Would hemodialysis patients benefit from a Staphylococcus aureus vaccine?

Staphylococcus aureus bloodstream infection can have potentially catastrophic consequences for patients on hemodialysis. Consequently, an effective vaccine to prevent S aureus infection would have a significant influence on morbidity and mortality in this group. To date, however, efforts to develop a vaccine have been unsuccessful. Previous antibody-inducing vaccine candidates did not prevent or attenuate S aureus infection in clinical trials. Recent advances have helped to elucidate the role of specific T-cell subsets, notably T-helper cell 1 and T-helper cell 17, in the immune response to S aureus. These cells are essential for coordinating an effective phagocytic response via cytokine production, indirectly leading to destruction of the organism. It is now widely accepted that next-generation S aureus vaccines must also induce effective T-cell-mediated immunity. However, there remains a gap in our knowledge: how will an S aureus vaccine drive these responses in those patients most at risk? Given that patients on hemodialysis are an immunocompromised population, in particular with specific T-cell defects, including defects in T-helper cell subsets, this is likely to affect their ability to respond to an S aureus vaccine. We urgently need a better understanding of T-cell-mediated immunity in this cohort if an efficacious vaccine is ever to be realized for these patients.

Clinical and pathologic characteristics of hereditary apolipoprotein A-I amyloidosis in Ireland.

AIM: Apolipoprotein A-I amyloidosis is a rare, autosomal dominant disorder characterized by progressive accumulation of amyloid fibrils in tissues, leading to renal and hepatic disease. We describe the clinical manifestations and pathologic features of kidney disease in three Irish families. METHODS: This observational study examines all known cases of chronic kidney disease due to hereditary apolipoprotein A-I amyloidosis in Ireland. Patients were identified by physician interview. In all of the affected individuals the disease was caused by the Gly26Arg heterozygous mutation. Immunohistochemistry confirmed that amyloid deposits were composed of apolipoprotein A-I fibrils. Family trees and clinical data were obtained via analysis of patient medical records. RESULTS: The vast majority of affected cases had demonstrable kidney disease, with variable liver disease. Renal disease most commonly manifested as slowly progressive renal impairment with mild proteinuria. In one kindred, a severe, debilitating peripheral neuropathy was common among affected family members. Histology demonstrated tubulointerstitial fibrosis with amyloid deposition in the medulla. There was very high penetrance within affected families. Of five patients who were transplanted, one transplant was lost after 5 years due to recurrent disease. One patient died from sepsis shortly after transplant. CONCLUSION: Hereditary apolipoprotein A-I amyloidosis is characterized by slowly progressive renal disease. Amyloid is deposited in the renal medulla highlighting the need to examine the medulla on renal biopsy. Overall, kidney transplantation conferred a survival advantage.

Effect of perioperative blood transfusions on long term graft outcomes in renal transplant patients.

BACKGROUND: It is established that blood transfusions will promote sensitization to human leucocyte antigen (HLA) antigens, increase time spent waiting for transplantation and may lead to higher rates of rejection. Less is known about how perioperative blood transfusion influence patient and graft outcome. This study aims to establish if there is an association between perioperative blood transfusion and graft or patient survival. MATERIALS AND METHODS: This was a single center, national, retrospective cohort study. Data was collected on patients who received kidney transplants over a 14-year period (n = 2,013). The primary outcomes were graft survival and mortality in patients who received blood transfusions in the perioperative period compared to those who did not. RESULTS: Patients who received blood transfusions had lower hemoglobin levels, were more likely to be male, and had higher rates of delayed graft function compared to those who did not receive a transfusion. The one year graft survival of those transfused was 83% compared to 94% in those not transfused (p = < 0.0001). Adjustment for confounding showed that the receipt of a blood transfusion remained associated with increased graft loss. Hemoglobin levels prior to transfusion did not have an influence on graft outcome. CONCLUSION: Perioperative blood transfusion is associated with reduced long-term graft survival.

Early results of a controlled non-heart-beating kidney donor programme.

