Impact of Glomerulitis on Long-term Outcomes After Kidney Transplantation.

The Banff classification scheme provides a framework for interpreting transplant kidney biopsies and has undergone various updates in the past 2 decades especially related to antibody-mediated rejection. The clinical significance of early glomerulitis seen within 4 mo on protocol biopsies has received limited attention. We hypothesized that early glomerulitis seen on protocol biopsies will lead to significant adverse outcomes as assessed by histopathology and allograft outcome. Methods: A single-center retrospective study of a cohort of patients who underwent protocol biopsies within 4 mo after transplantation with timely follow-up protocol biopsies were assessed. Patients with recurrent glomerulonephritis were excluded. Results: We calculated glomerulitis (g) scores for 2212 biopsy specimens and identified 186 patients with glomerulitis (g > 0) and 2026 patients without glomerulitis (g = 0). The progression to chronic transplant glomerulopathy at 1 and 2 y was higher in patients with g > 0 as compared with g = 0 (year 1, 10.7% versus 2.3% [P < 0.001]' respectively; year 2, 17.2% versus 4.3% [P < 0.001], respectively) with no difference in other chronic lesions. The death-censored graft failure rate was higher in patients with g > 0 as compared with g = 0 (hazard ratio, 1.68 [95% CI, 1.07-2.65]; P = 0.02). We did not find any difference in outcomes in glomerulitis group based on donor-specific antibody. Conclusion: Our findings suggest that early glomerulitis (seen within 4 mo after transplantation) may lead to clinically significant long-term changes and thus could be a target for early intervention therapies.

Role for exosomes with self-antigens and immune regulatory molecules in allo- and auto-immunity leading to chronic immune injury following murine kidney transplantation.

OBJECTIVE: Antibodies against donor human leukocyte antigen are a risk factor for chronic immune injury (CII) following renal transplantation; however, it is often not detectable. The main goal of this study is to gain new insights into the kinetics of exosome release and content in sensitized vs non-sensitized recipients. Towards this, we investigated the role for circulating exosomes with allo and self-antigens as well as immunoregulatory molecules in the development of CII and acute rejection. METHODS: Using murine kidney allograft rejection models, we investigated the role of exosomes on immune responses leading to allo- and auto-immunity to self-antigens resulting in rejection. Exosomes were analyzed for kidney self-antigens (Collagen-IV, fibronectin, angiotensin II receptor type 1), and immune-regulatory molecules (PD-L1, CD73) using western blot. Antibodies to donor MHC in serum samples were detected by immunofluorescence, self-antigens by enzyme-linked immunosorbent assay and kidney tissue infiltrating cells were determined by immunohistochemistry. RESULTS: BALB/c; H2d to C57BL/6; H2b renal transplantation (BALB/c), resulted in tubulitis and cellular infiltration by day 14, suggestive of acute inflammation, that was self-limiting with functioning graft. This contributed to CII on post-transplant day >100, which was preceded by induction of exosomes with donor and self-antigens leading to antibodies and immune-regulatory molecules. The absence of acute rejection in this allogenic transplant model is likely due to the induction of splenic and, graft-infiltrating CD4 + FoxP3+ T regulatory cells. In contrast, prior sensitization by skin graft followed by kidney transplantation induced antibodies to MHC and self-antigens leading to acute rejection. CONCLUSION: We demonstrate a pivotal role for induction of exosomes with immune-regulatory molecules, allo- and auto-immunity to self-antigens leading to chronic immune injury following murine kidney transplantation.

Correlation of Chronic Histologic Changes on Preimplantation Frozen Section Biopsy With Transplant Outcomes After Deceased Donor Kidney Transplantation.

CONTEXT.­: It is unclear if preimplantation frozen section biopsy correlates with outcomes after deceased donor kidney transplantation. OBJECTIVE.­: To assess if chronic histologic changes on the preimplant frozen section correlates with graft loss and estimated glomerular filtration rate independently of kidney donor profile index (KDPI). DESIGN.­: Seven hundred three preimplantation biopsies were reviewed and a Banff sum score was calculated using glomerular sclerosis, interstitial fibrosis, vascular intimal thickening, and arteriolar hyalinosis. The posttransplant outcomes were compared for preimplantation biopsy Banff sum 0-1, 2-3, and 4-9. The cohort was also stratified by KDPI 85 or less versus more than 85. RESULTS.­: For the entire biopsy cohort, graft survival, estimated glomerular filtration rate at 1 year, and chronic changes on a 1-year posttransplant biopsy were superior in the group with preimplantation Banff sum 0-1. After stratifying by KDPI, the Banff sum no longer correlated with graft survival. In a univariate mode, using the Banff sum score as a continuous variable, a higher Banff sum score was significantly associated with graft failure (P = .03); however, after adjusting the KDPI, the Banff sum score no longer correlated with graft failure (P = .45). The 1-year estimated glomerular filtration rate and 1-year biopsy changes were superior in the group with Banff sum 0-1 only in the cohort with KDPI 85 or less. CONCLUSIONS.­: In donor kidneys used for transplant, preimplantation biopsy chronic changes correlate with estimated glomerular filtration rate and biopsy findings at 1 year, but biopsies with mostly mild chronicity and Banff sum scores less than or equal to 5 did not impact graft survival beyond KDPI.

