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Deregulated expression of circular RNAs (circRNAs) is associated with various human diseases, including many types of cancer. Despite their growing links to cancer, there has been limited characterization of circRNAs in metastatic castration-resistant prostate cancer, the major cause of prostate cancer mortality. Here, through the analysis of an exome-capture RNA-seq dataset from 47 metastatic castration-resistant prostate cancer samples and ribodepletion and RNase R RNA-sequencing of patient-derived xenografts (PDXs) and cell models, we identified 13 circRNAs generated from the key prostate cancer driver gene-androgen receptor (AR). We validated and characterized the top four most abundant, clinically relevant AR circRNAs. Expression of these AR circRNAs was upregulated during castration-resistant progression of PDXs. The upregulation was not due to global increase of circRNA formation in these tumors. Instead, the levels of AR circRNAs correlated strongly with that of the linear AR transcripts (both AR and AR-variants) in clinical samples and PDXs, indicating a transcriptional mechanism of regulation. In cultured cells, androgen suppressed the expression of these AR circRNAs and the linear AR transcripts, and the suppression was attenuated by an antiandrogen. Using nuclear/cytoplasmic fractionation and RNA in-situ hybridization assays, we demonstrated predominant cytoplasmic localization of these AR circRNAs, indicating likely cytoplasmic functions. Overall, this is the first comprehensive characterization of circRNAs arising from the AR gene. With greater resistance to exoribonuclease compared to the linear AR transcripts and detectability of AR circRNAs in patient plasma, these AR circRNAs may serve as surrogate circulating markers for AR/AR-variant expression and castration-resistant prostate cancer progression. more...

Immunosuppression is a known risk for post-transplant infections. Little data exist on the risk contributions of specific agents for various infections.A triply robust propensity score-adjusted analysis was performed in a renal transplant cohort between February 2006 and January 2014. The study was performed to identify the incidence and the risk factors for developing a post-transplant infection. After initial bivariate analysis, a triply robust propensity score-adjusted multivariate logistic regression was performed.The mean age of the 717 renal transplant recipients was 50.0 ± 13.3 years, with the majority being male (61.6%) and 349 (48.7%) experiencing at least 1 post-transplant infection. Neither race, graft type, nor insurance status was associated with an increased incidence or risk of infection. In a fully adjusted regression model, the immunosuppressants mycophenolic acid mofetil (OR 0.38, 95% CI 0.21-0.71; P.001) and alemtuzumab (OR 0.40, 95% CI 0.19-0.85; P = .020) were protective.Alemtuzumab and mycophenolic acid mofetil as immunosuppressant agents in a multiagent protocol appear to decrease the incidence of infection. Cytomegalovirus antigenemia was the greatest risk for infection and mycophenolic acid mofetil possessed the greatest protective effect on viral infections. more...

Donor-specific antibodies have become an established biomarker predicting antibody-mediated rejection. Antibody-mediated rejection is the leading cause of graft loss after kidney transplant. There are several phenotypes of antibody-mediated rejection along post-transplant course that are determined by the timing and extent of humoral response and the various characteristics of donor-specific antibodies, such as antigen classes, specificity, antibody strength, IgG subclasses, and complement binding capacity. Preformed donor-specific antibodies in sensitized patients can trigger hyperacute rejection, accelerated acute rejection, and early acute antibody-mediated rejection. De novo donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy. The pathogeneses of antibody-mediated rejection include not only complement-dependent cytotoxicity, but also complement-independent pathways of antibody-mediated cellular cytotoxicity and direct endothelial activation and proliferation. The novel assay for complement binding capacity has improved our ability to predict antibody-mediated rejection phenotypes. C1q binding donor-specific antibodies are closely associated with acute antibody-mediated rejection, more severe graft injuries, and early graft failure, whereas C1q nonbinding donor-specific antibodies correlate with subclinical or chronic antibody-mediated rejection and late graft loss. IgG subclasses have various abilities to activate complement and recruit effector cells through the Fc receptor. Complement binding IgG3 donor-specific antibodies are frequently associated with acute antibody-mediated rejection and severe graft injury, whereas noncomplement binding IgG4 donor-specific antibodies are more correlated with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy. Our in-depth knowledge of complex characteristics of donor-specific antibodies can stratify the patient’s immunologic risk, can predict distinct phenotypes of antibody-mediated rejection, and hopefully, will guide our clinical practice to improve the transplant outcomes. more...

PURPOSE OF REVIEW: Parental brain research primarily employs general-linear-model-based (GLM-based) analyses to assess blood-oxygenation-level-dependent responses to infant auditory and visual cues, reporting common responses in shared cortical and subcortical structures. However, this approach does not reveal intermixed neural substrates related to different sensory modalities. We consider this notion in studying the parental brain. RECENT FINDINGS: Spatial independent component analysis (sICA) has been used to separate mixed source signals from overlapping functional networks. We explore relative differences between GLM-based analysis and sICA as applied to an fMRI dataset acquired from women while they listened to infant cries or viewed infant sad faces. SUMMARY: There is growing appreciation for the value of moving beyond GLM-based analyses to consider brain functional organization as continuous, distributive, and overlapping gradients of neural substrates related to different sensory modalities. Preliminary findings suggest sICA can be applied to the study of the parental brain. more...

Functional magnetic resonance imaging (fMRI) studies regularly use univariate general-linear-model-based analyses (GLM). Their findings are often inconsistent across different studies, perhaps because of several fundamental brain properties including functional heterogeneity, balanced excitation and inhibition (E/I), and sparseness of neuronal activities. These properties stipulate heterogeneous neuronal activities in the same voxels and likely limit the sensitivity and specificity of GLM. This paper selectively reviews findings of histological and electrophysiological studies and fMRI spatial independent component analysis (sICA) and reports new findings by applying sICA to two existing datasets. The extant and new findings consistently demonstrate several novel features of brain functional organization not revealed by GLM. They include overlap of large-scale functional networks (FNs) and their concurrent opposite modulations, and no significant modulations in activity of most FNs across the whole brain during any task conditions. These novel features of brain functional organization are highly consistent with the brain's properties of functional heterogeneity, balanced E/I, and sparseness of neuronal activity, and may help reconcile inconsistent GLM findings. more...

