Outcomes Among Undocumented Immigrant Kidney Transplant Recipients in California.

Importance: There are over 2 million undocumented immigrants (UI) in California, where currently, all individuals regardless of immigration status have access to kidney transplant. There is a medical perception that UI face a higher risk of transplant failure due to language barriers and lack of access to immunosuppressive medication and health care when compared with US residents (UR). Objective: To elucidate the kidney transplant outcomes of UI at an academic medical center in California. Design, Setting, and Participants: A retrospective cohort study was conducted from a single transplant center during an 8-year study period. Patients who received a kidney transplant at the University of California, Irvine, between January 1, 2012, and September 1, 2019, were included in this study. Data were analyzed from October 2020 to August 2021. Exposures: The primary exposure of this study was citizenship status. UI were defined as immigrants residing in the US without permission or legal documentation. Main Outcomes and Measures: The primary end point was all-cause graft loss defined as the return to dialysis, need for a second kidney transplant, or death. The secondary end points of this study were all-cause mortality and rejection. All-cause mortality between the 2 groups was compared using multiple Cox proportional hazard regression analysis. Other transplant outcomes, including all-cause graft loss and acute rejection, were examined by competing risks regressions with mortality and mortality plus graft loss serving as competing risks, respectively. Results: Of all 446 consecutive kidney transplant recipients, the mean (SD) age was 47 (13) years; 261 patients (59%) were male, and 114 (26%) were UI. During a median (IQR) follow-up time of 3.39 (0.04-8.11) years, 6 UI and 48 UR experienced all-cause graft loss. UR had a 192% (hazard ratio, 2.92; 95% CI, 1.21-6.85; P = .01) and 343% (hazard ratio, 4.34; 95% CI, 1.05-18.69; P = .04) significantly increased unadjusted risk for all-cause graft loss and all-cause mortality, respectively. These results became nonsignificant and were mostly attenuated when adjusted for age and ethnicity. Finally, there was no difference in incidence rate of kidney allograft rejection between the 2 groups (UR, 3.5 per 100 person-years vs UI, 2.4 per 100 person-years; rate ratio, 1.45; 95% CI, 0.90-5.05; P = .08). Conclusions and Relevance: This single-center cohort study found that kidney transplant outcomes of UI were not inferior to those of UR. Across the US, however, UI have consistently had unequal access to transplantation. These findings suggest that extending kidney transplants to UI is safe and does not portend worse outcomes. As a result, denying transplant according to immigration status not only results in higher costs but also worse end stage kidney disease outcomes for an already underserved population.

Translocation of nuclear chromatin distribution to the periphery reflects dephosphorylated threonine-821/826 of the retinoblastoma protein (pRb) in T24 cells treated with Bacillus Calmette-Guérin.

The standard treatment for non-muscle-invasive bladder cancer is intravesical Bacillus Calmette-Guérin (BCG) therapy, which is considered the only intravesical therapy that reduces the risk of progression to muscle-invasive cancer. BCG unresponsiveness, in which intravesical BCG therapy is ineffective, has become a problem. It is thus important to evaluate the effectiveness of BCG treatment for patients as soon as possible in order to identify the optimal therapy. Urine cytology is a noninvasive, easy, and cost-effective method that has been used during BCG treatment, but primarily only to determine benign or malignant status; findings concerning the efficacy of BCG treatment based on urine cytology have not been reported. We investigated the relationship between BCG exposure and nuclear an important criterion in urine cytology, i.e., nuclear chromatin patterns. We used three types of cultured cells to evaluate nuclear chromatin patterns and the cell cycle, and we used T24 cells to evaluate the phosphorylation of retinoblastoma protein (pRb) in six-times of BCG exposures. The results revealed that after the second BCG exposure, (i) nuclear chromatin is distributed predominantly at the nuclear periphery and (ii) the dephosphorylation of threonine-821/826 in pRb occurs. This is the first report of a dynamic change in the nuclear chromatin pattern induced by exposure to BCG. Molecular findings also suggested a relationship between this phenomenon and cell-cycle proteins. Although these results are preliminary, they contribute to our understanding of the cytomorphological changes that occur with BCG exposure.

