Immunosuppressive Management Research Articles

Immunosuppression considerations in simultaneous organ transplant.

Solid organ transplantation is a life-saving procedure for patients in the end stage of heart, lung, kidney, and liver failure. For patients with more than one failing organ, simultaneous organ transplantation has emerged as a viable treatment option. Immunosuppression strategies and outcomes for simultaneous organ transplant recipients have been reported, but often involve limited populations. Transplanting dual organs poses challenges in terms of balancing immunosuppression with immunologic risk and allograft damage from surgical complications. Furthermore, transplanting certain organs can impose considerations on the management of immunosuppression. For example, liver allografts may confer immunologic privilege and lower rates of rejection of other allografts. This review article evaluates immunosuppression strategies for simultaneous kidney-pancreas, liver-kidney, heart-kidney, heart-liver, heart-lung, lung-liver, and lung-kidney transplants. To date, no comprehensive review exists to address immunosuppressive strategies in simultaneous organ transplant populations. Our review summarizes the available literature and provides evidence-based recommendations regarding immunosuppression strategies in simultaneous organ transplant recipients.

Plasma cell rich acute rejection: Risk factors, treatment and outcomes.

Plasma cell-rich rejection is a rare and poorly defined entity. Its treatment is not clearly defined and has universally poor prognosis. More data should be published from various transplant centers around the world to identify the treatment that has the best outcomes and to formulate treatment guidelines for these cases. It is a retrospective analysis of kidney biopsies form 2008 to 2018. Four hundred biopsied were screened and 55 were found to have features of rejection and among them, 13 had plasma cell-rich rejection. Data of treatment given and the graft survival outcomes in these cases were retrieved by medical records. One patient had complete recovery, three had graft loss and the remaining nine had permanent decline in glomerular filtration rate. Decrease in immunosuppression and presence of infection are risk factors for plasma cell-rich acute rejection (PCAR). It can be acute cell-mediated rejection (ACR)/antibody-mediated rejection (AMR)/ACR+AMR. Resistant rejection, ACR+AMR, C4d positivity, and severe interstitial inflammation are poor prognostic factors. Overzealous decrease in immunosuppression should not be done. Management of immunosuppression during infection is most critical for the development of PCAR. Bortezomib is emerging as a therapeutic modality for the treatment of PCAR.

Effect of COVID-19 on Kidney Disease Incidence and Management.

The COVID-19 outbreak has had substantial effects on the incidence and management of kidney diseases, including AKI, ESKD, GN, and kidney transplantation. Initial reports from China suggested a lower AKI incidence in patients with COVID-19, but more recent studies from North America reveal a much higher incidence, likely due to the higher prevalence of comorbid conditions, such as hypertension, diabetes, and CKD. AKI in this setting is associated with worse outcomes, including the requirement for vasopressors or mechanical ventilation and death. Performing RRT in those with AKI poses challenges, such as limiting exposure of staff, preserving PPE, coagulopathy, and hypoxemia due to acute respiratory distress syndrome. Continuous RRT is the preferred modality, with sustained low-efficiency dialysis also an option, both managed without 1:1 hemodialysis nursing support. Regional citrate is the preferred anticoagulation, but systemic unfractionated heparin may be used in patients with coagulopathy. The ultrafiltration rate has to be set carefully, taking into consideration hypotension, hypoxemia, and responsiveness to presser and ventilatory support. The chance of transmission puts in-center chronic hemodialysis and other immunosuppressed patients at particularly increased risk. Limited data show that patients with CKD are also at increased risk for more severe disease, if infected. Little is known about the virus's effects on immunocompromised patients with glomerular diseases and kidney transplants, which introduces challenges for management of immunosuppressant regimens. Although there are no standardized guidelines regarding the management of immunosuppression, several groups recommend stopping the antimetabolite in hospitalized transplant patients and continuing a reduced dose of calcineurin inhibitors. This comprehensive review critically appraises the best available evidence regarding the effect of COVID-19 on the incidence and management of kidney diseases. Where evidence is lacking, current expert opinion and clinical guidelines are reviewed, and knowledge gaps worth investigation are identified.

