Description of a transient proximal tubulopathy induced by amino acids perfusion in peptide receptor radionuclide therapy

Abstract

Rationale: Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is a targeted internal radiotherapy method used to treat tumors expressing somatostatin receptors. Concomitant amino acids perfusion is systematically performed in order to inhibit the proximal tubular uptake of the radionuclide and thus prevent nephrotoxicity.Patient concerns: a 67-year-old woman with an intestinal neuroendocrine tumor with multiple lymphadenopathies and liver metastases. The patient displayed a carcinoid syndrome with flushes including facial erythrosis and paresthesia. During the treatment, the patient exhibited emesis and severe cramps.Diagnosis: We describe incomplete proximal tubulopathy induced by an amino acid therapy with [177Lu]-DOTA0-Tyr3-octreotate, which was reversible after treatment discontinuation. This diagnosis relies on metabolic acidosis, hypophosphatemia due to renal loss, tubular proteinuria and generalized aminoaciduria. Serum creatinine remained stable during and after the procedure.Interventions: PRRT with radiolabeled somatostatin analog ([177Lu]-DOTA0-Tyr3-octreotate). In order to prevent PRRT induced nephrotoxicity, we used a solution of 20 amino acids including 22 g/L Lysine and 16.8 g/L Arginine. Metoclopramide was successfully used to control vomiting. During the treatment and at the time of cramps, the blood sample showed hypophosphatemia at 0.3 mmol/ L justifying intravenous phosphate supplementation. The cramps disappeared after this infusion.Outcomes: Hypophosphatemia with low TmPO4/GFR was observed as well as an increase in b2-microglobulinuria, urinary polyclonal light chains, and amino aciduria involving all amino acids. All these disturbances disappeared the day after the treatment and there was no acute kidney injury after 5 PRRT sessions. Six months after PRRT discontinuation, the patient had neither renal failure nor proximal tubulopathy. Aminoacid induced tubulopathy involves the main ligands of the megalin receptor. It has recently been demonstrated that cilastatin is a megalin inhibitor in the proximal tubule and therefore could represent an attractive alternative to amino acids for this purpose.Lessons: This case report is a description of a nephroprotective strategy in which partial, and transient tubulopathy is induced, in order to decrease proximal absorption of a tubulotoxic molecule. This little known strategy could be used to prevent proximal tubular injury caused by others megalin-mediated nephrotoxicity medication.Abbreviations: 177Lu = Lutetium 177, PRRT = peptide receptor radionuclide therapy, TmPO4/GFR = ratio of maximum rate of renal tubular reabsorption of phosphate to glomerular filtration rate, TRP = fractional tubular reabsorption of phosphate.

EANM dosimetry committee recommendations for dosimetry of 177Lu-labelled somatostatin-receptor- and PSMA-targeting ligands

“…To reduce the risk of renal toxicity after administration of [177Lu]Lu-SSRT, protocols for renal protection have been developed involving co-infusion of amino acids that compete for the megalin receptor on tubular cells. Immediate and reversible side effects following therapy, like vomiting and cramps, are ascribed to renal-protection protocols rather than radiation exposure [ 52 , 53 ]. For [177Lu]Lu-SSRT, including concurrent kidney protection, the level of reported nephrotoxicity is limited to disease-related events, and for therapy with [177Lu]Lu-PSMA, it appears to be negligible at current activities [ 28 , 54 ].…”

Peptide Receptor Radionuclide Therapy: Looking Back, Looking Forward

“…However, it has also been shown that yttrium-90-labeled peptides had a higher chance of inducing high-grade renal toxicity compared to lutetium-177-labeled peptides, especially in patients with risk factors relevant for creatinine clearance loss [ 31 , 32 ]. Nevertheless, to limit renal toxicity, a cocktail of lysine and arginine can be administered to patients after which potential toxicity can be monitored, increasing the safety of the radiopeptide [ 33 - 34 ]. So far, maybe more promising is the combination of yttrium-90 and lutetium-177 for the treatment of NETs.…”