Modulation of ureteric Ca signaling and contractility in humans and rats by uropathogenic E. coli.

Ascending urinary tract infections, a significant cause of kidney damage, are predominantly caused by uropathogenic Escherichia coli (UPEC). However, the role and mechanism of changes in ureteric function during infection are poorly understood. We therefore investigated the effects of UPEC on Ca signaling and contractions in rat (n = 17) and human (n = 6) ureters. Ca transients and force were measured and effects of UPEC on the urothelium were monitored in live tissues. In both species, luminal exposure of ureters to UPEC strains J96 and 536 caused significant time-dependent decreases in phasic and high K depolarization-induced contractility, associated with decreases in the amplitude and duration of the Ca transients. These changes were significant after 3-5 h and irreversible over the next 5 h. The infection causes increased activity of K channels, causing inhibition of voltage-gated Ca entry, and K channel blockers could reverse the effects of UPEC on ureteric function. A smaller direct effect on Ca entry also occurs. Nonpathogenic E. coli (TG2) or abluminal application of UPEC did not produce changes in Ca signaling or contractility. UPEC exposure also caused significant impairment of urothelial barrier function; luminal application of the Ca channel blocker nifedipine caused a reduction in contractions as it entered the tissue, an effect not observed in untreated ureters. Thus, UPEC impairs ureteric contractility in a Ca-dependent manner, largely caused by stimulation of potassium channels and this mechanism is dependent on host-urothelium interaction.

Effect of conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium on maximum tolerated dose and gastrointestinal symptoms following kidney transplantation.

Despite the potential tolerability advantage of enteric-coated mycophenolate sodium (EC-MPS), no prospective, randomized trial has evaluated whether conversion from mycophenolate mofetil (MMF) to EC-MPS permits mycophenolic acid dose to be increased or gastrointestinal side-effects to be ameliorated. In a randomized, multicenter, open-label trial, kidney transplant recipients experiencing gastrointestinal side-effects either remained on MMF or switched to an equimolar dose of EC-MPS, adjusted 2 weeks subsequently to target the highest tolerated dose up to 1440 mg/day (EC-MPS) or 2000 mg/day (MMF). Patients were followed up to 12 weeks postrandomization. One hundred and thirty-four patients were randomized. The primary efficacy endpoint, the proportion of patients receiving a higher mycophenolic acid (MPA) dose at week 12 than at randomization, was significantly greater in the EC-MPS arm (32/68, 47.1%) than the MMF arm (10/61, 16.4%; P < 0.001). At the final visit, 50.0% (34/68) of EC-MPS patients were receiving the maximum recommended dose versus 26.2% (16/61) of MMF patients (P = 0.007). Kidney transplant patients receiving reduced-dose MMF because of gastrointestinal side-effects can tolerate a significant increase in MPA dose after conversion to EC-MPS. Patient-reported gastrointestinal outcomes with higher doses of EC-MPS remained at least as good as in MMF-treated controls.

Morphology, calcium signaling and mechanical activity in human ureter.

PURPOSE: We determined the mechanisms of calcium signaling in the human ureter, and the relationship to peristaltic contractions and bundular structure in living tissue, thereby advancing the understanding of ureteral function in health and obstruction and reflux. MATERIALS AND METHODS: Confocal imaging of 31 ureters was performed and simultaneous force and calcium measurements were made. Immunohistochemistry and Western blotting were also performed. RESULTS: Confocal imaging showed a 3-dimensional network of smooth muscle bundles with no defined longitudinal or circular layers. Fast propagating Ca waves spread throughout the bundles, were closely associated with contraction and depended on L-type Ca channel entry. Immunohistochemistry and Western blotting demonstrated L-type Ca channels, Ca dependent K channels, sarcoplasmic reticulum Ca-adenosine triphosphatase isoforms 2 and 3, inositol triphosphate, and ryanodine receptors. Modulation of Ca and K channel activity was a potent mechanism for affecting Ca and force, whereas manipulation of the sarcoplasmic reticulum had little effect. CONCLUSIONS: To our knowledge this study represents the first measurements of Ca signals in the human ureter obtained during phasic contractions and in response to agonists. Results show that it is controlled by fast propagating Ca waves, which spread rapidly between the muscle bundles, producing regular contractions, and drugs that interfere with excitability or Ca entry through L-type Ca channels have profound effects on Ca signaling and contractility. These data are discussed in relation to the treatment of patients with suspected ureteral dysfunction using Ca entry blockers.

