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The long-term impact of early subclinical inflammation (SCI) through surveillance biopsy has not been well studied. To do this, we recruited a prospective observational cohort that included 1000 sequential patients who received a kidney transplant from 2013-2017 at our center. A total of 586 patients who underwent a surveillance biopsy in their first year post-transplant were included after excluding those with clinical rejections, and those who were unable to undergo a surveillance biopsy. Patients were classified based on their biopsy findings: 282 with NSI (No Significant Inflammation) and 304 with SCI-T (SCI and Tubulitis) which was further subdivided into 182 with SC-BLR (Subclinical Borderline Changes) and 122 with SC-TCMR (Subclinical T Cell Mediated Rejection, Banff 2019 classification of 1A or more). We followed the clinical and immunological events including Clinical Biopsy Proven Acute Rejection [C-BPAR], long-term kidney function and death-censored graft loss over a median follow-up of five years. Episodes of C-BPAR were noted at a median of two years post-transplant. Adjusted odds of having a subsequent C-BPAR was significantly higher in the SCI-T group [SC-BLR and SC-TCMR] compared to NSI 3.8 (2.1-7.5). The adjusted hazard for death-censored graft loss was significantly higher with SCI-T compared to NSI [1.99 (1.04-3.84)]. Overall, SCI detected through surveillance biopsy within the first year post-transplant is a harbinger for subsequent immunological events and is associated with a significantly greater hazard for subsequent C-BPAR and death-censored graft loss. Thus, our study highlights the need for identifying patients with SCI through surveillance biopsy and develop strategies to prevent further alloimmune injuries.

For assessing human leukocyte antigen compatibility in deceased donor kidney transplantation, virtual crossmatch is used as an alternative to physical crossmatch and has potential to reduce cold ischemia time. The 2014 United States kidney allocation system prioritized highly sensitized candidates but led to increased shipping of kidneys. Using data from the Scientific Registry of Transplant Recipients, we evaluated changes in virtual crossmatch use with the new allocation policy and the impact of virtual crossmatch use on cold ischemia time and transplant outcomes. This was a retrospective cohort study of adult deceased donor kidney recipients in the United States (2011-2018) transplanted with either 9,632 virtual or 71,839 physical crossmatches. Before allocation change, only 9% of transplants were performed relying on a virtual crossmatch. After the 2014 allocation change, this increased by 2.4%/year so that 18% transplants in 2018 were performed with just a virtual crossmatch. There was significant variation in virtual crossmatch use among transplant regions (range 0.7-36%) and higher use was noted among large volume centers. Compared to physical crossmatches, virtual crossmatches were significantly associated with shorter cold ischemia times (mean 15.0 vs 16.5 hours) and similar death-censored graft loss and mortality (both hazard ratios HR 0.99) at a median follow-up of 2.9 years. Thus, our results show that virtual crossmatch is an attractive strategy for shortening cold ischemia time without negatively impacting transplant outcomes. Hence, strategies to optimize use and reduce practice variation may allow for maximizing benefits from virtual crossmatch.

Virtual crossmatch (VXM) is used as an alternative to or in conjunction with a cell-based physical crossmatch (PXM) for assessing HLA (human leukocyte antigen) compatibility prior to deceased donor kidney transplantation (DDKT). Data on practice patterns and perceptions regarding VXM use in the US are limited. We performed a survey of US HLA directors and transplant surgeons regarding HLA testing and crossmatch strategies. 53 (56 %) HLA directors and 68 surgeons (representing ∼ 23 % of US transplant centers) completed the survey. Both groups agreed that VXM could reduce cold ischemia time (CIT), costs and improve allocation efficiency. VXM use increased following the 2021 kidney allocation change. Reducing CIT was the primary reason for favoring VXM over PXM. Preference for VXM reduced as candidates' panel reactive antibodies increased. Regulations, program policies and limitations of HLA technology were cited as important reasons for preferring PXM over VXM. Surgeons reported similar perceptions, but findings are limited by the low response rate. Finally, half the labs reported lacking specific protocols for VXM use. In conclusion, improved HLA technology and protocols along with changes to institutional procedures and policy regulations are needed for safer expansion of VXM in DDKT.

Long-Term Survival after Kidney Transplantation This review discusses demographics, survival, and risks in kidney transplantation since the mid-1990s. It addresses postoperative events that impede ...