Considerations and controversies of pharmacologic management of the pediatric kidney transplant recipient.

Pediatric kidney transplantation has experienced considerable growth and improvement in patient and allograft outcomes over the past 20years, in part due to advancements in immunosuppressive regimens and management. Despite this progress, care for this unique population can be challenging due to limited pediatric transplant data and trials, intricacies related to differences in children and adolescents compared with their adult counterparts, and limitations to long-term survival facing all solid organ transplant populations. Immunosuppression and infection prevention practices vary from one pediatric transplant center to another and clinical controversies exist surrounding treatment and dosing. This review aims to summarize key aspects of pharmacologic management in this population and present pertinent data that describe the influence of practice to serve as a resource for practitioners caring for this unique specialty patient population. Additionally, this review highlights select controversies that exist within pediatric kidney transplantation.

Practicing With Uncertainty: Kidney Transplantation During the COVID-19 Pandemic

The coronavirus disease 2019 (COVID-19) pandemic required transplant nephrologists, surgeons, and care teams to make decisions about the full spectrum of transplant program operations and clinical practices in the absence of experience or data. Initially, across the country, there was a reduction in kidney transplant procedures and a striking pause in the conduct of living donation and living-donor transplant surgeries. Aspects of candidate evaluation and follow-up rapidly converted to telehealth. Months into the pandemic, much has been learned from experiences worldwide, yet many questions remain. In this Perspective, we reflect on some of the practice decisions made by the transplant community in the initial response to the pandemic and consider lessons learned, including those related to the risks, benefits, and logistical considerations of proceeding with versus delaying deceased-donor transplantation, living donation, and living-donor transplantation during the pandemic. We review the evolution of therapeutic strategies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their use in transplant recipients, current consensus related to immunosuppression management in infected transplant recipients, and emerging information on vaccination against SARS-CoV-2. We share our thoughts on research priorities, discuss the areas in which we are still practicing with uncertainty, and look ahead to the next phase of the pandemic response.

Characteristics and Outcomes of COVID-19 in Patients With Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

The coronavirus disease 2019 (COVID-19) pandemic has not only stressed medical systems with its acute presentations but also conferred an additional permutation to the management of various established diseases. This includes patients with autoimmune disease requiring immunosuppression. The optimal management of immunosuppression during the pandemic and in those with acute infection still remains a matter of debate. We recently reported significant disruption on the chronic care of patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV) as a result of the pandemic, with a sizeable proportion of patients having their immunosuppression held and that the risk of disease relapse likely far outweighs the risk of COVID-19.

High mortality associated with gram-negative bacterial bloodstream infection in liver transplant recipients undergoing immunosuppression reduction.

BACKGROUNDImmunosuppression is an important factor in the incidence of infections in transplant recipient. Few studies are available on the management of immunosuppression (IS) treatment in the liver transplant (LT) recipients complicated with infection. The aim of this study is to describe our experience in the management of IS treatment during bacterial bloodstream infection (BSI) in LT recipients and assess the effect of temporary IS withdrawal on 30 d mortality of recipients presenting with severe infection.AIMTo assess the effect of temporary IS withdrawal on 30 d mortality of LT recipients presenting with severe infection.METHODSA retrospective study was conducted with patients diagnosed with BSI after LT in the Department of Liver Surgery, Renji Hospital from January 1, 2016 through December 31, 2017. All recipients diagnosed with BSI after LT were included. Univariate and multivariate Cox regression analysis of risk factors for 30 d mortality was conducted in the LT recipients with Gram-negative bacterial (GNB) infection.RESULTSSeventy-four episodes of BSI were identified in 70 LT recipients, including 45 episodes of Gram-positive bacterial (GPB) infections in 42 patients and 29 episodes of GNB infections in 28 patients. Overall, IS reduction (at least 50% dose reduction or cessation of one or more immunosuppressive agent) was made in 28 (41.2%) cases, specifically, in 5 (11.9%) cases with GPB infections and 23 (82.1%) cases with GNB infections. The 180 d all-cause mortality rate was 18.5% (13/70). The mortality rate in GNB group (39.3%, 11/28) was significantly higher than that in GPB group (4.8%, 2/42) (P = 0.001). All the deaths in GNB group were attributed to worsening infection secondary to IS withdrawal, but the deaths in GPB group were all due to graft-versus-host disease. GNB group was associated with significantly higher incidence of intra-abdominal infection, IS reduction, and complete IS withdrawal than GPB group (P < 0.05). Cox regression showed that rejection (adjusted hazard ratio 7.021, P = 0.001) and complete IS withdrawal (adjusted hazard ratio 12.65, P = 0.019) were independent risk factors for 30 d mortality in patients with GNB infections after LT. CONCLUSIONIS reduction is more frequently associated with GNB infection than GPB infection in LT recipients. Complete IS withdrawal should be cautious due to increased risk of mortality in LT recipients complicated with BSI.IS