In order to help improving mental attention and sensory integration ability of mental retarded children, this paper proposes an interactive eyes-brain-hands coordination training system. This system realizes the principle of seeing, thinking and moving of hands by an interactive operation between the computer software custom icons and a touch control panel, so it can improve cognitive function and activity of daily living. The results show this training platform has a high degree of application and acceptance, and provides a portable training method for mental retarded children. more...

Background The Affordable Care Act initiated innumerable cost-containment measures, including promoting generic conversion from brand medications and directing the Food and Drug Administration to decrease requirements for generic approvals. Despite this mandate, few data existed on generic conversion of immunosuppressant medications with narrow therapeutic troughs. Methods A retrospective analysis of our initial experience with generic tacrolimus (n = 39) was performed using a control cohort from our renal transplant database. A rejection and cost analysis was performed using a consecutive 2-year prior cohort (n = 159) as a control to determine the effect of generic conversion on tacrolimus a narrow therapeutic index immunosuppressant medication. Results During the first year after transplantation, the generic group had a greater drug variability (20% ± change in trough levels) that required more dosage adjustments (5.42 vs 3.59 drug dosage changes; P = .038) to obtain a stable dose, required increased number of intravenous magnesium infusions (4.95 vs 1.68 infusions; P = .001), and incurred a greater incidence of rejection (23.1% vs 10.2%; P = .024). A yearly institutional cost was evaluated against a negotiated $18,000/yearly central pharmacy cost savings compared with a $652,862 institutional cost to treat unanticipated rejections. Conclusion Programmatic conversion from brand to generic tacrolimus resulted in increased drug variability, a greater incidence of magnesium wasting, and more episodes of rejection, leading to increases in institutional costs of care. This government-driven attempt at cost containment may be applicable to noncritical medications such as antibiotics and antihypertensives, but this policy should be reconsidered for narrow therapeutic index medications, such as tacrolimus and other immunosuppressant medications. more...

Background The purpose of this study was to determine the incidence and management strategies for post-transplant leukopenia/neutropenia in kidney recipients receiving alemtuzumab induction during the first year following transplantation. Methods We prospectively identified 233 adult patients who underwent kidney transplantation with alemtuzumab induction at a single institution. The incidence and severity of leukopenia (white blood cell count [WBC] ≤2500/mm3) and neutropenia (absolute neutrophil count [ANC] ≤500/mm3) were evaluated at 1, 3, 6, and 12 months post-transplantation. We determined any association with cytomegalovirus (CMV) infection, graft rejection, and infections requiring hospitalization. We also reviewed interventions performed, including medication adjustments, treatment with granulocyte stimulating factor, and hospitalization. Results The combined incidence of either leukopenia or neutropenia was 47.5% (n = 114/233) with an average WBC nadir of 1700 ± 50/mm3 at 131.0 ± 8.5 days and an average ANC nadir of 1500 ± 100/mm3 at 130.4 ± 9.6 days. No significant difference in graft rejection, CMV infection, or infections requiring hospitalization was found in the leukopenia/neutropenia group vs the normal WBC group (P = .3). The most common intervention performed for leukopenia/neutropenia group was prophylactic medication adjustment. Six patients (5.2%) required a change in >1 medication. The majority of these patients also required granulocyte stimulating factor (61.5%; 32/52), with an average of 2.5 doses given. A total of 25 patients (21.9%) required hospitalization due to leukopenia/neutropenia with an average length of stay of 6 days. Conclusions Kidney transplant patients receiving alemtuzumab induction required significant interventions due to leukopenia/neutropenia in the first year post-transplantation. These results suggest the need for additional studies aimed at defining the optimum management strategies of leukopenia/neutropenia in this population. more...

Allograft dysfunction is a common problem after kidney transplant. Allograft rejection is an important entity, and timely diagnosis and appropriate treatment are essential for caring transplant recipients. Hyperacute rejection is mediated by the preformed donor specific antibody, while accelerated acute rejection represents an anamnestic response by memory B and T cells. They occur early after transplant. Acute cellular rejection is relatively common and usually responds to pulse corticosteroids or antithymocyte globulin (ATG). The complexity of antibody-mediated rejection (AMR) as well as its detrimental effect has been increasingly recognized. The treatment of acute AMR requires a combination of several modalities, such as plasmapheresis or immunoadsorption, IVIG, corticosteroids, rituximab and ATG. After treatment of rejection episode, the maintenance immunosuppressive drugs should be adjusted to prevent further acute rejection and/or evolution into chronic active rejection. Chronic rejection is not reversible and it has been recognized as the most important cause of chronic graft dysfunction and failure. more...

The maximum oxygen uptake (V̇O2 max), determined from graded maximal or submaximal exercise tests, is used to classify the cardiorespiratory fitness level of individuals. The purpose of this study was to examine the validity and reliability of the YMCA submaximal exercise test protocol performed on a newly-designed rectilinear stepping ergometer (RSE) that used up and down reciprocating vertical motion in place of conventional circular motion and giving precise measurement of workload, to determine V̇O2 max in young healthy male adults. Thirty-two young healthy male adults (32 males; age range: 20-35 years; height: 1.75 ± 0.05 m; weight: 67.5 ± 8.6 kg) firstly participated in a maximal-effort graded exercise test using a cycle ergometer (CE) to directly obtain measured V̇O2 max. Subjects then completed the progressive multistage test on the RSE beginning at 50W and including additional stages of 70, 90, 110, 130, and 150W, and the RSE YMCA submaximal test consisting of a workload increase every 3 minutes until the termination criterion was reached. A metabolic equation was derived from the RSE multistage exercise test to predict oxygen consumption (V̇O2) from power output (W) during the submaximal exercise test (V̇O2 (mL·min-1 )=12.4 ×W(watts)+3.5 mL·kg-1·min-1×M+160mL·min-1, R2= 0.91, standard error of the estimate (SEE) = 134.8mL·min-1). A high correlation was observed between the RSE YMCA estimated V̇O2 max and the CE measured V̇O2 max (r=0.87). The mean difference between estimated and measured V̇O2 max was 2.5 mL·kg-1·min-1, with an SEE of 3.55 mL·kg-1·min-1. The data suggest that the RSE YMCA submaximal exercise test is valid for predicting V̇O2 max in young healthy male adults. The findings show that the rectilinear stepping exercise is an effective submaximal exercise for predicting V̇O2 max. The newly-designed RSE may be potentially further developed as an alternative ergometer for assessing cardiorespiratory fitness and the promotion of personalized health interventions for health care professionals. more...