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. To identify high-risk patients, we examined clinical/histological parameters using regression and non-linear dimensionality reduction (tSNE), and a biomarker based on peripheral blood transitional-1 B cell (T1B) IL-10/TNFα ratio. Compared to NI, early BL was associated with increased progression to late acute rejection (AR; 5-12mos), premature interstitial fibrosis and tubular atrophy (IFTA) and decreased seven-year graft survival. However, decreased graft survival was limited to BL patients who progressed to late AR or IFTA, and was not influenced by treatment. Although tSNE clustered patients into groups based on clinical factors, the ability of these factors to risk stratify BL patients was modest. In contrast, a low T1B IL-10/TNFα ratio at 3 months identified BL patients at high-risk for progression to AR (ROC AUC 0.87) and poor 7yr-graft survival (52% vs. 92%, p=0.003), while BL patients with a high ratio had similar graft survival to patients with NI (91%, p=NS). Thus, progressive early allograft inflammation manifest as BL that progresses to late AR in the first post-transplant year represents a high-risk clinical state for poor allograft outcomes. Such high-risk status can be predicted by the T1B IL-10/TNFα ratio before irreversible scarring sets in, thus allowing timely risk stratification.

High kidney-donor profile index (KDPI) kidneys have a shorter survival than grafts with lower KDPI values. It is still unclear, however, whether their shorter longevity depends on an inferior baseline function, faster functional decline, or the combination of both.We analyzed the estimated glomerular filtration rate (eGFR) of 605 consecutive recipients of deceased donor kidney transplants (KT) at 1, 3, 6, 12, 18, 24, 36, 48, and 60 months. Comparisons were performed among four groups based on KDPI quartile: Group I-KDPI ≤ 25% (n = 151), Group II-KDPI 26-50% (n = 182), Group III-KDPI 51-75% (n = 176), and Group IV-KDPI 〉 75% (n = 96). Linear mixed model analysis was subsequently used to assess whether KDPI was independently associated with the decline in eGFR during the first 5-years after KT. We also analyzed the incidence of delayed graft function (DGF), rejection within the first year after KT, patient survival, graft survival, and death censored graft survival based on KDPI group.High-KDPI grafts had lower eGFR immediately after KT, had a higher incidence of DGF and rejection. However, there were no signifcant differences in the adjusted rate (slope) of decline in eGFR among the four KDPI groups (P = .06). Although patient survival was signigicantly lower for recipients of high-KDPI grafts, death-censored graft survival was similar among the four KDPI groups (P = .33).The shorter functional survival of high-KDPI grafts seems to be due to their lower baseline eGFR rather than a more rapid functional decline after KT.

Anti-HLA Donor Specific Antibody (DSA) detection post kidney transplant has been associated with adverse outcomes, though the impact of early DSA screening on stable patients remain unclear. We analyzed impact of DSA detection through screening in 1st year stable patients (

Antithymocyte globulin (ATG) is a commonly used induction agent in kidney transplant recipients. However, the optimal dosing has not been well defined. Our protocol aims for a 5-6 mg/kg cumulative dose. It is unclear if a dose lower than 5 mg/kg is associated with more rejection. We performed a retrospective cohort study of patients who received a kidney transplant at our center between January 1, 2013 and December 31, 2016. Primary outcome was biopsy proven acute rejection (clinical and subclinical) in the first 6 months after kidney transplant. CMV viremia in high risk (D+/R-) recipients and BK viremia was compared as a secondary endpoint. Of the 543 patients, the Low Dose (LD) group (n = 56) received5 mg/kg ATG and Regular Dose (RD) group (n = 487) received ≧5 mg/kg. Patients in RD were more sensitized (higher PRA and CPRA). LD received a dose of 4 ± 1.1 mg/kg ATG whereas RD received 5.6 ± .3 mg/kg ATG (P.001). TCMR (Banff 1A or greater) was present in 34% of patients in LD versus 22% in RD (P = .04) (OR 2.1; 95%CI 1.12-3.81; P = .019). There was no difference in the incidence of CMV or BK viremia. ATG doses lower than 5 mg/kg may be associated with a heightened risk of rejection despite a low degree of sensitization.

