Renal uptake of different radiolabelled peptides is mediated by megalin: SPECT and biodistribution studies in megalin-deficient mice

Abstract

Purpose: Radiolabelled peptides used for peptide receptor radionuclide therapy are excreted mainly via the kidneys and are partly reabsorbed and retained in the proximal tubular cells. The resulting high renal radiation dose can cause nephrotoxicity, limiting the maximum activity dose and the effectiveness of peptide receptor radionuclide therapy. The mechanisms of kidney reabsorption of these peptides are incompletely understood, but the scavenger receptor megalin has been shown to play a role in the reabsorption of (111)In-octreotide. In this study, the role of megalin in the renal reabsorption of various relevant radiolabelled peptides was investigated.

Methods: Groups of kidney-specific megalin-deficient mice and wild-type mice were injected with (111)In-labelled somatostatin, exendin, neurotensin or minigastrin analogues. Single photon emission computed tomographic (SPECT) images of the kidneys were acquired and analysed quantitatively, or the animals were killed 3 h after injection and the activity concentration in the kidneys was measured.

Results: Megalin-deficient mice showed significantly lower uptake of all studied radiolabelled peptides in the kidneys, ranging from 22% ((111)In-octreotide) to 65% ((111)In-exendin) of uptake in wild-type kidneys. Quantitative analysis of renal uptake by SPECT and ex vivo measurements showed a very good correlation.

Conclusion: Megalin is involved in the renal reabsorption of radiolabelled octreotide, octreotate, exendin, neurotensin and minigastrin. This knowledge may help in the design of strategies to reduce this reabsorption and the resulting nephrotoxicity in peptide receptor radionuclide therapy, enabling more effective therapy. Small-animal SPECT is an accurate tool, allowing in vivo quantification of renal uptake and serial measurements in individual mice.

Fig. 1

Anti-megalin immunostaining of kidney cortex from a wild-type mouse (a) and from two megalin-deficient mice exhibiting relatively high (b) and relatively low (c) residual expression of megalin

Fig. 2

SPECT images of the kidneys of wild-type (a) and megalin-deficient (b) mice 3 h after injection of ¹¹¹In-minigastrin (left maximum intensity projections, right coronal slices)

Fig. 3

Renal uptake of ¹¹¹In-labelled peptides in wild-type and megalin-deficient mice, as measured by ex vivo biodistribution studies and SPECT 3 h after injection. Results are presented as mean %ID/g; error bars indicate standard error of the mean. *p < 0.05

Fig. 4

Autoradiography of kidneys of wild-type and megalin-deficient mice that received ¹¹¹In-exendin (a), ¹¹¹In-minigastrin (b) or ¹¹¹In-neurotensin (c)

Fig. 5

Correlation between renal uptake measured ex vivo and uptake measured by SPECT. The data are from individual mice that were studied ex vivo after the final SPECT scan (¹¹¹In-minigastrin and ¹¹¹In-exendin). Solid lines linear-fitted trend line with 95% confidence interval