Creating ophthalmology experiences in undergraduate medical education: pilot of a cased-based learning ophthalmology tool.

PURPOSE: To evaluate medical student perceptions of a novel ophthalmology resource delivered through facilitated workshops in the core clerkship curriculum. METHODS: We created www.2020sim.com, a free case-based learning (CBL) ophthalmology tool, adapted from NephSIM (www.nephsim.com). The tool was first piloted with the internal medicine (IM) residents. After confirming a need, we focused on undergraduate medical education (UME) by expanding the 20/20 SIM content and partnering with the neurology (pilot academic year [AY] 2020-2021) and pediatric clerkships (pilot AY 2021-2022) to deliver a facilitated one-hour ophthalmology workshop within each clerkship's didactic curriculum. We evaluated the tool using pre- and post-surveys and knowledge assessments. RESULTS: Of 80 IM residents, 33 (41.3%) completed the needs assessment. Of the 25 residents who attended the workshop, 23 (92.0%) completed the exit survey. IM residents reported discomfort in several ophthalmology domains (9 of 14 rated mean score < 3.0), confirming a need. Most (n = 21/23, 91.3%) rated the tool as good/excellent. Of 145 neurology clerkship students, 125 (86.2%) and at least 88 (60.7%) students completed the pre- and post-test/exit surveys, respectively. On average, participants highly rated the tool, perceiving 20/20 SIM to be relevant to their education [4.1 (0.8)]. Mean pre- to post-test knowledge scores increased from 7.5 to 8.5/10.0 points (p < 0.001). Of the 136 pediatric clerkship students, 67 (49.3%) and 51 (37.5%) completed the pre- and post-surveys, respectively. Respondents perceived increased comfort with ophthalmology topics after the facilitated workshop [3.8 (0.8)]. Mean pre- to post-test knowledge scores trended from 1.8 to 2.0/5.0 points (p = 0.30). Collectively, 20/139 (14.4%) of exit survey respondents visited www.2020sim.com within 1 month after the workshop. CONCLUSION: After identifying areas of greatest need with residents, we partnered with core clerkships to deliver cross-disciplinary ophthalmology content in UME. We found high engagement with 20/20 SIM, with trends toward increased knowledge.

Deep learning identified pathological abnormalities predictive of graft loss in kidney transplant biopsies.

Interstitial fibrosis, tubular atrophy, and inflammation are major contributors to kidney allograft failure. Here we sought an objective, quantitative pathological assessment of these lesions to improve predictive utility and constructed a deep-learning-based pipeline recognizing normal vs. abnormal kidney tissue compartments and mononuclear leukocyte infiltrates. Periodic acid- Schiff stained slides of transplant biopsies (60 training and 33 testing) were used to quantify pathological lesions specific for interstitium, tubules and mononuclear leukocyte infiltration. The pipeline was applied to the whole slide images from 789 transplant biopsies (478 baseline [pre-implantation] and 311 post-transplant 12-month protocol biopsies) in two independent cohorts (GoCAR: 404 patients, AUSCAD: 212 patients) of transplant recipients to correlate composite lesion features with graft loss. Our model accurately recognized kidney tissue compartments and mononuclear leukocytes. The digital features significantly correlated with revised Banff 2007 scores but were more sensitive to subtle pathological changes below the thresholds in the Banff scores. The Interstitial and Tubular Abnormality Score (ITAS) in baseline samples was highly predictive of one-year graft loss, while a Composite Damage Score in 12-month post-transplant protocol biopsies predicted later graft loss. ITASs and Composite Damage Scores outperformed Banff scores or clinical predictors with superior graft loss prediction accuracy. High/intermediate risk groups stratified by ITASs or Composite Damage Scores also demonstrated significantly higher incidence of estimated glomerular filtration rate decline and subsequent graft damage. Thus, our deep-learning approach accurately detected and quantified pathological lesions from baseline or post-transplant biopsies and demonstrated superior ability for prediction of post-transplant graft loss with potential application as a prevention, risk stratification or monitoring tool.

Recurrence of IgA Nephropathy after Kidney Transplantation in Adults.