Transplantation of kidneys from shorter donors into taller recipients may lead to suboptimal allograft survival. The effect of discrepancy in donor and recipient heights (ΔHeight) on long term transplant outcomes is not known. Adult patients ≥18 years undergoing living or deceased donor (LD or DD) kidney transplants alone from donors ≥18 years between 2000 and 2016 in the United States were included in this observational study. The cohort was divided into three groups based on ΔHeight of 5 inches as 1) Recipient < Donor (DD: 31,688, LD: 12,384), 2) Recipient = Donor (DD: 84,711, LD: 54,709), and 3) Recipient > Donor (DD: 21,741, LD: 18,753). Univariate analysis showed a higher risk of DCGL and mortality in both DD and LD (p < 0.001 for both). The absolute difference in graft and patient survival between the two extremes of ΔHeight was 5.7% and 5.7% for DD, and 0.4% and 1.4% for LD. On multivariate analysis, the HR of DCGL for Recipient < Donor and Recipient > Donor was 0.95 (p = 0.05) and 1.07 (p = 0.01) in DD and 0.98 (p = 0.55) and 1.14 (p < 0.001) in LD. Similarly, the corresponding HR of mortality were 0.97 (p = 0.07) and 1.07 (p = 0.003) for DD and 1.01 (p < 0.001) and 1.05 (p = 0.13) for LD. For DGF, the HR were 1.04 (p = 0.1) and 1.01 (p = 0.7) for DD and 1.07 (p = 0.45) and 0.89 (p = 0.13) for LD. Height mismatch between the donor and recipient influences kidney transplant outcomes.

Background We studied humoral responses after coronavirus disease 2019 (COVID-19) vaccination across varying causes of immunodeficiency. Methods Prospective study of fully vaccinated immunocompromised adults (solid organ transplant [SOT], hematologic malignancy, solid cancers, autoimmune conditions, human immunodeficiency virus [HIV]) versus nonimmunocompromised healthcare workers (HCWs). The primary outcome was the proportion with a reactive test (seropositive) for immunoglobulin G to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain. Secondary outcomes were comparisons of antibody levels and their correlation with pseudovirus neutralization titers. Stepwise logistic regression was used to identify factors associated with seropositivity. Results A total of 1271 participants enrolled: 1099 immunocompromised and 172 HCW. Compared with HCW (92.4% seropositive), seropositivity was lower among participants with SOT (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) (P < .01). Factors associated with poor seropositivity included age, greater immunosuppression, time since vaccination, anti-CD20 monoclonal antibodies, and vaccination with BNT162b2 (Pfizer) or adenovirus vector vaccines versus messenger RNA (mRNA)-1273 (Moderna). mRNA-1273 was associated with higher antibody levels than BNT162b2 or adenovirus vector vaccines after adjusting for time since vaccination, age, and underlying condition. Antibody levels were strongly correlated with pseudovirus neutralization titers (Spearman r = 0.89, P Conclusions Antibody responses to COVID-19 vaccines were lowest among SOT and anti-CD20 monoclonal recipients, and recipients of vaccines other than mRNA-1273. Among those with intermediate antibody levels, pseudovirus neutralization titers were lower in immunocompromised patients than HCWs. Additional SARS-CoV-2 preventive approaches are needed for immunocompromised persons, which may need to be tailored to the cause of immunodeficiency.

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. Compared to patients who do not develop DSA, those with DSA exhibit an increased incidence of both clinical and subclinical T-cell-mediated rejection (TCMR). The combination of TCMR plus DSA led to an almost three-fold increase in graft loss compared to either DSA or TCMR alone. Moreover, DSA was associated with higher Banff grade TCMR and chronic changes at one year. Antibody-mediated rejection was uncommon and always associated with TCMR. Amongst factors independently associated with DSA plus TCMR; non-adherence is potentially modifiable. Non-adherence, measured as intra-patient variability of calcineurin trough levels during the first post-transplant year, further risk-stratified patients with DSA plus TCMR such that about 75% of these patients had impending graft loss by four years, whereas adherent patients with DSA plus TCMR had outcomes comparable to other patient groups. Thus, early post-transplant DSA, especially in non-adherent patients, is associated with increased incidence of TCMR and represents a high-risk group of patients who might benefit from targeted therapeutic interventions.

