Borderline rejection: To treat or not to treat?

INTRODUCTION: It is unclear whether kidney transplant recipients with a biopsy diagnosis as a "borderline" acute T-cell mediated rejection (TCMR) requires the treatment with intravenous (iv) steroids pulse plus/minus intensification of the maintenance therapy (TRT) in comparison with the simple clinical follow-up (F-UP). METHODS: We retrospectively followed a consecutive series of kidney transplant recipients diagnosed with a borderline acute TCMR at biopsy by surveillance or clinical indication for 12 months and compared TRT and F-UP groups. We evaluated trends in renal function by measuring estimated glomerular filtration rate (eGFR) using multiple regression models. Repeated eGFR measures (REML) were adjusted for potential confounding factors for 12 months. The difference in 12-month eGFR values were observed in the TRT vs F-UP groups, type of biopsy, as well as the surveillance vs. clinical outcomes. RESULTS: Out of 59 included patients, 37% of them were in the TRT group and remaining 63% in the F-UP group. As expected, the TRT group had, at the time of biopsy, lower eGFR value of 39.0 ml/min/m2 [16.5] in comparison to 49.6 [19.6] ml/min/m2 in the F-UP group (P = 0.043), Similarly, the TRT group required more frequent clinical biopsies vs. F-UP group (68% vs. 32%; P = 0.014). However, the TRT group recovered kidney function reaching the eGFR values of the F-UP group at 12 months; the increase being significant only in patients who received indication biopsies (P < 0.001). The estimated adjusted TRT effect on 12-month eGFR change after indication biopsy was improved by +15.8 ml/min/1.73m2 (95%CI: +0.1 to +31.4 ml/min/1.73 m2; P = 0.048 by three-way interaction term) compared to the F-UP group. CONCLUSION: Our preliminary study supports the indication for the treatment of acute borderline TCMR only in cases with biopsies performed by clinical indication.

Immunosuppression of HLA identical living-donor kidney transplant recipients: A systematic review.

BACKGROUND: Kidney transplant (KT) recipients of HLA identical siblings (HLAid) have lower immunological risk, but there are no specific recommendations for immunosuppression. Our aim was to analyze evidence about results from HLAid living-donor recipients under different immunosuppression in the current era of immunological risk assessment. METHODS: Systematic review of studies describing associations between outcomes of HLAid living-donor KT recipients according to their immunological risk and applied immunosuppression. RESULTS: From 1351 studies, 16 (5636 KT recipients) were included in the analysis. All studies were retrospective, ten comparing immunosuppression strategies, and six immunological risk strata. Of those ten, six studies were published in 1990 or earlier and only three included tacrolimus. The evidence is poor, and the inclusion of calcineurin inhibitors does not demonstrate better results. Furthermore, only few studies describe different immunosuppression regimens according to the patient immunological risk and, in general, they do not include the assessment with new solid phase assays. CONCLUSIONS: There are no studies analyzing the association of outcomes of HLAid KT recipients with current immunological risk tools. In the absence of evidence, no decision or proposal of immunosuppression adapted to modern immunological risk assessment can be made currently by the Descartes Working Group.

Sarcopenic obesity and its relation with muscle quality and mortality in patients on chronic hemodialysis.

BACKGROUND & AIMS: Sarcopenia is prevalent in patients with end-stage kidney disease (ESKD) on hemodialysis (HD), and is associated with poor outcomes, while obesity may be protective. Sarcopenic obesity is associated with increased frailty, morbidity and mortality in the general population. Myosteatosis, i.e., muscle fat infiltration, has major effects on muscle strength and physical performance, but is poorly investigated in the nephrology setting. In the present study we aimed to assess the association between sarcopenic obesity, as diagnosed by abdominal CT, and mortality. Moreover, the relationship between myosteatosis, sarcopenic obesity and mortality was also investigated. METHODS: This is a retrospective study in which ESKD patients on HD submitted to unenhanced abdominal CT for clinical reasons at least 6 months after dialysis initiation were evaluated for sarcopenic obesity and myosteatosis, defined as intermuscular fat area and low attenuation muscle area. Sarcopenic obesity was diagnosed in cases of low abdominal skeletal muscle area and high total fat area. Receiver-operating characteristics (ROC) analysis with Youden index was used to determine the cut-off for high total fat area. Intermuscular fat area and low attenuation muscle area were evaluated by applying the Hounsfield unit of interest (-190; -30, and -29; +29 respectively). Cox regression analysis was used to evaluate the association between predictors and mortality risk. RESULTS: We enrolled 212 patients, aged 68.8 (±14.7) years, 65.5% (139/212) male. Median follow-up was 19.7 (interquartile range [IQR] 2.7-35) months. Sarcopenic obesity was diagnosed in 19.8% of patients and was associated with increased mortality (HR: 3.29 (1.72; 6.27), P < 0.001), and with the presence of myosteatosis. Both intermuscular fat area and low attenuation muscle area were associated with increased mortality in adjusted analyses. CONCLUSIONS: Patients with sarcopenic obesity have increased myosteatosis. Sarcopenic obesity and myosteatosis are associated with increased mortality in patients on HD.