BACKGROUND: We present our experience of a controlled non-heart beating donation (CNHBD) programme in a University Hospital. METHODS: Data from all referrals for CNHBD between January 2005 and January 2008 were collected prospectively. Donor and recipient data were analysed and compared to other cadaveric and HBD transplants performed during the same period. RESULTS: During the period, 79 donors were referred resulting in 35 proceeding to retrieval and 61 kidneys being successfully transplanted. The median time from withdrawal of therapy to asystole was 15 min (IQR 10.0-23.0). The median primary warm ischaemic time was 20 min (IQR 16.0-27.0). The mean cold ischaemia time was 16.6 +/- 4.21 h for CNHBD (16.6 +/- 5.91 for HBD) kidneys. Compared to HBD kidneys, CNHBD kidneys had more HLA mismatches and significantly more delayed graft function (44% versus 14%), and the mean time to halving of serum creatinine was significantly greater (12.8 versus 5 days). However, 1-year patient and graft survival (88% and 93%) were excellent and mean creatinine at 12 months for CNHB kidneys was not significantly different from HBD kidneys (141 mumol/l versus 131 mumol/l). CONCLUSIONS: Structured implementation resulted in a successful CNHBD programme providing 61 successful renal transplants from 35 donors in 3 years-contributing to approximately 50% of the total number of cadaveric renal transplants during the period. At 12 months, CNHBD kidney graft function was equivalent to HBD organs.

TNP-470, an angiogenesis inhibitor, attenuates the development of allograft vasculopathy.

Fischer 344 rat recipients of Lewis allografts were treated with TNP-470, a synthetic fumagillin derivative and a well-established angiogenesis inhibitor. TNP-470 alone resulted in some prolongation of graft survival as compared with untreated recipients, but all grafts ultimately failed. In contrast, treatment with cyclosporine (CsA) from day 0 to 30 resulted in prolonged graft survival and marked cardiac allograft vasculopathy (CAV) by histology (mean score 2.28+/-0.2). There were many neovessels within the intima of CAV lesions. When TNP-470 was administered in combination with CsA from day 0 to 30, the degree of CAV was similar to that with CsA alone (mean score 2.22+/-0.26). However, when TNP-470 was administered from day 30 to 120 after discontinuation of CsA, there was a marked reduction in the degree of CAV (mean score 1.08+/-0.11). Therefore, TNP-470 interrupts the progression of CAV when given late but does not prevent its development when given immediately posttransplantation.

Statin specific toxicity in organ transplant recipients: case report and review of the literature.

Statins are widely prescribed to organ transplant recipients with hyperlipidemia. We report the case of a cardiac transplant recipient who developed severe rhabdomyolysis and acute renal failure after being switched from pravastatin to simvastatin. The patient's other medications included cyclosporin A and diltiazem. Unlike pravastatin, the metabolism and tissue concentrations of simvastatin--and of other statins - can be greatly affected by these drugs. The propensity of the individual statins to interact with drugs commonly prescribed to transplant recipients is reviewed.

DNA microarrays: applicability to renal physiology and disease.

The utilization of DNA microarray is increasing in all areas of medical research as evidenced by the exponential increase in the number of publications on MedLine. Improvements in DNA microarray technology and the bioinformatic techniques for data analysis continue to take place and result in improved reliability, reproducibility, and volume of data. Replicate analysis remains important in order to allow statistical examination of significance. Expression of key genes should also be confirmed by alternative techniques. Single microarray experiments yield such vast amounts of data that shortage of manpower is the limiting factor to progression of full scientific discovery. Sharing of microarray data on the internet and its distribution to a broader scientific community will help overcome this manpower shortage. Currently, DNA microarray technology serves as a research tool. Ultimately, microarray technology may be used widely in the clinical setting as fingerprinting of cells, tissue, and disease states, though more targeted strategies using a limited repertoire of genes may be most valuable.

Arterio-venous fistula buttonhole cannulation technique: a retrospective analysis of infectious complications.

BACKGROUND: There are two main methods of accessing arterio-venous fistulas (AVFs); the 'buttonhole' and the 'rope-ladder' cannulation technique. Several small studies have hypothesized that the buttonhole technique is associated with increased rates of fistula-associated infection. This study addresses this hypothesis. METHODS: A retrospective review of all patients attending a large outpatient haemodialysis clinic was performed. Data were collected on the method of cannulation, infection rates, implicated microorganisms, complications of infection and time on haemodialysis. RESULTS: A total of 127 patients had received haemodialysis via an AVF: 53 via the rope-ladder technique and 74 via the buttonhole technique. Nine episodes of clinically significant bacteraemia were recorded in the buttonhole group. This equated to a rate of 0.073 bacteraemia events per 1000 AVF days. There were no episodes of bacteraemia in the rope-ladder group. Eight infections were due to methicillin-sensitive Staphylococcus aureus (MSSA); one was due to Staphylococcus epidermidis. Three patients with MSSA bacteraemia subsequently developed infective endocarditis. Five patients who developed bacteraemia events had been undergoing home haemodialysis. CONCLUSIONS: This study highlights the infectious complications associated with buttonhole cannulation techniques. All organisms isolated in our cohort were known skin colonizers. The reason for the increased rates of infection is unclear. Given this high rate of often life-threatening infection, we recommend regular audit of infection rates. We currently do not recommend this technique to our patients receiving haemodialysis.