The use of kidneys donated after circulatory death (DCD) provides an invaluable expansion of the organ supply for transplantation. Here we investigated the effect of DCD on fibrotic changes on 1-year post-transplant surveillance kidney allograft biopsy. Recipients of a deceased donor kidney transplant between 2013 and 2017 at a single institution, who survived 1 year and underwent surveillance biopsy, were included in the analysis (n = 333: 87 DCD kidneys, 246 kidneys donated after brain death [DBD]). Banff scores for interstitial fibrosis and tubular atrophy were summed as IFTA and compared between the groups. DCD and DBD groups were comparable for baseline characteristics. Delayed graft function was 39% in DCD vs. 19% in DBD, p = 0.0002. Patient and graft survival were comparable for DCD and DBD cohorts. IFTA scores were higher in DCD compared to DBD (2.43±0.13 vs. 2.01±0.08, p = 0.0054). On multivariate analysis, the odds of IFTA>2 in the DCD group was 2.5x higher (95%CI: 1.35-4.63) than in the DBD group. Within the DCD group, kidneys with IFTA>2 had inferior 5-year graft survival (p = 0.037). In conclusion, compared DBD kidneys, DCD kidneys developed a greater degree of fibrotic changes on 1-year post-transplant surveillance biopsy, which affected graft longevity within the DCD cohort. This article is protected by copyright. All rights reserved.

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. The biomarker also predicted subsequent late rejection with a lead time averaging 8 months. Among biomarker high-risk patients, 60% had early rejection, of which 48% recurred later in the first posttransplant year. Among high-risk patients without early rejection, 74% developed rejection later in the first year. In contrast, only 5% of low-risk patients had early and 5% late rejection. The biomarker also predicted rejection in an External Validation Set (n = 95) and in key patient subgroups, confirming generalizability. Biomarker high-risk patients exhibited progressively worse renal function and decreased 5-year graft survival compared to low-risk patients. Treatment of B cells with anti-TNFα in vitro augmented the IL-10/TNFα ratio, restored regulatory activity, and inhibited plasmablast differentiation. To conclude, the T1B IL-10/TNFα ratio was validated as a strong predictive biomarker of renal allograft outcomes and provides a rationale for preemptive therapeutic intervention with TNF blockade.

We studied diverse rejection management strategies across centers by conducting a UNOS survey of kidney transplant program directors in 2017. There were 104 total responses from 235 kidney transplant programs representing 88 unique transplant programs (response rate 37%). Information was collected on center-specific management practices. Pertinent center-specific data were obtained from the OPTN database. Of the respondents, 33% were considered large centers (>100 transplants/year). Thymoglobulin was the most commonly used induction agent at 84%, 72% responders do rapid steroid withdrawal, and mycophenolic acid (MPA) is the major antimetabolite (100%). For diagnosing TCMR, 100% used indication biopsy, 28% used protocol biopsy, 2% used serum biomarkers, and none used urine cytokines. For ABMR, 99% used indication biopsy, 34% used protocol biopsy, 72% used DSA, 21% used C1q positive DSA, and none used gene profiling (ENDATS). The treatment of subclinical and clinical TCMR included iv/PO steroids. PP/IVIG were the commonest treatments for ABMR. The use of rituximab, bortezomib, and eculizumab increased from C4D-ABMR to recurrent ABMR. There are diverse management practices for diagnosing and treating rejection. An effort to harmonize these diverse practices for management of TCMR and ABMR will give an opportunity to pool data for evaluating clinical outcomes.

Introduction: There are several studies of symptomatic hemodialysis patients with proven COVID-19 infection. However, there is paucity of data on asymptomatic COVID-19 infection in the outpatient hemodialysis population. The true prevalence and transmission of this infection in hemodialysis centres is unknown. This study was conducted across hemodialysis centers by testing all patients and staff for COVID-19 PCR and later for IgG antibody, irrespective of their symptoms. Methods: All 705 hemodialysis patients and 103 dialysis staff across nine centres, were tested for COVID-19 over a period of 54 days of the pandemic, and for COVID IgG antibody of available enrolled staff and patients, after 8 weeks of study termination. Results: The period prevalence of infection in patients and staff was 7.1% and 14.6% respectively. Mortality in patients was 18%, and all staff recovered. Clustering of patients and staff occurred at 3 of 9 centers. Of 26 HIV positive patients, only one contracted the COVID-19 infection and has recovered. Of those infected, seroconversion occurred in 80% of patients and 83% of staff. Seroconversion also occurred in 16% of patients and 37% of staff, who were asymptomatic and COVID PCR negative during the study period. Conclusions: Testing a patient only when symptomatic, identified only 26% (13/50) of infected patients. For every single symptomatic patient who tested positive, there were 3 other asymptomatic infected ones. There was a high seroconversion rates in infected subjects. But antibodies also developed in asymptomatic subjects, indicating silent transmission and antibody generation in this population.