The 3-Step Model of informed consent for living kidney donation: a proposal on behalf of the DESCaRTES Working Group of the European Renal Association.

Living donation challenges the ethical principle of non-maleficence in that it exposes healthy persons to risks for the benefit of someone else. This makes safety, informed consent (IC) and education a priority. Living kidney donation has multiple benefits for the potential donor, but there are also several known short- and long-term risks. Although complete standardization of IC is likely to be unattainable, studies have emphasized the need for a standardized IC process to enable equitable educational and decision-making prospects for the prevention of inequities across transplant centers. Based on the Three-Talk Model of shared decision-making by Elwyn et al., we propose a model, named 3-Step (S) Model, where each step coincides with the three ideal timings of the process leading the living donor to the decision to pursue living donation: prior to the need for kidney replacement therapy (team talk); at the local nephrology unit or transplant center, with transplant clinicians and surgeons prior to evaluations start (option talk); and throughout evaluation, after having learned about the different aspects of donation, especially if there are second thoughts or doubts (decision talk). Based on the 3-S Model, to deliver conceptual and practical guidance to nephrologists and transplant clinicians, we provide recommendations for standardization of the timing, content, modalities for communicating risks and assessment of understanding prior to donation. The 3-S Model successfully allows an integration between standardization and individualization of IC, enabling a person-centered approach to potential donors. Studies will assess the effectiveness of the 3-S Model in kidney transplant clinical practice.

Ethical and medical dilemmas in paid living kidney donor transplantation.

Due to the shortage of deceased and genetically- or emotionally-related living donors, living unrelated paid donor (LURpD) kidney transplantation has been considered; however, this practice may result in medical, ethical and social dilemmas, induce organ trading (commodification), and even criminal activities. Commodification also risks undermining public trust in the transplant system and impeding the development of proper altruistic or deceased donor programs by ignoring altruism, volunteerism, and dignity. However, despite many objections by authoritative organizations, black market practices are involved in up to 10% of all transplants worldwide. The authors strongly discourage any payment or rewards for organ donation, and instead urge the governments of all countries to provide adequate and accessible kidney health care. However, it is an undeniable fact that paid-living donor transplantation is increasing despite all objections, disapprovals and regulations. We feel it as our responsibility not to ignore this uncertain and undesirable practice, but rather to underline the necessity for strict rules and prohibitions to minimize unacceptable medical, social and ethical risks as long as it exists. Furthermore, economic profit, be it direct or indirect, must not be the goal of those involved, and the employment of intermediaries must be avoided entirely. Additionally, the donor should be in a position where not donating has no detrimental effect on his/her future in any way (free agency). In our view, every country has the obligation and responsibility to provide adequate kidney health care and to make kidney transplantation accessible to those in need. This provision is key to stop transplant tourism and commercialization of kidney transplantation. The nephrology community has a duty to establish structures that optimize organ availability within strict ethical limits. The legal position of LURpD varies considerably worldwide. Strictly respecting each country's legislation and local values is mandatory to minimize medical and ethical risks and controversies.

Kidney transplantation during mass disasters - from COVID-19 to other catastrophes A Consensus Statement by the DESCARTES Working Group and Ethics Committee of the ERA.

Mass disasters are characterized by a disparity between health care demand and supply, which hampers complex therapies like kidney transplantation. Considering scarcity of publications on previous disasters, we reviewed transplantation practice during the recent COVID-19 pandemic, and dwelled upon this experience for guiding transplantation strategies in the future pandemic and non-pandemic catastrophes. We strongly suggest continuing transplantation programs during mass disasters, if medical and logistic operational circumstances are appropriate. Postponing transplantations from living donors and referral of urgent cases to safe regions or hospitals are justified. Specific preventative measures in anticipated disasters (such as vaccination programs during pandemics or evacuation in case of hurricanes or wars) may be useful to minimize risks. Immunosuppressive therapies should consider stratifying risk status and avoiding heavy immune suppression in patients with a low probability of therapeutic success. Discharging patients at the earliest convenience is justified during pandemics, whereas delaying discharge is reasonable in other disasters, if infrastructural damage results in unhygienic living environments for the patients. In the outpatient setting, telemedicine is a useful approach to reduce the patient load to hospitals, to minimize the risk of nosocomial transmission in pandemics and the need for transport in destructive disasters. If it comes down to save as many lives as possible, some ethical principles may vary in function of disaster circumstances, but elementary ethical rules are non-negotiable. Patient education is essential to minimize disaster-related complications and to allow for an efficient use of health care resources.

