Management of organ transplant recipients attending a high-throughput skin cancer surgery and surveillance clinic in Queensland.

BACKGROUND: The incidence of skin cancer in organ transplant recipients (OTRs) is very high, due mainly to long-term immunosuppressive therapy. The problem is particularly severe for OTRs living in Queensland, Australia, and results in significant mortality. OBJECTIVES: To describe the experience of the first dedicated outpatient high-throughput transplant skin clinic in Queensland. METHODS: This prospective evaluation study was conducted at a newly established, outpatient transplant skin cancer surgery and surveillance clinic. Participants (89 OTRs and 12 non-OTRs) were referred to the Princess Alexandra Hospital Transplant Skin Clinic during December 2016 to May 2017, and were each followed for 3 months. Self-completed questionnaires were administered at baseline and the end of follow-up (n = 94), and details of any skin cancers occurring in that period were extracted from hospital records. RESULTS: In the 3-month follow-up of 101 participants, a total of 615 skin lesions were detected in the 3-month follow-up of 101 participants, of which 478 (78%) were treated in the clinic and 55 (9%) were referred to another specialist. Of the 478 treated lesions, 268 were histopathologically confirmed skin cancers, equivalent to 2·7 (95% confidence interval 2·5-2·8) skin cancers per participant per 3 months. The overall number needed to treat for any skin cancer was 1·4 (95% confidence interval 1·3-1·5). Three-quarters (374) of in-clinic treatments were surgical, and most (90%) were complete excisions. The median time from detection of skin cancer to excision was 7 days. CONCLUSIONS: This high-volume surgical outpatient transplant skin clinic enables efficient treatment of skin cancers in very-high-risk OTRs.

The effects of a multidisciplinary high-throughput skin clinic on healthcare costs of organ transplant recipients.

BACKGROUND: A long-term complication among organ transplant recipients (OTRs) is skin malignancies which are associated with level and duration of immunosuppressive treatment, sun exposure and age. Dermatological surveillance is recommended for OTRs at high risk of skin malignancies, but evidence is lacking on the benefits of such services. OBJECTIVE: To examine the economic impact on patients and on the hospital service of a multidisciplinary high-throughput skin cancer clinic in Brisbane, Australia, dedicated to dermatological and surgical care of high-risk OTRs. METHODS: In a pre/postdesign, hospital admission and cost data were obtained for 101 consecutively enrolled study participants from 12 months prior to the introduction of the clinic (to February 2016), the 3-month 'run-in' period (March to May 2016) and 12 months subsequent (to June 2017). Differences between pre- and post-clinic hospital costs were tested using non-parametric bootstrapping and interrupted time series analysis. A survey of patient out-of-pocket costs and perceived financial burden was also undertaken during the clinic. RESULTS: Overall hospital costs were higher after the clinic but 3-monthly hospital costs for skin procedures trended downwards. Despite 3-monthly mean, hospital visits increasing from 85 to 314, mean 3-monthly costs reduced by AU$1491 (P < 0.001) indicating greater cost efficiency. Total patient out-of-pocket costs were AU$18 377 over 3 months. CONCLUSION: Clinical costing data revealed higher, more rapid throughput and significantly lower per patient costs pre- and postestablishment of a multidisciplinary skin cancer clinic for OTRs.

Azathioprine and Risk of Skin Cancer in Organ Transplant Recipients: Systematic Review and Meta-Analysis.

Azathioprine, a purine antimetabolite immunosuppressant, photosensitizes the skin and causes the production of mutagenic reactive oxygen species. It is postulated to increase the risk of squamous cell carcinoma (SCC) and other skin cancers in organ transplant recipients (OTRs), but evidence from multiple, largely single-center studies to date has been inconsistent. We aimed to resolve the issue of azathioprine's carcinogenicity by conducting a systematic review of the relevant literature and pooling published risk estimates to evaluate the risks of SCC, basal cell carcinoma (BCC), keratinocyte cancers (KCs) overall and other skin cancers in relation to azathioprine treatment. Twenty-seven studies were included in total, with risk estimates from 13 of these studies able to be pooled for quantitative analysis. The overall summary estimate showed a significantly increased risk of SCC in relation to azathioprine exposure (1.56, 95% confidence interval [CI] 1.11-2.18). No significant associations between azathioprine treatment and BCC (0.96, 95% CI 0.66-1.40) or KC (0.84, 95% CI 0.59-1.21) risk were observed. There was significant heterogeneity between studies for azathioprine risk estimates and the outcomes of SCC, BCC and KC. The pooled findings of available evidence support the contention that treatment with azathioprine increases the risk of SCC in OTRs.

