Acute Kidney Injury: It's not just the 'big' burns.

BACKGROUND: Acute Kidney Injury (AKI) complicates the management of at least 25% of patients with severe burns and is associated with long term complications. Most research focuses on the patients with more severe burns, and whether the same factors are associated with the development of AKI in patients with burns between 10 and 19% total body surface area (TBSA) is unknown. The aims of this study were to examine the incidence of, and factors associated with, the development of AKI in patients with %TBSA≥10, as well as the relationship with hospital metrics such as length of stay (LOS). METHODS: Retrospective medical record review of consecutive burns patients admitted to The Alfred Hospital, the major adult burns centre in Victoria, Australia. Demographic and injury details were recorded. Factors associated with AKI were determined using multiple logistic regression. RESULTS: Between 2010 and June 2014, 300 patients were admitted with burn injury and data on 267 patients was available for analysis. Median age was 54.5 years with 78% being male. Median %TBSA was 15 (IQR 12, 20). The AKI incidence, as measured by the RIFLE criteria, was 22.5%, including 15% (27/184) in patients with %TBSA 10-19. Factors associated with AKI included increasing age and %TBSA (OR 1.05 p<0.001) as well as increased surgeries (p<0.041) and a cardiac comorbidity (p<0.01). All patients with renal comorbidity developed AKI. In the %TBSA 10-19 cohort, only increasing age (OR 1.05 p<0.001) was associated with AKI. After accounting for confounding factors, the probability of discharge from hospital in Non-AKI group was greater than for the AKI patients at all time points (P<0.001). CONCLUSION: This is the first study to show an association between patients with %TBSA 10-19 and AKI. Given the association between AKI and complications, prospective research is needed to further understand AKI in burns with the aim of risk reduction.

ABO incompatible renal transplantation following lung transplantation.

We present management strategies utilised for the first case of an urgent live-donor ABO incompatible B blood group renal transplant, in a patient with a prior A blood group lung transplant for cystic fibrosis. Three years on, renal function is excellent and stable, whilst lung function has improved.

ABO incompatible renal transplantation without antibody removal using conventional immunosuppression alone.

ABO incompatible living donor renal transplantation (ABOi) can achieve outcomes comparable to ABO compatible transplantation (ABOc). However, with the exception of blood group A2 kidneys transplanted into recipients with low titer anti-A antibody, regimens generally include antibody removal, intensified immunosuppression and splenectomy or rituximab. We now report a series of 20 successful renal transplants across a range of blood group incompatibilities using conventional immunosuppression alone in recipients with low baseline anti-blood group antibody (ABGAb) titers. Incompatibilities were A1 to O (3), A1 to B (2), A2 to O (2), AB to A (2), AB to B (1), B to A1 (9), B to O (1); titers 1:1 to 1:16 by Ortho. At 36 months, patient and graft survival are 100%. Antibody-mediated rejection (AbMR) occurred in one patient with thrombophilia and low level donor-specific anti-HLA antibody. Four patients experienced cellular rejection (two subclinical), which responded to oral prednisolone. This series demonstrates that selected patients with low titer ABGAb can undergo ABOi with standard immunosuppression alone, suggesting baseline titer as a reliable predictor of AbMR. This reduces morbidity and cost of ABOi for patients with low titer ABGAb and increases the possibility of ABOi from deceased donors.

Successful ABO-incompatible kidney transplantation with antibody removal and standard immunosuppression.

ABO-incompatible (ABOi) kidney transplantation is an established therapy, though its implementation to date has been in part limited by the requirement for additional immunosuppression. Here, we describe the outcomes of 37 patients undergoing ABOi kidney transplantation utilizing perioperative antibody depletion and receiving an identical tacrolimus-based immunosuppressive regimen to contemporaneous ABO-compatible (ABOc) recipients, with the exception that mycophenolate was commenced earlier (7-14 days pretransplant). Antibody depletion was scheduled according to baseline anti-ABO antibody titer (tube IAT method: median 1:128, range 1:8 to 1:4096). Patient and graft survival for the 37 ABOi recipients was 100% after a median 26 months (interquartile range [IQR] 18-32). Eight rejection episodes (two antibody-mediated and six cellular) in ABOi recipients were successfully treated with biopsy-proven resolution. Latest median eGFR is 50 mL/min × 1.73 m² (IQR 40-64) for ABOi patients and 54 mL/min × 1.73 m² (IQR 44-66) in the ABOc patients (p = 0.25). We conclude that ABOi transplantation can be performed successfully with perioperative antibody removal and conventional immunosuppression. This suggests that access to ABOi transplantation can include a broader range of end-stage kidney disease patients.