Incidence, risk factors, and outcomes of post‐transplant erythrocytosis after kidney transplantation

The incidence, risk factors, and outcomes of kidney transplant recipients (KTRs) with post-transplant erythrocytosis (PTE) in the modern era of strong, protocolized immunosuppressive management are unknown. In this study, we aim to identify the incidence and risk factors of PTE and outcomes associated with PTE. This study examined adult KTRs transplanted at our hospital between 01/2001 and 12/2016. Controls were KTRs without PTE and selected in a 1:5 ratio using incident density sampling. Patient survival, graft survival, and vascular thromboembolism (VTE) incidence were outcomes of interest. Of 4,317 kidney transplants during the study period, 214 (5%) had PTE and were compared with controls. In the multivariate analysis, recipients with older age (HR: 0.97, 95% CI 0.96-0.99, p=.001) were less likely to develop PTE, while male gender (HR: 3.2; 95% CI: 1.92-5.3, p<.001) and non-preemptive transplant (HR: 3.86, 95% CI 1.56-9.56, p=.003) were associated with increased risk of PTE. After adjustment for confounding factors, PTE was not associated with patient mortality (HR: 0.99, 95% CI 0.69-1.42, p=.97), graft failure (HR: 1.11, 95% CI 0.68-1.80, p=.69), or VTE (HR: 1.07, 95% CI 0.59-1.96, p=.81). The incidence of PTE is still substantial in this era, but with proper management PTE does not impact patient or graft survival.

Management of Immunosuppression After Kidney Transplant Failure: Effect on Patient Sensitization

BackgroundImmunosuppressive treatment is often interrupted in the first months following kidney transplant failure (KTF) to limit side effects. The aim of this study was to assess the effect of prolonged treatment (PT) of more than 3 months’ duration after KTF on HLA sensitization and treatment tolerance. MethodsWe performed a retrospective observational study involving 119 patients with KTF in 3 French kidney transplant centers between June 2007 and June 2017. Sensitization was defined as the development of HLA donor-specific antibodies (DSA). ResultsIn the PT group receiving calcineurin inhibitor (CNI) treatment, 30 of 52 patients (57.7%) were sensitized vs 52 of 67 patients (77.6%) who had early cessation of treatment (P = .02). The results were confirmed by multivariate analysis (odds ratio [OR] = 0.39, 95% confidence interval [CI] [0.16; 0.98], P = .04). The development of de novo DSAs after CNI treatment (n = 63/90 [70.0%]) was significantly more frequent than during CNI treatment, (n = 18/52 [34.6%], P = .01). Panel-reactive antibody ≥85% was lower in the PT group in multivariate analysis (OR = 0.28, 95% CI [0.10; 0.78], P = .02). No differences in the rates of infection, cardiovascular complications, neoplasia, and deaths were observed between the 2 groups. In multivariate analysis, continuation of corticosteroid treatment had no influence on sensitization but was associated with a higher rate of infection (OR = 2.66, 95% CI [1.09; 6.46], P = .03). ConclusionMaintenance of CNI treatment after return to dialysis in patients requesting a repeat transplant could avoid the development of anti-HLA sensitization with a good tolerance.

