Examining the Role for Donor-specific Antibody Testing in Simultaneous Liver-kidney Transplantation: A Single-center Analysis of Outcomes.

BACKGROUND: Simultaneous liver-kidney transplantation (SLKT) is increasingly used for patients with concurrent end-stage liver and renal disease. Emerging evidence suggests that simultaneous liver transplant can provide a tolerogenic benefit to multiorgan transplant recipients. Posttransplant donor-specific antibody (DSA) may be associated with worse outcomes; however, the role for testing DSA in SLKT is unclear. METHODS: This study retrospectively assessed the impact of DSA on outcomes following primary SLKT at a large-volume center between 2008 and 2018. Patients were grouped by positive DSA, negative DSA, and DSA not tested, and data were obtained from our institutional database and chart review. RESULTS: The cohort included 138 SLKT recipients with a mean age of 56.1 ± 9.7 y; 61.6% were male, and 55.8% were Hispanic. Overall, 62 patients were tested for DSA posttransplant, and 33 patients (23.9%) had at least 1 DSA detected. A total of 34 patients (24.6%) experienced at least 1 episode of liver rejection, and 23 patients (16.7%) experienced kidney rejection. Over 50% of patients with de novo DSA changed status during their posttransplant course. Rates of both liver and kidney rejection were slightly higher in the DSA + group, but liver allograft, kidney allograft, and patient survival did not differ when grouped by whether DSA testing was performed or DSA positivity. CONCLUSIONS: These data demonstrate that SLKT is associated with excellent long-term patient and allograft survival with a relatively low rate of rejection. In our experience, testing for DSA does not impact SLKT outcomes' and further multicenter analyses are needed to establish standard of care.

The need for a living donor wellness program.

PURPOSE OF REVIEW: Living donation has a tremendous impact in bridging the gap between the shortage of organs and the growing list of transplant candidates but remains underutilized as a percentage of total transplants performed. This review focuses on obesity and social determinants of health as potential barriers to the expansion of living kidney donation. RECENT FINDINGS: The growing rate of obesity and associated metabolic syndrome make many potential donors unacceptable as donor candidates because of the future risk for developing chronic health conditions, such as hypertension and diabetes. There is also increasing evidence demonstrating socioeconomic differences and racial disparities potentially limit access to living donation in certain populations. These potentially modifiable factors are not exclusive of each other and together serve as significant contributing factors to lower rates of living donation. SUMMARY: Living donors make sacrifices to provide the gift of life to transplant recipients, despite the potential risks to their own health. Studies describing risk factors to living donation call attention to the overall need for more action to prioritize and promote the health and well being of living donors.

Management of Post-transplant Hyperparathyroidism and Bone Disease.

Significant advances in immunosuppressive therapies have been made in renal transplantation, leading to increased allograft and patient survival. Despite improvement in overall patient survival, patients continue to require management of persistent post-transplant hyperparathyroidism. Medications that treat persistent hyperparathyroidism include vitamin D, vitamin D analogues, and calcimimetics. Medication side effects such as hypocalcemia or hypercalcemia, and adynamic bone disease, may lead to a decrease in the drugs. When medical management fails to control persistent post-transplant hyperparathyroidism, treatment is a parathyroidectomy. Surgical techniques are not uniform between centers and surgeons. Undergoing the surgery may include a subtotal technique or a technique including total parathyroid gland resection with partial heterotopic gland reimplantation. In addition, there are possible post-surgical complications. The ideal treatment for persistent post-transplant hyperparathyroidism is the treatment and prevention of the condition while patients are being managed for their late-stage chronic kidney disease and end-stage renal disease.

Immunoglobulin isotype switching of antibodies to vimentin is associated with development of transplant glomerulopathy following human renal transplantation.