Skin cancer surveillance in renal transplant recipients: re-evaluation of U.K. practice and comparison with Australian experience.

BACKGROUND: Nonmelanoma skin cancer (NMSC) is the most common tumour following solid organ transplantation. In 2000 a survey of U.K. centres managing renal transplant recipients (RTRs) showed that only 21% offered skin cancer surveillance. OBJECTIVES: The survey was repeated in 2006 in the U.K. and Australia. The aims were to determine if U.K. practice had changed since 2000, to define skin cancer surveillance practice in Australian RTRs and to compare this with that in the U.K. METHODS: Questionnaires were sent to 84 U.K. and 45 Australian centres providing long-term RTR follow-up. RESULTS: Fifty-six (67%) U.K. centres caring for 82% (n = 16 349) of the RTR population replied. Sixty-six per cent provided annual skin cancer surveillance and 39% offered full skin examination (FSE) compared with 21% and 20% in 2000. Eighty-one per cent of surveillance was performed by nondermatologists (n = 30), nine (30%) of whom had received formal training for the role. Thirty-one (69%) Australian centres covering 86% (n = 5392) of the RTR population responded. Ninety-seven per cent provided skin cancer surveillance, and 61% offered FSE. Forty per cent (n = 12) of skin cancer surveillance was conducted by nondermatologists. Two nondermatologists had received formal training. CONCLUSIONS: Despite a substantial improvement in the provision of skin cancer surveillance for RTRs in the U.K. between 2000 and 2006, only 39% of units offer FSE. In contrast, virtually all Australian centres offer annual skin cancer surveillance, with more dermatology involvement. Lack of training for nondermatologists involved in skin cancer surveillance is evident in both countries. The availability of dermatologists and the variation in NMSC risk between the populations may explain the different practices observed.

A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients.

In a randomized, open-label, multicenter study, de novo renal transplant patients received no steroids (n = 112), steroids to day 7 (n = 115), or standard steroids (n = 109) with cyclosporine microemulsion (CsA-ME), enteric-coated mycophenolate sodium (EC-MPS) and basiliximab. The primary objective, to demonstrate noninferiority of 12-month GFR in the steroid-free or steroid-withdrawal groups versus standard steroids, was not met in the intent-to-treat population. However, investigational groups were not inferior to standard steroids in the observed-case analysis. Median 12-month GFR was not significantly different in the steroid-free or steroid-withdrawal groups (58.6 mL/min/1.73 m(2) and 59.1 mL/min/1.73 m(2)) versus standard steroids (60.8 mL/min/1.73 m(2)). The 12-month incidence of biopsy-proven acute rejection (BPAR), graft loss or death was 36.0% in the steroid-free group (p = 0.007 vs. standard steroids), 29.6% with steroid withdrawal (N.S.) and 19.3% with standard steroids. BPAR was significantly less frequent with standard steroids than either of the other two regimens. Reduced de novo use of antidiabetic and lipid-lowering medication, triglycerides and weight gain were observed in one or both steroid-minimization group versus standard steroids. For standard-risk renal transplant patients receiving CsA-ME, EC-MPS and basiliximab, steroid withdrawal by the end of week 1 achieves similar 1-year renal function to a standard-steroids regimen, and may be more desirable than complete steroid avoidance.

Factors influencing growth and final height after renal transplantation.

