Deceased Donor Kidney Nonuse: A Systematic Approach to Improvement.

A large number of procured kidneys continue not to be transplanted, while the waiting list remains high. Methods: We analyzed donor characteristics for unutilized kidneys in our large organ procurement organization (OPO) service area in a single year to determine the reasonableness of their nonuse and to identify how we might increase the transplant rate of these kidneys. Five experienced local transplant physicians independently reviewed unutilized kidneys to identify which kidneys they would consider transplanting in the future. Biopsy results, donor age, kidney donor profile index, positive serologies, diabetes, and hypertension were risk factors for nonuse. Results: Two-thirds of nonused kidneys had biopsies with high degree of glomerulosclerosis and interstitial fibrosis. Reviewers identified 33 kidneys as potentially transplantable (12%). Conclusions: Reducing the rate of unutilized kidneys in this OPO service area will be achieved by setting acceptable expanded donor characteristics, identifying suitable well-informed recipients, defining acceptable outcomes, and systematically evaluating the results of these transplants. Because the improvement opportunity will vary by region, to achieve a significant impact on improving the national nonuse rate, it would be useful for all OPOs, in collaboration with their transplant centers, to conduct a similar analysis.

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.

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.

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.

Towards a Rational Balanced Pancreatic and Islet Allocation Schema.

Allocation of donated organs for transplantation is a complex process that considers numerous factors such as donor, organ and candidate characteristics and practical issues such as geography. Whole pancreas and isolated islet transplantation are lifesaving for certain individuals with diabetes. Herein, we suggest a revised allocation schema that matches donor characteristics with candidate medical condition while allowing for geographic considerations. It is hoped that adoption of this schema will shorten allocation time, decrease organ waste and optimize the parity between organ donor characteristics and candidate state of health.

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.

Kidney allograft infarction associated with transplant renal artery stenosis in a COVID-19 kidney transplant recipient.

Kidney allograft infarction is rare, but an urgent condition that requires prompt intervention to avoid allograft loss. Renal artery thrombosis is the leading cause of infarction. Apart from traditional risk factors for thrombosis, emerging SARS-CoV-2 predisposes patients to thrombotic diseases both in arterial and venous vasculatures. We report a case of kidney transplant recipient with known transplant renal artery stenosis (TRAS) status post angioplasty with severe COVID-19, complicated by oliguric acute kidney injury requiring continuous renal replacement therapy (CRRT). She did not have a history of thromboembolic disease. The hospital course was complicated by new-onset atrial and ventricular fibrillation and cardiac arrest requiring multiple rounds of cardiopulmonary resuscitation. She had no signs of renal recovery, and an abdominal CT scan showed evidence of allograft infarcts. She underwent an allograft nephrectomy. Pathology revealed diffuse thrombotic microangiopathy involving glomeruli, arterioles, and arteries associated with diffuse cortical infarction with negative SARS-CoV-2 immunostain and in situ hybridization. This is the first case of kidney allograft infarct with a history of TRAS in a COVID-19 patient. Underlying TRAS and COVID-19-associated thrombosis in this patient are unique and likely play a key role in allograft infarction from arterial thrombosis. Recognizing risk factors and early therapy for allograft infarction may improve transplant outcomes.

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.

Interactive Virtual Reality Renal Models as an Educational and Preoperative Planning Tool for Laparoscopic Donor Nephrectomy.

OBJECTIVE: To evaluate the efficacy of interactive virtual reality (iVR) in providing a three-dimensional (3D) experience with the donor's anatomy for surgeons and patients, we present a retrospective, case-controlled study assessing the impact of iVR renal models prior to LDN on both surgical outcomes and patients' understanding of the procedure. MATERIALS AND METHODS: Twenty patients undergoing LDN were prospectively recruited; their contrast-enhanced CT scans were transformed into iVR models. An iVR platform allowed the surgeons to rotate and deconstruct the renal anatomy; patients could also view their anatomy as the procedure was explained to them. Questionnaires assessed surgeons' understanding of renal anatomy after CT alone and after CT+iVR. Surgeons also commented on whether iVR impacted their preoperative plan. Patients assessed their anatomical understanding and anxiety level before and after iVR. Surgical outcomes for the iVR cohort were compared to a retrospectively matched, non-iVR cohort of LDN patients. RESULTS: Surgeons altered their preoperative plan in 18 of 20 LDNs after viewing iVR models. Patients reported better understanding of their anatomy (5/5) and noted decreased preoperative anxiety (5/5) after viewing iVR. When compared to the non-iVR group, the iVR group had a 25% reduction in median operative time (P < .001). In terms of surgical outcomes, patients in the iVR group had a 40% lower median relative change in postoperative creatinine (P < .001). CONCLUSION: Preoperative viewing of iVR models altered the operative approach, decreased the operative time, and improved donor patient outcomes. iVR models also reduced patients' preoperative anxiety.

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.

Approach and Management of Hypertension After Kidney Transplantation.