Implication of TIGIT+ human memory B cells in immune regulation.

Regulatory B cells (Bregs) contribute to immune regulation. However, the mechanisms of action of Bregs remain elusive. Here, we report that T cell immunoreceptor with Ig and ITIM domains (TIGIT) expressed on human memory B cells especially CD19+CD24hiCD27+CD39hiIgD-IgM+CD1c+ B cells is essential for effective immune regulation. Mechanistically, TIGIT on memory B cells controls immune response by directly acting on T cells and by arresting proinflammatory function of dendritic cells, resulting in the suppression of Th1, Th2, Th17, and CXCR5+ICOS+ T cell response while promoting immune regulatory function of T cells. TIGIT+ memory B cells are also superior to other B cells at expressing additional inhibitory molecules, including IL-10, TGFß1, granzyme B, PD-L1, CD39/CD73, and TIM-1. Lack or decrease of TIGIT+ memory B cells is associated with increased donor-specific antibody and TFH response, and decreased Treg response in renal and liver allograft patients. Therefore, TIGIT+ human memory B cells play critical roles in immune regulation.

Patient and allograft outcomes after kidney transplant for the Indigenous patients in the United States.

BACKGROUND: The objective is to assess cardiovascular (CV), malignancy, infectious, graft outcomes and tacrolimus levels for the Indigenous patients compared to Whites after kidney transplant (KTx). METHODS: 165 Indigenous and 165 White patients matched for the KTx year at Mayo Clinic Arizona from 2007-2015 were studied over a median follow-up of 3 years. Propensity score was calculated to account for baseline differences. RESULTS: Compared to Whites, Indigenous patients had the following characteristics: younger age, more obesity, diabetes, hypertension, and required dialysis prior to KTx (p<0.01). Indigenous patients had longer hospital stay for KTx, shorter follow-up and lived further from the transplant center (p<0.05). 210 (63.6%) received deceased donor KTx and more Whites received a living donor KTx compared to Indigenous patients (55.2% vs 17.6%, p<0.0001). Post-KTx, there was no difference in the CV event rates. The cumulative incidence of infectious complications was higher among the Indigenous patients (HR 1.81, p = 0.0005, 48.5% vs 38.2%, p = 0.013), with urinary causes as the most common. Malignancy rates were increased among Whites (13.3% vs 3.0%, p = 0.001) with skin cancer being the most common. There was a significant increase in the dose normalized tacrolimus level for the Indigenous patients compared to Whites at 1 months, 3 months, and 1 year post-KTx. After adjustment for the propensity score, there was no statistical difference in infectious or graft outcomes between the two groups but the mean number of emergency room visits and hospitalizations after KTx was significantly higher for Whites compared to Indigenous patients. CONCLUSIONS: Compared to Whites, Indigenous patients have similar CV events, graft outcomes and infectious complications after accounting for baseline differences.

Patient experience after kidney transplant: a conceptual framework of treatment burden.

BACKGROUND: Kidney transplant recipients face a lifelong regimen of medications, health monitoring and medical appointments. This work involved in managing one's health and its impact on well-being are referred to as treatment burden. Excessive treatment burden can adversely impact adherence and quality of life. The aim of this study was to develop a conceptual framework of treatment burden after kidney transplantation. Qualitative interviews were conducted with kidney transplant recipients (n = 27) from three Mayo Clinic transplant centers. A semi-structured interview guide originally developed in patients with chronic conditions and tailored to the context of kidney transplantation was utilized. Themes of treatment burden after kidney transplantation were confirmed in two focus groups (n = 16). RESULTS: Analyses confirmed three main themes of treatment burden after kidney transplantation: 1) work patients must do to care for their health (e.g., attending medical appointments, taking medications), 2) challenges/stressors that exacerbate felt burden (e.g., financial concerns, health system obstacles) 3) impacts of burden (e.g., role/social activity limitations). CONCLUSIONS: Patients describe a significant amount of work involved in caring for their kidney transplants. This work is exacerbated by individual, interpersonal and system-related factors. The framework will be used as a foundation for a patient-reported measure of treatment burden to promote better care after kidney transplantation.

Statin use and hip fractures in U.S. kidney transplant recipients.