Growth retardation occurs commonly in children and adolescents with chronic renal insufficiency. While some children exhibit catch-up growth following renal transplantation, for many children growth remains sub-optimal. The aim of the current study was to review the factors influencing growth and final height following renal transplantation. Data from all children who had a renal transplant performed between 1985 and 1998 at the Royal Melbourne and Royal Children's Hospitals, Melbourne (n = 85), were examined retrospectively. Two children who died in the first year post-transplant and one patient lost to follow-up within 6 months of their transplant were excluded. Children with multiple grafts had only growth following their most recent graft analyzed. The mean height standard deviation score (Ht-SDS) at the time of transplantation was -2.11 (range: -5.05 to 0.27), improving to -1.50 (range: -3.67 to 1.27) at 7 yr post-transplant. On univariate analysis, the dose of cyclosporin at 6 months and at 1 and 3 yr, and the graft function at 1 yr, had a significant positive correlation with the change in Ht-SDS (DeltaHt-SDS) at each of those time-points post-transplant. At all time-points there was a strong correlation between pretransplant height and subsequent growth. A sub-group of children who were 16 yr of age or older at December 1999, and who were considered to have reached their final height, were examined to determine predictors of final height. Multiple regression analysis of clinical and laboratory parameters from the sub-group of patients > or = 16 yr of age showed that height at the time of transplant, age at the time of transplant, and final glomerular filtration rate, were significant independent predictors of growth (r2 = 0.82, p = 0.01). In addition, the immunosuppressive regimen at 1, 3, and 5 yr post-transplant had a significant effect on growth. This study confirms the importance of each of these factors for post-transplant growth.

Molecular basis of mechanosensory transduction.

Mechanotransduction - a cell's conversion of a mechanical stimulus into an electrical signal - reveals vital features of an organism's environment. From hair cells and skin mechanoreceptors in vertebrates, to bristle receptors in flies and touch receptors in worms, mechanically sensitive cells are essential in the life of an organism. The scarcity of these cells and the uniqueness of their transduction mechanisms have conspired to slow molecular characterization of the ensembles that carry out mechanotransduction. But recent progress in both invertebrates and vertebrates is beginning to reveal the identities of proteins essential for transduction.

Critically timed auxiliary shock to weak field area lowers defibrillation threshold.

INTRODUCTION: This study tested the hypothesis that the defibrillation threshold (DFT) can be lowered by delivering a weak auxiliary shock in conjunction with a stronger primary shock to the cardiac region where the primary shock electric field is weakest. METHODS AND RESULTS: Eight swine were studied in each of two study parts. In both parts, DFTs were determined for dual shocks delivered through two electrode pairs. The biphasic primary shock was delivered through electrodes in the right ventricle and superior vena cava. The auxiliary shock was delivered through a separate electrode in the superior vena cava and a left ventricular electrode placed where the primary shock field was presumed to be weakest. In part I, a monophasic auxiliary shock of 50, 100, or 150 V was delivered either simultaneously with or 1, 20, or 40 msec before primary shock. When auxiliary shock was delivered simultaneously with or 1 msec before primary shock, DFT energy was reduced by approximately 50% compared with primary shock alone. In part II, a 150-V monophasic or biphasic auxiliary shock of either polarity was delivered 1 msec before or after primary shock. Regardless of waveform or polarity, all auxiliary shock delivered before primary shock lowered DFT energy by approximately 30% compared with primary shock alone. Depending on waveform and polarity, auxiliary shock delivered after primary shock either did not significantly change the DFT or elevated the DFT compared with primary shock alone. CONCLUSION: Application of a small auxiliary shock, just before or simultaneously with a primary shock, to the cardiac region where the primary shock field is weakest significantly lowers DFT.

The carriage of pro-inflammatory cytokine gene polymorphisms in recurrent pregnancy loss.

PROBLEM: Recurrent pregnancy loss (RPL) affects 2-4% of couples, and remains largely unexplained. Recent studies have examined the role of cytokines in the maintenance of normal pregnancy, which is linked with an increased expression of Th2 cytokines. Overexpression of Th1 cytokines is associated with RPL. Knowing that functional polymorphisms exist for certain cytokines, it has therefore been suggested that women with RPL may have a genetic predisposition to overexpress Th1 cytokines. METHOD OF STUDY: The genes for interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) carry functional gene polymorphisms. In both cases these are biallelic polymorphisms that can be detected by polymerase chain reaction followed by restriction fragment length polymorphism. The aim of this pilot study was to assess whether carriage of the rarer alleles (TNF*2 and IL-1B*2) could act as independent risk factors in recurrent miscarriage. RESULTS: We found an increased incidence in the carriage of TNF*2, more pronounced in those women with two or more miscarriages. Carriage of the IL-1B*2 either alone or in association with TNF*2 was not associated with recurrent miscarriage. CONCLUSION: There may be a role for these cytokine gene polymorphisms in RPL.

Evaluation and long-term outcome of pediatric renovascular hypertension.

