Comparison of basiliximab and daclizumab with triple immunosuppression in renal transplantation

Purpose

Graft rejection is a serious problem despite immunosuppressive agents. Immunosuppression has been achieved with monoclonal antibodies (mAb) that bind specifically to the α subunit of the interleukin (IL)-2 receptor present on activated T lymphocytes. We explored the effects of two of the mAbs-daclizumab and basiliximab-on graft function.

Materials and methods

Our 1543 renal transplant recipients received baseline therapy with cyclosporine or tacrolimus plus corticosteroids and mycophenolate mofetil. In addition standard dosages intravenously of daclizumab (n = 156) or basiliximab (n = 45) in were administered intravenously to 201 renal transplant patients who included 122 men and 79 women of overall mean age of 30 ± 13.7 years.

Results

Patient and donor characteristics including age, sex, causes of renal failure, presence of comorbidities, panel-reactive antibodies, and numbers of human leukocyte antigen-mismatched were similar between the groups. During a mean follow-up of 27 ± 20 months, biopsy-proven acute rejection was observed in three patients in the basiliximab group and 23 in the daclizumab group. Cytomegalovirus infection occurred in 13 patients. There was no case of posttransplant lymphoproliferative disorder. Three polyoma BK nephropathies were detected in the daclizumab group. No hypersensitivity reaction occurred in either group. One-year patient survival was 100% in the basiliximab group and 99% in the daclizumab group, with graft survivals of 95% versus 94%, respectively. The mean creatinine levels at discharge were 2 mg/dL versus 2.3 mg/dL and at 12 months, 1.3 mg/dL versus 1.2 mg/dL, respectively.

Conclusions

Acute rejection episodes remain a significant risk factor for the development of graft dysfunction and poor long-term graft survival. IL-2R antagonists were effective antibody therapies. There was no apparent difference between basiliximab and daclizumab treatment.     

Post‐transplant glucose status in 61 pediatric renal transplant recipients: Preliminary results of five Turkish pediatric nephrology centers

Buyan N, Bilge I, Turkmen MA, Bayrakci U, Emre S, Fidan K, Baskin E, Gok F, Bas F, Bideci A. Post‐transplant glucose status in 61 pediatric renal transplant recipients: Preliminary results of five Turkish pediatric nephrology centers.
Pediatr Transplantation 2010:14:203–211 © 2009 John Wiley & Sons A/S. Abstract: To assess the incidence, risk factors and outcomes of PTDM, a total of 61 non‐diabetic children (24 girls, 37 boys, age: 14.5 ± 2.1 yr) were examined after their first kidney transplantation (37.3 ± 21.6 months) with an OGTT. At baseline, 16 (26.2%) patients had IGT, 45 (73.8%) had NGT, and no patient had PTDM. No significant difference was shown between TAC‐ and CSA‐treated patients in terms of IGT. Higher BMI z‐scores (p = 0.011), LDL‐cholesterol (p < 0.05) and triglyceride levels (p < 0.01), HOMA‐IR (p = 0.013) and lower HOMA‐%β (p = 0.011) were significantly associated with IGT. Fifty‐four patients were re‐evaluated after six months; eight patients with baseline IGT (50%) improved to NGT, three (19%) developed PTDM requiring insulin therapy, five (31%) remained with IGT, and four patients progressed from NGT to either IGT (two) or PTDM (two). These 12 progressive patients had significantly higher total cholesterol (p < 0.05), triglycerides (p < 0.05), HOMA‐IR (p < 0.01) and lower HOMA‐%β (p < 0.0) than non‐progressive patients at baseline. We can conclude that post‐transplantation glucose abnormalities are common in Turkish pediatric kidney recipients, and higher BMI z‐scores and triglyceride concentrations are the main risk factors. Considering that the progressive patients are significantly more insulin resistant at baseline, we suggest that the utility of both HOMA‐IR and HOMA‐%β in predicting future risk of PTDM and/or IGT should be evaluated in children.     

Reno-vascular hypertension in childhood: a nationwide survey

Renovascular disease accounts for 8–10% of all cases of paediatric hypertension, whereas, in adults, its incidence is approximately 1%. The Turkish Paediatric Hypertension Group aimed to create the first registry database for childhood renovascular hypertension in Turkey. Twenty of the 28 paediatric nephrology centres in Turkey responded to the survey and reported 45 patients (27 girls, 18 boys) with renovascular hypertension between 1990 and 2005. The age at presentation ranged from 20 days to 17 years. The mean blood pressure at the diagnosis was 169/110 mmHg. Chief complaints of symptomatic patients were headache (38%), seizure (18%), epistaxis (4%), growth retardation (4%), cognitive dysfunction (4%), polyuria (2%), palpitation (2%), and hemiplegia (2%). Renovascular hypertension was found incidentally in 11 children. The diagnosis of renovascular hypertension was established with conventional angiography in 39 patients, MR angiography in three, CT angiography in two, and captopril diethylene triamine penta-acetic acid (DTPA) scintigraphy in one patient. Twenty-one children had bilateral renal artery stenosis and 24 had unilateral renal artery stenosis. Of these, 14 (31%) had fibromuscular dysplasia; 12 (27%) Takayasu’s arteritis; six (13%) neurofibromatosis; two (5%) Williams syndrome; one (2%) Kawasaki disease; one (2%) mid-aortic syndrome; one (2%) extrinsic compression to the renal artery, and eight (18%) unspecified bilateral renal artery stenosis. Hypertension was controlled with antihypertensive drugs in 17 patients. Percutaneous transluminal angioplasty (PTRA) or surgery had to be performed in 28 patients: PTRA in 16 patients, PTRA + surgery in one patient and surgery in 11 patients (four nephrectomies). The importance of vasculitic disease, especially Takayasu’s arteritis, should not be underestimated in children with renovascular hypertension.     

