The implications of donor-recipient size mismatch in renal transplantation.

INTRODUCTION: Transplanting kidneys small for recipient's size results in inferior graft function. Body surface area (BSA) is related to kidney size. We used the BSA index (BSAi) (Donor BSA/Recipient BSA) to assess whether the renal graft size is sufficient for the recipient. METHODS: We included 26,223 adult single kidney transplants (01/01/2007-31/12/2019) from the UK Transplant Registry. We divided renal transplants into groups: BSAi ≤ 0.75, 0.75 < BSA ≤ 1, 1 < BSAi ≤ 1.25, BSAi > 1.25. We compared delayed graft function rates, primary non-function rates and graft survival among them. (Reference category: BSAi ≤ 0.75). RESULTS: Cases with BSAi ≤ 0.75 had the highest delayed graft function rates in living-donor renal transplants (11.1%) (0.75 < BSAi ≤ 1: OR = 0.59, 95% CI = 0.32-1.1, p = 0.095, 1 < BSAi ≤ 1.25: OR = 0.46, 95% CI = 0.23-0.89, p = 0.022, BSAi > 1.25: OR = 0.32, 95% CI = 0.13-0.77, p = 0.011) and in renal transplants from donors after brain death (26.2%) (0.75 < BSAi ≤ 1: OR = 0.72, 95% CI = 0.55-0.96, p = 0.024, 1 < BSAi ≤ 1.25: OR = 0.62, 95% CI = 0.47-0.83, p = 0.001, BSAi > 1.25: OR = 0.65, 95% CI = 0.47-0.9, p = 0.01). There were no significant differences in renal transplants from donors after circulatory death regarding delayed graft function rates (~ 40% in all groups). Graft survival was similar among BSAi groups in renal transplants from living donors and donors after brain death. Renal transplants from donors after circulatory death with BSAi ≤ 0.75 had the shortest graft survival (0.75 < BSAi ≤ 1: HR = 0.55, 95% CI = 0.41-0.74, p < 0.001, 1 < BSAi ≤ 1.25: HR = 0.48, 95% CI = 0.35-0.66, p < 0.001, BSAi > 1.25: HR = 0.45, 95% CI = 0.31-0.66, p < 0.001). Ten-year graft survival rate was 58.4% for renal transplants from donors after circulatory death with BSAi ≤ 0.75. CONCLUSIONS: Delayed graft function risk is higher in renal transplants with BSAi ≤ 0.75 coming from living donors and donors after brain death. Graft survival is greatly reduced in renal transplants from donors after circulatory death with BSAi ≤ 0.75.

Ex vivo delivery of Mirococept: A dose-finding study in pig kidney after showing a low dose is insufficient to reduce delayed graft function in human kidney.

The complement system plays a pivotal role in the pathogenesis of ischemia-reperfusion injury in solid organ transplantation. Mirococept is a potent membrane-localizing complement inhibitor that can be administered ex vivo to the donor kidney prior to transplantation. To evaluate the efficacy of Mirococept in reducing delayed graft function (DGF) in deceased donor renal transplantation, we undertook the efficacy of mirococept (APT070) for preventing ischaemia-reperfusion injury in the kidney allograft (EMPIRIKAL) trial (ISRCTN49958194). A dose range of 5-25 mg would be tested, starting with 10 mg in cohort 1. No significant difference between Mirococept at 10 mg and control was detected; hence the study was stopped to enable a further dose saturation study in a porcine kidney model. The optimal dose of Mirococept in pig kidney was 80 mg. This dose did not induce any additional histological damage compared to controls or after a subsequent 3 hours of normothermic machine perfusion. The amount of unbound Mirococept postperfusion was found to be within the systemic dose range considered safe in the Phase I trial. The ex vivo administration of Mirococept is a safe and feasible approach to treat DGF in deceased donor kidney transplantation. The porcine kidney study identified an optimal dose of 80 mg (equivalent to 120 mg in human kidney) that provides a basis for further clinical development.

Hypoperfusion warm ischaemia time in renal transplants from donors after circulatory death.

