Arteriovenous fistulae vs. arteriovenous grafts: a retrospective review of 1,700 consecutive vascular access cases.

OBJECTIVE: Vascular access (VA) procedures are rapidly becoming the most prevalent surgery in the United States. It is estimated that there will be over 500,000 VA procedures done this year. Previously, surgeons in the US were attempting many more non-autogenous grafts than autogenous fistulae. In recent years, there has been a great push called 'Fistula First' to promote arteriovenous fistulae (AVF) as the first line of treatment vs. nonautogenous grafts. The goal of this investigation is to determine if too many fistulae are now being performed without attention to specific patient profiles. METHODS: A retrospective review of 1700 consecutive cases was performed by one surgeon at one institution between 1997 and 2005. Patients were categorized by demographics, co-morbidities, previous access procedures, access location, and type of graft. Patency was calculated. Kaplan-Meier, Cox regression and the Log Rank Test were used to analyze data. Access endpoints and complications were also documented. RESULTS: The study reviewed 1700 procedures. The median age was 52 (60.2% male) with 58.7% fistulae and 41.3% grafts. Median patency time was 10 months, with no statistically significant difference between access types. There was no significant difference in length of patency when comparing upper arm (70.1%), lower arm (24.5%) and thigh (5.4%). Graft infection rate was 9.5% and fistula infection rate was 0.9% (p<0.001). The overall infection rate was 4.5%, and decreased patency significantly (4 vs. 11 months). Thrombosis occurred in 24.7% of grafts and 9.0% of fistulae. Thrombosed grafts had better salvage rates (8 vs. 4 months, p<0.001). The data showed diabetes, HTN and HIV have no overall impact on patency. CONCLUSIONS: AVF and grafts are both useful in providing VA for patients requiring hemodialysis. Our data shows that grafts are equivalent in long-term patency. Therefore, it is apparent in those patients who are not candidates for an AV fistula; an AV graft for VA should be placed.

Molecular pharmacology and modeling of vasopressin receptors.

AVP receptors represent a logical target for drug development. As a new class of therapeutic agents, orally active AVP analogs could be used to treat several human pathophysiological conditions including neurogenic diabetes insipidus, the syndrome of inappropriate secretion of AVP (SIADH), congestive heart failure, arterial hypertension, liver cirrhosis, nephrotic syndrome, dysmenorrhea, and ocular hypertension. By immunoprecipitation and immunoblotting, we elucidated the phosphorylation pattern of green fluorescent protein-tagged AVP receptors and showed interactions with the specific kinases PKC and GRK5 that are agonist-, time- and receptor subtype-dependent. The tyrosine residue of the NPWIY motif present in the 7th helix of AVP receptors is rapidly and transiently phosphorylated after agonist stimulation. This phosphorylation is instrumental in the genesis of the mitogenic cascade linked to the activation of this receptor, presumably by establishing key intramolecular contacts and by participating in the creation of a scaffold of proteins that produce the activation of downstream kinases. The random screening of chemical entities and optimization of lead compounds recently resulted in the development of orally active non-peptide AVP receptor agonists and antagonists. Furthermore, the identification of the molecular determinants of receptor-ligand interactions should facilitate the development of more potent and very selective orally active compounds via the approach of structure-based drug design. We developed three-dimensional molecular docking models of peptide and non-peptide ligands to the human V1 vascular, V2 renal and V3 pituitary AVP receptors. Docking of the peptide hormone AVP to the receptor ligand binding pockets reflects its dual polar and non-polar structure, but is receptor subtype-specific. The characteristics of non-peptide AVP analogs docking to the receptors are clearly distinct from those of peptide analogs docking. Molecular modeling of the results of site-directed mutagenesis experiments performed in CHO cells stably transfected with the human AVP receptor subtypes revealed that non-peptide antagonists establish key contacts with a few amino acid residues of the receptor subtypes that are different from those involved in agonist binding. Moreover, these interactions are species-specific. These findings provide further understanding of the signal transduction pathways of AVP receptors and new leads for elucidation of drug-receptor interactions and optimization of drug design. NOTE TO THE READER: The recent cloning and molecular characterization of AVP/OT receptor subtypes call for the revision of their nomenclature. For the sake of clarity and reference to their main site of expression, we call the V1a receptor the V1 vascular receptor, the V2 receptor the V2 renal receptor and the V1b or V3 receptor the V3 pituitary receptor in the present review.

The basic and clinical pharmacology of nonpeptide vasopressin receptor antagonists.

The neurohypophysial hormone arginine vasopressin (AVP) is a cyclic nonpeptide whose actions are mediated by the stimulation of specific G protein--coupled membrane receptors pharmacologically classified into V1-vascular (V1R), V2-renal (V2R) and V3-pituitary (V3R) AVP receptor subtypes. The random screening of chemical compounds and optimization of lead compounds recently resulted in the development of orally active nonpeptide AVP receptor antagonists. Potential therapeutic uses of AVP receptor antagonists include (a) the blockade of V1-vascular AVP receptors in arterial hypertension, congestive heart failure, and peripheral vascular disease; (b) the blockade of V2-renal AVP receptors in the syndrome of inappropriate vasopressin secretion, congestive heart failure, liver cirrhosis, nephrotic syndrome and any state of excessive retention of free water and subsequent dilutional hyponatremia; (c) the blockade of V3-pituitary AVP receptors in adrenocorticotropin-secreting tumors. The pharmacological and clinical profile of orally active nonpeptide vasopressin receptor antagonists is reviewed here.