Management of COVID-19 in special populations with kidney disease.

Although the literature is limited, early evidence suggests that patients with chronic kidney disease, end-stage kidney disease, and kidney transplant recipients are at increased risk for severe COVID-19 disease and death. Hence, management should focus on both infection prevention and treatment. There is currently a lack of evidence and guideline recommendations on optimal management of immunosuppression in kidney transplant recipients with COVID-19 infection. This article focuses on the prevention and management of COVID-19 in patients with chronic kidney disease, patients with end-stage kidney disease on home hemodialysis and peritoneal dialysis, and kidney transplant recipients.

Nonalcoholic Fatty Liver Disease in the Post Liver Transplant Patient

Nonalcoholic fatty liver disease (NAFLD) may occur as a de novo or recurrent disease among recipients of liver transplant (LT). We seek to review the currently available information on the diagnosis, implications, and management of NAFLD in the post LT population with a focus on the practical medical management of this disease. Recent studies emphasize that NAFLD is the hepatic manifestation of the metabolic syndrome, mediated largely by insulin resistance, with liver recipient factors being the primary determinants of the development of graft steatosis. Post-transplant nonalcoholic steatohepatitis (NASH) may progress to the development of graft fibrosis and cirrhosis. Risk factors such as hypertension, dyslipidemia, hyperglycemia, and excess weight gain should be addressed proactively in the post-transplant period. Interventions to prevent or treat NAFLD in the patient who has undergone LT must take into account the specialized needs of the post-transplant care setting, including the management of immunosuppression, and the potential presence of high catabolic needs after surgery. Future research is needed to tailor NAFLD interventions to the post-transplant population.

COVID-19 in lung transplant recipients: A multicenter study.

This study describes the clinical presentation, treatment, and outcomes of SARS-CoV-2 infection in lung transplant recipients (LTRs). This is a multicenter, retrospective study of all adult LTRs with confirmed SARS-CoV-2 infection from March 4 until April 28, 2020 in six Spanish reference hospitals for lung transplantation. Clinical and radiological data, treatment characteristics, and outcomes were reviewed. Forty-four cases were identified in that period. The median time from transplantation was 4.2 (interquartile range: 1.11-7.3) years. Chest radiography showed acute parenchymal abnormalities in 32 (73%) cases. Hydroxychloroquine was prescribed in 41 (93%), lopinavir/ritonavir (LPV/r) in 14 (32%), and tocilizumab in 19 (43%) patients. There was a strong interaction between tacrolimus and LPV/r in all cases. Thirty-seven (84%) patients required some degree of respiratory support and/or oxygen therapy, and 13 (30%) were admitted to intermediate or intensive critical care units. Seventeen (39%) patients had died and 20 (45%) had been discharged at the time of the last follow-up. Deceased patients had a worse respiratory status and chest X-ray on admission and presented with higher D-dimer, interleukin-6, and lactate dehydrogenase levels. In this multicenter LTR cohort, SARS-CoV-2 presented with high mortality. Additionally, the severity of disease on presentation predicted subsequent mortality.

Management of lung transplantation in the COVID-19 era-An international survey.

It is unknown if solid organ transplant recipients are at higher risk for severe COVID-19. The management of a lung transplantation (LTx) program and the therapeutic strategies to adapt the immunosuppressive regimen and antiviral measures is a major issue in the COVID-19 era, but little is known about worldwide practice. We sent out to 180 LTx centers worldwide in June 2020 a survey with 63 questions, both regarding the management of a LTx program in the COVID-19 era and the therapeutic strategies to treat COVID-19 LTx recipients. We received a total of 78 responses from 15 countries. Among participants, 81% declared a reduction of the activity and 47% restricted LTx for urgent cases only. Sixteen centers observed deaths on waiting listed patients and eight centers performed LTx for COVID-19 disease. In 62% of the centers, COVID-19 was diagnosed in LTx recipients, most of them not severe cases. The most common immunosuppressive management included a decreased dose or pausing of the cell cycle inhibitors. Remdesivir, hydroxychloroquine, and azithromycin were the most proposed antiviral strategies. Most of the centers have been affected by the COVID-19 pandemic and proposed an active therapeutic strategy to treat LTx recipients with COVID-19.

