Guilty as charged: unmeasured urinary anions in a case of pyroglutamic acidosis.

A patient developed an unexplained metabolic acidosis with the characteristics of renal tubular acidosis. By correcting the serum anion gap for hypoalbuminaemia and analysing the urinary anions and cations, the presence of unmeasured anions was revealed. The diagnosis of pyroglutamic acidosis, caused by a combination of flucloxacillin and acetaminophen, was established. Strategies for solving complex cases of metabolic acidosis are discussed.

Molecular imaging of reduced renal uptake of radiolabelled [DOTA0,Tyr3]octreotate by the combination of lysine and Gelofusine in rats.

AIM: In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, kidney uptake of radiolabelled compound is the major dose-limiting factor. We studied the effects of Gelofusine (20 mg) and lysine (100 mg) and the combination of both after injection of therapeutic doses of radiolabelled [DOTA0,Tyr3]octreotate (60 MBq 111In or 555 MBq 177Lu labelled to 15 microg peptide) in male Lewis rats. METHODS: Kidney uptake was measured by single photon emission computed tomography (SPECT) scans with a four-headed multi-pinhole camera (NanoSPECT) at 24 h, 5 and 7 days p. i. and was quantified by volume of interest analysis. For validation the activity concentration in the dissected kidneys was also determined ex vivo using a gamma counter and a dose calibrator. RESULTS: Gelofusine and lysine both reduced kidney uptake of [177Lu-DOTA0,Tyr3]octreotate significantly by about 40% at all time points. The combination of Gelofusine and lysine resulted in a 62% inhibition of kidney uptake (p < 0.01 vs. lysine alone). A weak but significant dose-response relationship for Gelofusine, but not for lysine, was found. In a study with [111In-DOTA0,Tyr3]octreotate, conclusions drawn from NanoSPECT data were confirmed by biodistribution data. CONCLUSIONS: We conclude that rat kidney uptake of radiolabelled somatostatin analogues can be monitored for a longer period in the same animal using animal SPECT. Gelofusine and lysine had equal potential to reduce kidney uptake of therapeutic doses of [177Lu-DOTA0,Tyr3]octreotate. The combination of these compounds caused a significantly larger reduction than lysine or Gelofusine alone and may therefore offer new possibilities in PRRT. The NanoSPECT data were validated by standard biodistribution experiments.

In vivo radionuclide uptake quantification using a multi-pinhole SPECT system to predict renal function in small animals.

PURPOSE: In vivo quantification of radiopharmaceuticals has great potential as a tool in developing new drugs. We investigated the accuracy of in vivo quantification with multi-pinhole single-photon emission computed tomography (SPECT) in rats. METHODS: Fifteen male Lewis rats with different stages of renal dysfunction were injected with 50 MBq 99mTc-dimercaptosuccinic acid. Four to six hours after injection, SPECT of the kidneys was acquired with a new four-headed multi-pinhole collimator camera. Immediately after imaging the rats were sacrificed and the kidneys were counted in a gamma-counter to determine the absorbed activity. SPECT data were reconstructed iteratively and regions of interest (ROIs) were drawn manually. The absolute activity in the ROIs was determined. RESULTS: Uptake values ranging from 0.71% to 21.87% of the injected activity were measured. A very strong linear correlation was found between the determined activity in vivo and ex vivo (r2=0.946; slope m=1.059). CONCLUSION: Quantification in vivo using this multi-pinhole SPECT system is highly accurate.

Changes in renal tri-iodothyronine and thyroxine handling during fasting.

OBJECTIVE: Liver handling of thyroid hormones (TH) has been known to alter significantly during fasting. This study investigates whether renal handling of TH is also changed during fasting. METHODS: We measured urinary excretion rates and clearances of free tri-iodothyronine (T(3)) and free thyroxine (T(4)) in healthy subjects prior to and on the third day of fasting. RESULTS: During fasting, both mean T(3) and T(4) urinary excretion decreased significantly to a mean value of 42% of control. Also, total and free (F) serum T(3) concentrations declined significantly, but serum T(4) did not change. Both FT(3) and FT(4) clearance decreased significantly during fasting (62% and 42% of control). The fasting-induced decrease in uric acid clearance correlated well with the decrease in FT(3) clearance (r=0.94; P<0.001). Serum concentrations of non-esterified fatty acids (NEFA) were significantly elevated during fasting. CONCLUSIONS: The findings cannot be fully explained by the fasting-induced decrease in serum T(3), and are in accordance with inhibition of uptake of T(3) and T(4) at the basolateral membrane of the tubular cell. This inhibition may be caused by a decreased energy state of the tubular cell and by other factors such as ketoacidosis and/or increased NEFA concentrations during fasting.

