MIRD Pamphlet No. 20: The Effect of Model Assumptions on Kidney Dosimetry and Response—Implications for Radionuclide Therapy

Abstract

Renal toxicity associated with small-molecule radionuclide therapy has been shown to be dose-limiting for many clinical studies. Strategies for maximizing dose to the target tissues while sparing normal critical organs based on absorbed dose and biologic response parameters are commonly used in external-beam therapy. However, radiopharmaceuticals passing though the kidneys result in a differential dose rate to suborgan elements, presenting a significant challenge in assessing an accurate dose-response relationship that is predictive of toxicity in future patients. We have modeled the multiregional internal dosimetry of the kidneys combined with the biologic response parameters based on experience with brachytherapy and external-beam radiation therapy to provide an approach for predicting radiation toxicity to the kidneys. Methods: The multiregion kidney dosimetry model of MIRD pamphlet no. 19 has been used to calculate absorbed dose to regional structures based on preclinical and clinical data. Using the linear quadratic model for radiobiologic response, we computed regionally based surviving fractions for the kidney cortex and medulla in terms of their concentration ratios for several examples of radiopharmaceutical uptake and clearance. We used past experience to illustrate the relationship between absorbed dose and calculated biologically effective dose (BED) with radionuclide-induced nephrotoxicity. Results: Parametric analysis for the examples showed that high dose rates associated with regions of high activity concentration resulted in the greatest decrease in tissue survival. Higher dose rates from short-lived radionuclides or increased localization of radiopharmaceuticals in radiosensitive kidney subregions can potentially lead to greater whole-organ toxicity. This finding is consistent with reports of kidney toxicity associated with early peptide receptor radionuclide therapy and 166 Ho-phosphonate clinical investigations. Conclusion: Radionuclide therapy doseresponse data, when expressed in terms of biologically effective dose, have been found to be consistent with external-beam experience for predicting kidney toxicity. Model predictions using both the multiregion kidney and linear quadratic models may serve to guide the investigator in planning and optimizing future clinical trials of radionuclide therapy.

Dynamic and Static Small-Animal SPECT in Rats for Monitoring Renal Function After 177Lu-Labeled Tyr3-Octreotate Radionuclide Therapy

“…Although further clinical validation is warranted, the introduction of routine 99m Tc-MAG3 renography might be considered at more PRRT centers, especially in patients with compromised renal function. Also, patients receiving extra cycles of PRRT (7,8) are appropriate candidates for 99m Tc-MAG3 follow-up when doses exceed the accepted safe limit of 23-27 Gy absorbed kidney radiation dose, adapted from external beam radiation, or the 37-to 45-Gy limit of the biologically equivalent dose on the kidney, taking into account the kidney mass and nonuniform localization of renal radioactivity (36,37). The application of renal imaging using 99m Tc-DMSA or 99m Tc-MAG3 can be extended to follow up renal proximal tubule function in other diseases when the kidney is the organ at risk (26,38).…”

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

“…Doses of 23 Gy cause chronic kidney failure in approximately 5% of patients within 5 y (44). However, the reaction of tissue to radiation does not depend only on the total absorbed dose but also on dose rate, fractionation, microdistribution of dose within the organ, and radiation type (a-, b-, g-, or x-radiation) and energy (29,33,43). Typically, in PRRT, dose rates are much lower than in EBRT, distribution within the organ is more inhomogeneous, and the radiation has a shorter range of penetration.…”

“…Up to years after therapy, late myelotoxicity such as myelodysplastic syndrome and leukemia can develop, which may also be treated with bone marrow transplantation (29)(30)(31). However, the kidneys are sensitive to radiation as well, and given the relatively high renal retention of many radiolabeled peptides, the kidneys are often the dose-limiting organs in PRRT (5,32,33).…”

RADAR Commentary: Evolution and Current Status of Dosimetry in Nuclear Medicine

“…These findings represent important advancements for the use of radiolabeled peptides in the future, and the MIRD Committee's Pamphlet No. 20 (38) has stated that this approach leads to the best currently available predictive model to minimize nephrotoxicity in peptide radionuclide receptor therapy. Unfortunately, this MIRD pamphlet was issued with methodologic errors, questionable assumptions, and an incomplete consideration of different candidate radiobiologic models (39).…”