Anti-Oxidative Therapy in Islet Cell Transplantation.

Islet cell transplantation has become a favorable therapeutic approach in the treatment of Type 1 Diabetes due to the lower surgical risks and potential complications compared to conventional pancreas transplantation. Despite significant improvements in islet cell transplantation outcomes, several limitations hamper long-term graft survival due to tremendous damage and loss of islet cells during the islet cell transplantation process. Oxidative stress has been identified as an omnipresent stressor that negatively affects both the viability and function of isolated islets. Furthermore, it has been established that at baseline, pancreatic ß cells exhibit reduced antioxidative capacity, rendering them even more susceptible to oxidative stress during metabolic stress. Thus, identifying antioxidants capable of conferring protection against oxidative stressors present throughout the islet transplantation process is a valuable approach to improving the overall outcomes of islet cell transplantation. In this review we discuss the potential application of antioxidative therapy during each step of islet cell transplantation.

Anti-Oxidative Therapy in Diabetic Nephropathy.

Chronic kidney disease is generally progressive and currently has no reliable treatment to reverse a decline in kidney function or to slow the progression of the disease. Diabetic nephropathy is one of the leading causes of end-stage kidney failure. Kidney damage in diabetic nephropathy is largely attributed to the increased oxidative stress, affecting its metabolic activity, metabolic pathways, and hemodynamic pathways. In diabetic patients, hyperglycemia causes an increase in the production of reactive oxygen species that further increase oxidative stress. These reactive oxygen species are created through a variety of pathways, providing the opportunity for treatment using anti-oxidative defense mechanisms to prevent vascular injury. This review will give an overview of oxidative stress, along with the current treatments and limitations of diabetic nephropathy. We will also discuss the potential of antioxidative therapies, with an emphasis on the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.

Dysregulation of ß-Cell Proliferation in Diabetes: Possibilities of Combination Therapy in the Development of a Comprehensive Treatment.

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia as a result of insufficient insulin levels and/or impaired function as a result of autoimmune destruction or insulin resistance. While Type 1 DM (T1DM) and Type 2 DM (T2DM) occur through different pathological processes, both result in ß-cell destruction and/or dysfunction, which ultimately lead to insufficient ß-cell mass to maintain normoglycemia. Therefore, therapeutic agents capable of inducing ß-cell proliferation is crucial in treating and reversing diabetes; unfortunately, adult human ß-cell proliferation has been shown to be very limited (~0.2% of ß-cells/24 h) and poorly responsive to many mitogens. Furthermore, diabetogenic insults result in damage to ß cells, making it ever more difficult to induce proliferation. In this review, we discuss ß-cell mass/proliferation pathways dysregulated in diabetes and current therapeutic agents studied to induce ß-cell proliferation. Furthermore, we discuss possible combination therapies of proliferation agents with immunosuppressants and antioxidative therapy to improve overall long-term outcomes of diabetes.

Is It Time to Utilize Genetic Testing for Living Kidney Donor Evaluation?

Living donor kidney transplantation is an effective strategy to mitigate the challenges of solid organ shortage. However, being a living kidney donor is not without risk, as donors may encounter short- and long-term complications including the risk of developing chronic kidney disease, end-stage kidney disease, hypertension, and possible pregnancy-related complications. Although the evaluation of potential living donors is a thorough and meticulous process with the intention of decreasing the chance of complications, particularly in donors who have lifetime risk projection, risk factors for kidney disease including genetic predispositions may be missed because they are not routinely investigated. This type of testing may not be offered to patients due to variability and decreased penetrance of symptoms and lack of availability of appropriate genetic testing and genetic specialists. We report a case of a middle-aged woman with a history of gestational diabetes and preeclampsia who underwent an uneventful living kidney donation. She developed postdonation nonnephrotic range proteinuria and microscopic hematuria. Given the risk of biopsy with a solitary kidney, genetic testing was performed and revealed autosomal dominant Alport syndrome. Our case underscores the utility of genetic testing. Hopefully, future research will examine the incorporation of predonation genetic testing into living kidney donor evaluation.