Chinese expert consensus on diagnosis and management of immunosuppression in sepsis

This expert consensus uses clinical research evidence to explain the mechanism, monitoring and evaluation of sepsis-induced immunosuppression, and treatment with immune stimulation from two aspects: innate immunity and acquired immunity, aiming to help clinicians better understand sepsis-induced immune depression and its clinical significance. Clinical data suggest that the immune dysfunction is critically involved in the occurrence and development of sepsis. Quantitative detection of monocyte human leukocyte antigen DR and lymphocyte count can be used as important indicators to reflect the innate immune and acquired immune dysfunction in patients with sepsis. Immunomodulation therapy includes medication to improve innate immunity and acquired immunity, and immune stimulation combined with anti-inflammatory response.

Adequate tacrolimus exposure modulates the impact of HLA class II molecular mismatch: a validation study in an American cohort.

Clinicians have few tools to predict the risk of alloimmune injury that would guide immunosuppression management in renal transplant patients. We evaluated human leukocyte antigen (HLA)‐DR/DQ molecular mismatch to predict de novo donor‐specific antibodies (DSAs) during the first year of transplant and explored how differences in tacrolimus exposure may modulate this risk. HLA‐DR and ‐DQ eplet mismatches were determined between 444 donor‐recipient pairs in Denver, Colorado between 2007 and 2013. Previously defined mismatch thresholds stratified recipients into low‐ (N = 119), intermediate‐ (N = 153), and high‐ (N = 172) risk categories. The area under the curve for DSA at 1 year was 0.84 and 0.82 for HLA‐DR and HLA‐DQ eplet mismatches, respectively. Compared to low‐risk patients, there was a graded increase in risk of DR/DQ DSA in intermediate (HR 15.39, 95% CI 2.01‐118.09, p = .009) and high‐risk (HR 23.81, 95% CI 3.17‐178.66, p = 0.002) categories. Intermediate‐ and high‐risk patients with a mean tacrolimus <6 ng/ml versus >8 ng/ml had increased risk of DR/DQ DSA at 1 year (HR 2.34, 95% CI 1.05‐5.22, p = .04). HLA molecular mismatch represents a reproducible, objective, and clinically relevant tool to stratify patients by alloimmune risk and may help guide personalized immunosuppression management.

A proposed strategy for management of immunosuppression in heart transplant patients with COVID-19.

There is limited experience in management of orthotopic heart transplant (OHT) patients with COVID‐19. In this study, we present our initial experience using a standardized management algorithm. Data collection was performed on OHT patients with COVID‐19 after March 10, 2020 (declaration of state of emergency in Massachusetts). Among the 358 OHT patients currently followed at our program, 5 patients (1.4%) tested positive for COVID‐19 (median age 50 years [IQR, 49‐58], duration post‐OHT 21 years [IQR, 6‐25], and 4 of 5 [80%] were men). Among the 5 OHT patients, 2 of 5 (20%) had mild disease and had no change in baseline immunosuppression therapy. Two of 5 (20%) had moderate disease and received remdesivir as part of a clinical trial and reduced immunosuppression therapy. One patient (20%) died prior to presenting to the hospital, consistent with 20% case fatality rate. Four patients (80%) are doing well 4 weeks post‐discharge. In this small cohort of OHT patients with COVID‐19, we report a 1.4% COVID‐19 infection rate and 20% case fatality rate. All OHT patients managed under our clinical management algorithm had good short‐term outcomes. Further study to estimate the true risk profile of OHT patients and validate the proposed management strategy is warranted.