Detection of Recently Discovered Human Polyomaviruses in a Longitudinal Kidney Transplant Cohort.

A large number of human polyomaviruses have been discovered in the last 7 years. However, little is known about the clinical impact on vulnerable immunosuppressed patient populations. Blood, urine, and respiratory swabs collected from a prospective, longitudinal adult kidney transplant cohort (n = 167) generally pre-operatively, at day 4, months 1, 3, and 6 posttransplant, and at BK viremic episodes within the first year were screened for 12 human polyomaviruses using real-time polymerase chain reaction. Newly discovered polyomaviruses were most commonly detected in the respiratory tract, with persistent shedding seen for up to 6 months posttransplant. Merkel cell polyomavirus was the most common detection, but was not associated with clinical symptoms or subsequent development of skin cancer or other skin abnormalities. In contrast, KI polyomavirus was associated with respiratory disease in a subset of patients. Human polyomavirus 9, Malawi polyomavirus, and human polyomavirus 12 were not detected in any patient samples.

Atypical haemolytic uraemic syndrome treated with the complement inhibitor eculizumab: the experience of the Australian compassionate access cohort.

BACKGROUND/AIM: This study aimed to report the clinical characteristics and outcomes of Australian patients treated with eculizumab for atypical haemolytic uraemic syndrome (aHUS). METHODS: A retrospective cohort study was undertaken of all patients in Australia treated with eculizumab provided in a compassionate access programme for a clinical diagnosis of aHUS using prospectively collected clinical data. RESULTS: A total of 10 patients with a median age of 23.5 years (interquartile range (IQR) 24.83 years) received compassionate access eculizumab for aHUS in Australia. Eight patients were female, and three had a family history of aHUS. Three received eculizumab for an initial acute aHUS presentation, three for relapsing and refractory acute aHUS, two for de novo aHUS post-renal transplantation, and one each for aHUS recurrence post-transplantation and facilitation of transplantation with a history of aHUS. The median duration of eculizumab therapy has been 911.5 days (IQR 569 days) with a cumulative exposure of 9184 days. At baseline all patients had renal and extra-renal aHUS involvement, with up to three non-renal organs affected. All but one patient, who died from uncontrollable gastrointestinal aHUS manifestations, have continued. The nine continuing patients achieved remission of aHUS. Two of the four patients requiring renal replacement therapy (RRT) at eculizumab commencement subsequently ceased RRT. Clinical events occurring in this cohort while on eculizumab treatment included neutropenia (two), posterior reversible encephalopathy syndrome (one), cardiomyopathy (one), pulmonary embolus (one), antibody-mediated rejection resulting in renal graft failure (one), iron deficiency (one), gastrointestinal haemorrhage (one) and death (one). CONCLUSION: Eculizumab has been an effective therapy for aHUS in this cohort, including when other therapies have failed.

Uraemic toxins and cardiovascular disease across the chronic kidney disease spectrum: an observational study.