Measures of care in adult renal transplant recipients in the United Kingdom (chapter 11).

The total number of patients active on the transplant waiting list (adult and paediatric) on 31 December 2005 was 5736, an 8% increase from the previous year. On 31 December 2005, 45.7% of prevalent adult RRT patients in the UK, had a functioning renal transplant which equated to 19,074 patients. During 2005, the death rate in prevalent transplant patients was 2.7 per 100 patient years. An additional 3.1% of all prevalent transplants failed with patients returning to dialysis. During 2005, deceased heart beating donor numbers decreased by 18% compared to 2004. In comparison, non-heart beating donors and living kidney donors increased by 35% and 17%, respectively, in 2005. The proportion of renal transplants performed from deceased heart beating donors fell from 68% in 2004 to 60% in 2005. There is wide variation in prevalence per million population (pmp) of transplanted patients resident in each local authority area across the United Kingdom. Total 11.4% of incident transplants in 2005 were due to patients with diabetes. The median eGFR was 46.1 ml/min/1.73 m(2), with 18% of prevalent transplant recipients having an eGFR <30 ml/min/1.73 m(2). The median Hb in prevalent transplant recipients was 12.9 g/dl, with 10% of patients having an Hb <10 g/dl. The median systolic and diastolic BP was 136 and 79 mmHg, respectively, with only 25% of patients within guidelines. Transplant function analysed by CKD stages 1-2 (eGFR < 60), 3 (eGFR 30-59), 4 (eGFR 15-29) and 5 (eGFR < 15), shows that these categories account for 24%, 59%, 15% and 2.5% of patients, respectively. Haemoglobin values fall with decreasing eGFR such that of the 2.5% of transplant patients with eGFR <15 ml/min, 27% had an Hb <10 g/dl and 51% <11 g/dl. Control of iPTH was poor in transplant recipients in CKD stages 4 and 5, with 22% and 50% of patients, respectively, having a PTH > 32 pmol/l (=300 ng/l). Patients with failing transplants are less likely to achieve RA targets of key biochemical variables when compared to patients on dialysis. There is still wide variability in the completeness of data returns from individual units.

Mixed lymphocyte cultures can predict TCR Vbeta repertoires of T cells infiltrating kidney transplants during acute rejection episodes.

Alloreactive T cell populations can show skewing of T-cell antigen receptor (TCR) Vbeta gene usage. The aims of the experiments were to compare in vivo and in vitro T cell alloresponses against donor alloantigens for TCR Vbeta gene usage. T-cell cultures from renal biopsies taken during acute rejection and pretransplant mixed lymphocyte cultures (MLC) were established from five renal transplant patients. TCR Vbeta gene usage, assessed with Vbeta family specific antibodies, showed that up to five different Vbeta families were significantly expanded. In four of five cases, there was close concordance between Vbeta families expanded from the biopsy and in MLC. T-cell clones from one renal biopsy were specific for the mismatched donor alloantigen and showed similar TCR Vbeta gene usage to the original T-cell line. The results show very similar patterns of TCR Vbeta gene usage in alloreactive T cells generated ex vivo or in vitro.

The association of viral infection and chronic allograft nephropathy with graft dysfunction after renal transplantation.