Seventeen children with renovascular hypertension were managed at the Royal Children's Hospital, Melbourne, over the 20-year period from 1975 to 1996. The age at presentation ranged from 10 days to 18 years. All children presented with severe hypertension with mean systolic blood pressure 7 standard deviations above age-matched averages and mean diastolic blood pressure 5.5 standard deviations above age-matched averages. Neurofibromatosis was the most common etiology (58% of patients) and there were no cases of Takayasu's arteritis. Patients underwent a variety of biochemical and imaging investigations but in all cases renal angiography was necessary for definitive diagnosis and for planning therapy. Ten of the 17 patients had surgical procedures performed. Percutaneous transluminal angioplasty was performed in four patients but led to cure in only one patient following thrombosis of the affected artery producing segmental renal infarction. Other vascular reconstructive procedures, including the use of autologous or synthetic bypass grafts and autotransplantation, produced cure of hypertension in 50% of children with improvement in a further 30%. The long-term outlook for children treated with surgical reconstructive procedures was excellent. One patient underwent surgery for avulsion of an arterial graft following a pubertal growth spurt. No other patient originally cured by surgery has required reoperation with no cases of restenosis at a mean follow-up of 11 years 3 months.

Marked reduction of ventricular defibrillation threshold by application of an auxiliary shock to a catheter electrode in the left posterior coronary vein of dogs.

INTRODUCTION: For endocardial shocks near the defibrillation threshold (DFT), postshock activity originates from the lateral left ventricular apex, where the shock field is weak. This study tested the hypothesis that an auxiliary shock (AS) delivered between an electrode at this site and a superior vena cava (SVC) electrode before the primary endocardial shock (PS) would reduce the DFT. METHODS AND RESULTS: In six pentobarbital-anesthetized dogs (26 to 36 kg), catheter electrodes were placed in the right ventricular (RV) apex and the SVC. To simulate transvenous introduction, a small electrode was inserted into the posterior cardiac vein using an epicardial approach. For dual shock treatments, AS (2-msec monophasic) was applied to the coronary vein electrode at different time intervals before a biphasic PS (4 msec/3 msec) to the RV-SVC electrodes. The mean DFT energy for dual shocks treatments were significantly reduced (P < 0.05) in comparison to the control treatment (no AS, 26.5+/-8.8 J). Mean DFT energy after 10 seconds of electrically induced ventricular fibrillation for dual shocks, in which AS and PS were separated by 1, 5, 10, and 20 msec, were 10.2+/-4.1 J, 10.9+/-5.5 J, 11.3+/-6.3 J, and 15.4+/-7.2 J, respectively. These values were all significantly lower than the PS alone (26.5+/-8.8 J). CONCLUSION: Addition of an AS from the posterior cardiac vein before an endocardial PS reduces DFT energy by more than 50%. Such DFT reduction could improve therapeutic safety margin or permit reduction in volume of implantable cardioverter defibrillators.

A Drosophila mechanosensory transduction channel.

Mechanosensory transduction underlies a wide range of senses, including proprioception, touch, balance, and hearing. The pivotal element of these senses is a mechanically gated ion channel that transduces sound, pressure, or movement into changes in excitability of specialized sensory cells. Despite the prevalence of mechanosensory systems, little is known about the molecular nature of the transduction channels. To identify such a channel, we analyzed Drosophila melanogaster mechanoreceptive mutants for defects in mechanosensory physiology. Loss-of-function mutations in the no mechanoreceptor potential C (nompC) gene virtually abolished mechanosensory signaling. nompC encodes a new ion channel that is essential for mechanosensory transduction. As expected for a transduction channel, D. melanogaster NOMPC and a Caenorhabditis elegans homolog were selectively expressed in mechanosensory organs.

Influence of anti-rejection therapy on the timing of cytomegalovirus disease and other infections in renal transplant recipients.

Infections are an important cause of mortality and morbidity in renal transplant recipients. To study the impact of anti-rejection therapy on the timing of infections, the records of 599 consecutive renal transplants, performed prior to 31 December 1996 at the Royal Melbourne Hospital, were reviewed. Patients were grouped according to acute rejection (AR) episode and treatment during the first 6 months after transplantation. Group 1 [n = 168 (35%)] patients did not experience any episode of AR. Group 2 [n = 169 (35%)] patients had one or more episodes of AR and received high doses of steroids. Group 3 [n = 141 (30%)] patients had more than one episode of AR and received anti-lymphocyte antibodies in addition to high doses of steroids. Infections were more common in Groups 2 and 3 but only cytomegalovirus (CMV) disease occurred earlier in patients treated with lympholytics. Given the high incidence and early onset of CMV disease in patients receiving lympholytics and considering that an effective prophylactic protocol remains undetermined, pre-emptive treatment with ganciclovir in this high risk group appears justified.

