Inhibition of Kidney Uptake of Radiolabeled Somatostatin Analogs: Amino Acids or Gelofusine?

TO THE EDITOR: With great interest we read the papers by Van Eerd et al. (1) and Vegt et al. (2) on the effects of the succinylated gelatin plasma expander Gelofusine (B. Braun Medical) on renal uptake of [¹¹¹In-diethylenetriaminepentaacetic acid (DTPA)]octreotide. We congratulate the authors on their innovative work, as we believe this is fundamental and interesting research.

The authors reported that Gelofusine significantly inhibited kidney uptake of [¹¹¹In-DTPA]octreotide to a level comparable to the level of inhibition by currently applied amino acid solutions. This finding further expands on the previous clinical observation that Gelofusine infusion results in tubular proteinuria (3–5) of both albumin and β₂-microglobulin. Although the mechanism for this proteinuria is not completely understood, involvement of the megalin receptor system is likely, because both β₂-microglobulin and albumin are ligands for this receptor. The megalin system was recently shown to be essential for kidney uptake of radiolabeled somatostatin analogs (6), making interventions at the megalin level interesting potential targets for renal protection during peptide receptor radionuclide therapy (PRRT). The new findings of the group in Nijmegen (1,2) offer an additional way to further research this subject. We would like to comment on some conclusions and statements brought forward in the 2 papers.

On the basis of several reports, the authors stated that amino acid infusion for kidney protection may have several side effects such as vomiting and potentially fatal hyperkalemia. We previously reported on the safety and side effects of different amino acid solutions (7). On the basis of that study, we now use a combination of 25 g of l-lysine and 25 g of l-arginine, dissolved in 1 L (LysArg), as a standard 4-h infusion protocol for kidney protection during PRRT. During infusion with LysArg, the highest serum potassium level measured was 6.0 mmol/L in 1 of 11 patients. No electrocardiography changes were seen. Vomiting occurred in 1 patient, but this was not drug related (7). We then concluded that this LysArg solution was safe enough to be used as the standard procedure in our PRRT protocols. In the years following this publication, we have infused the LysArg solution more than 2,000 times in the PRRT setting. In our clinical setting, we have not encountered severe side effects, underlining the good toxicity profile for LysArg. In particular, no symptoms of volume overload have occurred in patients and no drug-related emergencies or fatalities have been registered. Vomiting occurs in about 15% of patients and nausea in about 30% (8), but it should be noted that vomiting may be caused in part by other factors, as we reported vomiting in at least 6% of patients who did not receive an amino acid infusion (7).

The authors stated that lysine itself may produce renal failure, and they cited two studies indeed showing that administration of lysine produced significant renal impairment (9,10). However, the doses used in these animal studies were approximately 4−6 times higher than the dose of lysine used in our (11) and their (1) animal experiments (400 mg/kg). To our knowledge, no studies have been published that describe toxicity from lysine in our dose range or in human subjects.

Most publications on plasma expanders deal with administration to critically ill patients—for instance, patients in septic shock, in hemorrhagic shock, or after surgery. Little is known, however, about infusion of plasma expanders in healthy subjects and patients with a normal circulation. The authors reported that infusion of Gelofusine volumes did not cause side effects in 5 healthy volunteers; it was not stated, however, which parameters in addition to blood pressure and heart rate were investigated (2).

An important point is that the incidence of allergic reactions is 12-fold higher for Gelofusine than for human albumin infusion (12), possibly because of the bovine origin of the gelatin fluid. More than 40 reports have been published on anaphylactic reactions that were due to the use of gelatin-derived plasma expanders. Also, a cross reactivity exists between the different gelatin solutions (13). A 0.038% frequency of severe reactions (shock, cardiac, or respiratory arrest) has been reported for gelatin solutions (14). The incidence of all grades of allergic reactions is between 0.06% and 0.78% (14–16). Although this incidence is low, any anaphylactic reaction in the PRRT setting is unwanted.

In conclusion, lowering the renal uptake of radiolabeled peptides, such as somatostatin analogs, using the plasma expander Gelofusine may be a promising method to protect the kidneys in PRRT. Although no side effects were noted in 5 healthy subjects, we must be aware that infusion of gelatin-based plasma expanders may cause side effects, such as anaphylactic reactions, in the target group of patients. Further validation studies on larger groups of healthy subjects and patients must be performed and compared with the current method using amino acid solutions to find out whether this new strategy is also safe and effective in the PRRT setting.