Effects of ligand priming and multiple-dose injection on tissue uptake of 111In-pentetreotide in rats.

In patients undergoing somatostatin receptor scintigraphy, treatment with octreotide (Sandostatin) is usually discontinued 24-48 h before and after injection with the radioligand 111In-pentetreotide ([111In-DTPA(O)]octreotide) (Octreoscan) because octreotide competes with radioligand for the same receptors. However, Dörr et al. and Soresi et al. reported improved visualization of carcinoid and small cell lung cancer lesions, respectively, during continued octreotide treatment. We found that intravenous administration of unlabeled octreotide to rats inhibited the binding of an optimal dose (0.5 microg) of 111In-pentetreotide to somatostatin receptors in pancreas and adrenals in a mass- and time-dependent way. Pretreatment with unlabeled octreotide never increased receptor binding of 111In-pentetreotide. Administration of 100 microg of octreotide decreased receptor-bound radioactivity if given simultaneously with or 10 or 20 min after injection of the radioligand, but had no effect if given 30 min after the radioligand. These findings indicate rapid processing of receptor-bound octreotide and suggest that octreotide treatment of patients undergoing 111In-pentetreotide scintigraphy may be reinitiated as soon as 1 h after radioligand administration.

D-lysine reduction of indium-111 octreotide and yttrium-90 octreotide renal uptake.

UNLABELLED: Indium-111-DTPA-octreotide (111In-DTPAOC) is used successfully for imaging somatostatin receptor-positive lesions. A new and promising application is its use in peptide-receptor radionuclide therapy (PRRT). For the latter purpose, [DOTA0,D-Phe1,Tyr3]octreotide (DOTATOC), which is suitable for stable radiolabeling with 90Y, is probably even more promising. Significant renal uptake of these octreotide analogs exists, however, reducing the scintigraphic sensitivity for detection of small tumors in the perirenal region and limiting the possibilities for PRRT. We showed that the renal uptake of 111In-DTPAOC could be reduced to about 50% of control by L-lysine administration in vivo in rats. This study compares the effects of several doses and different methods of administration of D- and L-lysine, in addition to time-related effects of D-lysine, on kidney uptake of 111In-DTPAOC and 90Y-DOTATOC. METHODS: Male Wistar rats (200-250 g) were given 111In-DTPAOC (0.2 MBq, 0.5 microg-0.5 mg intravenously, intraperitoneally or orally) in the presence or absence of D- or L-lysine. At 1, 4 or 24 hr, the rats were killed, and the organs were isolated and counted for radioactivity. In different experiments, male Wistar rats (200-250 g) were given 90Y-DOTATOC (1 MBq, 0.5 microg intravenously) in the presence or absence of D-lysine. At 24 hr, the rats were killed, and the organs were isolated and counted for radioactivity. RESULTS: Administration of D- or L-lysine in a single intravenous dose of 400 mg/kg, resulted in more than 50% inhibition of kidney uptake of 111In-DTPAOC at all time points tested, independently of the mass of 111In-DTPAOC used. Higher or repeated doses of lysine did not give a significantly higher percentage inhibition. D-lysine, given orally in a dose of 400 mg/kg at 30 or 15 min before 111In-DTPAOC injection, resulted in 30% and 20% inhibition of kidney uptake, respectively. L-lysine, given orally 30 min before 111In-DTPAOC administration, resulted in 30% inhibition as well. Inhibition of kidney uptake of 111In-DTPAOC by L-lysine after intraperitoneal administration was 40%. After L-lysine administration, 111In-DTPAOC was decreased in the kidneys and in somatostatin receptor-positive organs such as the pancreas and adrenal glands. In contrast, D-lysine did not have a significant effect on uptake in octreotide receptor-positive organs. Renal uptake of 90Y-DOTATOC was reduced by 65% by intravenous D-lysine, whereas radioactivity in blood, pancreas and adrenal glands was not affected. CONCLUSION: D-lysine may be preferred to L-lysine for reduction of renal uptake of radioactivity during scintigraphy and PRRT because of its lower toxicity and because it should not interfere with the natural amino acid metabolic balance.

