Johnson, Bradley K.

ABSTRACT Introduction With reports of expanding epidemiology of blastomycosis across the United States, the purpose of this study was to evaluate the incidence and outcomes associated with blastomycosis in solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients. Methods We conducted a retrospective case series of adult SOT and HCT recipients at a tertiary care medical center between January 1, 2005 and September 30, 2023. Cases were defined as culture‐proven blastomycosis. We performed descriptive statistical analysis to evaluate diagnosis, management, and outcomes (mortality) of blastomycosis in SOT. Results The cumulative incidence of blastomycosis was 0.11% with a median time to infection following transplant of 743 days. Of the 19 cases, the majority of patients were SOT recipients (90%). Supratherapeutic immunosuppression within 30 days of diagnosis was observed in 42% of cases with documented drug monitoring. Urine antigen testing was highly sensitive (100%). Fourteen (73.7%) patients received induction therapy with liposomal amphotericin B followed by azole therapy for a minimum of 12 months. Despite appropriate treatment, 1‐year mortality was high at 26.3%, with attributable mortality of 21.1%. Conclusions While rates of blastomycosis remain low among SOT and HCT recipients, infection is associated with poor posttransplant outcomes. Antigen testing can aid in timely assessment of disease severity and initiation of appropriate therapy. Among survivors, no relapses were observed while on lifelong secondary suppression. Future studies should aim to better define risk factors associated with developing blastomycosis and establish effective strategies for prevention.

BACKGROUND: Cardiorenal dysfunction with impaired cyclic GMP (cGMP) response is common in patients presenting with acute heart failure (HF). Type V phosphodiesterase (PDEV) is known to be upregulated in HF and may explain the dysfunction of renal response. The aim of this study was to determine whether B-type natriuretic peptide (BNP) alone or in combination with PDEV inhibition improves renal function and increases urinary sodium and cGMP excretion in acute HF. METHODS: This open-label study included 67 patients hospitalized with acute HF and renal dysfunction. Patients were randomized to standard care, low-dose intravenous BNP (0.005 µg/kg per minute), or combination BNP/PDEV inhibition with sildenafil (25 mg q12 hours) for 48 hours. The coprimary end points were the percent change in estimated glomerular filtration rate and blood urea nitrogen from baseline to 48 hours. RESULTS: Treatment with BNP and BNP/PDEV inhibitor significantly increased plasma cGMP at 24 hours (+25.6% [+9.8%, +84.7%] and +60.8% [+32.3%, +103.8%] for BNP and BNP/PDEV versus −13.5% [−29.1%, +14.2%] with standard care; P =0.001). However, there was no significant change in estimated glomerular filtration rate 0 (−10.8%, +12.7%) for standard care versus 0 (−15.3%, +11.8%) for the BNP group versus –8.8% (−14.3%, +8.3%) for the BNP/PDEV group ( P =0.60) or blood urea nitrogen −1.4% (−10.7%, +12.0%) for standard care versus –5.9% (−14.6%, +9.4%) for the BNP group versus +6.9% (−5.3%, +18.8%) for the BNP/PDEV group ( P =0.38) between groups. Hypotension was more common in the BNP/PDEV inhibitor group. CONCLUSIONS: BNP and combination BNP/PDEV inhibition increased plasma cGMP in patients with acute HF but did not improve renal function or urinary sodium/cGMP excretion. Our study does not support the use of intravenous low-dose BNP with or without PDEV inhibition to enhance renal function in patients admitted with acute HF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00972569.