BACKGROUND: Basic and translational research supports beneficial effects of statins on bone metabolism. Clinical studies suggest that statin use may reduce the risk of hip fractures in the general population. Whether statin use is associated with hip fracture risk in kidney transplant recipients, a particularly high-risk group for this outcome, is unknown. METHODS: From the U.S. Renal Data System (2007-2011), we identified all hip fracture events recorded in Medicare billing claims of first-time kidney transplant recipients. We then matched all cases to an unlimited number of controls on age (±3 years), sex, race (black vs. non-black), and time since transplant. Cases and controls were required to have >1 year of Medicare Parts A + B + D coverage and be without a recorded history of hip fracture. We ascertained any statin use in the previous year and defined adherent statin use as those who had filled prescriptions for statins to cover >80% of days in that year (proportion of days covered, PDC). We ascertained several potential confounders (demographics, comorbidities, BMI, transplant-related factors) and applied conditional logistic regression with multiple imputation for missing data to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: We identified 231 hip fracture cases (mean age 51.8 years; 53% female; 11.3% black; 6.9 years from transplant, and 9.9 years from ESRD) and 15,575 matched controls. Any prior statin use was present in 64.1% of cases and 60.3% of controls with 37.2% of cases and 33.9% of controls being found adherent. Unadjusted conditional logistic regression showed an OR of 1.17 (0.89-1.54) for any statin use, and a fully-adjusted OR of 0.89 (0.67-1.19). Compared with statin non-users, the adjusted OR for patients with lesser adherence (PDC ≤80%) and those with greater adherence (PDC >80%) were 0.93 (0.66-1.31) and 0.87 (0.63-1.20), respectively. CONCLUSION: Statin use was not associated with hip fracture risk in first-time kidney transplant recipients.

Thematic synthesis of qualitative studies on patient and caregiver perspectives on end-of-life care in CKD.

BACKGROUND: Although dialysis prolongs life for patients with end-stage kidney disease, 20% of deaths in this population are preceded by dialysis therapy withdrawal. Recently, there has been more focus on conservative (nondialytic) care as a legitimate option, particularly for elderly patients. This study aims to describe patients' and caregivers' perspectives on conservative treatment and end-of-life care in chronic kidney disease (CKD). STUDY DESIGN: Systematic review and thematic synthesis of qualitative studies. SETTING & POPULATION: Patients with CKD and caregivers. SEARCH STRATEGY & SOURCES: MEDLINE, Embase, PsycINFO, CINAHL, and reference lists were searched to May 2013. ANALYTICAL APPROACH: Thematic synthesis was used to analyze the findings. RESULTS: 26 studies involving more than 711 patients (non-dialysis dependent [n=41], hemodialysis [n=544], peritoneal dialysis [n=9]; unspecified dialysis modality [n=31], conservative management [n=86]) and 178 caregivers were included. We identified 5 themes: invasive suffering (bodily deterioration, loss of freedom and independence, unyielding fatigue and pain, resignation, treatment burden and harm, financial strain), personal vulnerability (imminence of death, misunderstanding and judgment, autonomy and dignity, medical abandonment, trust and safety), relational responsibility (being a burden, demonstrating loyalty, protecting others from grief), negotiating existential tensions (accepting natural course of life, disrupted aging, worthlessness, living on borrowed time, respecting sanctity of life, life satisfaction, preserving self-identity), and preparedness (decisional clarity, informational power, spirituality and hope). LIMITATIONS: Non-English articles were excluded; therefore, the transferability of findings to other populations is unclear. CONCLUSIONS: Some patients with CKD experience physical and psychosocial frailty and feel ambivalent about prolonging life. Some caregivers believe in providing relief from suffering, but are uncertain about making decisions regarding dialysis therapy initiation and discontinuation. We suggest that CKD management should encompass palliative care strategies that promote emotional resilience, sense of well-being, and self-value. Also, respectful and attentive communication may empower patients to convey their values and preferences about their own care.

Temporal trends in the incidence, treatment, and outcomes of hip fracture in older patients initiating dialysis in the United States.

BACKGROUND AND OBJECTIVES: Patients with ESRD experience a fivefold higher incidence of hip fracture than the age- and sex-matched general population. Despite multiple changes in the treatment of CKD mineral bone disorder, little is known about long-term trends in hip fracture incidence, treatment patterns, and outcomes in patients on dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fourteen annual cohorts (1996-2009) of older patients (≥67 years) initiating dialysis in the United States were studied. Eligible patients had Medicare fee-for-service coverage for ≥2 years before dialysis initiation and were followed for ≤3 years for a first hip fracture. Type of treatment (internal fixation or partial or total hip replacement) was ascertained along with 30-day mortality. Cox and modified Poisson regressions were used to describe trends in study outcomes. RESULTS: This study followed 409,040 patients over 607,059 person-years, during which time 17,887 hip fracture events were recorded (29.3 events/1000 person-years). Compared with patients incident for ESRD in 1996, adjusted hip fracture rates increased until the 2004 cohort (+41%) and declined thereafter. Surgical treatment included internal fixation in 56%, partial hip replacement in 29%, and total hip replacement in 2%, which remained essentially unchanged over time; 30-day mortality after hip fracture declined from 20% (1996) to 16% (2009). CONCLUSIONS: Hip fracture incidence rates remain higher today than in patients reaching ESRD in 1996, despite multiple purported improvements in the management of CKD mineral bone disorder. Although recent declines in incidence and steady declines in associated short-term mortality are encouraging, hip fractures remain among the most common and consequential noncardiovascular complications of ESRD.