Significance of anticardiolipin antibodies on short and long term allograft survival and function following kidney transplantation.

The significance of anticardiolipin antibodies (ACAs) prior to renal transplantation is unclear. We studied a cohort of 337 patients who underwent renal transplantation from 1996 to 2001. Follow-up continued until allograft loss, patient death or 31 December 2002. The primary outcome was a composite endpoint of death-censored allograft loss or a 25% reduction in estimated glomerular filtration rate (GFR) from 1-month post-transplant. Secondary outcomes were allograft loss, a 25% reduction in GFR, acute rejection and creatinine at 1 year. IgG and IgM ACA titers were positive (> or =15) in 18.1% of recipients. There were no significant differences at baseline between recipients, except coumadin therapy in those with positive ACA titers (20% vs. 7.4%). Post-transplant, there was no increase in the primary outcome in ACA-positive patients, even after adjustment for anticoagulation with coumadin (HR = 1.42 [0.68, 2.96]). There was no difference in secondary outcomes between those with or without positive titers. Two of five patients with very high titers (>50) who were not anticoagulated had early graft loss. A positive ACA titer prior to kidney transplantation was not associated with inferior renal outcomes after transplantation, although more research is required to address the prognostic significance of very high ACA titers.

Assessment by flow cytometry of intracellular cytokine production in the peripheral blood cells of renal transplant recipients.

INTRODUCTION: There is accumulating evidence that non-invasive immune monitoring may be useful in the early period after renal transplant, particularly with regard to predicting the presence of acute rejection. It is less clear whether chronic allograft nephropathy (CAN) is also associated with consistent changes in peripheral blood or urine cells. We hypothesized that patients with CAN would manifest different patterns of cytokine production (compared with non-CAN controls), detectable in peripheral blood mononuclear cells (PBMCs). METHODS: Flow cytometry was used to quantify production within PBMCs of multiple cytokines. RESULTS: A pilot study showed significant differences in cytokine production between healthy controls and transplanted subjects. However, differences between transplanted patients with and without CAN were small and non-significant. DISCUSSION: Flow cytometry is a potentially useful method for quantifying cytokine production by PBMCs of renal transplant recipients. The technique is sensitive enough to detect differences between distinct test groups but could not find differences between recipients with and without CAN. This probably reflects the lack of a true difference because pathological changes within the long-term allograft may simply not be reflected or detected in the total population of PBMCs. Further studies should explore the usefulness of this technique in assaying more defined populations of PBMCs (such as those activated by donor allopeptides) and in serial monitoring of individual patients.

Prevalence of renal cell carcinoma in patients with ESRD pre-transplantation: a pathologic analysis.

BACKGROUND: Acquired renal cystic disease (ARCD), renal adenoma (AD), and renal cell carcinoma (RCC) are more common in patients with end-stage renal disease (ESRD). However, the prevalence of these conditions in patients undergoing transplantation, and the clinical characteristics associated with their occurrence are unclear. METHODS: At our institution, the majority of patients undergo an ipsilateral native nephrectomy at the time of transplantation, providing a unique opportunity to study the prevalence and pathology of ARCD, AD and RCC in ESRD. We retrospectively reviewed all consecutive nephrectomy pathology reports over a six year period. Demographic and clinical characteristics associated with these lesions were identified. RESULTS: Two hundred and sixty nephrectomy reports were reviewed: ARCD, AD, RCC and oncocytoma were found in 33%, 14%, 4.2% and 0.6% of cases, respectively. On multivariable analysis, ARCD was positively associated with male sex and longer dialysis duration and negatively associated with peritoneal dialysis. Similarly, AD was positively associated with male sex, longer dialysis duration and greater age. There was a trend for RCC cases to share similar associations although the small total number of cases precluded findings of statistical significance. CONCLUSION: By pathologic analysis, renal tumors are more common in the pre-transplant ESRD population than previously reported (using radiologic methods). Our study also identifies risk factors for their occurrence. This may prove useful in designing screening studies for renal tumors in this patient population.