BACKGROUND: The donor hypoperfusion phase before asystole in renal transplants from donors after circulatory death (DCD) has been considered responsible for worse outcomes than those from donors after brain death (DBD). METHODS: We included 10 309 adult renal transplants (7128 DBD and 3181 DCD; 1 January 2010-31 December 2016) from the UK Transplant Registry. We divided DCD renal transplants into groups according to hypoperfusion warm ischaemia time (HWIT). We compared delayed graft function (DGF) rates, primary non-function (PNF) rates and graft survival among them using DBD renal transplants as a reference. RESULTS: The DGF rate was 21.7% for DBD cases, but ∼40% for DCD cases with HWIT ≤30 min (0-10 min: 42.1%, 11-20 min: 43%, 21-30 min: 38.4%) and 60% for DCD cases with HWIT >30 min (P < 0.001). All DCD groups showed higher DGF risk than DBD renal transplants in multivariable analysis {0-10 min: odds ratio [OR] 2.686 [95% confidence interval (CI) 2.352-3.068]; 11-20 min: OR 2.531 [95% CI 2.003-3.198]; 21-30 min: OR 1.764 [95% CI 1.017-3.059]; >30 min: OR 5.814 [95% CI 2.798-12.081]}. The highest risk for DGF in DCD renal transplants with HWIT >30 min was confirmed by multivariable analysis [versus DBD: OR 5.814 (95% CI 2.798-12.081) versus DCD: 0-10 min: OR 2.165 (95% CI 1.038-4.505); 11-20 min: OR 2.299 (95% CI 1.075-4.902); 21-30 min: OR 3.3 (95% CI 1.33-8.197)]. No significant differences were detected regarding PNF rates (P = 0.713) or graft survival (P = 0.757), which was confirmed by multivariable analysis. CONCLUSIONS: HWIT >30 min increases the risk for DGF greatly, but without affecting PNF or graft survival.

UK renal transplant outcomes in low and high BMI recipients: the need for a national policy.

INTRODUCTION: We assessed the effect of recipient body mass index (BMI) on the outcomes of renal transplantation and the management of obese patients with end-stage renal disease across the UK. METHODS: We analyzed data of 25539 adult renal transplants (2007-2016) from the UK Transplant Registry. Patients were divided in BMI groups [underweight: < 18.5, normal: 18.5-24.9 (reference group), overweight: 25-29.9, class I obese: 30-34.9, class II/III obese: ≥ 35]. We also conducted a national survey of all UK renal transplant centers on the influence of BMI on decisions regarding management of renal transplant candidates. RESULTS: BMI ≥ 25 was an independent risk factor for delayed graft function and primary non-function (p ≤ 0.001). Underweight (p = 0.001), class I obese (p = 0.017) and class II/III obese recipients (p < 0.001) had poorer graft survival, however, 5- and 10-year graft survival rates were good. Patient survival was shorter for underweight recipients (p < 0.001) and longer for overweight (p = 0.028) and class I obese recipients (p = 0.013). The national survey revealed significant variability among transplant centers in BMI threshold for listing patients on transplant waiting list and limited support with conservative or surgical procedures for weight control. CONCLUSIONS: Obesity alone should not be a barrier for renal transplantation. A national strategy is required to give all patients equal chances in transplantation.

Development of a multivariable gene-expression signature targeting T-cell-mediated rejection in peripheral blood of kidney transplant recipients validated in cross-sectional and longitudinal samples.

BACKGROUND: Acute T-cell mediated rejection (TCMR) is usually indicated by alteration in serum-creatinine measurements when considerable transplant damage has already occurred. There is, therefore, a need for non-invasive early detection of immune signals that would precede the onset of rejection, prior to transplant damage. METHODS: We examined the RT-qPCR expression of 22 literature-based genes in peripheral blood samples from 248 patients in the Kidney Allograft Immune Biomarkers of Rejection Episodes (KALIBRE) study. To account for post-transplantation changes unrelated to rejection, we generated time-adjusted gene-expression residuals from linear mixed-effects models in stable patients. To select genes, we used penalised logistic regression based on 27 stable patients and 27 rejectors with biopsy-proven T-cell-mediated rejection, fulfilling strict inclusion/exclusion criteria. We validated this signature in i) an independent group of stable patients and patients with concomitant T-cell and antibody-mediated-rejection, ii) patients from an independent study, iii) cross-sectional pre-biopsy samples from non-rejectors and iv) longitudinal follow-up samples covering the first post-transplant year from rejectors, non-rejectors and stable patients. FINDINGS: A parsimonious TCMR-signature (IFNG, IP-10, ITGA4, MARCH8, RORc, SEMA7A, WDR40A) showed cross-validated area-under-ROC curve 0.84 (0.77-0.88) (median, 2.5th-97.5th centile of fifty cross-validation cycles), sensitivity 0.67 (0.59-0.74) and specificity 0.85 (0.75-0.89). The estimated probability of TCMR increased seven weeks prior to the diagnostic biopsy and decreased after treatment. Gene expression in all patients showed pronounced variability, with up to 24% of the longitudinal samples in stable patients being TCMR-signature positive. In patients with borderline changes, up to 40% of pre-biopsy samples were TCMR-signature positive. INTERPRETATION: Molecular marker alterations in blood emerge well ahead of the time of clinically overt TCMR. Monitoring a TCMR-signature in peripheral blood could unravel T-cell-related pro-inflammatory activity and hidden immunological processes. This additional information could support clinical management decisions in cases of patients with stable but poor kidney function or with inconclusive biopsy results.