BACKGROUND: Immune responses to tissue-restricted self-antigens are thought to play a role in chronic rejection after solid organ transplantation. De novo development of antibodies (Abs) to vimentin have been reported to be associated with interstitial fibrosis/tubular atrophy after kidney transplant, and it has been suggested that immunoglobulin isotype switching of Abs to vimentin may occur during this process. We aimed to determine the correlation between immunoglobulin isotype switching of Abs to vimentin and development of transplant glomerulopathy (TG) after kidney transplant, and to determine whether citrullinated modification of vimentin is required for de novo anti-vimentin development. METHODS: Sera were collected from 24 patients with TG (diagnosed on biopsy), 24 matched stable kidney transplant recipients (KTxRs) and 22 normal healthy subjects who did not undergo transplant. Serum vimentin Abs concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Immunoglobulin isotypes of anti-vimentin were determined using isotype-specific Abs conjugated with horseradish peroxidase. Samples were considered positive to vimentin Abs if the values were above mean+2× standard deviations of the levels in the healthy control subjects. Specificities of anti-vimentin for mutated citrullinated vimentin and anti-mutated citrullinated vimentin were measured by ELISA. RESULTS: In this retrospective analysis of 24 KTxRs with TG, 16/24 (67%) patients with biopsy-proven TG developed Abs to vimentin (645±427ng/ml). In contrast, only 4/24 (17%) stable KTxRs had detectable Abs to vimentin (275±293ng/ml; p=0.001). Of the patients with TG, 15/24 (63%) developed Abs to vimentin of IgG isotype (572±276ng/ml), whereas only 6/24 (25%) stable KTxRs (310±288ng/ml) had anti-vimentin of IgG isotype (p=0.002). However, no significant difference was noted in the concentration of IgM isotype anti-vimentin between KTxRs with TG (9/24 [38%], 407±401ng/ml) and stable KTxRs (5/24 [21%], 348±439ng/ml; p=0.631). The serum concentration of Abs specific for the mutated form of citrullinated vimentin was not significantly different between KTxRs with TG and stable KTxRs. CONCLUSIONS: Patients with biopsy-proven TG demonstrated significantly increased levels of anti-vimentin Abs of the IgG isotype compared with stable KTxRs. Anti-vimentin in stable KTxRs was primarily of IgM isotype. Therefore, the observed isotype switching of anti-vimentin from IgM to IgG isotype strongly suggests ongoing immune responses to vimentin in KTxRs diagnosed with TG. Furthermore, as opposed to patients with rheumatoid arthritis (who develop immune responses primarily to citrullinated vimentin), KTxRs diagnosed with TG developed immune responses to non-citrullinated vimentin, suggesting that modification of vimentin protein via citrullination is not required for the de novo anti-vimentin response seen in patients with TG.

Development of immune response to tissue-restricted self-antigens in simultaneous kidney-pancreas transplant recipients with acute rejection.

Simultaneous kidney-pancreas transplantation (SKP Tx) is a treatment for end-stage kidney disease secondary to diabetes mellitus. We investigated the role of immune responses to donor human leukocyte antigens (HLA) and tissue-restricted kidney and pancreas self-antigens (KSAgs and PSAgs, respectively) in SKP Tx recipients (SKP TxRs). Sera collected from 39 SKP TxRs were used to determine de novo Abs specific for KSAgs (collagen-IV, Col-IV; fibronectin, FN) and PSAgs (insulin, islet cells, glutamic acid decarboxylase, and pancreas-associated protein-1) by ELISA. KSAg-specific IFN-γ, IL-17, and IL-10 cytokines were enumerated by ELISpot. Abs to donor HLA classes I and II were determined by Luminex assay. Abs to KSAgs and PSAgs were detectable in recipients with rejection compared with stable recipients (P<.05). Kidney-only rejection recipients had increased Abs against KSAgs compared with stable (P<.05), with no increase in Abs against PSAgs. Pancreas-only rejection recipients showed increased Abs against PSAgs compared to stable (P<.05), with no Abs against KSAgs. SKP TxRs with rejection showed increased frequencies of KSAg-specific IFN-γ and IL-17 with reduction in IL-10-secreting cells. SKP TxRs with rejection developed Abs to KSAgs and PSAgs demonstrated increased frequencies of kidney or pancreas SAg-specific IFN-γ and IL-17-secreting cells with reduced IL-10, suggesting loss of peripheral tolerance to SAgs.

The Privilege of Induction Avoidance and Calcineurin Inhibitors Withdrawal in 2 Haplotype HLA Matched White Kidney Transplantation.

