Risk factors for renal dysfunction after isolated intestinal transplantation.

INTRODUCTION: Kidney dysfunction is a known complication of intestinal transplantation; however, the rate of development and risk factors for chronic kidney disease (CKD) remain poorly defined. METHODS: This was a single-center retrospective review of isolated adult intestinal allograft recipients from 2011 to 2019. Patients who died or experienced graft loss within 1-year or had a prior transplant were excluded. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation at 0-, 6- and 12-months post-transplant, and multivariable linear regression was performed to identify variables associated with adjusted eGFR at 1-year. Independent variables included age, ethnicity, BMI, history of diabetes/hypertension, vasopressor use, TPN and stoma days, urinary or bloodstream infections, intravenous contrast exposure, rejection, concomitant immunosuppression, and time above the therapeutic range of tacrolimus. Variables with a p < .1 in univariate analysis were considered for multivariable modeling. RESULTS: Thirty-three patients were included with a mean age of 43.9 ± 13.0. A mean 42.3% decline in eGFR was observed at 1-year post-transplant, with 15.2% of patients developing new stage 4/5 CKD. Factors associated with a greater decline in adjusted eGFR in the univariate model included increasing age, decreased BMI, stoma days, and vasopressor use. In the adjusted multivariable model patient age (ß = -.77, p < .01) and stoma days (ß = -.06, p < .01) remained significant. Tacrolimus and sirolimus exposure were not associated with decline in eGFR at 1 year. CONCLUSIONS: Renal dysfunction is common following intestinal transplantation. The need for stoma creation should be carefully considered, and reversal should be performed when feasible for renal protection.

Comparison of Intensive Insulin Versus Oral Regimens on Early Glycemic Control Following Kidney Transplant.

Introduction: Insulin is commonly prescribed to manage early post-kidney transplant hyperglycemia due to its flexibility. Studies comparing the effectiveness of oral therapies on glycemic outcomes remain limited. Project aims: The purpose of this program evaluation was to analyze our experience using oral antiglycemic agents immediately post-kidney transplant, compared to patients managed with insulin monotherapy. Design: This was a single-center, retrospective review of adult kidney transplant recipients with new or worsening hyperglycemia between 01/2014-05/2020. Patients were excluded if they had a prior or combined organ transplant, type 1 diabetes, or were previously on intensive insulin. Patients discharged on oral medications were 1:1 matched to patients receiving intensive insulin based on pre-specified clinical parameters. The primary endpoint was the number of diabetes-related readmissions within 6-months of transplant. Key secondary endpoints included mean serum glucose and hemoglobin A1c levels. Results: Thirty patients prescribed oral therapies were successfully matched to patients receiving intensive insulin. Baseline characteristics were similar between groups, except for more whites in the insulin group. There were no differences in diabetes-related (6.7% vs 3.3%; P = 1.00) or all-cause readmissions within 6-months. Mean serum glucose (P = .99) and hemoglobin A1c (P = .49) levels were also similar between patients receiving oral agents and insulin. However, 7 patients in the oral group were eventually converted to standing insulin. Conclusion: Our experience suggested that the early use of oral antiglycemics post-kidney transplant in select patients can result in similar outcomes relative to insulin. Meticulous follow-up is necessary as one-quarter of patients may require conversion to insulin within 1-month.

AMPK mediates regulation of glomerular volume and podocyte survival.

Herein, we report that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without focal segmental glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease (MCD), where podocyte Fyn inactivation was reported, also showed lower glomerular volumes than FSGS. We hypothesized that lower glomerular volume prevented the progression to podocytopenia. To test this hypothesis, we utilized unilateral and 5/6th nephrectomy models in Shroom3-KD mice. Knockdown mice exhibited less glomerular and podocyte hypertrophy after nephrectomy. FYN-knockdown podocytes had similar reductions in podocyte volume, implying that Fyn was downstream of Shroom3. Using SHROOM3 or FYN knockdown, we confirmed reduced podocyte protein content, along with significantly increased phosphorylated AMPK, a negative regulator of anabolism. AMPK activation resulted from increased cytoplasmic redistribution of LKB1 in podocytes. Inhibition of AMPK abolished the reduction in glomerular volume and induced podocytopenia in mice with FPE, suggesting a protective role for AMPK activation. In agreement with this, treatment of glomerular injury models with AMPK activators restricted glomerular volume, podocytopenia, and progression to FSGS. Glomerular transcriptomes from MCD biopsies also showed significant enrichment of Fyn inactivation and Ampk activation versus FSGS glomeruli. In summary, we demonstrated the important role of AMPK in glomerular volume regulation and podocyte survival. Our data suggest that AMPK activation adaptively regulates glomerular volume to prevent podocytopenia in the context of podocyte injury.