BACKGROUND: The long-term effect of viral infections on graft dysfunction and rejection after renal transplantation is uncertain. METHODS: A cohort of 37 renal transplant recipients was followed prospectively for 3 years. Creatinine clearance rate at 6 months and 3 years and chronic allograft nephropathy were correlated with the detection of cytomegalovirus (CMV), human herpesvirus 6 and human herpesvirus 7 and BK virus DNA, CMV disease, and acute rejection. RESULTS: CMV disease was significantly associated with poor graft function at 6 months, whereas chronic allograft nephropathy was associated with graft dysfunction at 3 years. Both CMV disease and detection of human herpesvirus 6 DNA were associated with chronic allograft nephropathy. CONCLUSIONS: CMV disease was a significant cause of early graft dysfunction, whereas the presence of chronic allograft nephropathy was the main determinant of poor long-term graft function. The role of viral infections in chronic allograft nephropathy deserves further investigation.

Prevention better than cure. Avoiding steal syndrome with proximal radial or ulnar arteriovenous fistulae.

BACKGROUND: Steal syndrome is a significant complication of arteriovenous fistulae (AVF). We wanted to assess an alternative technique to reduce the incidence of steal syndrome and add an extra option for vascular access for long-term hemodialysis patients METHODS: All patients who underwent proximal radial or ulnar artery AVF between 2003 and 2007 were evaluated retrospectively. RESULTS: There were 58 patients, 35 men and 23 women, and the median age was 60 years (range 19-85 years). The proximal radial artery was used in 50 (89%) of cases and the ulnar artery in 8. Three fistulae (5%) failed in the first week, 3 others failed later, prior to use leading to a 90% successful patency rate. One diabetic patient developed steal syndrome and re-presented to the surgeons at a late stage when they had finger ulceration and it was decided to ligate the fistula in this case. Thus, the overall incidence of steal syndrome was low at 2%. CONCLUSIONS: It is suggested that arterio-venous fistulae using proximal radial or ulnar arteries can be performed before brachio-cephalic fistulae since they offer long-term patency and reduced incidence of steal syndrome. Brachio-cephalic AVF can be performed subsequently if necessary.

Early experience with the Amplatzer Vascular Plug II for occlusive purposes in arteriovenous hemodialysis access.

The Amplatzer Vascular Plug Type II (AVP II) has proven effective in the therapeutic embolization of various vascular lesions. It benefits from very rapid occlusion of the target lesion and can be deployed, retrieved, and redeployed if required. There is no literature available on use of the AVP II in the maintenance, closure, and management of complicated arteriovenous access in hemodialysis patients. In this series, we present our clinical experience with the use of the AVP II for embolization of problematic hemodialysis access. The AVP II is a self-expandable Nitinol wire-mesh device. Mounted on a delivery wire it has the capability to be deployed, recaptured, and redeployed. In total seven patients (four males: one diabetic, all nonsmokers), with ages ranging from 44 to 81 years (mean, 63 years), were treated between July 2008 and January 2009. One patient had not started dialysis. The remaining six patients had varied histories, with the time on hemodialysis ranging from 1 to 21 years. Retrospective review of clinical notes revealed patient demographics, type of access, device size, deployment site, and outcomes. Indications for embolization included steal syndrome (one patient), high-flow tributaries (two patients), and limb swelling (four patients). All patients had clinical and sonographical follow-up to 3 months. Surgical ligation had either failed, was considered a contraindication due to concerns regarding wound healing, or was considered difficult due to complex venous anatomy. Only one device was used in each patient, ranging from 6 to 16 mm in diameter. Immediate technical success was seen in 100%. All these patients were followed up clinically in the vascular access radiology clinic at 4 weeks and 3 months. Occlusion of the treated vessel and resolution of symptoms were reconfirmed in 100% of cases at 3 months. It was also noted whether patients were having successful dialysis, if required. There were no complications. Average procedural time was 19 min. We conclude that the AVP II is an efficient, safe, and technically simple occlusion device for use in arteriovenous access.

Iatrogenic arteriovenous fistula in the groin presenting as cardiac failure.

A patient presented with cardiac failure and investigations revealed a right femoral arteriovenous fistula (AVF) 5 weeks after the insertion of a femoral dialysis catheter for haemodialysis. No ultrasound had been used for catheter insertion. The iatrogenic AVF was repaired, and her episodes of cardiac failure ceased. It is recommended that femoral dialysis catheters are inserted using ultrasound guidance to avoid inadvertent arterial puncture.