Abstract Background/Introduction Hypertension (HTN) and metabolic syndrome (MetS) are both leading risk factors for major cardiovascular diseases, which frequently coexist as a complicated cardiometabolic disorder. The cardiac hormone atrial natriuretic peptide (ANP) plays a key role in both blood pressure and metabolic regulation through activation of the guanylyl cyclase-A receptor (GC-A) and the second messenger 3’,5’ cyclic guanosine monophosphate (cGMP). Indeed, ANP decreases blood pressure, induces lipolysis by increasing plasma levels of non-esterified fatty acids (NEFA) and improves insulin-sensitivity. MANP is a new Mayo Clinic designed natriuretic peptide consisting of the native ANP with a 12-amino-acid C-terminus extension and its biological actions are mediated by the GC-A/cGMP pathway. MANP is less susceptible to neprilysin degradation and exert more sustained cGMP dependent biological actions than ANP. Purpose In a proof-of-principle human study, for the first time we aimed to determine the cardiovascular and metabolic properties of MANP, a novel ANP analog, in the clinical setting of HTN with MetS. Methods We conducted a double-blind, placebo-controlled trial in 22 patients (17 receiving MANP) with HTN and MetS involving single subcutaneous injection of MANP (2.5 µg/kg) or placebo (NCT03781739). Blood pressure (BP) and circulating cGMP were monitored for 24 hours post treatment. Circulating metabolic parameters including insulin, glucose, non-esterified fatty acids (NEFA) and insulin resistance (HOMA-IR) and insulin sensitivity (HOMA-IS) indexes were assessed for the first 4 hours post treatment. Results Compared to baseline, MANP increased plasma cGMP at 30 minutes (delta: 4.8 ± 2.0 pmol/mL, P = 0.02) and 1 hour (delta: 2.9 ± 1.3 pmol/mL, P = 0.03) post injection. At 6 hours, systolic BP decreased by 5.7 ± 2.9 mmHg (P = 0.06) in the MANP group, whereas no reduction in BP was observed in placebo group. Among the 17 subjects receiving MANP, lower baseline cGMP levels were associated with greater mean reductions in systolic BP (ρ = 0.66, P = 0.005). After MANP injection, glucose levels decreased at 2 (delta: -4.7 ± 2.1 mg/mL, P = 0.04) and 4 hours (delta: -13.1 ± 3.9 mg/mL, P = 0.003) compared to baseline while insulin levels remained stable. During the first 4 hours post injection, we also observed a trend of increase in insulin sensitivity index (HOMA2-IS) and decrease in insulin resistance index (HOMA2-IR) with MANP, both were opposite to the trends in placebo. At 1 hour post MANP administration, NEFA increased by 108.2 ± 37.4 µM compared to baseline (P = 0.01). Conclusion(s) Our findings support the favorable cardiovascular and metabolic actions of MANP as a potential therapeutic strategy for HTN with MetS.

Background. Mortality risk assessment before kidney transplantation (KT) is imperfect. An emerging risk factor for death in nontransplant populations is physiological age as determined by the application of artificial intelligence to the electrocardiogram (ECG). The aim of this study was to examine the relationship between ECG age and KT waitlist mortality. Methods. We applied a previously developed convolutional neural network to the ECGs of KT candidates evaluated 2014 to 2019 to determine ECG age. We used a Cox proportional hazard model to examine whether ECG age was associated with waitlist mortality. Results. Of the 2183 patients evaluated, 59.1% were male, 81.4% were white, and 11.4% died during follow-up. Mean ECG age was 59.0 ± 12.0 y and mean chronological age at ECG was 53.3 ± 13.6 y. After adjusting for chronological age, comorbidities, and other characteristics associated with mortality, each increase in ECG age of >10 y than the average ECG age for patients of a similar chronological age was associated with an increase in mortality risk (hazard ratio 3.59 per 10-y increase; 95% confidence interval, 2.06-5.72; P < 0.0001). Conclusions. ECG age is a risk factor for KT waitlist mortality. Determining ECG age through artificial intelligence may help guide risk-benefit assessment when evaluating candidates for KT.

AbstractBackgroundKidney transplant recipients are at increased risk for invasive aspergillosis (IA), a disease with poor outcomes and substantial economic burden. We aimed to determine risk factors for posttransplant IA by using a national database and to assess the association of IA with mortality and allograft failure.MethodsUsing the United States Renal Data System database, we performed a retrospective case-control study of patients who underwent kidney transplant from 1998 through 2017. To evaluate risk factors for IA, we performed conditional logistic regression analysis by comparing characteristics between IA-infected patients and their matched uninfected controls. We performed Cox regression analysis to evaluate the effects of IA on mortality and death-censored allograft failure.ResultsWe matched 359 patients with IA to 1436 uninfected controls (1:4). IA was diagnosed at a median of 22.5 months (interquartile range, 5.4–85.2 months) after kidney transplant. Risk factors for IA were Black/African American race, duration of pretransplant hemodialysis, higher Elixhauser Comorbidity Index score, weight loss, chronic pulmonary disease, need for early posttransplant hemodialysis, and a history of cytomegalovirus infection. Receiving an allograft from a living donor was protective against IA. IA was a strong independent predictor of 1-year mortality (adjusted hazard ratio [aHR], 5.02 [95% confidence interval {CI}, 3.58–7.04], P &lt; .001). Additionally, IA was associated with 1-year allograft failure (aHR, 3.37 [95% CI, 1.96–5.77], P &lt; .001).ConclusionsOur findings emphasize the importance of timely transplant to mitigate the risk of posttransplant IA. An individualized approach to disease prevention is essential to decrease mortality and allograft failure.