BACKGROUND AND AIMS: There is a growing body of evidence supporting the nephrovascular toxicity of indoxyl sulphate (IS) and p-cresyl sulphate (PCS). Nonetheless, a comprehensive description of how these toxins accumulate over the course of chronic kidney disease (CKD) is lacking. METHODS AND RESULTS: This cross-sectional observational study included a convenience sample of 327 participants with kidney function categorised as normal, non-dialysis CKD and end-stage kidney disease (ESKD). Participants underwent measurements of serum total and free IS and PCS and assessment of cardiovascular history and structure (carotid intima-media thickness [cIMT, a measure of arterial stiffness]), and endothelial function (brachial artery reactivity [flow-mediated dilation (BAR-FMD); glyceryl trinitrate (BAR-GTN)]). Across the CKD spectrum there was a significant increase in both total and free IS and PCS and their free fractions, with the highest levels observed in the ESKD population. Within each CKD stage, concentrations of PCS, total and free, were significantly greater than IS (all p < 0.01). Both IS and PCS, free and total, were correlated with BAR-GTN (ranging from r = -0.33 to -0.44) and cIMT (r = 0.19 to 0.21), even after adjusting for traditional risk factors (all p < 0.01). Further, all toxins were independently associated with the presence of cardiovascular disease (all p < 0.02). CONCLUSION: More advanced stages of CKD are associated with progressive increases in total and free serum IS and PCS, as well as increases in their free fractions. Total and free serum IS and PCS were independently associated with structural and functional markers of cardiovascular disease. Studies of therapeutic interventions targeting these uraemic toxins are warranted.

Association of micropapillary urothelial carcinoma of the bladder and BK viruria in kidney transplant recipients.

INTRODUCTION: BK virus (BKV) is an ubiquitous human polyomavirus that establishes latency in urothelium. BKV is known to re-activate in immunosuppressed individuals, and is an increasingly important cause of nephropathy and graft loss in kidney transplant recipients. Animal studies have demonstrated BKV has a potential role as a tumor virus. However, its role in precipitating or facilitating oncogenesis in humans is still debated. REPORT: We report 2 cases of aggressive micropapillary urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria and preserved graft function. RESULTS: In both cases, polyomavirus immunohistochemistry performed on the tumor specimens was strongly positive, and limited to the malignant tissue. BKV DNA, viral protein 1, and large T antigen mRNA were detected in the tumor; however, no viral particles were seen on electron microscopy. CONCLUSION: In one of the cases, BKV integration into the host genome was identified, leading to the truncation of the major viral capsid gene. This finding raises the concern that persisting BK viruria may be a risk factor for this aggressive form of bladder cancer. Further studies to determine screening and management strategies are required.

Higher mycophenolate dosage is associated with an increased risk of squamous cell carcinoma in kidney transplant recipients.

BACKGROUND: Kidney transplant recipients are at increased risk of keratinocyte cancers, namely squamous cell and basal cell carcinomas (SCCs and BCCs). This is primarily due to the high levels of immunosuppression that are required to prevent allograft rejection. Different immunosuppressive medications confer different risks, and the effect of mycophenolate mofetil on SCC and BCC risk is unclear. We explored the relationship between mycophenolate dose prescribed over the entire transplant period and the risk of SCC and BCC. METHODS: Kidney transplant recipients from Queensland, Australia, were recruited between 2012 and 2014 and followed until mid-2016. During this time transplant recipients underwent regular skin examinations to diagnose incident SCCs and BCCs. Immunosuppressive medication regimens were obtained from hospital records, and the average mycophenolate dose/day over the entire transplantation period was calculated for each patient. Doses were divided into three ranked groups, and adjusted relative risks (RRadj) of developing SCC and BCC tumours were calculated using negative binomial regression with the lowest dosage group as reference. Recipients who had used azathioprine previously were excluded; further sub-group analysis was performed for other immunosuppressant medications. RESULTS: There were 134 kidney transplant recipients included in the study. The average age was 55, 31% were female and 69% were male. At the highest median mycophenolate dose of 1818 mg/day the SCC risk doubled (RRadj 2.22, 95% CI 1.03-4.77) when compared to the reference group of 1038 mg/day. An increased risk persisted after accounting for ever-use of ciclosporin, ever-use of tacrolimus, and when excluding mammalian target of rapamycin users. This increased risk was mainly carried by kidney transplant recipients immunosuppressed for five or more years (RRadj = 11.05 95% CI 2.50-48.81). In contrast, there was no significant association between BCC incidence and therapy with the highest compared with the lowest mycophenolate dosage (RRadj = 1.27 95% CI 0.56-2.87). CONCLUSION: Higher mycophenolate dosage is associated with increased SCCs in kidney transplant recipients, particularly those immunosuppressed for more than five years. The increased SCC risk persists after accounting for usage of other immunosuppressant medications.