Kidney transplantation during mass disasters - from COVID-19 to other catastrophes.

Mass disasters are characterized by a disparity between health care demand and supply, which hampers complex therapies like kidney transplantation. Considering scarcity of publications on previous disasters, we reviewed transplantation practice during the recent COVID-19 pandemic, and dwelled upon this experience for guiding transplantation strategies in the future pandemic and non-pandemic catastrophes. We strongly suggest continuing transplantation programs during mass disasters, if medical and logistic operational circumstances are appropriate. Postponing transplantations from living donors and referral of urgent cases to safe regions or hospitals are justified. Specific preventative measures in anticipated disasters (such as vaccination programs during pandemics or evacuation in case of hurricanes or wars) may be useful to minimize risks. Immunosuppressive therapies should consider stratifying risk status and avoiding heavy immune suppression in patients with a low probability of therapeutic success. Discharging patients at the earliest convenience is justified during pandemics, whereas delaying discharge is reasonable in other disasters, if infrastructural damage results in unhygienic living environments for the patients. In the outpatient setting, telemedicine is a useful approach to reduce the patient load to hospitals, to minimize the risk of nosocomial transmission in pandemics and the need for transport in destructive disasters. If it comes down to save as many lives as possible, some ethical principles may vary in function of disaster circumstances, but elementary ethical rules are non-negotiable. Patient education is essential to minimize disaster-related complications and to allow for an efficient use of health care resources.

Detecting, preventing and treating non-adherence to immunosuppression after kidney transplantation.

Medication non-adherence (MNA) is a major issue in kidney transplantation and it is associated with increased risk of rejection, allograft loss, patients' death and higher healthcare costs. Despite its crucial importance, it is still unclear what are the best strategies to diagnose, prevent and treat MNA. MNA can be intentional (deliberate refusal to take the medication as prescribed) or unintentional (non-deliberate missing the prescribed medication). Its diagnosis may rely on direct methods, aiming at measuring drug ingestions, or indirect methods that analyse the habits of patients to adhere to correct drug dose (taking adherence) and interval (time adherence). Identifying individual risk factors for MNA may provide the basis for a personalized approach to the treatment of MNA. Randomized control trials performed so far have tested a combination of strategies, such as enhancing medication adherence through the commitment of healthcare personnel involved in drug distribution, the use of electronic reminders, therapy simplification or various multidisciplinary approaches to maximize the correction of individual risk factors. Although most of these approaches reduced MNA in the short-term, the long-term effects on MNA and, more importantly, on clinical outcomes remain unclear. In this review, we provide a critical appraisal of traditional and newer methods for detecting, preventing and treating non-adherence to immunosuppression after kidney transplantation from the perspective of the practising physician.

Issues regarding COVID-19 in kidney transplantation in the ERA of the Omicron variant: a commentary by the ERA Descartes Working Group.

The Omicron variant, which has become the dominant strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide, brings new challenges to preventing and controlling the infection. Moreover, the widespread implementation of vaccination policies before and after transplantation, and the development of new prophylactic and treatment strategies for coronavirus disease 2019 (COVID-19) over the past 12-18 months, has raised several new issues concerning kidney transplant recipients. In this special report, the ERA DESCARTES (Developing Education Science and Care for Renal Transplantation in European States) Working Group addresses several questions related to everyday clinical practice concerning kidney transplant recipients and to the assessment of deceased and live kidney donors: what is the current risk of severe disease and of breakthrough infection, the optimal management of immunosuppression in kidney transplant recipients with COVID-19, the role of passive immunization and the efficacy of antiviral drugs in ambulatory patients, the management of drug-to-drug interactions, safety criteria for the use of SARS-CoV-2-positive donors, issues related to the use of T cell depleting agents as induction treatment, and current recommendations for shielding practices.