Hypertension is one of the most common cardiovascular co-morbidities after successful kidney transplantation. It commonly occurs in patients with other metabolic diseases, such as diabetes mellitus, hyperlipidemia, and obesity. The pathogenesis of post-transplant hypertension is complex and is a result of the interplay between immunological and non-immunological factors. Post-transplant hypertension can be divided into immediate, early, and late post-transplant periods. This classification can help clinicians determine the etiology and provide the appropriate management for these complex patients. Volume overload from intravenous fluid administration is common during the immediate post-transplant period and commonly contributes to hypertension seen early after transplantation. Immunosuppressive medications and donor kidneys are associated with post-transplant hypertension occurring at any time point after transplantation. Transplant renal artery stenosis (TRAS) and obstructive sleep apnea (OSA) are recognized but common and treatable causes of resistant hypertension post-transplantation. During late post-transplant period, chronic renal allograft dysfunction becomes an additional cause of hypertension. As these patients develop more substantial chronic kidney disease affecting their allografts, fibroblast growth factor 23 (FGF23) increases and is associated with increased cardiovascular and all-cause mortality in kidney transplant recipients. The exact relationship between increased FGF23 and post-transplant hypertension remains poorly understood. Blood pressure (BP) targets and management involve both non-pharmacologic and pharmacologic treatment and should be individualized. Until strong evidence in the kidney transplant population exists, a BP of <130/80 mmHg is a reasonable target. Similar to complete renal denervation in non-transplant patients, bilateral native nephrectomy is another treatment option for resistant post-transplant hypertension. Native renal denervation offers promising outcomes for controlling resistant hypertension with no significant procedure-related complications. This review addresses the epidemiology, pathogenesis, and specific etiologies of post-transplant hypertension including TRAS, calcineurin inhibitor effects, OSA, and failed native kidney. The cardiovascular and survival outcomes related to post-transplant hypertension and the utility of 24-h blood pressure monitoring will be briefly discussed. Antihypertensive medications and their mechanism of actions relevant to kidney transplantation will be highlighted. A summary of guidelines from different professional societies for BP targets and antihypertensive medications as well as non-pharmacological interventions, including bilateral native nephrectomy and native renal denervation, will be reviewed.

Hyponatremia: A possible immuno-neuroendocrine interface with COVID-19 in a kidney transplant recipient.

There is fast-emerging, cumulative clinical data on coronavirus disease 2019 (COVID-19) in kidney transplant recipients. Although respiratory tract symptoms are often the initial presentation among kidney transplant recipients who contract COVID-19, other clinical features which may indicate underlying SARS-CoV-2-related inflammation, such as gastrointestinal symptoms, are not uncommon. Hyponatremia can develop and may reflect underlying inflammation. Interferon-6 is an important pro-inflammatory cytokine involved in the pathogenesis of severe COVID-19 complications and may play a role in the inappropriately higher secretion of antidiuretic hormone leading to hyponatremia. This pathway is the so-called immuno-neuroendocrine interface. Hyponatremia in COVID-19 has been reported in a few case series of non-kidney transplant patients and only one reported kidney transplant recipient. However, the clinical course and prognostic value of hyponatremia in this population are not described in detail. We report a kidney transplant recipient who was infected with COVID-19 and exhibited severe hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion. Hyponatremia is one of the clinical presentations of COVID-19, although less common, and may occur more frequently in kidney transplant recipients. Thus, the possible underlying immuno-neuroendocrine relationship related to the inflammatory process of COVID-19 leading to hyponatremia and its prognostic value are reviewed.

Inflammatory biomarkers in the blood and pancreatic tissue of organ donors that predict human islet isolation success and function.

The pancreas of brain-dead donors is the primary source of islets for transplantation. However, brain death mediates systemic inflammation, which may affect the quantity and quality of isolated islets. Our aim was to identify inflammatory biomarkers in donor blood and/or pancreatic tissue capable of predicting islet isolation success. Blood samples were collected from 21 pancreas donors and 14 healthy volunteers. Pancreatic tissue samples were also collected from the corresponding donor during organ procurement. Six serum cytokines were measured by a fluorescent bead-based immunoassay, and the expression of fifteen inflammatory target genes was quantified by quantitative reverse transcription polymerase chain reaction (RT-qPCR). There was no correlation between serum inflammatory cytokines and mRNA expression of the corresponding genes in peripheral blood mononuclear cells (PBMCs) or pancreatic tissue. The IL6 expression in pancreatic tissue correlated negatively with post-isolation islet yield. Islets isolated from donors highly expressing IFNG in PBMCs and MAC1 in pancreatic tissue functioned poorly in vivo when transplanted in diabetic NODscid mice. Furthermore, the increased MAC1 in pancreatic tissue was positively correlated with donor hospitalization time. Brain death duration positively correlated with higher expression of IL1B in PBMCs and TNF in both PBMCs and pancreatic tissue but failed to show a significant correlation with islet yield and in vivo function. The study indicates that the increased inflammatory genes in donor pancreatic tissues may be considered as biomarkers associated with poor islet isolation outcome.