Tacrolimus time-in-therapeutic range is associated with freedom from acute rejection and graft failure following intestinal transplantation.

BACKGROUND: Trough-adjusted tacrolimus is commonly prescribed following intestinal transplantation to prevent allograft rejection. Despite established practice, there remains limited direct evidence linking tacrolimus levels with improved clinical outcomes. METHODS: This was a single-center review of all adult non-liver containing intestinal allograft recipients from 2011 to 2018. Patients received lymphocyte depleting induction and maintenance immunosuppression consisting of tacrolimus and a corticosteroid taper. Tacrolimus time-in-therapeutic range (TAC-TTR) was calculated for all patients from the date of transplant until 1-year post-transplant using Rosendaal's method. Cox-Proportional hazards modeling was utilized to assess freedom from acute rejection and graft failure stratified by TAC-TTR quartile. RESULTS: 47 patients were included in the review. Mean TAC-TTR for the cohort was 30.2% ± 11.4. Fifteen episodes of acute rejection were observed, 8 of which were severe. Patients in the highest TAC-TTR quartile >36% had a lower incidence of acute rejection and graft failure relative to patients with a TAC-TTR <20%. Cox-Proportional hazards modeling found a 10% decrease in TAC-TTR was associated with an increased hazard for acute rejection (2.03), severe acute rejection (2.19), and graft loss (3.33). CONCLUSION: The results of this study suggest that decreasing TAC-TTR is a risk factor for both acute rejection as well as intestinal allograft failure.

Influence of patient characteristics and immunosuppressant management on mortality in kidney transplant recipients hospitalized with coronavirus disease 2019 (COVID-19).

The influence of patient characteristics and immunosuppression management on COVID-19 outcomes in kidney transplant recipients (KTRs) remains uncertain. We performed a single-center, retrospective review of all adult KTRs admitted to the hospital with confirmed COVID-19 between 03/15/2020 and 05/15/2020. Patients were followed from the date of admission up to 1 month following hospital discharge or study conclusion (06/15/2020). Baseline characteristics, laboratory parameters, and immunosuppression were compared between survivors and patients who died to identify predictors of mortality. 38 KTRs with a mean baseline eGFR of 52.5 ml/min/1.73 m2 were hospitalized during the review period. Maintenance immunosuppression included tacrolimus (84.2%), mycophenolate (89.5%), and corticosteroids (81.6%) in the majority of patients. Eleven patients (28.9%) died during the hospitalization. Older age (OR = 2.05; 1.04-4.04), peak D-dimer (OR = 1.20; 1.04-1.39), and peak white blood cell count (OR = 1.11; 1.02-1.21) were all associated with mortality among KTRs hospitalized for COVID-19. Increased mortality was also observed among KTRs with concomitant HIV infection (87.5% vs. 36.1%; p < .01). Conversely, immunosuppression intensity and degree of reduction following COVID-19 diagnosis were not associated with either survival or acute allograft rejection. Our findings potentially support a strategy of individualization of immunosuppression targets based on patient-specific risk factors, rather than universal immunosuppression reduction for KTRs at risk from COVID-19.

A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant.

Immune checkpoint inhibitors (ICIs) are widely used for various malignancies. However, their safety and efficacy in patients with a kidney transplant have not been defined. To delineate this, we conducted a multicenter retrospective study of 69 patients with a kidney transplant receiving ICIs between January 2010 and May 2020. For safety, we assessed the incidence, timing, and risk factors of acute graft rejection. For efficacy, objective response rate and overall survival were assessed in cutaneous squamous cell carcinoma and melanoma, the most common cancers in our cohort, and compared with stage-matched 23 patients with squamous cell carcinoma and 14 with melanoma with a kidney transplant not receiving ICIs. Following ICI treatment, 29 out of 69 (42%) patients developed acute rejection, 19 of whom lost their allograft, compared with an acute rejection rate of 5.4% in the non-ICI cohort. Median time from ICI initiation to rejection was 24 days. Factors associated with a lower risk of rejection were mTOR inhibitor use (odds ratio 0.26; 95% confidence interval, 0.09-0.72) and triple-agent immunosuppression (0.67, 0.48-0.92). The objective response ratio was 36.4% and 40% in the squamous cell carcinoma and melanoma subgroups, respectively. In the squamous cell carcinoma subgroup, overall survival was significantly longer in patients treated with ICIs (median overall survival 19.8 months vs. 10.6 months), whereas in the melanoma subgroup, overall survival did not differ between groups. Thus, ICIs were associated with a high risk of rejection in patients with kidney transplants but may lead to improved cancer outcomes. Prospective studies are needed to determine optimal immunosuppression strategies to improve patient outcomes.