Immunosuppressive therapy is a key component for successful kidney transplantation. It is commonly believed that more intensive immunosuppression is needed initially to prevent rejection episodes and less immunosuppression is subsequently maintained to minimize the overall risk of infection and malignancy. The selection of drugs should be guided by a comprehensive assessment of the immunologic risk, patient comorbidities, financial cost, drug efficacy and adverse effects. Lymphocyte-depleting antibody induction is recommended for patients with high immunologic risk, while IL-2R antibody can be used for low or moderate risk patients. Patients with very low risk may be induced with intravenous steroids without using an antibody. A maintenance regimen typically consists of a low-dose of steroid combined with two of the four class drugs: calcineurin inhibitor (tacrolimus or cyclosporine), antimetabolite (mycophenolate mofetil or enteric coated mycophenolate sodium), mTOR inhibitor (sirolimus or everolimus) and costimulation blocker (belatacept). Currently in the USA, the most popular maintenance is the combination of corticosteroid, mycophenolic acid and tacrolimus. Steroid minimization, or calcineurin inhibitor free or withdrawal should be limited to the highly selected patients with low immunological risk. Recently, the novel biological agent belatacept-based maintenance has demonstrated a significantly better renal function and improved cardiovascular and metabolic profile, which may provide hope for an ultimate survival benefit. more...

Background Kidney transplantation (KTx) alone in patients with cirrhosis and renal failure (end-stage renal disease [ESRD]) infected with hepatitis C virus (HCV) is controversial. The aim of this study was to compare outcomes of HCV+ patients with ESRD and cirrhosis (C group) versus HCV+ patients with ESRD but with no cirrhosis (NC group) listed for KTx. Methods Ninety HCV+ patients with ESRD were evaluated for KTx between 2003 and 2010. Listed patients underwent transjugular liver biopsy with hepatic portal venous gradient (HPVG) measurements. Only patients with HPVG less than 10 mm Hg were considered for KTx alone. We analyzed patient demographics, waitlist/liver disease characteristics, and posttransplant outcomes between groups. Results Sixty-four patients listed for KTx alone were studied. Twelve patients (18.75%) showed biopsy-proven cirrhosis. Thirty-seven patients underwent KTx alone (9 from C and 28 from NC). No patients developed decompensation of their liver disease, although one patient for NC group developed metastatic hepatocellular carcinoma 16 months after transplantation. One- and three-year graft survival rates were 75% and 75% versus 92.1% and 75.1% for groups C and NC, respectively (P=0.72). One- and three-year patient survival rates were 88.9% and 88.9% versus 96.3% and 77.9% for groups C and NC, respectively (P=0.76). Only increasing recipient age and decreasing albumin levels were significantly associated with worse graft and patient survival. Conclusions Our study suggests that KTx alone may be safe in patients with compensated HCV, cirrhosis, and ESRD with HPVG less than 10 mm Hg. A simultaneous liver-kidney transplantation may be an unnecessary use of a liver allograft in these patients. more...

Veno-occlusive disease (VOD) of the liver is an extremely rare complication of azathioprine (AZT) use in patients with kidney transplants (KTs). Although VOD is frequently seen in bone marrow transplant patients, so far only 24 cases have been reported in KT patients. Our case adds to the available data on the disease, and we also reviewed the published data on this entity to establish the characteristics of VOD in the setting of KT. Our case highlights the importance of this potentially life-threatening complication and provides an overview of VOD in KT patients. more...

Summary Undertaking transplantation in highly sensitized African American (AA) patients as transplant recipients represents a unique challenge. We retrospectively compared the outcomes of AA with non-African American (NAA) patients who had panel reactive antibody >80% and received deceased donor (DD) kidneys by virtual crossmatch. Immunosuppressive regimen included basiliximab induction and tacrolimus, mycophenolate acid and steroids maintenance. Among 835 consecutive transplants from 1998 to 2007, 142 (17%) were sensitized patients including 89 (16.6%) AA and 53 (17.7%) NAA patients. The AA group had similar 5-year incidence of acute rejection as NAA group (21.4% vs. 26.4%, P = 0.25). Kaplan–Meier estimated graft survival at 1, 3 and 5 years were 91%, 85% and 82% in AA group, and 94%, 79% and 71% in NAA group (P = 0.08). The death-censored graft survival at 1, 3, and 5 years were 93%, 86% and 84% in AA group, and 96%, 83% and 78% in NAA group (P = 0.11). The 1, 3, and 5 years patient survivals were 93%, 88% and 85% in AA group, and 96%, 96% and 94% in NAA group (P = 0.17). Highly sensitized AA patients could be transplanted with DD kidneys at a similar rate as NAA patients, and they may not have a higher incidence of rejection or an inferior graft survival than NAA patients. more...

Paramesh AS, Zhang R, Baber J, Yau CL, Slakey DP, Killackey MT, Ren Q, Sullivan K, Heneghan J, Florman SS. The effect of HLA mismatch on highly sensitized renal allograft recipients. Clin Transplant 2010: 24: E247–E252. © 2010 John Wiley & Sons A/S. Abstract: Introduction: We examined the effects of increasing human leukocyte antigen (HLA) mismatches (MM) on long-term graft outcomes in patients transplanted with a panel reactive antibody (PRA) >80% over a 10-yr period. Methods: A total of 142 recipients were divided into three groups based on the number of HLA MM with their allograft (0–2, 3–4 and 5–6 MM; Groups I, II and III). All patients received the same immunosuppression protocol. Results: The higher MM groups had a higher incidence of rejection (4.4% vs. 11.4% vs. 31.3%, p 80%, a higher HLA MM is associated with higher incidence of acute rejection. Acute rejection was the only significant variable affecting graft loss. We found a trend toward more CMV infections and worse graft outcomes with higher MM. Closer HLA matching and immunologic monitoring needs to be considered to improve graft outcomes among sensitized recipients. more...

