Albumin-derived peptides efficiently reduce renal uptake of radiolabelled peptides

Contains fulltext : 88022.pdf (publisher's version ) (Closed access)PURPOSE: In peptide-receptor radionuclide therapy (PRRT), the maximum activity dose that can safely be administered is limited by high renal uptake and retention of radiolabelled peptides. The kidney radiation dose can be reduced by coinfusion of agents that competitively inhibit the reabsorption of radiolabelled peptides, such as positively charged amino acids, Gelofusine, or trypsinised albumin. The aim of this study was to identify more specific and potent inhibitors of the kidney reabsorption of radiolabelled peptides, based on albumin. METHODS: Albumin was fragmented using cyanogen bromide and six albumin-derived peptides with different numbers of electric charges were selected and synthesised. The effect of albumin fragments (FRALB-C) and selected albumin-derived peptides on the internalisation of (111)In-albumin, (111)In-minigastrin, (111)In-exendin and (111)In-octreotide by megalin-expressing cells was assessed. In rats, the effect of Gelofusine and albumin-derived peptides on the renal uptake and biodistribution of (111)In-minigastrin, (111)In-exendin and (111)In-octreotide was determined. RESULTS: FRALB-C significantly reduced the uptake of all radiolabelled peptides in vitro. The albumin-derived peptides showed different potencies in reducing the uptake of (111)In-albumin, (111)In-exendin and (111)In-minigastrin in vitro. The most efficient albumin-derived peptide (peptide #6), was selected for in vivo testing. In rats, 5 mg of peptide #6 very efficiently inhibited the renal uptake of (111)In-minigastrin, by 88%. Uptake of (111)In-exendin and (111)In-octreotide was reduced by 26 and 33%, respectively. CONCLUSIONS: The albumin-derived peptide #6 efficiently inhibited the renal reabsorption of (111)In-minigastrin, (111)In-exendin and (111)In-octreotide and is a promising candidate for kidney protection in PRRT.1 februari 201

Dose-response effect of Gelofusine on renal uptake and retention of radiolabelled octreotate in rats with CA20948 tumours

Purpose: Peptide receptor radionuclide therapy using β-emitting radiolabelled somatostatin analogues like DOTA,Tyr3-octreotate shows beneficial results in patients suffering from somatostatin receptor overexpressing tumours. However, after high-dose therapy partial renal reabsorption of radiopeptides may lead to nephrotoxicity. Co-infusion of lysine/arginine lowers renal retention of these radiopeptides without affecting tumour uptake. Recently co-administration of Gelofusine has been described to have a comparable kidney-protecting effect in rats. In the present study optimal dosing of Gelofusine co-administration was studied in tumour-bearing rats. Methods: Doses of 40, 80, 120 or 160 mg/kg Gelofusine were co-injected with 15 μg DOTA,Tyr3-octreotate, labelled with 3 MBq111In for biodistribution (24 h post-injection, n=4 per group) and with 60 MBq111In for microSPECT imaging experiments at 3, 24 and 48 h post-injection. An additional group of rats received 80 mg/kg Gelofusine plus 400 mg/kg lysine co-injection. Biodistribution studies were performed both in older (475 g) and younger (300 g) rats, the latter bearing CA20948 tumours. Results: Co-injection of 40 mg/kg Gelofusine resulted in 40-50% reduction of renal uptake and retention of111In-DOTA,Tyr3-octreotate, whereas higher doses further increased the reduction to 50-60% in both groups of rats. Combining Gelofusine and lysine caused 70% reduction of renal uptake. The uptake of radiolabelled octreotate both in somatostatin receptor-expressing normal tissues and tumours was not affected by Gelofusine co-injection. Conclusion: In rats co-injection of 80 mg/kg Gelofusine resulted in maximum reduction of renal retention of111In-DOTA,Tyr3- octreotate, which was further improved when combined with lysine. Tumour uptake of radiolabelled octreotate was not affected, resulting in an increased tumour to kidney ratio

Effects of therapy with [177Lu-DOTA0,Tyr3]octreotate on endocrine function

Purpose: Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues is a novel therapy for patients with somatostatin receptor-positive tumours. We determined the effects of PRRT with [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) on glucose homeostasis and the pituitary-gonadal, pituitary-thyroid and pituitary-adrenal axes. Methods: Hormone levels were measured and adrenal function assessed at baseline and up to 24 months of follow-up. Results: In 35 men, mean serum inhibin B levels were decreased at 3 months post-therapy (205 ± 16 to 25 ± 4 ng/l, p 550 nmol/l, n = 18). Five patients developed elevated HbA1clevels (> 6.5%). Conclusion: In men177Lu-octreotate therapy induced transient inhibitory effects on spermatogenesis, but non-SHBG-bound T levels remained unaffected. In the long term, gonadotropin levels decreased significantly in postmenopausal women. Only a few patients developed hypothyroidism or elevated levels of HbA1c. Therefore, PRRT with177Lu-octreotate can be regarded as a safe treatment modality with respect to short-and long-term endocrine function

Kidney transplantation in patients with Fabry disease

Introduction and Aims: Fabry disease is an X-linked lysosomal storage disorder caused by absence or deficient activity of the lysosomal enzyme alpha-galactosidase A. Renal manifestations occur early in life in a significant proportion of children, in many women and in almost all men with Fabry disease. These manifestations ultimately progress to end-stage renal disease in nearly all males and in some female patients. Data on kidney transplantation in patients with Fabry disease who are receiving enzyme replacement therapy (ERT), however, are scarce. Methods: We examined the clinical characteristics of kidney transplant recipients (KTRs) in the Fabry Outcome Survey (FOS) - a European database of patients with Fabry disease that was established to monitor the safety and outcome of ERT. Results: Of the 752 patients enrolled in FOS up to October 2005, 34 (4.5%) were reported to be KTRs. The mean age of these 32 male and 2 female patients was 45 ± 9 years, the median time since the transplant was 9 years, the median estimated glomerular filtration rate (eGFR) was 46 mL/min/1.73 m2 and the median level of proteinuria was 180 mg/24 hours. ERT was well tolerated, with mild infusion-related reactions reported in only one patient. Amongst these patients, 53% were reported to have hypertension, 71% left ventricular hypertrophy, 27% cardiac valve disease and 27% arrhythmia. A total of 23 (68%) of the patients (1 female, 22 males) were receiving ERT with agalsidase alfa (Replagal; Shire Human Genetic Therapies, UK), with a median duration of treatment of 2.5 years. There were no differences in age or time since transplantation between treated and untreated patients. The median eGFRs were 46 and 49 mL/min/1.73 m2 and the median levels of proteinuria were 200 and 160 mg/24 hours, respectively. Conclusions: KTRs represent a significant minority of individuals enrolled in a large international registry of patients with Fabry disease (FOS). Approximately two-thirds of KTRs with Fabry disease enrolled in FOS receive ERT with agalsidase alfa, which is well tolerated. Comparison of treated and untreated patients has the potential to examine effects of ERT on the progression of renal and cardiovascular disease