Liver transplant immunosuppression during the COVID-19 pandemic

SARS CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the population, the hepatologists who follow these patients have tried to coordinate efforts to produce a protocol the management of immunosuppression during SARS Cov-2 infection. Although there are no solid studies to support general recommendations, experiences with other viral infections (hepatitis C, cytomegalovirus) suggest that management of immunosuppression without mycophenolate mofetil or m-Tor inhibitors (drugs that are also associated with leukopenia and lymphopenia) may be beneficial. It is also important to pay attention to possible drug interactions, especially in the case of tacrolimus, with some of the treatments with antiviral effect given in the context of COVID 19 (lopinavir/ritonavir, azithromycin). Finally, the immunosuppressive effect of immunomodulating drugs (tocilizumab and similar) administered to patients with severe lung disease should be taken into account. The mechanisms of action of the different immunosuppressive drugs are reviewed in this article, as well as their potential effect on Cov-2 SARS infection, and suggests guidelines for the management of immunosuppression.

Characteristics and Graft Survival of Kidney Transplant Recipients with Renal Cell Carcinoma

Background: The incidence of renal cell carcinoma (RCC) is higher in kidney transplant recipients (KTRs) compared to the general population. However, the risk factors and outcomes based on the diagnosis of RCC after kidney transplantation are limited. Methods: We analyzed risk factors for the development of RCC in KTRs transplanted at our institution between 1994 and 2016. We compared the incidence of graft failure and mortality in KTRs with RCC to matched controls using 5:1 event density sampling. Identifying the risk factors of RCC and patient and graft survival were outcomes of interest. Results: There were 4,178 KTRs performed at our institution during the study period, and 51 patients were diagnosed with RCC. Recipients were followed until graft failure or death. We did not identify commonly looked at baseline characteristics associated with the risk of RCC. Comparing KTRs with RCC to matched controls, RCC patients were younger (47.5 vs. 49.6 years, p < 0.01), received basiliximab induction more commonly (p = 0.01), had hypertension and glomerulonephritis as causes of end-stage renal disease (p = 0.01), and were more likely to be smokers (p < 0.01). RCC was significantly associated with death-censored graft failure (adjusted hazard ratio [HR]: 1.76; 95% CI: 1.02–3.03; p = 0.04) but not patient death (adjusted HR: 0.95; 95% CI: 0.50–1.83; p = 0.89). Conclusion: In our experience, RCC had a detrimental impact on graft survival among KTRs, highlighting the potential benefit of early diagnosis and optimal immunosuppression management in optimizing graft survival.

Post-transplant immunosuppression and COVID-19: From a double whammy to a mixed blessing.

The coronavirus pandemic (COVID-19) has had an unprecedented effect on various disease processes and their management. COVID-19 is likely to have a complex pathophysiological interplay with the post-transplant patients; one affecting the clinical course and outcome of the other. In the absence of validated data from trials, there is strong dependence on experience based on previous similar epidemics (SARS/MERS), and from consensus based on expert opinions. Despite the fact that our knowledge is rapidly evolving with time, there still is relatively limited objective data on the effect of COVID-19 on the human body. Numerous questions remain unanswered, one of which involves the management of immunosuppression in the post-transplant recipient during this contagion. The core tenet of which continues to be that of establishing an equipoise between infection and rejection. This review summarises the current knowledge on immune interactions of the virus, the immunomodulatory effects that may be at play, and its relation to the art of immunosuppression.

Securing the future of kidney transplantation by addressing the challenges of transplant nephrology.

Kidney transplant is a life-changing procedure, and transplant nephrologists, as part of a larger transplant team, play an important role in the field by managing the complex medical needs of transplant patients. The subspecialty of transplant nephrology, however, faces structural challenges related to its workforce, reporting structures, compensation, research and innovation, and health care information technology. The position of transplant nephrology at the academic and operational intersection of medicine and surgery may limit its access to critical resources, hinder academic promotion, and contribute to physician burnout. The authors provide an overview of the subspecialty transplant nephrology and propose solutions. Collaborative efforts that fortify the subspecialty of transplant nephrology will ultimately improve the lives of patients suffering from kidney disease.