Obesity is a worldwide epidemic and public health crisis associated with severe comorbidity leading to end organ dysfunction and poorer transplant outcome. Large population studies show decreased patient and graft survival in obese kidney transplant patients. Despite the poorer outcomes, kidney transplant is considered because of the survival benefit as compared to the wait-listed dialysis patients. In liver transplantation, the benefit of transplant as compared to remaining on the list is obvious because there is no viable liver dialysis at this time.Obesity in potential organ donors impacts both medical and surgical issues. Obesity-related kidney disease affects both the remaining and transplanted kidney. Pancreas donor organs are associated with decreased early graft survival. Liver donor organs with significant steatosis lead to an increased risk for delayed function or nonfunction of the organ.Immunosuppressive drugs with variable lipophilicity and altered volume of distribution can greatly affect the therapeutic usefulness of these drugs.Transplant candidates benefit from a multidisciplinary team approach to their care. As the epidemic progresses and less invasive treatments for metabolic surgery evolve, we are likely to see more patients lose weight before transplant as we continue to strive for improved outcomes. more...

Tertiary hyperparathyroidism (tHPT) usually regresses after renal transplantation. Persistent tHPT after successful renal transplantation may require parathyroidectomy (PTX). PTX has been reported to be associated with deterioration of renal function and graft survival. We retrospectively analyzed 794 kidney transplants performed at our center with at least 3 years of follow-up to examine the effect of PTX on the renal function and graft survival. Forty-nine of the 794 renal transplant recipients were diagnosed with hyperparathyroidism (HPT) before transplant. Nineteen of 49 patients had persistent tHPT and underwent PTX after kidney transplants. Patients with HPT and non-HPT had similar 3-year graft survival (88% versus 84%, P = 0.51). PTX was associated with a decreased glomerular filtration rate at 3 years (44.7 +/- 20.0 versus 57.7 +/- 23.7 mL/min, P = 0.04); however, there was no statistical difference in the 3-year graft survival (71% versus 88%, P = 0.06). PTX in renal transplant recipients seems to be a safe and effective therapy for persistent tHPT. PTX may be associated with worsening glomerular filtration rate, but it may not be associated with significantly decreased long-term graft survival. more...

BACKGROUND The effect of HLA match on renal graft survival has become controversial as has the policy of mandatory sharing of kidneys. METHOD We performed a retrospective analysis of HLA matched (M) and mismatched (MM) kidney transplants in our center. Tacrolimus, mycophenolic acid, and steroids were used as maintenance therapy and basiliximab induction was added for high-risk patients. RESULT A total of 229 kidney transplants were included with median follow-up of 5.1 years. The 5-year death-censored graft survival by Kaplan-Meier method was significantly higher in the M group than in the MM group for deceased-donor kidney transplants (log-rank, p = .018). This graft survival advantage was detected in patients with a peak panel reactive antibody (PRA) greater than 20% (p = .023), but not in those with a PRA level of less than 20% (p = .32). The graft survival was not statistically different for live donor kidney transplants (p = .077). A mismatched kidney was an independent risk for graft loss (hazard ratio: 2.27, 95% confidence interval: 1.009–5.09, p = .047) and acute rejection was a significant cause of graft loss in mismatched deceased-donor transplants (p = .035). CONCLUSION Acute rejection remains a significant cause of graft loss in HLA-6-antigen mismatched deceased-donor kidney transplants. Our data support mandatory sharing of HLA-matched kidneys in sensitized patients with a PRA level greater than 20%. more...

Myeloma kidney and myeloma-associated renal disorders including light chain deposition disease can occur as recurrent or de novo disease in renal allografts. These kidney disorders usually manifest with worsening allograft function and proteinuria. Identification of the precise cause of kidney disorder often requires kidney biopsy and demonstration of monoclonal light chains in the kidney. Here, we present an unusual case of light chain nephropathy in a living-related kidney transplant recipient involving light chain crystallization in the proximal tubule occurring within less than three months after transplant. The etiology of renal failure prior to transplant in our patient is not clear. To the best of our knowledge, the ultrastructural changes seen in our patient have not been described in literature previously. Our patient was treated with steroids, which resulted in short-term improvement in allograft dysfunction. more...

Background: There is insufficient data on the impact of recipient body mass index (BMI) on the long-term graft survival of adult patients transplanted with single pediatric kidneys. Methods: We performed a retrospective analysis of adult patients transplanted with single pediatric kidneys at our center. The recipients were classified into 2 groups: group 1 (BMI ≥30) and group 2 (BMI Results: There was no significant difference in donor/recipient demographics between the 2 groups. In group 1, the death-censored graft survival (DCGS) at 1, 3 and 5 years was 90% at all 3 time points, and in group 2 it was 86, 68 and 60%, respectively (p = 0.05). The mean glomerular filtration rate (with standard deviation in parentheses) at 1, 3 and 5 years was, respectively, 55 (15), 59 (19) and 55 (28) ml/min for group 1, compared to 65 (28), 69 (23) and 67 (20) ml/min in group 2 (p = NS). Multivariate analysis revealed a hazard ratio of 5.12 (95% confidence interval 1.06–24.7; p = 0.04) for graft loss in nonobese patients when compared to obese patients. Obese patients had an increased risk for acute rejections within the first month of transplant (p = 0.02). Conclusion: Patients with a BMI ≥30 transplanted with single pediatric kidneys have better DCGS rates when compared to nonobese patients. more...

BACKGROUND Laparoscopic donation has become the most common technique for living donor kidney transplantation. Despite claims of greater patient acceptance, Significant increases in living donation, relative to the waiting list, have not been realized. Defining laparoscopic donors′ long-term psychosocial impressions may allow for strategies to increase rates of living donation. METHODS The study method was a retrospective telephone survey inquiring into pre-donation perceptions, hospital experiences, and post-donation psychosocial issues. RESULTS Eighty-one patients who had undergone laparoscopic donation with at least a 1-year follow-up were interviewed. Twenty-one percent first heard about this procedure from sources other than healthcare workers or their recipients. Overall, 99% believed they were adequately informed, and 35% reported pre-operative testing was difficult. Seventy-four percent of patients reported a positive impression of the hospital stay, although 52% reported more post-operative pain then expected. Sixty-one percent of patients returned to work within a month. Nine percent reported financial burden, and 6% reported difficulties with insurance. Eighty-four percent believed the recipient had a good outcome. Ninety-four percent would donate again if possible. CONCLUSION This study confi rms that long-term donor perceptions of laparoscopic nephrectomy remain favorable. Most donors are knowledgeable about this procedure, but perceptions may be erratic because of varied sources. Early contact with the transplant team is essential in providing an educational and streamlined experience to the laparoscopic donor in renal transplant. more...