Intraoperative Near-Infrared Spectroscopy Monitoring of Renal Allograft Reperfusion in Kidney Transplant Recipients: A Feasibility and Proof-of-Concept Study.

Conventional renal function markers are unable to measure renal allograft perfusion intraoperatively, leading to delayed recognition of initial allograft function. A handheld near-infrared spectroscopy (NIRS) device that can provide real-time assessment of renal allograft perfusion by quantifying regional tissue oxygen saturation levels (rSO2) was approved by the FDA. This pilot study evaluated the feasibility of intraoperative NIRS monitoring of allograft reperfusion in renal transplant recipients (RTR). Intraoperative renal allograft rSO2 and perfusion rates were measured in living (LDRT, n = 3) and deceased donor RTR (DDRT, n = 4) during the first 50 min post-reperfusion and correlated with renal function markers 30 days post-transplantation. Intraoperative renal allograft rSO2 for the DDRT group remained significantly lower than the LDRT group throughout the 50 min. Reperfusion rates were significantly faster in the LDRT group during the first 5 min post-reperfusion but remained stable thereafter in both groups. Intraoperative rSO2 were similar among the upper pole, renal hilum, and lower pole, and strongly correlated with allograft function and hemodynamic parameters up to 14 days post-transplantation. NIRS successfully detected differences in intraoperative renal allograft rSO2, warranting future studies to evaluate it as an objective method to measure ischemic injury and perfusion for the optimization of preservation/reperfusion protocols and early prediction of allograft function.

Heterologous functional expression of ascidian Nav1 channels and close relationship with the evolutionary ancestor of vertebrate Nav channels.

Voltage-gated sodium channels (Nav1s) are responsible for the initiation and propagation of action potentials in neurons, muscle, and endocrine cells. Many clinically used drugs such as local anesthetics and antiarrhythmics inhibit Nav1s, and a variety of inherited human disorders are caused by mutations in Nav1 genes. Nav1s consist of the main α subunit and several auxiliary ß subunits. Detailed information on the structure-function relationships of Nav1 subunits has been obtained through heterologous expression experiments and analyses of protein structures. The basic properties of Nav1s, including their gating and ion permeation, were classically described in the squid giant axon and other invertebrates. However, heterologous functional expression of Nav1s from marine invertebrates has been unsuccessful. Ascidians belong to the Urochordata, a sister group of vertebrates, and the larval central nervous system of ascidians shows a similar plan to that of vertebrates. Here, we report the biophysical properties of ascidian Ciona Nav1 (CiNav1a) heterologously expressed in Xenopus oocytes. CiNav1a exhibited tetrodotoxin-insensitive sodium currents with rapid gating kinetics of activation and inactivation. Furthermore, consistent with the fact that the Ciona genome lacks orthologous genes to vertebrate ß subunits, the human ß1 subunit did not influence the gating properties when coexpressed with CiNav1a. Interestingly, CiNav1a contains an ankyrin-binding motif in the II-III linker, which can be targeted to the axon initial segment of mammalian cortical neurons. Our findings provide a platform to gain insight into the evolutionary and biophysical properties of Nav1s, which are important for the development of targeted therapeutics.

Current Pharmacological Intervention and Medical Management for Diabetic Kidney Transplant Recipients.

Hyperglycemia after kidney transplantation is common in both diabetic and non-diabetic patients. Both pretransplant and post-transplant diabetes mellitus are associated with increased kidney allograft failure and mortality. Glucose management may be challenging for kidney transplant recipients. The pathophysiology and pattern of hyperglycemia in patients following kidney transplantation is different from those with type 2 diabetes mellitus. In patients with pre-existing and post-transplant diabetes mellitus, there is limited data on the management of hyperglycemia after kidney transplantation. The following article discusses the nomenclature and diagnosis of pre- and post-transplant diabetes mellitus, the impact of transplant-related hyperglycemia on patient and kidney allograft outcomes, risk factors and potential pathogenic mechanisms of hyperglycemia after kidney transplantation, glucose management before and after transplantation, and modalities for prevention of post-transplant diabetes mellitus.

