Aravind Cherukuri

We analyzed whether there is an interaction between the Kidney Donor Index (KDPI) and cold ischemia time (CIT) in recipients of deceased donor kidney transplant (KT). Adults who underwent KTs in the United States between 2014 and 2020 were included and divided into three KDPI groups (< 20%, 21-85%, > 85%) and four CIT strata (< 12, 12-17.9, 18-23.9, ≥ 24 hours). Multivariate analyses were used to test the interaction between KDPI and CIT for the following outcomes: primary graft non-function (PGNF), delayed graft function (DGF), estimated glomerular filtration rate at 6 and 12 months, patient survival, graft survival, and death-censored graft survival...

Regulatory B cells (Breg) modulate the immune response in diverse disease settings including transplantation. Despite the lack of a specific phenotypic marker or transcription factor, their significance in transplantation is underscored by their ability to prolong experimental allograft survival, the possibility for their clinical use as immune monitoring tools, and the exciting prospect for them to form the basis for cell therapy. Interleukin (IL)-10 expression remains the most widely used marker for Breg...

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Borderline rejection (BL) in renal transplantation is associated with decreased allograft survival, yet many patients with BL maintain stable graft function. Identifying patients with early BL at-risk for shortened allograft survival would allow for timely targeted therapeutic intervention aimed at improving outcomes. 851/1187 patients transplanted between 2013-18 underwent early biopsy (0-4mos). 217/851 (25%) had BL and were compared to 387/851 without significant inflammation (NI). Serial surveillance and for-cause biopsies and seven-year follow-up were used to evaluate histological and clinical progression...

PURPOSE OF THE REVIEW: Regulatory B cells (Bregs) play a prominent role in various disease settings. While progress has been hindered by the lack of a specific Breg marker, new findings highlight their role modulating the alloimmune response and promoting allograft survival. RECENT FINDINGS: Herein, we focus on the recent advances in Breg biology and their role in transplantation. We review studies showing that T-cell immunoglobulin and mucin domain 1 (TIM-1) is an inclusive and functional Breg marker in mice that may have human relevance...

In this issue, Burton et al. describe a convincing method to identify and enumerate human leukocyte antigen-specific B cells and subsets using biotinylated human leukocyte antigen proteins. Importantly, they demonstrate that these antigen-specific B cells are found at a greater frequency in sensitized kidney transplant recipients when compared with healthy volunteers. Finally, using an indirect antigen-specific enzyme-linked immunosorbent spot assay, they uncover the complexity of B- and T-cell interactions and the influence of regulatory T cells on such interactions in vitro...

Early immunological biomarkers that predict rejection and chronic allograft loss are needed to inform preemptive therapy and improve long-term outcomes. Here, we prospectively examined the ratio of interleukin-10 (IL-10) to tumor necrosis factor-α (TNFα) produced by transitional-1 B cells (T1B) 3 months after transplantation as a predictive biomarker for clinical and subclinical renal allograft rejection and subsequent clinical course. In both Training ( n = 162) and Internal Validation ( n = 82) Sets, the T1B IL-10/TNFα ratio 3 months after transplantation predicted both clinical and subclinical rejection anytime in the first year...

Regulatory B cells (Bregs) ameliorate autoimmune disease and prevent allograft rejection. Conversely, they hinder effective clearance of pathogens and malignancies. Breg activity is mainly attributed to IL-10 expression, but also utilizes additional regulatory mechanisms such as TGF-β, FasL, IL-35, and TIGIT. Although Bregs are present in various subsets defined by phenotypic markers (including canonical B cell subsets), our understanding of Bregs has been limited by the lack of a broadly inclusive and specific phenotypic or transcriptional marker...

IL-10+ regulatory B cells (Bregs) inhibit immune responses in various settings. While Bregs appear to inhibit inflammatory cytokine expression by CD4+ T cells and innate immune cells, their reported impact on CD8+ T cells is contradictory. Moreover, it remains unclear which effects of Bregs are direct versus indirect. Finally, the subanatomical localization of Breg suppressive function and the nature of their intercellular interactions remain unknown. Using novel tamoxifen-inducible B cell-specific IL-10 knockout mice, we found that Bregs inhibit CD8+ T cell proliferation and inhibit inflammatory cytokine expression by both CD4+ and CD8+ T cells...

Post-transplant donor specific antibody (DSA) is associated with poor renal allograft outcomes. However, variable timing of DSA assessment and inclusion of patients who undergo desensitization treatments have hindered our understanding of its consequences and limited its predictive value. Here we prospectively studied non-desensitized patients to determine factors associated with poor four-year outcomes in patients who developed post-transplant DSA. Using serial monitoring, 67 of 294 patients were found to develop DSA by one year...

B cells shape the alloimmune response through polarized subsets. These cells inhibit or promote immune responses by expressing suppressive or proinflammatory cytokines. Their summed activity dictates the influence of B cells on the alloimmune response. We review the evidence for regulatory B cells and effector B cells in mice and humans, discuss current limitations in their phenotypic identification, and discuss regulatory B cells as a signature for clinical renal allograft tolerance and predictive markers for allograft outcomes...