Bone disease after kidney transplantation has a complex pathophysiology and heterogeneous histology. Pre-existing renal osteodystrophy may not resolve completely, but continue or evolve into a different osteodystrophy. Rapid bone loss immediately after transplant can persist, at a lower rate, for years to come. These greatly increase the risk of bone fracture and vertebral collapse. Hypovitaminosis D, hyperparathyroidism and hyperaluminemia may resolve after kidney transplant, but many patients have other risk factors of bone loss, such as steroids usage, hypogonadism, persistent hyperparathyroidism, poor allograft function, aging, and chronic diseases. Clinical management requires a comprehensive approach to address the underlying and ongoing disease processes. Successful prevention of bone loss has been shown with vitamin D analogues, bisphosphonates and calcitonin. Novel approaches to restore the normal bone remodeling and improve the bone quality may be needed in order to effectively decrease bone fractures in kidney transplant recipients. more...

We compare the outcomes of induction therapies with either methylprednisolone (group 1, n = 58), basiliximab (group 2, n = 56) or alemtuzumab (group 3, n = 98) in primary deceased donor kidney transplants with delayed graft function (DGF). Protocol biopsies were performed. Maintenance was tacrolimus and mycophenolate with steroid (group 1 and 2) or without steroid (group 3). One-year biopsy-confirmed acute rejection (AR) rates were 27.6, 19.6 and 10.2 % in group 1, 2 and 3 (p = 0.007). AR was significantly lower in group 3 (p = 0.002) and group 2 (p = 0.03) than in group 1. One-year graft survival rates were 90, 96 and 100 % in group 1, 2 and 3 (log rank p = 0.006). Group 1 had inferior graft survival than group 2 (p = 0.03) and group 3 (p = 0.002). The patient survival rates were not different (96.6, 98.2 and 100 %, log rank p = 0.81). Multivariable analysis using methylprednisolone induction as control indicated that alemtuzumab (OR 0.31, 95 % CI 0.11–0.82; p = 0.03) and basiliximab (OR 0.60, 95 % CI 0.23–0.98; p = 0.018) were associated with lower risk of AR. Therefore, alemtuzumab or basiliximab induction decreases AR and improves graft survival than methylprednisolone alone in patients with DGF. Alemtuzumab induction might also allow patients with DGF to be maintained with contemporary steroid-withdrawal protocol. more...

African Americans (AA) have traditionally been thought to have higher immunologic risk than Caucasians (CA) for rejection and allograft loss. The impact of ethnicity on the outcome of simultaneous pancreas-kidney (SPK) transplant with basiliximab induction has not been reported. In this study, we retrospectively analyze the long-term results of 36 AA and 55 CA recipients of primary SPK. The actual patient survival rates of AA and CA groups were 91.7% vs. 90.1% at 1 year, 93.3% vs. 88.1% at 3 years, and 94.4% vs. 83.3% at 5 years. The actual kidney survival of AA and CA were 91.7% vs. 89.1% at 1 year, 90% vs. 81% at 3 years, and 83.3% vs. 75% at 5 years. The actual pancreas survival of AA and CA were 88.9% vs. 85.5% at 1 year, 83.3% vs. 78.6% at 3 years and 72.2% vs. 70.8% at 5 years. Death-censored analyses also found no difference in pancreas and kidney graft survival rates over 5 years. Higher rejection rate, but the same low CMV infection, and comparable quality of graft function were noted in AA group. AA may not have worse long-term outcomes than CA recipients of SPK with basiliximab induction and tacrolimus (TAC), mycophenolate acid (MFA) and steroid maintenance immunotherapy. more...

The epidemic of metabolic syndrome contributes to the rapid growth of cardiovascular and renal diseases. Hyper-hemodynamics, impaired pressure natriuresis, excess excretory load, insulin resistance, endothelial dysfunction, chronic inflammation, and prothrombotic status individually and interdependently initiate renal injury in metabolic syndrome. The prevention and treatment of kidney disease require a multifactorial approach. Weight loss through diet control and exercise can reverse many pathophysiologic processes. Pharmacologic intervention includes insulin sensitizers, tight glycemic and lipid control, blockage of renin angiotensin aldosterone system, and anti-inflammatory and antithrombotic therapies. Each peroxisome proliferator-activated receptor isoform plays a distinct role in metabolic syndrome, and their agonists may prevent or reverse the early renal injuries. more...

The cause of hypertension in the metabolic syndrome is complex and multifactorial and all of the elements of the metabolic syndrome, including obesity, insulin resistance, and the characteristic dyslipidemia probably are involved in mediating changes ultimately resulting in hypertension and modifying its course. Of these elements, obesity may play the most important and pivotal role in creating the conditions that lead to hypertension in the metabolic syndrome. This is not to say that the other elements of the syndrome are less important, and, as we gain more insight into the processes involved, we should be able to better manage the disease and tailor our therapeutic interventions appropriately. more...

Left ventricular hypertrophy (LVH) in patients with hypertension is associated with an increased risk for many cardiovascular events and predicts a higher mortality rate. The pathogenesis of LVH is complicated. In addition to the hemodynamic burden (pressure or volume overload) and demographic factors, several trophic humoral factors, such as angiotensin II, aldosterone, endothelin, leptin, and catecholamines, may also contribute to the development and progression of LVH. Effective antihypertensive therapy can reverse LVH as well as prevent its development. Regression of LVH decreases subsequent cardiovascular morbidity and mortality. The commonly used drugs have various effects on LVH. Angiotensin receptor blockers and angiotensin-converting enzyme inhibitors seem most effective. Several new agents, including direct antifibrotic drugs, aldosterone blockade, vasopeptidase inhibitors, and endothelin receptor antagonists that more specifically target the underlying pathogenesis of LVH may provide us with innovative approaches to treat LVH. more...