Fibrillation is more complex in the left ventricle than in the right ventricle.

INTRODUCTION: The mechanisms that maintain ventricular fibrillation (VF) are not completely understood. It has been proposed that increased ventricular wall thickness destabilizes VF wavefronts and therefore is an important determinant of VF activation patterns. We hypothesized that if this is the case, then VF patterns on the thin-walled right ventricle (RV) should be simpler than those on the thick-walled left ventricle (LV). METHODS AND RESULTS: In seven open chest pigs, we mapped VF simultaneously from two epicardial recording arrays, one on the RV and one on the LV. Each array contained 504 unipolar electrodes (in a 21 x 24 grid) spaced by 2 mm. We used specialized pattern analysis methods to compute quantitative descriptors of RV and LV activation patterns. Our data show that VF is more organized in the RV than the LV, containing fewer, larger wavefronts that follow fewer distinct pathways and are less likely to fragment or collide with other wavefronts. The incidence, size, and cycle length of reentrant circuits were similar in the two ventricles, but RV reentry persisted for more cycles. These results are not predicted by the differences in electrophysiologic properties between LV and RV that have been reported in mammalian hearts. CONCLUSION: The geometry of the ventricular wall, particularly wall thickness, is an important determinant of VF activation patterns.

A notch-independent activity of suppressor of hairless is required for normal mechanoreceptor physiology.

Suppressor of Hairless [Su(H)]/Lag-1/RBP-Jkappa/CBF1 is the only known transducing transcription factor for Notch receptor signaling. Here, we show that Su(H) has three distinct functions in the development of external mechanosensory organs in Drosophila: Notch-dependent transcriptional activation and a novel auto-repression function, both of which direct cell fate decisions, and a novel auto-activation function required for normal socket cell differentiation. This third phase of activity, the first known Notch-independent activation function for Su(H) in development, depends on a cell type-specific autoregulatory enhancer that is active throughout adult life and is required for proper mechanoreception. These results establish a direct link between a broadly deployed cell signaling pathway and an essential physiological function of the nervous system.

Impact of acute rejection therapy on infections and malignancies in renal transplant recipients.

BACKGROUND: Infections and malignancies are important causes of mortality and morbidity in renal allograft recipients. Their risk increases with increasing immunosuppression. METHODS: In an attempt to quantitate the increase in the risk of these complications in association with antirejection therapy, we reviewed the records of all renal allograft recipients of our center transplanted during the cyclosporin era. We sub-divided the patients into three groups based on acute rejection episodes during the first 6 months posttransplant, and the treatment for acute rejection: those who did not develop AR--group 1 (n=168); those who had one or more episodes of acute rejection and were treated with high dose corticosteroids --group 2 (n=169); those who in addition to corticosteroids required cytolytics (OKT3) and/or other drugs--group 3 (n=141). RESULTS: 52% patients in group 1, 71% patients in group 2 and 86% patients in group 3 had one or more episodes of infection during the first 6 months posttransplantation. Relative risk for group 2 and 3 were 1.56 (P=0.0002) and 2.98 (P<0.00001), respectively. Infection/patient rates at 6 months were 0.67, 1.23, and 2.79 in groups 1, 2, and 3 respectively. Groups 1 and 2 had a similar number of cases with squamous and basal cell carcinoma, however, there were few cases with these malignancies in group 3. No case of lymphoma was seen in group 1; there were four cases in group 2 and nine in group 3. There was no significant difference in patient survival in group 1 and 2, however, patients in group 3 had a reduced patient survival (1 vs. 3 P<0.001, 2 vs. 3 P=0.067). Graft survival was best in group 1 and worst in group 3 (1 vs. 2 P<0.05; 1 vs. 3 P<0.00001; 2 vs. 3 P<0.01). CONCLUSIONS: In renal transplant recipients the risk of infections and lymphoma increases with increasing immunosuppression and hence mortality and morbidity associated with it. When adding a potent immunosuppressive agent to rescue a kidney one needs to consider the serious and at times fatal side effects given the modest beneficial effect on long-term outcome.