BACKGROUND AND OBJECTIVES: In patients with kidney failure due to IgA nephropathy, IgA deposits can recur in a subsequent kidney transplant. The incidence, effect, and risk factors of IgA nephropathy recurrence is unclear, because most studies have been single center and sample sizes are relatively small. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a multicenter, international, retrospective study to determine the incidence, risk factors, and treatment response of recurrent IgA nephropathy after kidney transplantation. Data were collected from all consecutive patients with biopsy-proven IgA nephropathy transplanted between 2005 and 2015, across 16 "The Post-Transplant Glomerular Disease" study centers in Europe, North America, and South America. RESULTS: Out of 504 transplant recipients with IgA nephropathy, recurrent IgA deposits were identified by kidney biopsy in 82 patients; cumulative incidence of recurrence was 23% at 15 years (95% confidence interval, 14 to 34). Multivariable Cox regression revealed a higher risk for recurrence of IgA deposits in patients with a pre-emptive kidney transplant (hazard ratio, 3.45; 95% confidence interval, 1.31 to 9.17) and in patients with preformed donor-specific antibodies (hazard ratio, 2.59; 95% confidence interval, 1.09 to 6.19). After kidney transplantation, development of de novo donor-specific antibodies was associated with subsequent higher risk of recurrence of IgA nephropathy (hazard ratio, 6.65; 95% confidence interval, 3.33 to 13.27). Immunosuppressive regimen was not associated with recurrent IgA nephropathy in multivariable analysis, including steroid use. Graft loss was higher in patients with recurrence of IgA nephropathy compared with patients without (hazard ratio, 3.69; 95% confidence interval, 2.04 to 6.66), resulting in 32% (95% confidence interval, 50 to 82) graft loss at 8 years after diagnosis of recurrence. CONCLUSIONS: In our international cohort, cumulative risk of IgA nephropathy recurrence increased after transplant and was associated with a 3.7-fold greater risk of graft loss.

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.

Implementation of a quality improvement strategy to increase outpatient kidney transplant referrals.

BACKGROUND: Kidney transplantation remains the optimal therapy for patients with end stage kidney disease (ESKD), though a small fraction of patients on dialysis are on organ waitlists. An important barrier to both preemptive kidney transplantation and successful waitlisting is timely referral to a kidney transplant center. We implemented a quality improvement strategy to improve outpatient kidney transplant referrals in a single center academic outpatient nephrology clinic. METHODS: Over a 3 month period (July 1-September 30, 2016), we assessed the baseline kidney transplantation referral rate at our outpatient nephrology clinic for patients 18-75 years old with an estimated glomerular filtration rate (eGFR) of less than 20 mL/min/1.73m2 (2 values over 90 days apart). Charts were manually reviewed by two reviewers to look for kidney transplant referrals and documentation of discussions about kidney transplantation. We then performed a root cause analysis to explore potential barriers to kidney transplantation. Our intervention began on July 1, 2017 and included the implementation of a column in the electronic medical record (EMR) which displayed the patient's last eGFR as part of the clinic schedule. In addition, physicians were given a document listing their patients to be seen that day with an eGFR of < 20 mL/min/1.73m2. Annual education sessions were also held to discuss the importance of timely kidney transplant referral. RESULTS: At baseline, 54 unique patients with eGFR ≤20 ml/min/1.73 m2 were identified who were seen in the Clinic between July 1, 2016 and September 30, 2016. 29.6% (16) eligible patients were referred for kidney transplantation evaluation. 69.5% (37) of these patients were not referred for kidney transplant evaluation. 46.3% (25) did not have documentation regarding kidney transplant in the EMR. nephrologist's most recent note. Following the intervention, 66 unique patients met criteria for eligibility for kidney transplant evaluation. Kidney transplant referrals increased to 60.6% (p <  0.001). CONCLUSIONS: Our pilot implementation study of a strategy to improve outpatient kidney transplant referrals showed that a free, simple, scalable intervention can significantly improve kidney transplant referrals in the outpatient setting. This intervention targeted the nephrologist's role in the transplant referral, and facilitated the process of patient recognition and performing the referral itself without significantly interrupting the workflow. Next steps include further investigation to study the impact of early referral to kidney transplant centers on preemptive and living donor kidney transplantation as well as successful waitlisting.

Severe hypercalcemia preceding a diagnosis of Pneumocystis jirovecii pneumonia in a liver transplant recipient.