Conversion to belatacept maintenance immunosuppression in HIV-positive kidney transplant recipients.

There are only scattered case reports documenting belatacept use in HIV + kidney transplant recipients. We performed a retrospective review to describe short-term outcomes following conversion to belatacept in a cohort of HIV + patients. Patients were included if they were converted to belatacept between May 2015 and May 2019, had an HIV- donor, and received ≥4 doses of belatacept. All patients were treated with non-depleting induction and triple maintenance immunosuppression. Allograft and HIV-related outcomes were collected from the date of belatacept infusion until May 2020. Ten HIV + kidney transplant recipients were identified, who were converted to belatacept a median of 364 days post-transplant. At last follow-up (median 3.3 years), 8 patients remained on belatacept therapy, and all patients were alive with functioning allografts. Mean estimated glomerular filtration rates (eGFR) improved from 31.6 mL/min at baseline to 42.8 mL/min at 1 year (P = .03). Two patients developed acute rejection, with one necessitating conversion back to tacrolimus. All patients maintained undetectable HIV-1 viral loads at last follow-up. One patient each developed pneumocystis pneumonia and Kaposi sarcoma following conversion, which were responsive to standard medical therapy. In our cohort of stable HIV + kidney transplant recipients, conversion to belatacept was associated with excellent early patient and allograft survival and improved eGFR at 1 year.

Conversion to belatacept within 1-year of renal transplantation in a diverse cohort including patients with donor-specific antibodies.

Early conversion from a calcineurin inhibitor to belatacept has the potential to improve long-term renal allograft function; however, there remains limited experience with this strategy among African Americans and patients with preformed donor-specific antibodies (DSA). To examine these subgroups, we performed a single-center review of kidney transplant recipients converted to belatacept within 1-year of transplant between 01/2011 and 10/2017. All patients received lymphocyte-depleting induction with maintenance tacrolimus and mycophenolate +/- corticosteroids. Patients were switched to belatacept for clinical indication and followed from date of conversion until allograft failure or study conclusion. The primary endpoint at 1-year was a composite of allograft loss, biopsy proven rejection, de novo DSA formation, proteinuria, and declining renal function. Thirty-two patients were included in the review. The majority were African American, and 28.1% had DSA at transplant. Patient and allograft survival at 1-year was 96.9% and 93.8%, respectively, and estimated glomerular filtration rate improved from 41.9 to 58.4 mL/min. No African Americans or patients with pretreatment DSA developed rejection or allograft failure within 1-year. The only clinical variable correlated with suboptimal allograft function was baseline weight ≥80 kg (OR = 6.2; 95% CI, 1.2-32.3). Early conversion to belatacept appears safe for select patients with DSA and African Americans receiving lymphocyte-depleting induction.

Kidney transplantation using lymphocyte depleting induction and standard maintenance immunosuppression at the height of the SARS-CoV-2 pandemic in New York City: A single-center experience.

BACKGROUND: Concerns have been raised regarding proceeding with kidney transplantation using standard immunosuppression in COVID-19 endemic areas. METHODS: We performed a single-center review of all adult kidney transplants performed during the COVID-19 pandemic in New York City. Patients were managed with standard immunosuppression protocols, including lymphocyte depleting induction and trough-guided tacrolimus. Retrospective data were collected for 3 months from the date of transplantation or until study conclusion (5/7/2020). The primary outcomes assessed included patient and allograft survival as well as COVID-19 related hospital readmission. RESULTS: 30 kidney transplants were performed during the height of the COVID-19 pandemic. After a median follow-up of 51.5 days, 93.3% of patients were alive with 100% death-censored allograft survival. 9 patients were readmitted to the hospital during the study period, 4 (13.3%) related to infection with COVID-19. Infections were mild in 3/4 patients, with one patient developing severe disease leading to respiratory failure. Patients readmitted with COVID-19 were numerically more likely to be African American, have a BMI > 30 kg/m2, have a lymphocyte count ≤ 300 cells/mL, and be on maintenance corticosteroids. CONCLUSIONS: Kidney transplantation in areas endemic to COVID-19 using standard induction and maintenance immunosuppression appears to be associated with a modest risk for severe COVID-19 related disease.