Novel options for failing allograft in kidney transplanted patients to avoid or defer dialysis therapy.

PURPOSE OF REVIEW: Despite improvement in short-term renal allograft survival in recent years, renal transplant recipients (RTR) have poorer long-term allograft outcomes. Allograft function slowly declines with periods of stable function similar to natural progression of chronic kidney disease in nontransplant population. Nearly all RTR transitions to failing renal allograft (FRG) period and require transition to dialysis. Conservative chronic kidney disease management before transition to end-stage renal disease is an increasingly important topic; however, there is limited data in RTR regarding how to delay dialysis initiation with conservative management. RECENT FINDINGS: Since immunological and nonimmunological factors unique to RTR contribute to decline in allograft function, therapies to slow progression of FRG should take both sets of factors into account. Renal replacement therapy either incremental dialysis or rekidney transplantation should be explored. This required taking benefits and risks of continuing immunosuppressive medications into account when allograft nephrectomy may be necessary. SUMMARY: FRG may benefit from various interventions to slow progression of worsening allograft function. Until there are stronger evidence to guide interventions to preserve renal function, extrapolating evidence from nontransplant patients and clinical judgment are necessary. The goal is to provide individualized care for conservative management of RTR with FRG.

Current Management of Patients With Acquired Solitary Kidney.

Persons with acquired solitary kidney, including those who have had a unilateral nephrectomy for living kidney donation, renal malignancies, or trauma, have decreased renal mass that leads to increased intraglomerular pressure and glomerular hyperfiltration. These physiologic adaptations of solitary kidney may exacerbate other preexisting and genetic conditions that could create a predisposition to or worsen glomerular pathologies, leading to unfavorable renal outcomes. Hence, these persons may benefit from special care and lifestyle modifications, including nutritional interventions. There is a lack of consensus and evidence for proper surveillance and management after nephrectomy, and misconceptions in both directions of having a "normal" versus "abnormal" kidney status may cause confusion among patients and healthcare providers pertaining to long-term kidney health monitoring and management. We have reviewed available data on the impact of lifestyle modifications, particularly nutritional measures, and pharmacologic interventions, on short- and long-term outcomes after nephrectomy. We recommend avoidance of excessively high dietary protein intake (>1 g/kg per day) and high dietary sodium intake (>4 grams/d), adequate dietary fiber intake from plant-based foods, a target body mass index of <30 kg/m2 (in non-athletes and non-bodybuilders), and judicious management of risk factors of progressive chronic kidney disease (CKD), and future studies should help to better determine optimal care practices for these persons.

Precision Medicine and Personalized Approach to Renal Transplantation.

Successful renal transplantation is a highly effective endeavor that improves and prolongs the lives of patients with chronic kidney disease. Transplant surgery and immunosuppression carries risk and the demand for donor kidneys outstrips supply by far. These realities mandate thoughtful allocation and utilization of this limited resource to select candidates. As the criteria for candidates and donor grafts continue to expand, the field must adapt and seek new approaches. The complex process-from evaluation of candidates, transplant surgery, immunosuppression, and follow-up care after transplantation-is, of necessity, tightly structured and regulated. However, each patient has distinctive characteristics that must be taken into account to optimize individual outcomes. The personalized approach to renal transplantation, which uses precision medicine concepts, identifies unique aspects of candidates/recipients that require consideration using a combination of time-honored guidelines, emerging concepts, new medications, and refinements of care.

Effective endothelial cell and human pluripotent stem cell interactions generate functional insulin-producing beta cells.

AIMS/HYPOTHESIS: Endothelial cells (ECs) play an essential role in pancreatic organogenesis. We hypothesise that effective in vitro interactions between human microvascular endothelial cells (HMECs) and human pluripotent stem cells (hPSCs) results in the generation of functional pancreatic beta cells. METHODS: Embryoid bodies (EBs) derived from hPSCs were cultured alone (controls) or with ECs in collagen gels. Subsequently, cells were analysed for pancreatic beta cell markers, and then isolated and expanded. Insulin secretion in response to glucose was evaluated in vitro by static and dynamic (perifusion) assays, and in vivo by EB transplantation into immunodeficient mice. RESULTS: Co-cultured EBs had a higher expression of mature beta cells markers and enhanced insulin secretion in vitro, compared with controls. In mice, transplanted EBs had higher levels of human C-peptide secretion with a significant reduction in hyperglycaemia after the selective destruction of native pancreatic beta cells. In addition, there was significant in vitro upregulation of bone morphogenetic proteins 2 and 4 (BMP-2, 4) in co-cultured cells, compared with controls. CONCLUSIONS/INTERPRETATION: ECs provide essential signalling in vitro, such as activation of the BMP pathway, for derivation of functional insulin-producing beta cells from hPSCs.