Duration of delayed graft function and outcomes after kidney transplantation from controlled donation after circulatory death donors: a retrospective study.

The impact of the duration of delayed graft function (DGF) on graft survival is poorly characterized in controlled donation after circulatory death (DCD) donor kidney transplantation. A retrospective analysis was performed on 225 DCD donor kidney transplants between 2011 and 2016. When patients with primary nonfunction were excluded (n = 9), 141 recipients (65%) had DGF, with median (IQR) duration of dialysis dependency of 6 (2-11.75) days. Longer duration of dialysis dependency was associated with lower estimated glomerular filtration rate at 1 year, and a higher rate of acute rejection. On Kaplan-Meier analysis, the presence of DGF was associated with lower graft survival (log-rank test P = 0.034), though duration of DGF was not (P = 0.723). However, multivariable Cox regression analysis found that only acute rejection was independently associated with lower graft survival [HR (95% CI) 4.302 (1.617-11.450); P = 0.003], whereas the presence of DGF and DGF duration were not. In controlled DCD kidney transplantation, DGF duration itself may not be independently associated with graft survival; rather, it may be that acute rejection associated with prolonged DGF is the poor prognostic factor.

Chronic histological changes in deceased donor kidneys at implantation do not predict graft survival: a single-centre retrospective analysis.

The use of preimplantation kidney biopsies (PIKBs) to aid deceased donor kidney utilization decisions is controversial. Outcomes of transplants that had been biopsied after the decision had been made to implant were analysed, in order to determine the association between chronic histological changes at implantation and graft outcomes. A retrospective analysis of transplants between the year range 2006-2015 was performed. Karpinski scores on biopsies were collected, and graft outcomes were analysed using univariate and multivariable techniques. Also, Karpinski scores from single and dual kidney transplants from older donors were examined to determine if knowledge of the score preoperatively would have altered utilization. Four hundred and eight single kidneys were transplanted. Although kidneys with scores >4 had lower 1- and 3-year median (IQR) estimated glomerular filtration rates (eGFRs) than those scoring 0-4 (51 (37-66) vs. 35 (26-52) ml/min/1.73 m2 , P < 0.001, and 52 (34-64) vs. 35 (24-52) ml/min/1.73 m2 , P < 0.001, respectively), there was no significant association between Karpinski score and death-censored graft survival on univariate or multivariable analyses. The utilization analysis (75 single and 25 dual kidney transplant recipients) suggested that systematic use of PIKBs would have resulted in 29% fewer patients being transplanted. This analysis does not support the systematic use of PIKBs to determine deceased donor kidney utilization.

Outcomes in Third and Fourth Kidney Transplants Based on the Type of Donor.

BACKGROUND: An increasing number of patients are requiring multiple retransplants. We assessed outcomes of third and fourth kidney transplants, to aid decision making on the most suitable donor type. METHODS: Data were collected retrospectively for 2561 transplants, including 69 third and 8 fourth, performed from 2000 to 2017. Demographics and outcomes for the combined third/fourth group were compared to first and second transplants. Within the third/fourth kidney transplant group, comparisons were made between deceased donors (n = 39), live donor HLA-compatible (n = 23) and -incompatible (n = 13) transplants, as well as between standard (n = 25) and extended-criteria (n = 14) deceased donor transplants. RESULTS: Patient survival did not differ significantly by transplant number (P = 0.532), whereas death-censored graft survival declined progressively, from 89% at 5 years in first, 85% in second and 74% in the third/fourth transplant group (P < 0.001). Within the combined third/fourth transplant subgroup, 5-year graft survival was found to be 100% in recipients of HLA-compatible live donors, compared to 75% in deceased donors and 53% in HLA-incompatible live donors, although this difference did not reach statistical significance (P = 0.083). No significant difference in patient survival (P = 0.356) or complication rates (P = 0.757) were detected between these groups. For recipients of deceased donors in the third/fourth transplant group, there were no significant differences between standard versus extended-criteria donors for any of the outcomes considered. CONCLUSIONS: Despite variable functional outcomes, third and fourth kidney transplant recipients experience comparable patient survival rates to first and second transplants, regardless of the donor type. In selected patients, HLA-incompatible live donors and extended-criteria deceased donors should be considered.