Background. Renal transplantation is the treatment of choice for patients with end-stage renal disease. Because kidneys are the primary excretory organs for various drugs/drug metabolites, changes in renal graft function would significantly alter the clearance and exposure of renally secreted drugs. Renal allografts from living and deceased donors normally undergo numerous insults, including injuries associated with prolonged cold ischemic time, reperfusion, and nephrotoxicity due to calcineurin inhibitors. These physiologic and pharmacologic stresses can alter the expression and functional capacity of renal organic anionic transporters (OATs). Methods. The objectives of this study were to assess the longitudinal changes in renal anionic secretion in kidney transplant patients, to study the effect of prolonged cold ischemic time on OAT secretion in kidney transplant patients (living- versus deceased-donor recipients), and to compare OAT secretory capacity of renal transplant recipients with healthy volunteers. Cefoxitin was used as a probe drug to assess OAT secretion. Cefoxitin pharmacokinetics was studied in 15 de novo renal transplant recipients following intravenous administration of 200 mg cefoxitin within 14 d and beyond 90 d posttransplantation. Results. No longitudinal changes in real OAT secretion in early posttransplant period were observed, and there were no differences in renal OAT secretion between living- and deceased-donor renal transplant recipients. Overall, cefoxitin exposure was 2.6-fold higher and half-life increased by 2.2-fold in renal transplant recipients when compared with historical healthy controls. Conclusions. These results suggest that OAT system is functioning well, but renal transplant recipients would need significantly lower dosage of drugs that are primarily secreted via the OAT system compared with normal subjects.

Transplantation of kidneys from deceased donors with acute kidney injury (AKI) can expand the donor pool. We investigated the effect of donor AKI on renal function and chronic changes on protocol biopsies at 1-year post-transplant. Donor AKI was defined according to Acute Kidney Injury Network (AKIN) criteria. Between 2013 and 2017, 333 kidneys were transplanted and subsequently biopsied after 1 year. Fifty-three kidneys from AKI donors (AKIN stage I n = 42, stage II n = 8, stage III n = 3) were compared to 280 kidneys from non-AKI donors. At 1-year follow-up, patient and graft survival were comparable. Donor AKI was not predictive of IFTA (Banff interstitial fibrosis plus tubular atrophy scores) at 1-year post-transplant biopsy (2.10 ± 1.28 in AKI, 2.09 ± 1.22 in non-AKI, P = .95). Donor AKI was also not associated with progression of IFTA from 3 to 12 months (P = .69), or inferior glomerular filtration rate (eGFR, P = .94). In a multivariate analysis, the odds of IFTA >2 were comparable between AKI and non-AKI groups. In conclusion, the transplantation of kidneys from donors with predominantly stage I AKI results in comparable function and degree of fibrosis on protocol biopsies 1-year post-transplant. Selected grafts from donors with AKI are a valuable tool for expanding the donor pool for kidney transplantation.

Kidney donors face a small but definite risk of end-stage renal disease 15 to 30 years postdonation. The development of proteinuria, hypertension with gradual decrease in kidney function in the donor after surgical resection of 1 kidney, has been attributed to hyperfiltration. Genetic variations, physiological adaptations, and comorbidities exacerbate the hyperfiltration-induced loss of kidney function in the years after donation. A focus on glomerular hemodynamics and capillary pressure has led to the development of drugs that target the renin-angiotensin-aldosterone system (RAAS), but these agents yield mixed results in transplant recipients and donors. Recent work on glomerular biomechanical forces highlights the differential effects of tensile stress and fluid flow shear stress (FFSS) from hyperfiltration. Capillary wall stretch due to glomerular capillary pressure increases tensile stress on podocyte foot processes that cover the capillary. In parallel, increased flow of the ultrafiltrate due to single-nephron glomerular filtration rate elevates FFSS on the podocyte cell body. Although tensile stress invokes the RAAS, FFSS predominantly activates the cyclooxygenase 2-prostaglandin E2-EP2 receptor axis. Distinguishing these 2 mechanisms is critical, as current therapeutic approaches focus on the RAAS system. A better understanding of the biomechanical forces can lead to novel therapeutic agents to target FFSS through the cyclooxygenase 2-prostaglandin E2-EP2 receptor axis in hyperfiltration-mediated injury. We present an overview of several aspects of the risk to transplant donors and discuss the relevance of FFSS in podocyte injury, loss of glomerular barrier function leading to albuminuria and gradual loss of renal function, and potential therapeutic strategies to mitigate hyperfiltration-mediated injury to the remaining kidney.