PURPOSE OF REVIEW: Regulatory B cells (Bregs) are potent inhibitors of the immune system with the capacity to suppress autoimmune and alloimmune responses. Murine transplant models showing that Bregs can promote allograft tolerance are now supported by clinical data showing that patients who develop operational tolerance have higher frequency of Bregs. Breg function has been widely studied resulting in improved understanding of their biology and effector mechanisms. However, our overall understanding of Bregs remains poor due the lack of specific marker, limited knowledge of how and where they act in vivo, and whether different Breg subpopulations exhibit different functions...

Early histological progression that associates with delayed graft function (DGF) and its relationship to graft outcomes is less well-understood. We systematically evaluated early acute and chronic histological changes associated with DGF through serial biopsies (protocol: 3 and 12 months; for-cause) and related them to graft outcomes. 56/294 (19.04%) of our patients had DGF. DGF was associated with a progressive increase in both Banff 't' and 'i' scores from 2 weeks to 3 and 12 months with a resultant increase in T cell mediated rejection (TCMR) that was significantly greater than those with primary graft function (PGF)...

The impact of subclinical inflammation (SCI) noted on early kidney allograft biopsies remains unclear. This study evaluated the outcome of SCI noted on 3-month biopsy. A total of 273/363 (75%) kidney transplant recipients with a functioning kidney underwent allograft biopsies 3-months posttransplant. Among those with stable allograft function at 3 months, 200 biopsies that did not meet the Banff criteria for acute rejection were identified. These were Group I: No Inflammation (NI, n = 71) and Group II: Subclinical Inflammation (SCI, n = 129)...

Human transitional B cells express relatively high IL-10 and low TNF-α levels, which correlate with B regulatory activity in vitro. Herein, we aim to further define B regulatory phenotype and determine whether B regulatory activity can serve as a prognostic marker for renal allograft dysfunction (graft loss or 2-fold fall in estimated glomerular filtration rate). Transitional B cells can be divided into T1 and T2 subsets based on surface phenotype. T1 cells express a significantly higher ratio of IL-10 to TNF-α than T2 cells or other B subsets...

Human B cells with immunoregulatory properties in vitro (Bregs) have been defined by the expression of IL-10 and are enriched in various B-cell subsets. However, proinflammatory cytokine expression in B-cell subsets is largely unexplored. We examined the cytokine profiles of human PBMCs and found that subsets of CD24(hi)CD38(hi) transitional B cells (TrBs), CD24(hi)CD27(+) memory B cells, and naïve B cells express IL-10 and the proinflammatory cytokine TNF-α simultaneously. TrBs had the highest IL-10/TNF-α ratio and suppressed proinflammatory helper T cell 1 (Th1) cytokine expression by autologous T cells in vitro more potently than memory B cells did, despite similar IL-10 expression...

BACKGROUND: Accurate prediction of kidney transplant failure remains imperfect. The objective of this study was to develop and validate risk scores predicting 5-year transplant failure, based on data available 12 months posttransplantation. STUDY DESIGN: Development and then independent multicenter validation of risk scores predicting death-censored and overall transplant failure. SETTING & PARTICIPANTS: Outcomes of kidney transplant recipients (n=651) alive with transplant function 12 months posttransplantation in Birmingham, United Kingdom, were used to develop models predicting transplant failure risk 5 years posttransplantation...

BACKGROUND: The use of alemtuzumab as induction immunosuppression for renal transplantation introduces the possibility of long-term tacrolimus monotherapy, avoiding maintenance with both corticosteroids and mycophenolate mofetil (MMF). METHODS: We conducted a single-center, prospective, open-label, randomized controlled trial comparing two steroid avoidance regimens between December 2006 and November 2010. One hundred and sixteen adult patients were randomized to either basiliximab induction followed by tacrolimus and MMF maintenance or to alemtuzumab induction followed by tacrolimus monotherapy...

The pathogenesis of BK polyomavirus (BKV) infection and associated nephropathy in renal transplant recipients is not clearly understood. To gain insight, urine and plasma samples were collected from 112 renal transplant recipients before and after transplantation and tested for the presence of BKV by polymerase chain reaction. Detection of BKV infection very early (ie, 5 days) after transplantation was identified as a risk factor for subsequent BKV viremia and BKV-associated nephropathy. Phylogenetic analysis of VP1 sequences with corresponding ethnicity data suggests that reactivation was of donor origin...

INTRODUCTION: Acute kidney injury (AKI) is common among critically ill patients and associated with a high mortality. We report here on the outcomes of patients with AKI who received renal replacement therapy (RRT) on our intensive care unit (ICU). We were interested in which parameters measured at the time of ICU admission were predictive of mortality and the long term renal sequelae for these patients. PATIENTS AND METHODS: All ICU patients in a large UK teaching hospital who received RRT for AKI over a 6-year period were identified and reviewed retrospectively...