AbstractBackgroundThe incidence and impact of de novo fungal airway colonization and infection in lung transplant recipients (LTRs) with known chronic lung allograft dysfunction (CLAD) has not been established. We aimed to determine the 1‐year cumulative incidence and risk factors of de novo fungal colonization or infection in LTRs with CLAD and assess the impact of colonization or infection on post‐CLAD survival.MethodsProspectively collected Toronto Lung Transplant Program database and chart review were used for double‐LTRs who were diagnosed with CLAD from January 1, 2016 to January 1, 2020 and who were free of airway fungi within 1 year prior to CLAD onset. International Society for Heart and Lung Transplantation definitions were used to define clinical syndromes. Cox‐Proportional Hazards Models were used for risk‐factor analysis. Survival analysis could not be completed secondary to low number of fungal events; therefore, descriptive statistics were employed for survival outcomes.ResultsWe found 186 LTRs diagnosed with CLAD meeting our inclusion criteria. The 1‐year cumulative incidence for any fungal event was 11.8% (7.0% for infection and 4.8% for colonization). Aspergillus fumigatus was a causative pathogen in eight of 13 (61.5%) patients with infection and six of nine (66.7%) patients with colonization. No patients with fungal colonization post‐CLAD developed fungal infection. Peri‐CLAD diagnosis (3 months prior or 1 month after) methylprednisolone bolus (hazards ratio: 8.84, p = .001) increased the risk of fungal events. Most patients diagnosed with fungal infections (53.8%) died within 1‐year of CLAD onset.ConclusionDe novo IFIs and fungal colonization following CLAD onset were not common. Fungal colonization did not lead to fungal infection. Methylprednisolone bolus was a significant risk factors for post‐CLAD fungal events. image

Background. Limited health literacy (HL) is associated with decreased kidney function and death in patients with chronic kidney disease. Less is known about the impact of HL on kidney transplant (KT) outcomes. The aim of this study was to examine the relationship between HL and KT outcomes, including rates of waitlisting, healthcare utilization, acute rejection, renal allograft function, renal allograft failure, and death. Methods. We performed a retrospective review of HL data previously collected at our center. HL was assessed in a convenience sample of consecutive, English-speaking patients age ≥18 y who were evaluated for KT at Mayo Clinic in Minnesota between June 2015 and March 2017 as part of a practice improvement feasibility project (n = 690). HL was assessed using the 4-item Brief Health Literacy Screening Tool modified for the outpatient KT evaluation process. The 4 items assess confidence completing forms, reading comprehension, and oral literacy. Results. Overall, 30.4% of patients had limited or marginal HL. Patients with limited or marginal HL were less likely than those with adequate HL to be waitlisted for KT (hazard ratio = 0.62 and 0.69, respectively), even after adjusting for age, marital status, body mass index, Charlson comorbidity index, or dialysis dependency. Patient HL was not associated with post-KT healthcare utilization, acute rejection, or renal allograft function. Patients with limited or marginal HL appeared to experience a higher risk of renal allograft failure and post-KT death, but the number of events was small, and the relationship was statistically significant only for marginal HL. Conclusions. Inadequate HL is common in KT candidates and independently associated with decreased waitlisting for KT. We observed no statistically significant relationship between HL and posttransplant outcomes in our cohort. Further efforts to improve communication in patients with inadequate HL may improve access to KT.

Abstract Background Treatment burden refers to the work involved in managing one’s health and its impact on well-being and has been associated with nonadherence in patients with chronic illnesses. No kidney transplant (KT)-specific measure of treatment burden exists. The aim of this study was to develop a KT-specific supplement to the Patient Experience with Treatment and Self-Management (PETS), a general measure of treatment burden. Methods After drafting and pretesting KT-specific survey items, we conducted a cross-sectional survey study involving KT recipients from Mayo Clinic in Minnesota, Arizona, and Florida. Exploratory factor analysis (EFA) was used to identify domains for scaling the KT-specific supplement. Construct and known-groups validity were determined. Results Survey respondents (n = 167) had a mean age of 61 years (range 22–86) and received a KT on average 4.0 years ago. Three KT-specific scales were identified (transplant function, self-management, adverse effects). Higher scores on the KT-specific scales were correlated with higher PETS treatment burden, worse physical and mental health, and lower self-efficacy (p < 0.0001). Patients taking more medications reported higher transplant self-management burden. Conclusions We developed a KT-specific supplement to the PETS general measure of treatment burden. Scores may help providers identify recipients at risk for nonadherence.