The Role of Oxidative Stress in Pancreatic ß Cell Dysfunction in Diabetes.

Diabetes is a chronic metabolic disorder characterized by inappropriately elevated glucose levels as a result of impaired pancreatic ß cell function and insulin resistance. Extensive studies have been conducted to elucidate the mechanism involved in the development of ß cell failure and death under diabetic conditions such as hyperglycemia, hyperlipidemia, and inflammation. Of the plethora of proposed mechanisms, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and oxidative stress have been shown to play a central role in promoting ß cell dysfunction. It has become more evident in recent years that these 3 factors are closely interrelated and importantly aggravate each other. Oxidative stress in particular is of great interest to ß cell health and survival as it has been shown that ß cells exhibit lower antioxidative capacity. Therefore, this review will focus on discussing factors that contribute to the development of oxidative stress in pancreatic ß cells and explore the downstream effects of oxidative stress on ß cell function and health. Furthermore, antioxidative capacity of ß cells to counteract these effects will be discussed along with new approaches focused on preserving ß cells under oxidative conditions.

The Role of the Nrf2 Signaling in Obesity and Insulin Resistance.

Obesity, a metabolic disorder characterized by excessive accumulation of adipose tissue, has globally become an increasingly prevalent disease. Extensive studies have been conducted to elucidate the underlying mechanism of the development of obesity. In particular, the close association of inflammation and oxidative stress with obesity has become increasingly evident. Obesity has been shown to exhibit augmented levels of circulating proinflammatory cytokines, which have been associated with the activation of pathways linked with inflammation-induced insulin resistance, a major pathological component of obesity and several other metabolic disorders. Oxidative stress, in addition to its role in stimulating adipose differentiation, which directly triggers obesity, is considered to feed into this pathway, further aggravating insulin resistance. Nuclear factor E2 related factor 2 (Nrf2) is a basic leucine zipper transcription factor that is activated in response to inflammation and oxidative stress, and responds by increasing antioxidant transcription levels. Therefore, Nrf2 has emerged as a critical new target for combating insulin resistance and subsequently, obesity. However, the effects of Nrf2 on insulin resistance and obesity are controversial. This review focuses on the current state of research on the interplay of inflammation and oxidative stress in obesity, the role of the Nrf2 pathway in obesity and insulin resistance, and the potential use of Nrf2 activators for the treatment of insulin resistance.

Nuclear co-expression of p21 and p27 induced effective cell-cycle arrest in T24 cells treated with BCG.

A proposed mechanism underlying the effect of bacillus Calmette-Guérin (BCG) treatment for bladder cancer cells is as follows: BCG-induced crosslinking of cell-surface receptors results in the activation of signaling cascades, including cell-cycle regulators. However, the clinical significance of cell-cycle regulators such as p21 and p27 is controversial. Here we investigated the relationship between BCG exposure and p21 and p27. We used confocal laser microscopy to examine the expression levels of pKi67, p21 and p27 in T24 cells (derived from human urothelial carcinoma) exposed six times to BCG. We performed dual immunofluorescence staining methods for p21 and p27 and observed the localization of nuclear and cytoplasm expressions. We investigated the priority of p27 over p21 regarding nuclear expression by using p27 Stealth RNAi™ (p27-siRNA). With 2-h BCG exposure, the nuclear-expression level of p21 and p27 was highest, while pKi67 was lowest. The percentage of double nuclear-expression of p21 and p27 in BCG cells was significantly higher than that in control cells during the 1st to 6th exposure (P < 0.05), and the expression of pKi67 showed the opposite of this pattern. Approximately 10% of the nuclear p21 was independent of p27, whereas the cytoplasmic p21 was dependent on p27. Our results suggested that the nuclear co-expression of p21 and p27 caused effective cell-cycle arrest, and thus the evaluation of the nuclear co-expression of p21 and p27 might help determine the effectiveness of BCG treatment.