In this paper a general positioning subsystem that used for several kinds of mobile robot is presented. The subsystem consist of a Optical Fiber Gyroscope(OFG) with high precision and a Orthogonal Passive Wheel System(OPWS) which is combination of Swedish Wheels and Optical Encoders. The OPWS is an independent planar odometer which is regarded as the local reference of the kinematic model, while the OFG provides the instant angle between global and local reference frame of the robot. A dead recking model is developed regardless of the specific robot base structure. The error sources of the proposed positioning method is analyzed in allusion to an omnidirectional robot configuration. Calibration method based on geometric trajectory tracking is introduced according to the error sources, followed by the experimental results that confirm both feasibility of the positioning method and effectiveness of the calibration method. more...

Obesity-associated hypertension is a common disease that involves a complex pathogenesis. Failure to control hypertension (HTN) in obese subjects provides a great threat to their renal and cardiovascular functions. The treatment of obesity-associated HTN is often difficult, and requires nonpharmacological and/or pharmacological approaches. Weight reduction is the cornerstone of the therapies of obesity-HTN, as it reverses the multiple components of its pathogenesis. When weight loss cannot be sustained or fails, pharmacological means should then be used. Angiotensin-converting enzyme inhibitors (ACEI) are the drug of choice: they can reduce blood pressure, protect the kidney and heart, and improve the metabolic abnormalities in obese subjects. Angiotensin-2 type-1 receptor blockers have a renoprotective benefit similar to ACEI, and they provide an important alternative to the use of ACEI. Diuretics are very effective in African-American obese hypertensives, but small doses should be used to avoid adverse effects on metabolic profiles. Long-acting calcium channel blockers are also effective and have the advantage of no adverse metabolic effects. Nondihydropyridine calcium channel blockers may provide additional renal and cardiovascular protective effects. The beta-adrenergic receptor blockers can cause further weight gain and metabolic abnormalities in obese subjects; therefore, careful monitoring is needed. There are few clinical data that support the efficacy and benefit of centrally acting alpha-2 agonists and alpha-adrenergic receptor antagonists in the treatment of obesity-HTN. more...

AIM: To study the long-term outcome of ketoconazole and tacrolimus combination in kidney transplant recipients. METHODS: From 2006 to 2010, ketoconazole was given in 199 patients and was continued for at least 1 year or until graft failure (Group 1), while 149 patients did not receive any ketoconazole (Group 2). A combination of tacrolimus, mycophenolate and steroid was used as maintenance therapy. High risk patients received basiliximab induction. RESULTS: Basic demographic data was similar between the 2 groups. The 5-year cumulative incidence of biopsy-confirmed and clinically-treated acute rejection was significantly higher in Group 1 than in Group 2 (34% vs 18%, P = 0.01). The 5-year Kaplan-Meier estimated graft survival (74.3% vs 76.4%, P = 0.58) and patient survival (87.8% vs 87.5%, P = 0.93) were not different between the 2 groups. Multivariable analyses identified ketoconazole usage as an independent risk of acute rejection (HR = 2.33, 95%CI: 1.33-4.07; P = 0.003) while tacrolimus dose in the 2nd month was protective (HR = 0.89, 95%CI: 0.75-0.96; P = 0.041). CONCLUSION: Co-administration of ketoconazole and tacrolimus is associated with significantly higher incidence of acute rejection in kidney transplant recipients. more...

With in-depth understanding of transplant immunology, more sensitive assays have been developed for immunological risk assessment, crossmatch, and detection of donor-specific antibodies. The discovery of potent immunosuppressive drugs has successfully reduced the risk of acute rejection and graft loss from rejection. Kidney transplant has become the preferred therapy for treating patient with ESRD. It not only improves the quality of life but also prolongs life. Living donor kidney transplant provides better allograft and patient survival than deceased donor kidney transplant. Novel approaches of living donor exchange and desensitization protocol have been increasingly used to facilitate ABO and/or HLA incompatible kidney transplant. Pancreas transplant, either simultaneously with a deceased donor kidney or after a living donor kidney transplant, has benefited many ESRD patients with insulin-dependent diabetes. Pancreas transplant alone can also be considered for Type 1 diabetes suffering life-threatening metabolic complication despite of insulin therapy. Modern immunosuppressive protocol typically includes an initial induction therapy with T-cell depleting antibody or IL-2 receptor antibody and a long-term maintenance. Maintenance regimen usually consists of two to three drugs of steroids, calcineurin inhibitor, antimetabolite, target-of-rapamycin inhibitor, or costimulation blocker. Careful monitoring and appropriate management of surgical and medical complications are the crucial part in post-transplant patient care, especially rejection, infection, metabolic syndrome, cardiovascular disease, and malignancy. more...

Methylacetoin (3-hydroxy-3-methylbutan-2-one) and 2-methyl-2,3-butanediol are currently obtained exclusively via chemical synthesis. Here, we report, to the best of our knowledge, the first alternative route, using engineered Escherichia coli. The biological synthesis of methylacetoin was first accomplished by reversing its biodegradation, which involved modifying the enzyme complex involved, switching the reaction substrate, and coupling the process to an exothermic reaction. 2-Methyl-2,3-butanediol was then obtained by reducing methylacetoin by exploiting the substrate promiscuity of acetoin reductase. A complete biosynthetic pathway from renewable glucose and acetone was then established and optimized via in vivo enzyme screening and host metabolic engineering, which led to titers of 3.4 and 3.2 g l−1 for methylacetoin and 2-methyl-2,3-butanediol, respectively. This work presents a biodegradation-inspired approach to creating new biosynthetic pathways for small molecules with no available natural biosynthetic pathway. more...

Background We evaluated urine free light chains (FLC) as a potential biomarker for acute kidney allograft injury (AKAI). Methods Urine κ and λ FLC were compared with urine β-2 microglobulin (β2-M), retinol-binding protein (RBP), kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and microalbuminuria (MAB) in biopsy-confirmed acute rejection (AR) and acute tubular necrosis (ATN). Healthy volunteers (normal) and transplant recipients with normal allograft function (control) were used as references. Results Compared with control or normal group (N = 15), urine FLC, MAB, and RBP were higher in ATN (N = 29) and AR (N = 41) groups (p more...