The Association of New-Onset Acute Kidney Injury and Mortality in Critically Ill Patients With COVID-19 With Less Severe Clinical Conditions at Admission: A Moderation Analysis.

Acute kidney injury (AKI), electrolyte, and acid-base disorders complicate the clinical course of critically ill patients with coronavirus-associated disease (COVID-19) and are associated with poor outcomes. It is not known whether the severity of clinical conditions at admission in the intensive care unit (ICU) changes the clinical significance of AKI and/or electrolyte or acid-base disorders developing during ICU stay. We conducted a retrospective study in critically ill patients with COVID-19 to evaluate whether the severity of clinical conditions at admission in the ICU affects the impact of AKI and of serum electrolytes or acid-base status on mortality. We carried out a 28-day retrospective follow-up study on 115 critically ill patients consecutively admitted to ICU for severe COVID-19 at a tertiary care university hospital and surviving longer than 24 h. We collected baseline demographic and clinical characteristics, and longitudinal data on kidney function, kidney replacement therapy, serum electrolytes, and acid-base status. We used Cox proportional hazards multiple regression models to test the interaction between the time-varying variates new-onset AKI or electrolyte or acid-base disorders and Sequential Organ Failure Assessment (SOFA) or Acute Physiology and Chronic Health Evaluation II (APACHE II) score at admission. After adjusting for age, sex, Charlson's comorbidity index, and AKI present at ICU admission, new-onset AKI was significantly associated with 28-day mortality only in the patients in the lowest and middle SOFA score tertiles [lowest SOFA tertile, hazard ratio (HR) 4.27 (95% CI: 1.27-14.44; P = 0.019), middle SOFA tertile, HR 3.17 (95% CI: 1.11-9.04, P = 0.031), highest SOFA tertile, HR 0.77 (95% CI: 0.24-2.50; P = 0.66); P = 0.026 for interaction with SOFA as a continuous variable]. After stratifying for APACHE II tertile, results were similar [adjusted HR (aHR) in the lowest tertile 6.24 (95% CI: 1.85-21.03, P = 0.003)]. SOFA or APACHE II at admission did not affect the relationship of serum electrolytes and acid-base status with mortality, except for new-onset acidosis which was associated with increased mortality, with the HR of death increasing with SOFA or APACHE II score (P < 0.001 and P = 0.013, respectively). Thus, unlike in the most severe critically ill patients admitted to the ICU for COVID-19, in patients with the less severe conditions at admission the development of AKI during the stay is a strong indicator of increased hazard of death.

Management of obesity in kidney transplant candidates and recipients: A clinical practice guideline by the DESCARTES Working Group of ERA.

The clinical practice guideline Management of Obesity in Kidney Transplant Candidates and Recipients was developed to guide decision-making in caring for people with end-stage kidney disease (ESKD) living with obesity. The document considers the challenges in defining obesity, weighs interventions for treating obesity in kidney transplant candidates as well as recipients and reflects on the impact of obesity on the likelihood of wait-listing as well as its effect on transplant outcomes. It was designed to inform management decisions related to this topic and provide the backdrop for shared decision-making. This guideline was developed by the European Renal Association's Developing Education Science and Care for Renal Transplantation in European States working group. The group was supplemented with selected methodologists to supervise the project and provide methodological expertise in guideline development throughout the process. The guideline targets any healthcare professional treating or caring for people with ESKD being considered for kidney transplantation or having received a donor kidney. This includes nephrologists, transplant physicians, transplant surgeons, general practitioners, dialysis and transplant nurses. Development of this guideline followed an explicit process of evidence review. Treatment approaches and guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence and the strength of recommendations followed the Grading of Recommendations Assessment, Development and Evaluation approach. Limitations of the evidence are discussed and areas of future research are presented.

Chemotherapy, targeted therapy and immunotherapy: Which drugs can be safely used in the solid organ transplant recipients?

In solid organ transplant recipients, cancer is associated with worse prognosis than in the general population. Among the causes of increased cancer-associated mortality, are the limitations in selecting the optimal anticancer regimen in solid organ transplant recipients, because of the associated risks of graft toxicity and rejection, drug-to-drug interactions, reduced kidney or liver function, and patient frailty and comorbid conditions. The advent of immunotherapy has generated further challenges, mainly because checkpoint inhibitors increase the risk of rejection, which may have life-threatening consequences in recipients of life-saving organs. In general, there are no safe or unsafe anticancer drugs. Rather, the optimal choice of the anticancer regimen results from a careful risk/benefit assessment, from the awareness of potential pharmacokinetic and pharmacodynamic drug-to-drug interactions, and of the risk of drug overexposure in patients with kidney or liver dysfunction. In this review, we summarize general principles that may help the oncologists and transplant physicians in the multidisciplinary management of recipients of solid organ transplantation with cancer who are candidates for chemotherapy, targeted therapy, or immunotherapy.