Cutaneous manifestations of cytomegalovirus disease in renal transplant recipients: a case series.

Cytomegalovirus (CMV) is an important and well-described opportunistic virus in the immunocompromised host, with infection occurring mainly after the first month in the new renal transplant recipient. CMV can present as primary infection, reinfection, or reactivation of latent disease. It is capable of protean manifestations. Cutaneous manifestations are variable, rare, and diagnosis often delayed. We present 3 cases of cutaneous CMV disease in renal transplant recipients. Manifestations in our patients included ulceration of the tongue and perianal areas, facial petechiae, and nodular lesion involving the ear. This case series serves to highlight the importance of early skin biopsy in the diagnosis and management of cutaneous CMV disease.

Cardiovascular disease in patients with chronic kidney disease. A clinical review.

Cardiovascular disease (CVD) remains the most common cause of premature death in the chronic kidney disease (CKD) population. Individuals with CKD are at 10-20 times greater risk of cardiac death than controls without CKD, despite stratification for age, race, sex and diabetes. Heightened CVD mortality begins with mild kidney disease and rises further with more advanced kidney disease. Traditional risk factors account for up to 50% of cardiovascular disease in CKD, whilst renal specific markers, including anemia, disordered bone mineral metabolism and oxidative stress, also likely contribute to the total cardiovascular burden in CKD. Despite the increased mortality, there has been a dearth of interventional cardiovascular randomized controlled trials (RCTs) in the CKD population. Furthermore, many patients with kidney disease have been excluded from the majority of mainstream cardiovascular interventional trials. While recently published RCTs on traditional and non-traditional risk factors including dyslipidemia (PPP, 4D and ALERT, VA-HIT), cardiomyopathy (FOSIDIAL, telmisartan, carvedilol), anemia (US Normal Hematocrit, CHOIR and CREATE trials), hyperhomocystenemia (ASFAST, US folic acid trial, HOST), disordered bone mineral metabolism (Cunningham meta-analysis, DCOR), oxidative stress therapy (SPACE, HOPE and ATIC, N-acetylcysteine) and multidisciplinary multiple cardiovascular risk factor intervention clinics (LANDMARK) have added to the available pool of clinical data, level 1 clinical evidence remains significantly lacking. The negative findings in many of these trials highlight the potential dangers of extrapolating findings from non kidney disease patients to those with CKD. Further large, well-designed trials are urgently required to address this issue.

Does renal failure cause an atherosclerotic milieu in patients with end-stage renal disease?

PURPOSE: Atherosclerotic vascular disease is the main cause of morbidity and mortality in patients with end-stage renal disease, but the independent contribution of renal failure rather than associated risk factors is unclear. We sought to examine the relative contribution of these factors to the severity of atherosclerosis by measuring intima-medial thickness and brachial artery reactivity in uremic patients and controls. SUBJECTS AND METHODS: Cardiovascular risk factors, including lipid and homocysteine levels, were evaluated in 213 patients (69 on hemodialysis, 60 on peritoneal dialysis, and 82 nonuremic controls). High-resolution B-mode ultrasonography with automated off-line analysis was used to measure the intima-medial thickness in the common carotid artery and to measure the lumen diameter of the brachial artery at rest, during reactive hyperemia, and after sublingual nitroglycerine. The correlations of risk factors with intima-medial thickness and brachial reactivity were examined using a general linear regression model. RESULTS: Patients with renal failure had a greater mean (+/- SEM) maximum intima-medial thickness than controls (0.83 +/- 0.02 mm versus 0.70 +/- 0.02 mm, P < 0.05), but the brachial artery response to reactive hyperemia was not significantly different between the renal failure patients and the control group (4.7% +/- 6.1% versus 6.1% +/- 8.6% dilatation, P > 0.05). The uremic state was an independent predictor of intima-medial thickness (r2 = 0.16, P < 0.001) but not of brachial artery reactivity (P = 0.99). CONCLUSION: The atherosclerotic burden in patients with renal failure, as indicated by an increased intima-medial thickness, may reflect effects of uremia that are independent of cardiovascular risk factors.