Methylacetoin (3-hydroxy-3-methylbutan-2-one) and 2-methyl-2,3-butanediol are currently obtained exclusively via chemical synthesis. Here, we report, to the best of our knowledge, the first alternative route, using engineered Escherichia coli. The biological synthesis of methylacetoin was first accomplished by reversing its biodegradation, which involved modifying the enzyme complex involved, switching the reaction substrate, and coupling the process to an exothermic reaction. 2-Methyl-2,3-butanediol was then obtained by reducing methylacetoin by exploiting the substrate promiscuity of acetoin reductase. A complete biosynthetic pathway from renewable glucose and acetone was then established and optimized via in vivo enzyme screening and host metabolic engineering, which led to titers of 3.4 and 3.2 g l(-1) for methylacetoin and 2-methyl-2,3-butanediol, respectively. This work presents a biodegradation-inspired approach to creating new biosynthetic pathways for small molecules with no available natural biosynthetic pathway. more...

Patients in the BENEFIT-EXT study received extended criteria donor kidneys and a more intensive (MI) or less intensive (LI) belatacept immunosuppression regimen, or cyclosporine A (CsA). Patients who remained on assigned therapy through year 3 were eligible to enter a long-term extension (LTE) study. Three hundred four patients entered the LTE (n = 104 MI; n = 113 LI; n = 87 CsA), and 260 continued treatment through year 5 (n = 91 MI; n = 100 LI; n = 69 CsA). Twenty patients died during the LTE (n = 5 MI; n = 9 LI; n = 6 CsA), and eight experienced graft loss (n = 2 MI; n = 1 LI; n = 5 CsA). Three patients experienced an acute rejection episode (n = 2 MI; n = 1 LI). The incidence rate of serious adverse events, viral infections and fungal infections was similar across groups during the LTE. There were four cases of posttransplant lymphoproliferative disorder (PTLD) from the beginning of the LTE to year 5 (n = 3 LI; n = 1 CsA); two of three PTLD cases in the LI group were in patients who were seronegative for Epstein-Barr virus (EBV(-)) at transplantation. Mean ± SD calculated GFR at year 5 was 55.9 ± 17.5 (MI), 59.0 ± 29.1 (LI) and 44.6 ± 16.4 (CsA) mL/min/1.73 m(2) . Continued treatment with belatacept was associated with a consistent safety profile and sustained improvement in renal function versus CsA over time. more...

Summary Transplanting single pediatric donor kidneys into adult recipients has an increased risk of hyperfiltration injury and graft loss. It is unknown if renin-angiotensin system (RAS) blockers are beneficial in this setting. We retrospectively analyzed 94 adults who received single kidneys from donors more...

The epidemic of obesity and metabolic syndrome (MS) contributes to the rapid growth of chronic kidney disease (CKD) and end-stage renal disease (ESRD). There is a reverse epidemiology, known as the "obesity paradox," in ESRD patients receiving maintenance dialysis. Obese patients are routinely referred for kidney transplant, and they have more surgical and medical complications than non-obese patients. However, compared to dialysis, kidney transplant provides a survival benefit for obese patients. After kidney transplant, obese patients tend to gain more body weight, and non-obese patients can develop new-onset obesity/MS. Obesity/MS is not only associated with serious morbidities, but also compromises the long-term graft and patient survival. The immunosuppressive drugs commonly used as maintenance therapy, including corticosteroids, calcineurin inhibitors and mammalian target-of-rapamycin inhibitors, contribute to obesity/MS. Development of novel immunosuppressive drugs free of metabolic adverse effects is needed, so that the full potential and benefits of kidney transplantation can be realized. more...

Background Cytomegalovirus (CMV) disease is a serious infection after kidney transplantation. The risk factors and the impact of CMV disease in African-American (AA) kidney transplant patients have not been well characterized. Methods We performed a retrospective analysis on 448 AA patients transplanted between 1996 and 2005. A 3-month universal chemoprophylaxis with ganciclovir or valganciclovir was administered to CMV donor-positive/recipient-negative (D+/R−) patients and to those treated with anti-thymocyte globulin for rejection, but not routinely to those with other D/R serostatus. Results A total of 31 AA patients (7%) developed clinical CMV disease. Compared with other D/R serostatus groups, the D+/R− group had the highest 3-year cumulative incidence of CMV disease (16.9% vs. 6.3% in D+/R+, 4.9% in D−/R+, and 2.4% in D−/R−). The D+/R− group also had the worst 3-year death-censored allograft survival (75% vs. 92% in D+/R+, 94% in D−/R+, and 96% in D−/R−, log-rank P = 0.01). Multivariate analysis found that D+/R− serostatus (odds ratio [OR] 5.4, 95% confidence interval [CI] 0.6–48.2, P = 0.003) and donor age > 60 years (OR 9.1, 95% CI 1.3–65, P = 0.03) were independent risk factors for CMV disease. Conclusion The D+/R− group has the highest incidence of CMV disease and the worst 3-year renal allograft survival despite 3-month universal prophylaxis. Prolonged chemoprophylaxis may be needed to prevent the late development of CMV disease and to improve allograft survival in the high-risk group of AA kidney transplant recipients. more...

Human immunodeficiency virus (HIV) seropositivity has historically been an absolute contraindication for solid organ transplantation. However, the successful application of HAART (highly active anti-retroviral therapy) drug regimens has greatly prolonged the life expectancy of HIV-positive patients. Therefore, it has become appropriate to consider this patient population for transplantation. HIV positive transplants are being performed around the country in controlled settings, usually as part of a research protocol. The aim of our study is to describe the Louisiana experience with organ transplantation into HIV-positive patients. We identified seven HIV-positive patients who underwent kidney or kidney/pancreas transplantation at our center between 2007 and 2010. We performed a retrospective chart review to ascertain graft function, as well as virologic and immunologic status post-transplant. Renal function (glomerular filtration rate and serum creatinine concentrations) improved in all subjects post-transplant, and six of seven (85.8%) subjects remained virologically suppressed with no progression to Acquired Immunodeficiency Syndrome (AIDS). Overall, two-year graft and patient survival rates were 85.5%. HIV seropositive End Stage Renal Disease (ESRD) patients represent a new population of patients that can be successfully transplanted. This offers a new dimension in care for successful HAART therapy to prolong the life of HIV-infected patients. more...