Safety of direct-acting oral anticoagulants relative to warfarin in a matched cohort of liver transplant recipients.

Despite increasingly widespread utilization of direct-acting oral anticoagulants (DOACs), there remains limited experience with the use of these agents following liver transplantation. We performed a single-center, retrospective review of liver transplant recipients prescribed DOACs or warfarin between January 2014 and January 2018. Patients receiving DOACs were matched with warfarin-treated controls based on discrete clinical parameters and followed from the time of anticoagulant prescription, until treatment discontinuation or study conclusion. The primary endpoint for this review was the incidence of clinically relevant major or non-major bleeding among the treatment groups. Twenty-seven patients prescribed DOACs were identified for inclusion in the review, of which 20 could be matched with suitable warfarin controls. At the conclusion of the study, warfarin-treated patients had a significantly higher incidence of clinically relevant bleeding (45% vs 15%; P = .01). No statistically significant differences were found in the rate of new or recurrent thrombotic events. Multivariable logistic regression demonstrated that warfarin treatment was associated with a significantly higher odds of a bleeding event compared to treatment with a DOAC (OR = 6.9; 95% CI, 1.1-44.6). DOAC use appears relatively safe compared with warfarin in select liver transplant recipients. Patient-specific factors still bear consideration when selecting between the various anticoagulant options.

Is There a Role for Desensitization in Intestinal Transplantation?

Human leukocyte antigen allosensitization prior to transplant can increase the risk of early graft loss and prolong waitlist times for intestinal transplant candidates. Desensitization offers a potential therapeutic option to reduce the quantity of preformed antibodies prior to organ allocation and facilitate transplantation with a more immunologically compatible donor allograft. However, there remains a paucity of data to guide the use of desensitization in the setting of intestinal transplantation. As a result, in this review we evaluate the existing literature supporting the role of desensitization therapy in intestinal transplant, describe our own experience with the implementation of a risk-stratified desensitization protocol, and finally explore barriers and unanswered questions that continue to limit the widespread adoption of desensitization as a management strategy for highly sensitized intestinal transplant candidates.

The Impact of Cirrhosis and Prescription Medications on QTc Interval Before and After Liver Transplantation.

BACKGROUND:: Higher rates of corrected QT (QTc) prolongation have been reported in patients with cirrhosis. The impact of liver transplantation and prescription medications on the natural history of QTc prolongation has yet to be well characterized. METHODS:: This was a single-center review of patients receiving (group 1) or listed for (group 2) a liver transplant during 2014. Patients in group 1 were followed prospectively from the date of transplantation to assess rates of QTc normalization posttransplant. In group 2, patients were evaluated from the date of listing up until December 2015 to assess the prevalence of QTc prolongation among liver transplant candidates. RESULTS:: In group 1, 22 (75.9%) patients with QTc intervals >460 milliseconds at the time of transplant established normal baseline QTc intervals following transplantation. The median time to this QTc normalization was 17 days. In group 2, 30 (16.9%) patients had at least 1 documented QTc interval >500 milliseconds with prevalence rates of 42.9%, 19.0%, and 10.2% in patients with natural model of end-stage liver disease scores of >30, 16 to 30, and <16, respectively ( P < .01). Overall, 49.4% of patients in group 1 and 47.5% of patients in group 2 were prescribed QTc prolonging medications. CONCLUSION:: QTc prolongation will resolve following transplantation in the majority of patients and generally occurs within the first several weeks. Among the listed liver transplant candidates, higher rates of clinically significant QTc prolongation may be observed in patients with more severe underlying cirrhosis. QTc prolonging medications are commonly prescribed in this population and warrant monitoring following initiation.