BACKGROUND: White recipients of 2-haplotype HLA-matched living kidney transplants are perceived to be of low immunologic risk. Little is known about the safety of induction avoidance and calcineurin inhibitor withdrawal in these patients. METHODS: We reviewed our experience at a single center and compared it to Organ Procurement and Transplantation Network (OPTN) registry data and only included 2-haplotype HLA-matched white living kidney transplants recipients between 2000 and 2013. RESULTS: There were 56 recipients in a single center (where no induction was given) and 2976 recipients in the OPTN. Among the OPTN recipients, 1285 received no induction, 903 basiliximab, 608 thymoglobulin, and 180 alemtuzumab. First-year acute rejection rates were similar after induction-free transplantation among the center and induced groups nationally. Compared with induction-free transplantation in the national data, there was no decrease in graft failure risk over 13 years with use of basiliximab (adjusted hazard ratio [aHR], 0.86; confidence interval [CI], 0.68-1.08), Thymoglobulin (aHR, 0.92; CI, 0.7-1.21) or alemtuzumab (aHR, 1.18; CI, 0.72-1.93). Among induction-free recipients at the center, calcineurin inhibitor withdrawal at 1 year (n = 27) did not significantly impact graft failure risk (HR,1.62; CI, 0.38-6.89). CONCLUSIONS: This study may serve as a foundation for further studies to provide personalized, tailored, immunosuppression for this very low-risk population of kidney transplant patients.

Use of hemodialysis for the treatment of intracerebral hemorrhage in patients on dabigatran with normal renal function.

Dabigatran is a direct thrombin inhibitor which is approved by the Food and Drug Administration (FDA) for prevention of embolic stroke in patients with atrial fibrillation. Dabigatran has been shown to be non- inferior to warfarin in preventing stroke in patients with atrial fibrillation [1, 6]. The rate of major bleeding in patients taking dabigatran is also similar to that seen in patients on warfarin [1]. Unlike warfarin, there is currently no antidote available for reversal of anticoagulant effects of dabigatran [2, 3]. Dabigatran is excreted renally and accumulates in patients with acute kidney injury (AKI). Hemodialysis has been reported to increase clearance of dabigatran in patients with acute kidney injury and life-threatening bleeding [4, 5]. We present two cases of dabigatran-associated intracranial hemorrhage where hemodialysis was used to accelerate clearance of dabigatran from the blood in patients with normal renal function.

Chronic kidney disease in the elderly.

Chronic kidney disease (CKD) is increasingly being recognized as a disease of elderly individuals. In recent years the definition and categorization of kidney disease has been standardized. There are concerns that this standardization has led to an increase in the number of older individuals labeled as having CKD. This article addresses the definitions of CKD, recently published revised CKD stages with risk stratifications, and limitations of using formulas to assess renal function in the elderly. Also discussed are management of common risk factors of progression CKD, nonrenal-related outcomes, prognosis of CKD in older individuals, and criteria for referral to nephrology.

Extracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience.

BACKGROUND AND OBJECTIVES: Dabigatran is an oral direct thrombin inhibitor that is Food and Drug Administration-approved for prevention of stroke in patients with atrial fibrillation. No antidote is available for reversal of dabigatran's anticoagulant effect. Despite limited clinical data, hemodialysis has been suggested as a strategy to remove dabigatran during acute bleeding. This work presents five cases, in which extracorporeal therapy was performed for dabigatran removal in acutely bleeding patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The series is comprised of five consecutive cases of patients receiving dabigatran 150 mg per os two times daily who were admitted with life-threatening bleeding between March of 2012 and January of 2013. Dabigatran plasma concentrations ranged from 149 to 1200 ng/ml. Treatment included administration of blood products to all patients and then, high-flux intermittent hemodialysis alone or followed by continuous renal replacement therapy. RESULTS: Dabigatran concentrations decreased by 52%-77% during intermittent hemodialysis but rebounded up to 87% within 2 hours after completion of dialysis. Initiation of continuous renal replacement therapy after intermittent hemodialysis attenuated the rebound effect in one patient and contributed to a reduction in dabigatran concentrations of 81% over 30 hours. CONCLUSIONS: Extracorporeal therapy lowered dabigatran concentrations, suggesting that it removed the drug and may effectively accelerate total clearance, especially in patients with impaired kidney function. The use of prolonged intermittent hemodialysis or intermittent hemodialysis followed by continuous renal replacement therapy is recommended for the management of life-threatening bleeding in patients receiving dabigatran. The advantage of extracorporeal therapy should be weighed against the risk of bleeding with catheter insertion.