Guidelines for reporting experiments involving animals: the ARRIVE guidelines

British Journal of Pharmacology (BJP) is pleased to publish a new set of guidelines for reporting research involving animals, simultaneously with several other journals; the ‘ARRIVE’ guidelines (Animals in Research: Reporting In Vivo Experiments). This editorial summarizes the background to the guidelines, gives our view of their significance, considers aspects of specific relevance to pharmacology, re-states BJP''s guidelines for authors on animal experiments and indicates our commitment to carrying on discussion of this important topic. We also invite feedback via the British Pharmacological Society website.     

Role of the signal peptide in the synthesis and processing of the glucagon-like peptide-1 receptor

Background and purpose:

The glucagon-like peptide-1 receptor (GLP-1R) belongs to Family B of the G protein-coupled receptor superfamily and is a target for treatment of type 2 diabetes. Family B G protein-coupled receptors contain a putative N-terminal signal peptide, but its role in receptor synthesis and trafficking are unclear. Further, the signal peptide is not cleaved in at least one family member.

Experimental approach:

We examined receptor glycosylation and the role of the signal peptide in GLP-1R synthesis and trafficking using constructs containing epitope tags at the N- and/or C-terminus and in which the signal peptide sequence was either present or absent.

Key results:

The signal peptide was absolutely required for GLP-1R synthesis but could be substituted to some extent by increasing positive charge in the N-terminal region of the receptor flanking the signal peptide. The signal peptide is cleaved during synthesis and processing of the receptor. An enhanced GFP-epitope tag at the N-terminus of the receptor permitted synthesis of the receptor but blocked signal peptide cleavage and prevented trafficking to the plasma membrane. Cleavage site mutation allowed synthesis of a full-length receptor, blocked signal peptide cleavage and caused retention within the endoplasmic reticulum.

Conclusions and implications:

Signal peptide cleavage was not essential for receptor synthesis but was obligatory for processing and trafficking of receptors to the plasma membrane. Further, the GLP-1R is subject to N-linked glycosylation and only the mature, fully glycosylated form of the receptor is present in the plasma membrane. Inhibition of glycosylation prevents processing and cell surface expression of the GLP-1R.     

SOMAN-INDUCED CARDIAC TOXICITY: SINGLE-CELL COMPUTER SIMULATIONS OF ACETYLCHOLINE OVERLOAD

Cardiac toxicity caused by organophosphonates (OPs) and expressed through acetylcholine (ACh) overload was studied by simulating the divergence of the action potential (AP) from baseline. Three cardiac structures–the sinoatrial (SA) node, the Purkinje fibers, and the ventricles–were studied with regard to their sensitivity to ACh overload and to determine which is most vulnerable to electrical failure. In addition, based on results of simulations with increased extracellular concentrations, a new model for soman-induced cardiac toxicity is proposed. It was shown that hyperkalemia must be considered in strategies for the prophylaxis of soman poisoning.     

Computed tomography calcium score scan for attenuation correction of N-13 ammonia cardiac positron emission tomography: effect of respiratory phase and registration method

The use of coronary calcium scoring (CaScCT) for attenuation correction (AC) of ¹³N-ammonia PET/CT studies (NH₃) is still being debated. We compare standard ACCT to CaScCT using various respiratory phases and co-registration methods for AC. Forty-one patients underwent a stress/rest NH₃. Standard ACCT scans and CaScCT acquired during inspiration (CaScCTinsp, 26 patients) or expiration (CaScCTexp, 15 patients) were used to correct PET data for photon attenuation. Resulting images were compared using Pearson’s correlation and Bland–Altman (BA) limits of agreement (LA) on segmental relative and absolute coronary blood flow (CBF) using both manual and automatic co-registration methods (rigid-body and deformable). For relative perfusion, CaScCTexp correlates better than CaScCTinsp with ACCT when using manual co-registration (r = 0.870; P < 0.001 and r = 0.732; P < 0.001, respectively). Automatic co-registration provides the best correlation between CaScCTexp and ACCT for relative perfusion (r = 0.956; P < 0.001). Both CaScCTinsp and CaScCTexp yielded excellent correlations with ACCT for CBF when using manual co-registration (r = 0.918; P < 0.001; BA mean bias 0.05 ml/min/g; LA: ?0.42 to +0.3 ml/min/g and r = 0.97; P < 0.001; BA mean bias 0.1 ml/min/g; LA: ?0.65 to +0.5 ml/min/g, respectively). The use of CaScCTexp and deformable co-registration is best suited for AC to quantify relative perfusion and CBF enabling substantial radiation dose reduction.