AngioJet thrombectomy for occluded dialysis fistulae: outcome data.

This study evaluates AngioJet thrombectomy of occluded autogenous dialysis fistulae and polytetrafluoroethylene (PTFE) grafts in a UK hemodialysis population. Comparison is made with published data of alternative percutaneous thrombectomy methods. All patients with occluded dialysis fistulae who sought care at the Royal Liverpool University Hospital between October 2006 and June 2008 were included in the study. All patients were treated with the AngioJet Rheolytic Thrombectomy Device (Possis, Minneapolis, MN). Demographics, time of occlusion, adjunctive therapies, complications, and follow-up data have been prospectively recorded. A total of 64 thrombectomy procedures were performed in 48 patients. Forty-four autogenous fistulas were treated in 34 patients (19 brachiocephalic, 8 radiocephalic, and 7 transposed brachiobasilic). Twenty PTFE grafts were treated in 14 patients (9 brachioaxillary, 3 brachiocephalic loop grafts, 1 brachiobasilic, and 1 femoro-femoral). The average length of occlusion was 24 cm. Average time to intervention was 4 days. Immediate primary patency was 91%. Primary patency at 1, 3, and 6 months, respectively, was 71%, 60%, and 37%. Secondary patency at 3, 6, and 12 months was 87%, 77%, and 62%, respectively. Angioplasty was carried out in all procedures. Patients required stent insertion in 34 of the 64 thrombectomies to treat angioplasty-resistant stenoses. Complications included a puncture-site hematoma, and three angioplasty-related vein ruptures in one patient, all treated with covered stent grafts. Two cases of distal brachial arterial embolization were successfully treated by thrombosuction. AngioJet thrombectomy in dialysis access occlusion is safe and effective, comparing favorably with other methods.

Cytomegalovirus-specific CD8+ T cells do not develop in all renal transplant patients at risk of virus infection.

Cytomegalovirus (CMV) is an important pathogen in immunosuppressed renal transplant patients. At greatest risk are CMV IgG seronegative recipients (R-) of kidneys from CMV IgG seropositive donors (D+), although not all develop CMV disease. The aims of the study were to determine whether D+/R- patients who do or do not go on to develop CMV disease differ in their CD8+ T cell responses to CMV. Responses to the immunodominant NLVPMVATV peptide from the CMV structural protein pp65 in HLA-A2+ renal transplant patients were quantified using HLA tetramers/pentamers. Most D+/R+ patients had detectable tetramer+ cells while most D-/R- patients did not. Around 50% of D+/R- patients had some CD8+ tetramer+ cells and there was a strong correlation between % tetramer+ cells and the occurrence of a CMV infection post-transplantation (P<0.005). 18/41 (44%) of CMV negative patients receiving a kidney from a CMV+ donor failed to develop a detectable CMV infection, or significant numbers of tetramer+ cells. There was no relationship between CMV infection and acute cellular rejection. There was a tendency for patients who were given pre-emptive antiviral therapy to have lower levels of tetramer+ cells but this was not statistically significant. Hence the results show that CMV- patients receiving a kidney from a CMV+ donor do not inevitably acquire CMV infection. Those without CMV disease did not show any T cell response while most patients with detectable CMV developed specific CD8+ T cells.

Successful renal transplantation during pregnancy.

Little is known about the implications of performing a renal transplant on a patient who is already pregnant. This case study reports a successful outcome of pregnancy, diagnosed coincidentally following renal transplantation at 13 weeks gestation. The recipient was a 23-year-old woman with chronic kidney disease who received a live-related renal transplant from her father. Pregnancy was discovered at routine ultrasound scanning of the renal allograft at 5 days posttransplant and estimated at 13 weeks gestation. She received ciclosporin monotherapy as immunosuppression throughout the pregnancy, and was given valacyclovir as prophylaxis against cytomegalovirus (CMV) infection. Renal function remained stable throughout the pregnancy, which progressed normally, resulting in the vaginal delivery of a healthy, liveborn male infant at 37 weeks gestation. This case study demonstrates that transplantation during pregnancy can have a successful outcome.