Acute Kidney Injury (AKI) before and after Kidney Transplantation: Causes, Medical Approach, and Implications for the Long-Term Outcomes.

Acute kidney injury (AKI) is a common finding in kidney donors and recipients. AKI in kidney donor, which increases the risk of delayed graft function (DGF), may not by itself jeopardize the short- and long-term outcome of transplantation. However, some forms of AKI may induce graft rejection, fibrosis, and eventually graft dysfunction. Therefore, various strategies have been proposed to identify conditions at highest risk of AKI-induced DGF, that can be treated by targeting the donor, the recipient, or even the graft itself with the use of perfusion machines. AKI that occurs early post-transplant after a period of initial recovery of graft function may reflect serious and often occult systemic complications that may require prompt intervention to prevent graft loss. AKI that develops long after transplantation is often related to nephrotoxic drug reactions. In symptomatic patients, AKI is usually associated with various systemic medical complications and could represent a risk of mortality. Electronic systems have been developed to alert transplant physicians that AKI has occurred in a transplant recipient during long-term outpatient follow-up. Herein, we will review most recent understandings of pathophysiology, diagnosis, therapeutic approach, and short- and long-term consequences of AKI occurring in both the donor and in the kidney transplant recipient.

COVID-19 and kidney transplantation: Results from the TANGO International Transplant Consortium.

Kidney transplant recipients may be at a high risk of developing critical coronavirus disease 2019 (COVID-19) illness due to chronic immunosuppression and comorbidities. We identified hospitalized adult kidney transplant recipients at 12 transplant centers in the United States, Italy, and Spain who tested positive for COVID-19. Clinical presentation, laboratory values, immunosuppression, and treatment strategies were reviewed, and predictors of poor clinical outcomes were determined through multivariable analyses. Among 9845 kidney transplant recipients across centers, 144 were hospitalized due to COVID-19 during the 9-week study period. Of the 144 patients, 66% were male with a mean age of 60 (±12) years, and 40% were Hispanic and 25% were African American. Prevalent comorbidities included hypertension (95%), diabetes (52%), obesity (49%), and heart (28%) and lung (19%) disease. Therapeutic management included antimetabolite withdrawal (68%), calcineurin inhibitor withdrawal (23%), hydroxychloroquine (71%), antibiotics (74%), tocilizumab (13%), and antivirals (14%). During a median follow-up period of 52 days (IQR: 16-66 days), acute kidney injury occurred in 52% cases, with respiratory failure requiring intubation in 29%, and the mortality rate was 32%. The 46 patients who died were older, had lower lymphocyte counts and estimated glomerular filtration rate levels, and had higher serum lactate dehydrogenase, procalcitonin, and interleukin-6 levels. In sum, hospitalized kidney transplant recipients with COVID-19 have higher rates of acute kidney injury and mortality.

Frailty and Sarcopenia in Older Patients Receiving Kidney Transplantation.

Kidney transplantation is the treatment of choice for most of the patients with end-stage renal disease (ESRD). It improves quality of life, life expectancy, and has a lower financial burden to the healthcare system in comparison to dialysis. Every year more and more older patients are included in the kidney transplant waitlist. Within this patient population, transplanted subjects have better survival and quality of life as compared to those on dialysis. It is therefore crucial to select older patients who may benefit from renal transplantation, as well as those particularly at risk for post-transplant complications. Sarcopenia and frailty are frequently neglected in the evaluation of kidney transplant candidates. Both conditions are interrelated complex geriatric syndromes that are linked to disability, aging, comorbidities, increased mortality, and graft failure post-transplantation. Chronic kidney disease (CKD) and more importantly ESRD are characterized by multiple metabolic complications that contribute for the development of sarcopenia and frailty. In particular, anorexia, metabolic acidosis and chronic low-grade inflammation are the main contributors to the development of sarcopenia, a key component in frail transplant candidates and recipients. Both frailty and sarcopenia are considered to be reversible. Frail patients respond well to multiprofessional interventions that focus on the patients' positive frailty criteria, while physical rehabilitation and oral supplementation may improve sarcopenia. Prospective studies are still needed to evaluate the utility of formally measuring frailty and sarcopenia in the older candidates to renal transplantation as part of the transplant evaluation process.