Erratum: Short-Term Outcomes for Veterans Receiving Basal Insulin, Metformin, and a Sulfonylurea Who Are Started on a Third Noninsulin Agent Versus Prandial Insulin. Diabetes Spectrum 2018;31:261-266 (doi.org/10.2337/ds17-0068).

[This corrects the article on p. 261 in vol. 31, PMID: 30140142.].

Short-Term Outcomes for Veterans Receiving Basal Insulin, Metformin, and a Sulfonylurea Who Are Started on a Third Noninsulin Agent Versus Prandial Insulin.

AIMS: Despite numerous recent advances in the management of patients with type 2 diabetes, there remains a paucity of data to guide sequential treatment intensification. METHODS: This was a single-center, retrospective cohort study of patients receiving metformin, basal insulin, and a sulfonylurea who were started on a third noninsulin agent or prandial insulin. The primary outcome for this study was change in A1C at 6 months after treatment intensification. Secondary outcomes included change in weight at 6 months, change in A1C at 1 year, percentage of patients achieving an A1C <7.5% at 1 year, documented episodes of hypoglycemia, and time to progression to prandial insulin. RESULTS: A total of 62 patients were identified for inclusion in the study: 28 receiving prandial insulin and 34 treated with a noninsulin agent. There was no significant difference in A1C change between the two treatment arms at either 6 months (-0.53 vs. -0.84%, P = 0.31) or 1 year (-0.67 vs. -0.86%, P = 0.61) after intervention. Patients receiving noninsulin agents gained significantly less weight at 6 months (-2.09 vs. 1.99 kg, P <0.01) and experienced fewer annual episodes of hypoglycemia (1.0 vs. 2.6, P = 0.01). Among patients treated with noninsulin agents, those receiving a glucagon-like peptide 1 receptor agonist were more likely to have an A1C <7.5% at 1 year than patients receiving a dipeptidyl peptidase 4 inhibitor (50 vs. 13%, P = 0.05). CONCLUSION: These results highlight that, in select patients, noninsulin therapies can be added to a backbone of metformin, basal insulin, and a sulfonylurea with similar A1C reductions but improved metabolic parameters relative to intensive insulin therapy.

Antiviral treatment of BK virus viremia after kidney transplantation.

PURPOSE: The various antiviral treatment options in the management of BK virus (BKV) viremia and BKV-associated nephropathy (BKVAN) are reviewed. SUMMARY: Review of the PubMed database from 1990 to 2016 for all English language case series, cohort studies, and randomized controlled trials detailing antiviral treatment of BKV viremia or BKVAN in kidney transplant recipients returned only 16 published reports. The majority of these reports were based on small case series or protocol-based cohort studies, with no prospective head-to-head data and only modest benefit reported for cidofovir, leflunomide, i.v. immunoglobulin (IVIG), and fluoroquinolone therapy. Given the lack of comparative data, appropriate antiviral treatment of BKV viremia should be determined based on institutional immunosuppressive protocols and posttransplantation outcomes. In appropriate patients who are not immunologically sensitized, substituting leflunomide for mycophenolate as part of immunosuppression reduction is reasonable and may result in viral clearance in up to 43% of patients at 4 weeks. In patients with persistent viremia despite immunosuppression reduction, either IVIG 2 g/kg administered over 2-5 days or cidofovir 0.5 mg/kg per week until viral clearance is achieved is generally well tolerated. Otherwise, there is insufficient evidence to recommend the use of fluoroquinolone therapy in either the treatment or prophylaxis of BKV viremia at this time. CONCLUSION: A review of the published literature revealed that certain populations of patients with BKV viremia or BKVAN can benefit from cidofovir, leflunomide, and IVIG therapy, but these data were derived from case series or protocol-driven cohort studies. Providers should treat patients on an individual basis to maximize clinical effectiveness while limiting adverse reactions.

Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients.

The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant. However, despite the long use of tacrolimus in clinical practice, the best way to use this agent is still a matter of intense debate. The start of the genomic era has generated new research areas, such as pharmacogenetics, which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body. This variability seems to be correlated with the presence of genetic polymorphisms. Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus; also, unlike phenotypic tests, the genotype is a stable characteristic that needs to be determined only once for any given gene. However, prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication. At present, research has been able to reliably show that the CYP3A5 genotype, but not the CYP3A4 or ABCB1 ones, can modify the pharmacokinetics of tacrolimus. However, it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity. For these reasons, pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing.