in the cortex at week 5 (C) and IRDye TMAX delay (D) at week 5.Data points represent individual animals (circles = control, n = 5; squares = ADR-administered, n = 6). Trendlines for control (dashed line) and ADR-administered (solid line) animals are displayed.
Mentions: Next, we evaluated whether the two novel minimally invasive dye clearance methods we have used here to detect kidney filtration function, are suitable for long-term regenerative medicine therapy studies through their statistical association with detected glomerular damage. Importantly, since we had observed a wide range in the proportions of scarred glomeruli (as assessed by the above criteria) in the ADR kidneys, we questioned whether specific glomerular damage in individual mice was associated with specific measures of kidney function. Therefore, we examined the relationship in individual animals between glomerular histological lesions and (i) albuminuria, (ii) FITC-sinistrin half-life and (iii) IRDye excretion kinetics in individual animals (Fig. 5). In ADR mice, there was no significant association between glomerular histological damage (week 5) and the amount of albuminuria measured at the maximum (weeks 2–3) or at the final point of urine collection in week 4 (Table 2). Therefore, albuminuria is not a reliable measure of glomerular histological damage in this model. By contrast, assessment of the relationship between FITC-sinistrin half-life and the proportion of histologically damaged glomeruli revealed a significant positive correlation between FITC-sinistrin half-life values at week 4 and glomerular damage at week 5 (coefficient = 0.94, p = 0.001; see Table 2).

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