Inhibition of renal uptake of indium-111-DTPA-octreotide in vivo.

UNLABELLED: Indium-111-DTPA-octreotide has been successfully used for imaging of somatostatin receptor-positive lesions. However, significant renal uptake of 111In-DTPA-octreotide exists, reducing the scintigraphic sensitivity for detection of small tumors in the perirenal region and the possibilities for radiotherapy. The aim of the present study was to determine whether renal uptake of 111In-DTPA-octreotide could be reduced in vivo in rats. METHODS: Male Wistar rats (200-250 g) were placed in metabolic cages and injected with 111In-DTPA-octreotide (0.2 MBq and 0.5 microgram octreotide), in the presence or absence of re-uptake blockers. At time t = 20 hr after injection, rats were sacrificed and organs were isolated and counted for radioactivity. RESULTS: Adding NH4Cl or NaHCO3 to the food, resulting in the production of more acid or alkaline urine respectively, resulted in less radioactivity in the kidneys 20 hr after injection compared to controls. Lysine in a single dose of 400 mg/kg resulted in an inhibition of kidney uptake of 40%. When lysine was injected 30 min before 111In-DTPA-octreotide, the inhibition was 25%. Arginine had less effect on tubular uptake of 111In-DTPA-octreotide than lysine (20% inhibition). Sodium maleate inhibited kidney uptake of 111In-DTPA-octreotide most successfully. Acetazolamide (100 mg/kg), succinylacetone (100 mg/kg), cystine dimethylester (340 mg/kg) and increase in urinary flow did not influence 111In-DTPA-octreotide retention in the kidneys. CONCLUSION: It appeared possible to reduce re-uptake of 111In-DTPA-octreotide in the rat kidney in vivo. The most pronounced effects were seen after administration of sodium maleate or lysine but, because of the described toxic effects of maleate, we will study further only the effects of lysine in a clinical setting.

Evaluation in vitro and in rats of 161Tb-DTPA-octreotide, a somatostatin analogue with potential for intraoperative scanning and radiotherapy.

The characteristics of terbium-161 diethylene triamine penta-acetic acid (DTPA) labelled octreotide with respect to specific binding to somatostatin (octreotide) receptors on rat brain cortex membranes, biological activity, uptake and excretion by isolated perfused rat livers and metabolism in vivo in normal and tumour-bearing rats were determined and compared to those of indium-111 DTPA-octreotide. The results of the binding studies demonstrate that 161Tb-DTPA-octreotide is a high-affinity radioligand for somatostatin receptors, with an affinity comparable to that of 111In-DTPA-octreotide. Rat growth hormone secretion inhibition experiments showed that 161Tb-DTPA-octreotide has a similar potency to 111In-DTPA-octreotide. 161Tb-DTPA-octreotide appeared to be taken up even less by the isolated perfused rat liver than 111In-DTPA-octreotide, as almost no tracer disappeared from the perfusion medium. Furthermore, hardly any radioactivity was found in the liver, and excretion into the bile was negligible. The biodistribution studies showed that for octreotide receptor-positive organs, such as pancreas and adrenals, uptake of 161Tb-DTPA-octreotide is lower then that of 111In-DTPA-octreotide. However, as the clearance from the blood of the former compound is faster than that of the latter, the tissue/blood ratio is higher in the case of 161Tb-DTPA-octreotide than with 111In-DTPA-octreotide. Furthermore, these studies demonstrated that the uptake of 161Tb-DTPA-octreotide by the renal tubular cells after glomerular filtration can be reduced by administration of lysine or sodium maleate. Increase in urine production before and during the experiment had no effect on the kidney uptake of 161Tb-DTPA-octreotide.(ABSTRACT TRUNCATED AT 250 WORDS)