J Curr Surg

Journal of Current Surgery, ISSN 1927-1298 print, 1927-1301 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Curr Surg and Elmer Press Inc

Journal website https://www.currentsurgery.org

Original Article

Volume 11, Number 1, March 2021, pages 8-14

Predicting the Effective Dose of 5-Aminolevulinic Acid to Protect Humans From Renal Ischemia-Reperfusion Injury: A Study in Micro Miniature Pigs

Figures

Figure 1. Surgical renal ischemia in the micro miniature pigs. (a, b) The left kidney was exposed and Gerota’s fascia was stripped from the left outer side. Renal arteries and veins are visible. (c) A vascular clip was placed on the left renal arteries and veins, and warm ischemia was performed on the left kidney. (d) One hour after inducing ischemia, the clip was removed, and blood reperfusion was confirmed.

Figure 2. Pathological evaluation of renal ischemia from five fields of view each of the cortex and medulla (including the corticomedullary junction), for a total of 10 fields. The fields of view were imaged randomly under a magnification of 200 × and scored according to the incidence rate of pathological changes, as described in the main text.

Figure 3. (a) Values represent the mean histopathological scores ± SD for nine aspects in each group. One-way analysis of variance revealed a statistically significant difference (P < 0.001). *Indicates significant difference vs. control in Dunnett’s multiple comparison test (P < 0.05). (b) Correlation between histopathological sores and serum 5-ALA concentration. SD: standard deviation; ALA: aminolevulinic acid.

Figure 4. (a) Histopathological score vs. maximum drug concentration (Cmax) of 5-ALA in micro miniature pigs. Approximate curve was used to assume the required concentration from the expected drug efficacy index (histopathological score). (b) Cmax vs. dose of 5-ALA in humans. The approximate curve was used to calculate the required dose of 5-ALA from the assumed blood concentration in (a). Thus, by defining the drug efficacy parameters that correlated with blood concentrations of 5-ALA and obtaining an approximate expression in micro miniature pigs, we were able to estimate the dose of 5-ALA required for humans from the expected index of drug efficacy. 5-ALA: 5-aminolevulinic acid.

Table

**Table 1.** Histopathological Scores in the Kidney After Renal Ischemia of Different Groups
Group		Control									5-ALA
Dose (mg/kg)		0									10									100
Control No.		1 - 2			2 - 2			1 - 4			1 - 1			1 - 2			2 - 1			1 - 1			1 - 3			2 - 2
Animal No.		4,135 (female)			4,192 (male)			4,206 (female)			4,183 (female)			4,187 (female)			4,128 (male)			4,134 (female)			4,188 (female)			4,178 (male)
	Field/slide No.	-1	-2	-3	-1	-2	-3	-1	-2	-3	-1	-2	-3	-1	-2	-3	-1	-2	-3	-1	-2	-3	-1	-2	-3	-1	-2	-3
5-ALA: 5-aminolevulinic acid.
Cortex	1	5	5	4	5	4	5	5	5	5	4	5	4	5	5	4	5	5	4	4	4	3	5	5	5	3	4	5
	2	5	5	5	5	4	5	5	5	5	5	5	4	4	5	5	5	5	5	4	4	4	5	4	4	4	3	4
	3	4	5	4	5	5	5	5	5	5	4	4	5	5	5	4	4	5	5	4	4	3	5	5	4	5	4	4
	4	4	4	5	5	5	5	5	5	5	5	5	4	5	5	5	4	4	5	4	4	4	4	4	4	4	4	4
	5	4	5	4	4	4	5	5	5	5	5	4	5	5	4	5	5	4	5	5	4	5	5	4	5	4	4	4
Medulla and cortico-medulla	6	5	4	4	5	5	4	4	4	4	5	3	4	5	5	5	4	5	5	4	4	4	3	4	3	3	2	2
	7	5	4	5	5	5	4	4	5	5	3	3	4	4	4	5	4	4	3	3	2	4	2	3	3	2	2	3
	8	5	5	5	4	4	4	4	5	4	5	4	1	5	5	4	2	4	3	4	4	4	4	4	3	2	2	2
	9	5	5	5	5	4	5	4	5	5	3	3	2	4	5	4	3	4	4	3	4	4	2	3	3	4	3	3
	10	5	5	4	5	4	4	5	5	5	5	4	3	5	5	4	4	4	4	4	3	4	3	4	3	2	2	3
Score	Mean	4.7	4.7	4.5	4.8	4.4	4.6	4.6	4.9	4.8	4.4	4.0	3.6	4.7	4.8	4.5	4.0	4.4	4.3	3.9	3.7	3.9	3.8	4.0	3.7	3.3	3.0	3.4
	Total mean	4.7									4.3									3.6
	SD	0.2									0.4									0.3