A double-blind randomised controlled investigation into the efficacy of Mirococept (APT070) for preventing ischaemia reperfusion injury in the kidney allograft (EMPIRIKAL): study protocol for a randomised controlled trial.

BACKGROUND: Delayed graft function (DGF) is traditionally defined as the requirement for dialysis during the first week after transplantation. DGF is a common complication of renal transplantation, and it negatively affects short- and long-term graft outcomes. Ischaemia reperfusion injury (IRI) is a prime contributor to the development of DGF. It is well established that complement system activation plays a pivotal role in the pathogenesis of IRI. Mirococept is a highly effective complement inhibitor that can be administered ex vivo to the donor kidney just before transplantation. Preclinical and clinical evidence suggests that Mirococept inhibits inflammatory responses that follow IRI. The EMPIRIKAL trial (REC 12/LO/1334) aims to evaluate the efficacy of Mirococept in reducing the incidence of DGF in cadaveric renal transplantation. METHODS/DESIGN: EMPIRIKAL is a multicentre double-blind randomised case-control trial designed to test the superiority of Mirococept in the prevention of DGF in cadaveric renal allografts, as compared to standard cold perfusion fluid (Soltran®). Patients will be randomised to Mirococept or placebo (Pbo) and will be enrolled in cohorts of N = 80 with a maximum number of 7 cohorts. The first cohort will be randomised to 10 mg of Mirococept or Pbo. After the completion of each cohort, an interim analysis will be carried out in order to evaluate the dose allocation for the next cohort (possible doses: 5-25 mg). Immunosuppression therapy, antibiotic and antiviral prophylaxis will be administered as per local centre protocols. The enrolment will take approximately 24 months, and patients will be followed for 12 months. The primary endpoint is DGF, defined as the requirement for dialysis during the first week after transplantation. Secondary endpoints include duration of DGF, functional DGF, renal function at 12 months, acute rejection episodes at 6 and 12 months, primary non-function and time of hospital stay on first admission and in the first year following transplant. Safety evaluation will include the monitoring of laboratory data and the recording of all adverse events. DISCUSSION: The EMPIRIKAL trial is the first study to evaluate the efficacy of an ex vivo administered complement inhibitor (Mirococept) in preventing DGF in cadaveric human renal transplantation. Mirococept has a unique 'cytotopic' property that permits its retention in the organ microvasculature. TRIAL REGISTRATION: ISRCTN registry, ISRCTN49958194 . Registered on 3 August 2012.

Successful medical treatment of emphysematous pyelonephritis in chronic hemodialysis.

Emphysematous pyelonephritis (EPN) is a life-threatening renal infection caused by gas-producing bacteria and fungi. It usually occurs in patients with diabetes and patients with urinary tract obstruction. A combination of systemic antibiotics, percutaneous catheter drainage, or open nephrectomy is typically required to achieve cure. Because of grim prognosis, resorting to interventional methods is frequently inevitable. We report the case of a 77-year-old woman with diabetes and end-stage renal disease on chronic hemodialysis that presented with fever and left flank pain. A bubbly gas pattern inside the left kidney was demonstrated on abdominal computed tomography scan and blood cultures grew Escherichia coli. She was successfully treated solely with systemic antibiotics. This highlights the fact that prompt recognition of imaging findings associated with benign prognosis is essential for a favorable outcome. It allows for an effective management avoiding high-risk interventions, especially in frail patients with multiple comorbidities. Finally, we review all published cases of EPN in chronic dialysis patients.

Perioperative administration of high-dose recombinant human erythropoietin for delayed graft function prevention in kidney transplantation: a meta-analysis.

