Renal Toxicity of Radiolabeled Peptides and Antibody Fragments: Mechanisms, Impact on Radionuclide Therapy, and Strategies for Prevention

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FIGURE 1.
Overview of glomerular and proximal tubular handling of proteins and peptides. AA = amino acid transporter; OCT = organic cation transporter; PEPT = oligopeptide transporter.

TABLE 1

Processes and Factors in Renal Handling and Retention of Radiolabeled Peptides and Strategies to Interfere

Site	Process	Methods to reduce nephrotoxicity	Examples
Glomerulus	Ultrafiltration	Increase binding to albumin or other proteins	Albumin binding sequence
		Increase size	PEGylation
Proximal tubule	Degradation by brush border enzymes	Insert cleavable linker	Glycyl-lysine linker
	Reabsorption by endocytosis or transporters	Saturate with competitive inhibitors	Coinfusion of lysine/arginine/succinylated gelatin
		Decrease affinity by modification of structure or charge of the peptide	Substitution, addition or removal of charged groups; PEGylation
		Decrease endocytosis (i.e., by reduction of energy supply or interference with formation or trafficking of endosomes)	Maleate, colchicine
	Degradation and retention in lysosomes	Use nonresidualizing radiolabels	Conventionally iodinated peptides
	Peritubular absorption	Block transporters	Probenecid
Whole kidney	Radiation damage and repair	Use short-range radionuclides to limit radiation dose to the glomeruli	¹⁷⁷Lu instead of ⁹⁰Y
		Scavenging of free radicals using radioprotectors	Amifostine
		Increase time to repair sublethal damage	Dose fractionation
		Mitigate damaging processes	Spironolactone, L-158,809