Supplemental Digital Content is available in the text., IgA Nephropathy (IgAN) is a common cause of end-stage kidney disease worldwide. Unfortunately, the exact pathogenesis of IgAN remains uncertain without any targeted therapy. While kidney transplantation remains the gold standard treatment for those with end-stage kidney disease from IgAN, recurrence occurs frequently and may lead to early kidney transplant loss. Research has suggested that insulin-like growth factor-1 may play a role in mesangial cell proliferation in IgAN and Somatostatin may inhibit insulin-like growth factor-1. In this single case study, we report the use of octreotide, a somatostatin analogue, as a potential novel therapy for early recurrent IgAN post kidney transplant.

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). We evaluated differences in kidney function at 24-months and allograft histology score at 12-month biopsy. SCI patients had a higher serum creatinine (1.6 ± 0.7 vs 1.38 ± 0.45; P = .02) at 24-months posttransplant, and at last follow-up at a mean of 42.5 months (1.69 ± 0.9 vs 1.46 ± 0.5 mg/dL; P = .027). The allograft chronicity score (ci + ct + cg + cv) at 12-months posttransplant was higher in the SCI group (2.4 ± 1.35 vs 1.9 ± 1.2; P = .02). The incidence of subsequent rejections within the first year in SCI and NI groups was 24% vs 10%, respectively (P = .015). De novo donor-specific antibody within 12 months was more prevalent in the SCI group (12/129 vs 1/71, P = .03). SCI is likely not a benign finding and may have long-term implications for kidney allograft function.

Rituximab is a chimeric anti-CD20 monoclonal protein used in various clinical scenarios in kidney transplant recipients. However, its evidence-based use there remains limited due to lack of controlled studies, limited sample size, short follow-up and poorly defined endpoints. Rituximab is indicated for CD20+ posttransplant lymphoproliferative disorder. It may be beneficial for treating recurrent membranous nephropathy and recurrent allograft antineutrophilic cytoplasmic antibody vasculitis and possibly for recurrent focal segmental glomerulosclerosis. Rituximab, in combination with IVIg/plasmapheresis, appears to decrease antibody level and increase the odds of transplantation in sensitized recipients. The role of Rituximab in ABOi transplant remains unclear, as similar outcomes are achieved without its use. Rituximab is not efficacious in antibody-mediated rejection/chronic antibody-mediated rejection. Strict randomized control trials are necessary to elucidate its true role in these settings.

Due to shortage of donor, kidney transplants (KTs) from donors with acute kidney injury (AKI) are expanding. Although previous studies comparing clinical outcomes between AKI and non-AKI donors in KTs have shown comparable results, data on high-volume analysis of KTs outcomes with AKI donors are limited. This study aimed to analyze the selection trends of AKI donors and investigate the impact of AKI on graft failure using the United states cohort data. We analyzed a total 52,757 KTs collected in the Scientific Registry of Transplant Recipient (SRTR) from 2010 to 2015. The sample included 4,962 (9.4%) cases of KTs with AKI donors (creatinine ≥ 2 mg/dL). Clinical characteristics of AKI and non-AKI donors were analyzed and outcomes of both groups were compared. We also analyzed risk factors for graft failure in AKI donor KTs. Although the incidence of delayed graft function was higher in recipients of AKI donors compared to non-AKI donors, graft and patient survival were not significantly different between the two groups. We found donor hypertension, cold ischemic time, the proportion of African American donors, and high KDPI were risk factors for graft failure in AKI donor KTs. KTs from deceased donor with AKI showed comparable outcomes. Thus, donors with AKI need to be considered more actively to expand donor pool. Caution is still needed when donors have additional risk factors of graft failure.

Background. Early acute kidney rejection remains an important clinical issue. Methods. The current study included 552 recipients who had 1–2 surveillance or indication biopsy within the 1 y posttransplant. We evaluated the impact of type of allograft inflammation on allograft outcome. They were divided into 5 groups: no inflammation (NI: 95), subclinical inflammation (SCI: 244), subclinical T cell–mediated rejection (TCMR) (SC-TCMR: 110), clinical TCMR (C-TCMR: 83), and antibody-mediated rejection (AMR: 20). Estimated glomerular filtration rate (eGFR) over time using linear mixed model, cumulative chronic allograft scores/interstitial fibrosis and tubular atrophy (IFTA) ≥2 at 12 mo, and survival estimates were compared between groups. Results. The common types of rejections were C-TCMR (15%), SC-TCMR (19.9%), and AMR (3.6%) of patients. Eighteen of 20 patients with AMR had mixed rejection with TCMR. Key findings were as follows: (i) posttransplant renal function: eGFR was lower for patients with C-TCMR and AMR (P