Progressive loss of renal allograft function after the first year of kidney transplant is often referred to as chronic rejection, transplant nephropathy, transplant glomerulopathy or chronic allograft nephropathy (CAN) and the use of these terms is often interchangeable. Clinically, it is usually diagnosed by a slowly rising serum creatinine level, increasing proteinuria and worsening hypertension (Zhang et al., 2004). CAN is the second most common cause of graft loss after the leading cause, death with a functioning graft (DWFG) (Zhang et al., 2004). According to estimates, 25-30% of patients currently awaiting kidney transplant have received a transplant before. more...

Metabolic bone disease after kidney transplantation has a complex pathophysiology and heterogeneous histology. Pre-existing renal osteodystrophy may not resolve completely, but continue or evolve into a different osteodystrophy. Rapid bone loss immediately after transplant can persist, at a lower rate, for years to come. These greatly increase the risk of bone fracture and vertebral collapse. Each patient may have multiple risk factors of bone loss, such as steroids usage, hypogonadism, persistent hyperparathyroidism (HPT), poor allograft function, metabolic acidosis, hypophosphatemia, vitamin D deficiency, aging, immobility and chronic disease. Clinical management requires a comprehensive approach to address the underlying and ongoing disease processes. Successful prevention of bone loss has been shown with vitamin D, bisphosphonates, calcitonin as well as treatment of hypogonadism and HPT. Novel approach to restore the normal bone remodeling and improve the bone quality may be needed in order to effectively decrease bone fracture rate in kidney transplant recipients. more...

Antibody induction therapy is frequently used as an adjunct to the maintenance immunosuppression in adult kidney transplant recipients. Published data support antibody induction in patients with immunologic risk to reduce the incidence of acute rejection (AR) and graft loss from rejection. However, the choice of antibody remains controversial as the clinical studies were carried out on patients of different immunologic risk and in the context of varying maintenance regimens. Antibody selection should be guided by a comprehensive assessment of immunologic risk, patient comorbidities, financial burden as well as the maintenance immunosuppressives. Lymphocyte-depleting antibody (thymoglobulin, ATGAM or alemtuzumab) is usually recommended for those with high risk of rejection, although it increases the risk of infection and malignancy. For low risk patients, interleukin-2 receptor antibody (basiliximab or daclizumab) reduces the incidence of AR without much adverse effects, making its balance favorable in most patients. It should also be used in the high risk patients with other medical comorbidities that preclude usage of lymphocyte-depleting antibody safely. There are many patients with very low risk, who may be induced with intravenous steroids without any antibody, as long as combined potent immunosuppressives are kept as maintenance. In these patients, benefits with antibody induction may be too small to outweigh its adverse effects and financial cost. Rituximab can be used in desensitization protocols for ABO and/or HLA incompatible transplants. There are emerging data suggesting that alemtuzumab induction be more successful than other antibody for promoting less intensive maintenance protocols, such as steroid withdrawal, tacrolimus monotherapy or lower doses of tacrolimus and mycophenolic acid. However, the long-term efficacy and safety of these unconventional strategies remains unknown. more...

Although living donation is the preferred method of kidney transplant, many donors are not a match with their intended recipient. One unique way of overcoming this is by performing a donor paired exchange. By swapping donors, transplant centers may be able to bring about multiple transplants that would not have otherwise been possible. This manuscript describes the first three way domino paired donor exchange transplant in Louisiana. Because of a single altruistic donor, we were able to facilitate three recipients getting transplanted. We discuss the formulation of this unique program, the choosing of potential donor/recipient pairs and outcomes. A review of the controversies of paired kidney donation is also presented. more...

CHIP28k is an important water-transporting protein in the kidney proximal tubule and the thin descending limb of Henle [Zhang, Skach, Hasegawa, Van Hoek, & Verkman (1993) J. Cell Biol. 120, 359-369] that is homologous to human erythrocyte CHIP28 [Preston & Agre (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 11110-11114]. Oligonucleotide-directed mutagenesis was used to identify the cysteine(s) involved in inhibition of the water-transporting function of CHIP28k by the mercurial HgCl2. Each of the four cysteines (at positions 87, 102, 152, and 189) were mutated to serine individually, or in combinations. In vitro transcribed cRNA was expressed in Xenopus oocytes for measurement of osmotic water permeability (Pf) in the absence or presence of 0.3 mM HgCl2. Pf (in cm/s x 10(-4) measured at 10 degrees C) was 7 +/- 1 in water-injected oocytes. In wild-type CHIP28k, Pf was 58 +/- 7 (-HgCl2) and 12 +/- 1 (+HgCl2). Mutation of cysteine 87, 102, or 152, individually or in combinations, had little effect on oocyte Pf or on the inhibition by HgCl2. Mutation of cysteine 189 to serine or glycine gave similar Pf values of 49-56 (-HgCl2); however, Pf was not inhibited up to 1 mM HgCl2. Mutation of cysteine 189 to the larger amino acid tryptophan gave a low Pf of 9 +/- 1; coexpression with wild-type CHIP28k indicated that the tryptophan mutation was not dominant negative. Mutation of the asparagine 42 and 205 glycosylation sites to threonine had little effect on Pf.(ABSTRACT TRUNCATED AT 250 WORDS) more...

Undertaking transplantation in highly sensitized African American (AA) patients as transplant recipients represents a unique challenge. We retrospectively compared the outcomes of AA with non-African American (NAA) patients who had panel reactive antibody80% and received deceased donor (DD) kidneys by virtual crossmatch. Immunosuppressive regimen included basiliximab induction and tacrolimus, mycophenolate acid and steroids maintenance. Among 835 consecutive transplants from 1998 to 2007, 142 (17%) were sensitized patients including 89 (16.6%) AA and 53 (17.7%) NAA patients. The AA group had similar 5-year incidence of acute rejection as NAA group (21.4% vs. 26.4%, P = 0.25). Kaplan-Meier estimated graft survival at 1, 3 and 5 years were 91%, 85% and 82% in AA group, and 94%, 79% and 71% in NAA group (P = 0.08). The death-censored graft survival at 1, 3, and 5 years were 93%, 86% and 84% in AA group, and 96%, 83% and 78% in NAA group (P = 0.11). The 1, 3, and 5 years patient survivals were 93%, 88% and 85% in AA group, and 96%, 96% and 94% in NAA group (P = 0.17). Highly sensitized AA patients could be transplanted with DD kidneys at a similar rate as NAA patients, and they may not have a higher incidence of rejection or an inferior graft survival than NAA patients. more...