Delayed graft function (DGF) due to ischemia-reperfusion injury is a major early complication of kidney transplantation (KT). Recombinant human erythropoietin (rHuEPO) has been shown to exert nephroprotective action in animal models. We conducted a meta-analysis to explore the impact of rHuEPO on DGF in KT. Eligible studies comparing perioperative high-dose rHuEPO with placebo or no therapy for prevention of DGF were identified through MEDLINE, CENTRAL, and Transplant Library. Their design and data were assessed by two independent reviewers. Among 737 examined studies, four randomized controlled trials, involving 356 recipients of kidney allografts from deceased donors, fulfilled inclusion criteria. Statistical heterogeneity across studies was not significant (P = 0.98, I(2) = 0%). In a random effects model, no significant difference was found in the occurrence of DGF (odds ratio: 0,74, 95% CI: 0.47-1.18, P = 0.21). At 4 weeks after KT, the rHuEPO group exhibited higher systolic blood pressure (mean difference: 6.47 mmHg, 95% CI: 1.25-11.68, P = 0.02). Perioperative, high-dose rHuEPO administration does not prevent DGF in deceased donor KT. Furthermore, it is associated with higher systolic blood pressure leading to safety concerns. Nonerythropoietic rHuEPO derivatives, designed for nephroprotective action without increasing cardiovascular risk, might prove an alternative but still are at early stages of development.

Effect of Smad pathway activation on podocyte cell cycle regulation: an immunohistochemical evaluation.

BACKGROUND: Mature podocytes are in cell cycle arrest and their inability to proliferate successfully is a consequence of negative cell-cycle regulators' expression, such as p57. Phosphorylated smad2/smad3 (pSmad2/3) is an intracellular heteromeric mediator of transforming growth factor beta (TGF-ß) signals and, together with co-activators such as P300, regulates gene transcription, including cell cycle regulator proteins. METHODS: In order to investigate Smad pathway activation and podocyte cell cycle regulation in glomerular injury, we studied the glomerular immunohistochemical expression of p57, pSmad2/3 and P300 in samples from 67 patients with various types of glomerulonephritis (GN) and 10 normal kidney tissue specimens. RESULTS: pSmad2/3 and p300 expression were found significantly increased in all glomerular cell types in both proliferative and nonproliferative GN, while a significant reduction in p57-positive podocytes was observed when compared to controls. Staining for p57 was found to inversely correlate to pSmad2/3 suggesting that glomerular Smad pathway activation is related to down-regulation of p57 expression in proliferative glomerulonephritis. To our knowledge, this is the first study that indicates a relation between the TGF-beta/Smad signalling pathway and the cell cycle regulatory protein p57 in human GN. CONCLUSION: The increased pSmad2/3 staining together with the reduced p57 expression found in biopsy specimens with intense interstitial inflammation, indicate a possible relation between interstitial inflammation, glomerular Smad pathway activation and podocyte cell-cycle deregulation.

Statins in chronic kidney disease and kidney transplantation.

HMG-CoA reductase inhibitors (statins) have been shown to improve cardiovascular (CV) outcomes in the general population as well as in patients with cardiovascular disease (CVD). Statins' beneficial effects have been attributed to both cholesterol-lowering and cholesterol-independent "pleiotropic" properties. By their pleiotropic effects statins have been shown to reduce inflammation, alleviate oxidative stress, modify the immunologic responses, improve endothelial function and suppress platelet aggregation. Patients with chronic kidney disease (CKD) exhibit an enormous increase in CVD rates even from early CKD stages. As considerable differences exist in dyslipidemia characteristics and the pathogenesis of CVD in CKD, statins' CV benefits in CKD patients (including those with a kidney graft) should not be considered unequivocal. Indeed, accumulating clinical evidence suggests that statins exert diverse effects on dialysis and non-dialysis CKD patients. Therefore, it seems that statins improve CV outcomes in non-dialysis patients whereas exert little (if any) benefit in the dialysis population. It has also been proposed that dyslipidemia might play a causative role or even accelerate renal injury. Moreover, ample experimental evidence suggests that statins ameliorate renal damage. However, a high quality randomized controlled trial (RCT) and metaanalyses do not support a beneficial role of statins in renal outcomes in terms of proteinuria reduction or retardation of glomerular filtration rate (GFR) decline.

Dyslipidemia, statins, and CKD patients' outcomes - review of the evidence in the post-sharp era.

Hyperlipidemia in the general population is strongly associated with an increased incidence of major adverse cardiovascular (CV) events (MACE). It is well established that HMG-CoA reductase inhibitors (statins) reduce CV and all-cause mortality in the general population, as well as in patients with CV disease (CVD). However, such a finding has not been definitively confirmed in patients with chronic kidney disease (CKD). Given that CV risk gradually increases with increasing stages of CKD (and is even higher in dialysis patients), it is of major relevance and importance to identify whether CKD patients might also benefit from alteration of lipid fractions, and how this might best be achieved. Bearing in mind that animal model and preclinical evidence suggests dyslipidemia might also be a factor promoting worsening renal function, it could legitimately be asked whether treating it may also therefore have a nephroprotective effect.