Several groups have reported extended survival of genetically engineered pig organs in nonhuman primates, varying from almost 10 months for life-supporting kidney grafts and more than 2 years for non-life-supporting heart grafts to less than 1 month for life-supporting liver and lung grafts. We have attempted to define groups of patients who may not have an option to wait for an allograft. These include kidney, heart, and lung candidates who are highly-allosensitized. In addition, some kidney candidates (who have previously lost at least 2 allografts from rapid recurrence of native kidney disease) have a high risk of further recurrence and will not be offered a repeat allotransplant. Patients with complex congenital heart disease, who may have undergone previous palliative surgical procedures, may be unsuitable for ventricular assist device implantation. Patients dying of fulminant hepatic failure, for whom no alternative therapy is available, may be candidates for a pig liver, even if only as a bridge until an allograft becomes available. When the results of pig organ xenotransplantation in nonhuman primates suggest a realistic potential for success of a pilot clinical trial, highly selected patients should be offered participation.

This prospective observational cohort study compared the impact of subclinical tubulitis with or without interstitial inflammation to interstitial inflammation alone and to no inflammation in early post kidney transplant biopsies. A study cohort of 415 patients (living and deceased donor recipients) was divided into three groups on the basis of their three-month biopsy: 149 patients with No Inflammation (NI), 83 patients with Isolated Interstitial Inflammation (IIF), and 183 patients with Tubulitis [(with or without interstitial inflammation) (TIF) but not meeting criteria for Banff IA]. TIF was further divided into 56 patients with tubulitis without interstitial inflammation (TIF0) and 127 patients with tubulitis alongside interstitial inflammation (TIF1). TIF was significantly associated with higher incidence of subsequent T-cell mediated rejection (clinical or subclinical) at one year compared to IIF (31% vs 15%) and NI (31% vs 17%). Chronicity on one-year biopsy was significantly higher in TIF compared to IIF (22% vs 11%) and NI (22% vs 7%). De novo donor-specific antibody development was significantly higher in TIF compared to NI (6% vs 0.7%). Tubulitis subgroups (TIF0 and TIF1) revealed comparable effects on de novo donor-specific antibody and interstitial fibrosis/tubular atrophy development. However, tubulitis with interstitial inflammation had a significantly higher incidence of subsequent rejection and posed an increased hazard for the composite end point (subsequent acute rejection and death censored graft loss) compared to other groups [adjusted hazard 2.1 (95% confidence interval 1.2-3.5)]. Thus, subclinical tubulitis is a marker of adverse immunological events, but tubulitis with interstitial inflammation has a worse prognosis. Hence, the Banff 1997 (TIF1) and Banff 2005 classifications (TIF) for borderline change may have different implications.

The aim of the study is to provide a comprehensive overview of identical twin kidney transplantation in the modern era. We provide epidemiologic trends in the US twin population from 1959 to 2000, current methods to identify zygosity, outcomes for identical twin transplants, and a comprehensive management strategy for identical twin kidney transplantation. By 2019, we project that 433 010 dizygotic and monozygotic twins will be alive and at risk for developing ESRF. Monozygosity between a donor-recipient pair can be confirmed by concordance in sex, blood type, and HLA antigen match with precision testing using 13/17 Short Tandem Repeat sequencing to a likelihood of nearly 100%. Among identical twin transplants from 2001 to 2017, excellent patient and kidney graft survival rates were noted. Approximately 50% of kidney transplant recipients of identical twins transplant did not receive maintenance immunosuppression, and no differences in graft survival were noted among patients with and without immunosuppression at 6 and 12 months (P = .8 and .7). Patients with glomerulonephritis as the cause of ESRF had lower graft survival (P = .06) suggesting that recurrent glomerulonephritis as a likely cause of graft loss among these recipients.