Macrophage migration inhibitory factor expression in human renal allograft rejection.

BACKGROUND: Macrophage migration inhibitory factor (MIF) plays a pivotal role in immune-mediated diseases. Despite the long-standing association of MIF with the delayed-type hypersensitivity response, the potential role of MIF in allograft rejection is unknown. METHODS: MIF expression was assessed by in situ hybridization and immunohistochemistry staining in 62 biopsies of human renal allograft rejection and in normal human kidney. RESULTS: MIF mRNA and protein is constitutively expressed in normal kidney, being largely restricted to tubular epithelial cells, some glomerular epithelial cells, and vascular smooth muscle cells. In both acute and chronic renal allograft rejection, there was marked up-regulation of MIF mRNA and protein expression by intrinsic kidney cells such as tubular epithelial cells and vascular endothelial and smooth muscle cells. There was also MIF expression by infiltrating macrophages and T cells. Of note, macrophage and T cell infiltrates were largely restricted to areas with marked up-regulation of MIF expression, potentially contributing to the development of severe tubulitis and intimal or transmural arteritis. Quantitative analysis found that increased MIF expression in allograft rejection gave a highly significant correlation with macrophage and T cell accumulation in both the glomerulus and interstitium (P<0.001). In addition, the number of MIF+ tubules and interstitial MIF+ cells correlated significantly with the severity of allograft rejection (P<0.01), and the loss of renal function (P<0.01). In contrast, no up-regulation of renal MIF expression and no leukocyte accumulation was seen in allograft biopsies without evidence of rejection. CONCLUSIONS: This is the first study to demonstrate that local MIF expression is up-regulated during allograft rejection. The association between up-regulation of MIF expression, macrophage and T cell infiltration and the severity of renal allograft rejection suggests that MIF may be an important mediator in the process of allograft rejection.

Mechanisms of glomerular macrophage infiltration in lipid-induced renal injury.

BACKGROUND: A number of studies have demonstrated an important role for macrophages (M phi) in lipid-induced glomerular injury; however, little is known of the mechanisms that facilitate M phi infiltration in this disease. This study examined the expression of M phi chemotactic molecules M phi migration inhibitory factor (MIF) and leukocyte adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) during the induction of glomerular M phi infiltration in ExHC rats, a strain that is susceptible to lipid-induced glomerular injury. METHODS: Groups of five ExHC rats were fed a high-cholesterol diet (HCD) containing 3% cholesterol, 0.6% sodium cholate, and 15% olive oil and were killed after three days or one, two, or six weeks. Control animals were killed on day 0 or after six weeks on a normal diet. RESULTS: ExHC rats fed an HCD showed marked hypercholesterolemia in the absence of any increase in plasma triglyceride levels from day 3 and developed mild proteinuria and segmental glomerular lesions at week 6. Immunoperoxidase staining identified a significant increase in glomerular ED1+ M phi at week 1, which was further increased at week 6, when M phi-derived foam cells were seen in almost all glomeruli. Many of the infiltrating glomerular M phi expressed lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4), which are ligands for ICAM-1 and VCAM-1, respectively. Coincident with the induction of hypercholesterolemia on day 3 and prior to significant M phi infiltration, combined in situ hybridization and immunohistochemistry staining demonstrated a marked up-regulation of M-CSF and MIF mRNA expression by glomerular mesangial cells and podocytes. There was also a significant increase in ICAM-1 and VCAM-1 mRNA expression by intrinsic glomerular cells, including endothelial cells, on day 3 of the HCD. CONCLUSION: These results suggest that hypercholesterolemia can induce a classic proinflammatory response within the kidney glomerulus, involving production of well-described M phi chemotactic and adhesion molecules, which results in M phi recruitment and the development of glomerular injury.

Heroin overdose and myoglobinuric acute renal failure.