BACKGROUND: Incidence of the opportunistic infection Pneumocystis jirovecii pneumonia (PJP) in solid organ transplant patients ranges from 5 to 15% with a mortality of up to 38%. CASE PRESENTATION: We present a liver transplant recipient who developed hypoxemic respiratory failure related to PJP soon after treatment for allograft rejection. His presentation was preceded by severe hypercalcemia of 14.6 mg/dL and an ionized calcium of 1.7 mmol/L which remained elevated despite usual medical management and eventually required renal replacement therapy. As approximately 5% of PJP cases have granulomas, here we review the role of pulmonary macrophages and inflammatory cytokines in the pathophysiology of granuloma-mediated hypercalcemia. We also discuss the interpretation of our patient's laboratory studies, response to medical therapy, and clinical risk factors which predisposed him to PJP. CONCLUSIONS: It is important for clinicians to consider PJP as an etiology of granulomatous pneumonia and non-parathyroid hormone mediated hypercalcemia in chronically immunosuppressed organ transplant recipients for timely diagnosis and management.

A Peripheral Blood Gene Expression Signature to Diagnose Subclinical Acute Rejection.

BACKGROUND: In kidney transplant recipients, surveillance biopsies can reveal, despite stable graft function, histologic features of acute rejection and borderline changes that are associated with undesirable graft outcomes. Noninvasive biomarkers of subclinical acute rejection are needed to avoid the risks and costs associated with repeated biopsies. METHODS: We examined subclinical histologic and functional changes in kidney transplant recipients from the prospective Genomics of Chronic Allograft Rejection (GoCAR) study who underwent surveillance biopsies over 2 years, identifying those with subclinical or borderline acute cellular rejection (ACR) at 3 months (ACR-3) post-transplant. We performed RNA sequencing on whole blood collected from 88 individuals at the time of 3-month surveillance biopsy to identify transcripts associated with ACR-3, developed a novel sequencing-based targeted expression assay, and validated this gene signature in an independent cohort. RESULTS: Study participants with ACR-3 had significantly higher risk than those without ACR-3 of subsequent clinical acute rejection at 12 and 24 months, faster decline in graft function, and decreased graft survival in adjusted Cox analysis. We identified a 17-gene signature in peripheral blood that accurately diagnosed ACR-3, and validated it using microarray expression profiles of blood samples from 65 transplant recipients in the GoCAR cohort and three public microarray datasets. In an independent cohort of 110 transplant recipients, tests of the targeted expression assay on the basis of the 17-gene set showed that it identified individuals at higher risk of ongoing acute rejection and future graft loss. CONCLUSIONS: Our targeted expression assay enabled noninvasive diagnosis of subclinical acute rejection and inflammation in the graft and may represent a useful tool to risk-stratify kidney transplant recipients.

Higher rates of rejection in HIV-infected kidney transplant recipients on ritonavir-boosted protease inhibitors: 3-year follow-up study.

Rejection rates in HIV-infected kidney transplant (KTx) recipients are higher than HIV-negative recipients. Immunosuppression and highly active antiretroviral therapy (HAART) protocols vary with potentially significant drug-drug interactions, likely influencing outcomes. This is an IRB-approved, single-center, retrospective study of adult HIV-infected KTx patients between 5/2009 and 12/2014 with 3-year follow-up, excluding antibody-depleting induction. A total of 42 patients were included; median age was 52 years, 81% male, 50% African American, 29% Hispanic, 17% Caucasian. The most common renal failure etiology was hypertensive nephrosclerosis (50%) with 5.8 median years of pre-transplant dialysis. All patients received IL-2 receptor antagonist, were maintained on tacrolimus (76%) or cyclosporine (17%), and 40% received ritonavir-boosted PI-based HAART (rtv+) regimen. Patient and graft survival at 3 years were 93% and 90%. At 1-, 2-, and 3-year time points, median serum creatinine was 1.49, 1.35, and 1.67; treated biopsy-proven rejection was 38%, 38%, and 40.5%; and 92% of episodes were acute rejection. At these time points, rejection rates were significantly higher with boosted PI HAART regimens compared to other HAART regimens, 59% vs 24% (P = 0.029), 59% vs 24% (P = 0.029), and 68% vs 24% (P = 0.01). Despite higher rejection rates, HIV-infected KTx recipients have reasonable outcomes. Given significantly higher rejection rates using rtv+ regimens, alternative HAART regimens should be considered prior to transplantation.

A large, international study on post-transplant glomerular diseases: the TANGO project.