Clinical outcome of cadaveric renal allografts contaminated before transplantation.

This analysis was performed to define the incidence of pretransplant microbial contamination of donor kidneys, and to assess the resultant morbidity including infections requiring therapy, and graft loss. Case records of all 638 renal allograft recipients patients transplanted in our centre during the period June 1990 to October 2000 were studied. All the recipients were given a single dose of intravenous antibiotics at the time of induction of anaesthesia. A total of 775 microbiology reports on perfusion fluid, kidney swabs and ureteric tissue were retrieved. Fifty-eight of 638 (9.1%) patients were transplanted with a graft that showed preoperative contamination. 18 of these 58 patients (31%) subsequently required antibiotic treatment. Thirty of 32 patients who received kidney contaminated with skin flora had a benign course (i.e. no unexplained, no positive blood cultures or graft infection). By contrast, seven of nine recipients with grafts whose perfusion fluid yielded lactose fermenting coliforms (LFCs) required antibiotics and three of nine of them suffered graft loss as a result. Two of these patients had bacteraemia caused by LFC, and one died. Three of five patients with positive cultures due to yeast required treatment with antifungals. None of the four patients who had graft contaminated by Staphylococcus aureus became infected. One-year 49/58 (85%) of these patients survived with functioning graft. Overall 1-year patient survival was 53/55 (92%). These data suggest that contamination of renal allografts by LFCs or yeasts need to be treated preemptively before the onset of clinical manifestations. By contrast, contamination with skin contaminants does not pose a risk to the graft.

Utility of serial Doppler ultrasound scans for the diagnosis of acute rejection in renal allografts.

This study aims to explore the utility of serial duplex scanning and to compare its results with those of single time-point scans of renal allografts in the diagnosis of acute rejection (AR). A retrospective analysis of 6017 serial duplex scans (mean: 9.8 scans per patient, 5.7 of which were done during the first 10 days) was performed in 614 patients with 462 episodes of AR from 1992-2000. Even in the absence of AR (n=278), there were day-to-day fluctuations in pulsatility index (PI) and resistive index (RI). An increase of >10% in intra-renal indices was noted 0.95 days (mean) before the commencement of treatment for AR (SD 1.3, range 1-6 days). In patients with acute tubular necrosis (ATN), who have high base line indices, sensitivity of single value of PI and RI was 58% (cut-off level 1.8) and 68% (cut-off level 0.8), with specificity of 66% and 56%, respectively. By contrast, a >10% increase over the previous 'best' in PI and RI had a sensitivity of 78% and 60% respectively, and a specificity of 78% and 90%, respectively. Reversal of flow during diastole (n=50) was found to be associated with 22% graft loss within 3 months of transplantation. We can conclude that a considerable overlap between the indices of patients with AR and those with ATN greatly limits the diagnostic yield of duplex scanning. Nonetheless, serial scanning of renal allografts is more likely to herald the need for biopsy in the diagnosis of AR than one-time scanning.

Delayed pseudoaneurysm after renal artery angioplasty.

PURPOSE: To report delayed pseudoaneurysm formation after percutaneous renal artery angioplasty. CASE REPORTS: A 56-year-old woman succumbed to complications of a ruptured right juxtarenal aortic pseudoaneurysm 2 years after right renal artery stenting for renal impairment. The juxtarenal aorta had been normal on aortography at the time of angioplasty. She gave a history of right-sided back pain that started within 8 months of the angioplasty. A 21-year-old woman with left renal artery stenosis due to fibromuscular dysplasia was treated with balloon angioplasty, after which there was evidence of active extravasation. The completion angiogram, after a period of observation, documented cessation of the leak. Follow-up angiography because of persisting hypertension disclosed a large, asymptomatic, intrarenal pseudoaneurysm that was repaired with bench surgery and autotransplantation. CONCLUSIONS: We advise that patients with symptoms referable to the site of renal artery intervention and those who have had complicated interventions should have follow-up imaging to exclude pseudoaneurysm formation.