BACKGROUND: Heroin abuse is an increasing problem in Australia. In our hospitals we have noted an apparent increase in drug-related admissions. In this study we aimed to examine the incidence of renal failure due to heroin-related rhabdomyolysis and to determine any predisposing factors to the requirement for dialysis in these patients. PATIENTS AND METHODS: We identified a group of 27 patients who developed renal failure after recent intravenous heroin use. There was a significant rise in the incidence during 1997-1998 compared with the previous seven years (p < 0.05). RESULTS: Rhabdomyolysis was the likely cause of renal failure in all cases. Eight patients required dialysis for an average of 14 days (range 3-26). Patients who required dialysis had a higher admission creatine kinase (115 x 10(3) U/l (1-316), median (range), versus 9 x 10(3) (0-91 ), p < 0.05 ), a higher admission creatinine (3.8 mg/dl (2.1- 6.7) versus 2.4 (1.4-8.1), p < 0.05 ), a higher peak creatinine kinase (129 x 10(3) U/l (2-316) versus 22 x 10(3) (3-197), p < 0.05), a lower urine output in the initial 24 hours (0.91/24 hrs (0.1-1.5) versus 3.9(1.0-11.1), p < 0.005) and a longer length of hospitalization (37 days (17-112) versus 12 (5-87), p < 0.05). No patient died and all patients had independent renal function at last review. The majority of patients had significant comorbidities. The incidence of serological evidence of exposure to blood-borne viruses was HIV 5% (n = 1), hepatitis B 10% (n = 2) and hepatitis C 74% (n = 17) of patients tested. Pneumonia occurred in 52% (n = 14) and 26% (n = 7) developed respiratory failure requiring intubation. 22% (n = 6) developed a compartment syndrome requiring fasciotomy and 37% (n = 10) had significant residual limb weakness at discharge. CONCLUSION: There is an increase in patients admitted with rhabdomyolysis-induced renal failure associated with heroin use in our hospitals. We found a varied approach to an increasing clinical problem and suggest that a consistent investigative and therapeutic approach be introduced. Although renal recovery can be expected, long-term disability may occur due to potential serious complications.

Oral versus intravenous iron supplementation in peritoneal dialysis patients.

The vast majority of erythropoietin (EPO)-treated peritoneal dialysis (PD) patients require iron supplementation. Most authors and clinical practice guidelines recommend primary oral iron supplementation in PD patients because it is more practical and less expensive. However, numerous studies have clearly demonstrated that oral iron therapy is unable to maintain EPO-treated PD patients in positive iron balance. Once patients become iron-deficient, intravenous iron administration has been found to more effectively augment iron stores and hematologic response than does oral therapy. We recently performed a prospective, cross-over trial in 28 iron-replete PD patients and showed that twice-monthly outpatient iron polymaltose infusions (200 mg) were a practical and safe alternative to oral iron. That treatment produced significant increases in hemoglobin concentration and body iron stores. The additional expense of intravenous iron therapy was completely offset by reductions in EPO dosage. Careful monitoring of iron stores is important in patients receiving intravenous iron supplementation in view of epidemiologic links with infection and cardiovascular disease. Nevertheless, a growing body of evidence suggests that, as has been found for hemodialysis patients, intravenous iron therapy is superior to oral iron supplementation in EPO-treated PD patients.

Peritoneal homocysteine clearance is inefficient in peritoneal dialysis patients.