Long-term safety and efficacy of renin-angiotensin blockade in atherosclerotic renal artery stenosis.

PURPOSE: The activation of the renin-angiotensin-aldosterone system caused by renal ischaemia in atherosclerotic renal artery stenosis (ARAS) may be responsible for serious cardiovascular and renal consequences. The aim of the study was to assess the long-term safety, tolerability and outcomes of the use of angiotensin I-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) in patients with ARAS. METHODS: Thirty-six patients with angiographically defined ARAS (managed either with revascularization or only with medical treatment) were prospectively assessed for the safety, tolerability and outcomes of the use of ACEis or ARBs. RESULTS: The mean period of follow-up was 88.9 ± 37.8 months. A statistically significant reduction in systolic and diastolic blood pressure was recorded over time (P < 0.001). While estimated glomerular filtration rate remained almost stable during the study period (0.816), nuclear EDTA-GFR showed a significant reduction over time (P = 0.03). Mean time from diagnosis/intervention to end-stage renal disease for the cohort of 36 patients was 165.38 ± 13.62 months. Mean overall patient survival was 135.36 ± 15.25 months, with fourteen deaths (38.8%) occurring during the observational period. ACEi/ARB therapy was discontinued transiently in only 4 subjects. CONCLUSIONS: The use of ACEis/ARBs is safe and effective in patients with ARAS independently of any parameters.

Statins and prostate cancer: molecular and clinical aspects.

The field of the potential applications of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) beyond their unambiguous cardiovascular beneficial effects is steadily increasing. In this regard, statins have also been shown to possess anti-inflammatory, immunomodulatory, antioxidant and growth inhibitory properties. Regarding their role in carcinogenesis, both preclinical and clinical studies report conflicting results. Intriguingly, accumulating evidence suggests that statins may relate to decreased prostate cancer incidence and recurrence risk. However, data from clinical studies seem to be still weak and are confounded by several factors. Nonetheless, preclinical data suggest that statins might exert a chemopreventive role against prostate cancer by inhibiting the proliferation and inducing apoptosis of prostate cancer cells and also inhibiting angiogenesis, inflammation and metastasis. Cholesterol lowering as well as statin pleiotropy through inhibition of the synthesis of isoprenoids have both been implicated in their anticancer properties. In this review, we discuss the preclinical and clinical evidence supporting the preventive or potentially harmful effects of statins on prostate tumourigenesis and conclude that statins should not be recommended for the prevention of prostate cancer development or progression based on the current data.

Impaired desensitization of a human polymorphic α2B-adrenergic receptor variant enhances its sympatho-inhibitory activity in chromaffin cells.

BACKGROUND: α2-adrenergic receptors (ARs) mediate many cellular actions of epinephrine and norepinephrine and inhibit their secretion from adrenal chromaffin cells. Like many other G-protein coupled receptors (GPCRs), they undergo agonist-dependent phopshorylation and desensitization by GPCR Kinases (GRKs), a phenomenon recently shown to play a major role in the sympathetic overdrive that accompanies and aggravates chronic heart failure. A deletion polymorphism in the human α2B-AR gene (Glu301-303) causes impaired agonist-promoted receptor phosphorylation and desensitization in heterologous cell lines. Given the importance of α2-ARs in regulation of catecholamine secretion from chromaffin cells, we sought to investigate, in the present study, the desensitization properties and the sympatho-inhibitory activity of this variant in a chromaffin cell line. For this purpose, we expressed this variant and its wild type counterpart in the well-established chromaffin cell line PC12, and performed receptor phosphorylation and desensitization studies, as well as in vitro catecholamine secretion assays. RESULTS: Both the agonist-induced phosphorylation and agonist-dependent desensitization of the human Glu301-303 deletion polymorphic α2B-AR are significantly impaired in PC12 cells, resulting in enhanced signaling to inhibition of cholinergic-induced catecholamine secretion in vitro. CONCLUSION: This α2B-AR gene polymorphism (Glu301-303 deletion) might confer better protection against conditions characterized and aggravated by sympathetic/catecholaminergic overstimulation in vivo.