BACKGROUND: Long-term outcomes in kidney transplantation (KT) have not significantly improved during the past twenty years. Despite being a leading cause of graft failure, glomerular disease (GD) recurrence remains poorly understood, due to heterogeneity in disease pathogenesis and clinical presentation, reliance on histopathology to confirm disease recurrence, and the low incidence of individual GD subtypes. Large, international cohorts of patients with GD are urgently needed to better understand the disease pathophysiology, predictors of recurrence, and response to therapy. METHODS: The Post-TrANsplant GlOmerular Disease (TANGO) study is an observational, multicenter cohort study initiated in January 2017 that aims to: 1) characterize the natural history of GD after KT, 2) create a biorepository of saliva, blood, urine, stools and kidney tissue samples, and 3) establish a network of patients and centers to support novel therapeutic trials. The study includes 15 centers in America and Europe. Enrollment is open to patients with biopsy-proven GD prior to transplantation, including IgA nephropathy, membranous nephropathy, focal and segmental glomerulosclerosis, atypical hemolytic uremic syndrome, dense-deposit disease, C3 glomerulopathy, complement- and IgG-positive membranoproliferative glomerulonephritis or membranoproliferative glomerulonephritis type I-III (old classification). During phase 1, patient data will be collected in an online database. The biorepository (phase 2) will involve collection of samples from patients for identification of predictors of recurrence, biomarkers of disease activity or response to therapy, and novel pathogenic mechanisms. Finally, through phase 3, we will use our multicenter network of patients and centers to launch interventional studies. DISCUSSION: Most prior studies of post-transplant GD recurrence are single-center and retrospective, or rely upon registry data that frequently misclassify the cause of kidney disease. Systematically determining GD recurrence rates and predictors of clinical outcomes is essential to improving post-transplant outcomes. Furthermore, accurate molecular phenotyping and biomarker development will allow better understanding of individual GD pathogenesis, and potentially identify novel drug targets for GD in both native and transplanted kidneys. The TANGO study has the potential to tackle GD recurrence through a multicenter design and a comprehensive biorepository.

Translational studies of A20 in atherosclerosis and cardiovascular disease.

Cardiovascular disease (CVD) is the biggest killer in the Western World despite significant advances in understanding its molecular underpinnings. Chronic inflammation, the classical hallmark of atherogenesis is thought to play a key pathogenic role in the development of atherosclerotic lesions from initiation of fatty streaks to plaque rupture. Over-representation of mostly pro-inflammatory nuclear factor kappa B (NF-kappaB) target genes within atherosclerotic lesions has led to the common-held belief that excessive NF-kappaB activity promotes and aggravates atherogenesis. However, mouse models lacking various proteins involved in NF-kappaB signaling have often resulted in conflicting findings, fueling additional investigations to uncover the molecular involvement of NF-kappaB and its target genes in atherogenesis. In this chapter we will review the role of the NF-kappaB-regulated, yet potent NF-kappaB inhibitory and anti-inflammatory gene A20/TNFAIP3 in atherogenesis, and highlight the potential use of its atheroprotective properties for the prevention and treatment of cardiovascular diseases.

Value of electrocardiographic and ankle-brachial index abnormalities for prediction of coronary atherosclerosis in asymptomatic subjects with type 2 diabetes mellitus.

Type 2 diabetes mellitus (DM) is associated with increased cardiovascular risk, in part due to accelerated subclinical atherosclerosis. Electrocardiographic (ECG) and ankle-brachial index (ABI) abnormalities are used to screen for cardiovascular risk in the clinic. However, their capacity to identify patients with type 2 DM with nonobstructive subclinical atherosclerosis is unknown. Associations of ECG and ABI abnormalities with coronary artery calcium (CAC), a measure of coronary atherosclerosis, were examined using multivariable ordinal regression modeling in 589 asymptomatic patients with type 2 DM. Sensitivity, specificity, and positive and negative predictive values were determined. CAC was prevalent (44% CAC>00; 32% CAC>5th percentile score) despite normal electrocardiograms (64%) and ABIs (97%) in most subjects. Neither ECG nor ABI changes predicted CAC after adjusting for age, gender, and race. ECG abnormalities were neither sensitive nor specific for detection of CAC>100, >400, or>75th percentile (sensitivities 0.43, 0.45, and 0.34; specificities 0.69, 0.66, and 0.63, respectively). ABI abnormalities were not sensitive (0.03, 0.04, and 0.03) but had high specificity (0.98, 0.98, and 0.98). In subjects with normal electrocardiograms and ABIs, extensive CAC was remarkably prevalent (CAC>00 in 24%). In conclusion, ECG and ABI abnormalities failed to detect patients with subclinical coronary atherosclerosis and therefore may be of limited value in identifying many asymptomatic patients with type 2 DM at increased risk of cardiovascular disease.