OBJECTIVES: To investigate the degree and the determinants of peritoneal homocysteine (Hcy) clearance and to compare measured Hcy clearance with the Hcy clearance predicted based on molecular weight (MW). DESIGN: Cross-sectional observational analysis. SETTING: Tertiary care institutional dialysis center. PATIENTS: Sixty-five stable peritoneal dialysis (PD) patients. OUTCOME MEASURES: Fasting blood and 24-hour pooled dialysate effluents were collected for determination of peritoneal clearances of Hcy (CpHcy), urea (CpUr), and creatinine (CpCr). The dialysate-to-plasma creatinine ratio at 4 hours (D/P Cr 4 h) and levels of red cell folate, B12, ferritin, and C-reactive protein (CRP) were measured concurrently. Observed CpHcy was compared with predicted clearance, based on Hcy plasma protein binding and the relative molecular weights of Hcy, urea, and creatinine. RESULTS: Plasma concentrations of Hcy averaged 24.6 +/- 1.1 micromol/L and were elevated above the upper limit of normal in 59 (91%) patients. The mean dialysate concentration of Hcy was 2.9 +/- 0.3 micromol/L, equating to a daily peritoneal elimination of 34.6 +/- 3.6 micromol. Observed CpHcy was closely approximated by predicted CpHcy (8.7 +/- 0.6 L/week/1.73 m2 vs 9.0 +/- 0.3 L/week/1.73 m2 respectively, p = 0.55). Patients maintained on automated PD (n = 5) had a CpHcy similar to that of patients treated with continuous ambulatory peritoneal dialysis (8.9 +/- 1.0 L/week/1.73 m2 vs 8.7 +/- 0.6 L/week/1.73 m2, p = 0.92). The CpHcy was significantly correlated with C-reactive protein (CRP), D/P creatinine, CpUr, CpCr, and peritoneal protein loss, but not with plasma Hcy, albumin, B12, ferritin, age, dialysis duration, peritonitis episodes, or daily dialysate effluent volume. By multivariate analysis, the only variables that remained significant independent predictors of CpHcy were CRP and D/P Cr 4 h. High and high-average transporters had a higher CpHcy than low and low-average transporters (9.7 +/- 0.8 L/week/1.73 m2 vs 7.0 +/- 0.7 L/week/1.73 m2, p < 0.05), despite comparably elevated plasma Hcy concentrations [25.2 +/- 1.5 micromol/L vs 23.4 +/- 1.6 micromol/L, p = nonsignificant (NS)]. CONCLUSIONS: Elevated plasma concentrations of Hcy are not efficiently reduced by PD. The relatively low peritoneal clearance of Hcy is largely accounted for by a high degree of plasma protein binding and is significantly influenced by peritoneal membrane permeability.

Donation after cardiac death in non-survivable burns.

Major burns have previously been considered a contraindication to solid organ donation. We present two cases of successful organ donation and transplantation, after Maastricht category III cardiac death in adult patients with non-survivable burns injury. The implications of the outcome of these cases are that major burns should not be considered a contraindication to organ donation, and that cardiac death provides opportunity for patients with non-survivable burns to contribute to the pool of potential organ donors.

Recent clinical trials of pharmacologic cardiovascular interventions in patients with chronic kidney disease.

End stage kidney disease (ESKD) is associated with a 10- to 20-fold increased risk of cardiovascular mortality compared with age- and sex-matched controls without CKD. In spite of this marked increase in risk, the vast majority of cardiovascular intervention clinical trials to date have specifically excluded subjects with CKD. The aim of this paper is to critically review the recently published clinical trial evidence that cardiac outcomes in CKD patients are modified by cardiovascular risk factor interventions, including erythropoiesis stimulating agent therapy (US Normal Hematocrit, CHOIR and CREATE trials), statins (PPP, 4D and ALERT), fibrates (VA-HIT), folic acid (ASFAST, US folic acid trial, HOST), anti-oxidative stress therapy (SPACE, HOPE and ATIC), N-acetylcysteine, sevelamer (D-COR), cinacalcet (Cunningham meta-analysis), carvedilol, angiotensin converting enzyme inhibitor (FOSIDIAL), telmisartan, aspirin (HOT study re-analysis) and multidisciplinary multiple cardiovascular risk factor intervention clinics (LANDMARK). Although none of these studies could be considered conclusive, the negative trials to date should raise significant concerns about the heavy reliance of current clinical practice guidelines on extrapolation of findings from cardiovascular intervention trials in the general population. It may be that cardiovascular disease in dialysis populations is less amenable to intervention, either because of the advanced stage of CKD or because the pathogenesis of cardiovascular disease in CKD patients is different to that in the general population. Further large, well-conducted, multi-centre randomised controlled trials in this area are urgently required.