We investigated the effect of clinical and subclinical T cell-mediated rejection (C-TCMR and SC-TCMR) on allograft histology, function, and progression.Adult kidney recipients with 2 protocol biopsies were divided into No-TCMR on biopsies (n = 104), SC-TCMR (n = 56), and C-TCMR (n = 32) in at least 1 biopsy. Chronicity (ci + ct + cg + cv) scores, renal function, and the burden of renal disease measured by area under the curve (serum creatinine, mg mo/dL) were compared.Baseline characteristics were similar except for mean donor age and Kidney Donor Profile index scores. Patients with C-TCMR had higher mean serum creatinine, lower mean estimated glomerular filtration rate, and higher area under the curve with 95% confidence interval (75.2 [67.7-82.7]) as opposed to patients with SC-TCMR and No-TCMR (58.3 [53.6-62.9], 65.1 [58.8-71.5]), P = 0.0004. Chronicity scores were higher at 3 months in C-TCMR (2.30 ± 1.58) compared with SC-TCMR (2.02 ± 1.42) and No-TCMR (1.31 ± 1.18), P = 0.0001 and also at 12 months. At last follow-up, 18.8% patients with C-TCMR had ≥50% decline in estimated glomerular filtration rate from 3 months compared with 7% and 1% among No-TCMR and SC-TCMR groups (P = 0.038). Multivariate analyses revealed higher odds of Δ-creatinine ≥ 0.5 mg/dL from 3 months to last follow-up for C-TCMR (3.39 [95% confidence interval, 1.25-9.20]) versus No-TCMR (P = 0.016).Kidney transplant recipients with C-/SC-TCMR have heightened early allograft chronicity and worse renal function compared with those with No-TCMR. Progressive renal dysfunction was noted among patients with C-TCMR as opposed to SC-TCMR and No-TCMR.

Supplemental digital content is available in the text., Background High calcineurin inhibitor (CNI) intrapatient variability (IPV) has been associated with poor kidney allograft outcomes. However, the relationship between early allograft histological changes, their progression, and CNI-IPV is less well studied. Hence, we evaluated effect of CNI-IPV defined by the degree of fluctuation of CNI levels in all kidney transplant patients over 2 to 12 months posttransplant on early allograft inflammation, subsequent chronicity, and later clinical outcomes. Methods Two hundred eighty-six patients transplanted from January 2013 to November 2014 were enrolled with protocol and indication biopsies. The mean CNI-IPV was 28.5% and a quarter of our cohort had IPV of 35% or greater (high CNI IPV). Baseline demographic differences were similar between high and low CNI IPV groups. Results High CNI-IPV was associated with a higher incidence of acute rejection (AR) within 1 year (52% vs 31% P < 0.001), more persistent/recurrent AR by 1 year (18.2% vs 6.2%, P = 0.002), higher-grade AR (≥Banff 1B, 27.5% vs 7.3%, P < 0.001), and worse interstitial fibrosis/tubular atrophy (P = 0.005). High CNI-IPV was associated with increased graft loss (GL) and impending graft loss (iGL, defined as eGFR30% decline in eGFR from baseline), regardless of donor-specific antibody, delayed graft function, rejection, or race. In a multivariate Cox Proportional Hazards Model, high CNI-IPV was independently associated with GL + iGL (hazard ratio, 3.1; 95% confidence interval, 1.6–5.9, P < 0.001). Conclusions High CNI-IPV within 1 year posttransplant is associated with higher incidence of AR, severe AR, allograft chronicity, GL, and iGL. This represents a subset of patients who are at risk for poor kidney transplant outcomes and potentially a modifiable risk factor for late allograft loss.

Background The burden of cytomegalovirus infection in CMV high-risk (donor positive to recipient negative) kidney transplant recipients getting thymoglobulin induction and six months of valganciclovir is not well characterized. Additionally, the role of post-prophylaxis surveillance remains unclear. Methods One-year observational study of forty-eight high-risk CMV kidney transplant recipients transplanted under thymoglobulin between January 2013 and July 2014. All received valganciclovir for six months, followed by monthly CMV PCR for three months. Results CMV infection defined as viremia with or without symptoms occurred in 40% (19/48). Of these, 47% (9/19) occurred during prophylaxis, 32% (6/19) during surveillance and 21% (4/19) during post-surveillance period (9–12 months). Among breakthrough infections, suboptimal valganciclovir dosing was present in 55% (5/9). With routine surveillance, there was a trend toward lower CMV-related hospitalization (17% vs 56% and 75% during prophylaxis and post-surveillance, respectively [P=.23]) and lower mean peak viral loads (19 432 copies/mL vs 97 925 copies/mL and 536 021 copies/mL during prophylaxis and post-surveillance, respectively [P=.07]). Conclusion CMV infection remains a significant problem with thymoglobulin induction despite six months of valganciclovir. Suboptimal valganciclovir dosing was common among breakthrough infections. Monthly surveillance post-prophylaxis appears to detect early CMV infection with lower degree of viremias requiring fewer hospitalizations.