Prognostic Value of Exercise Capacity in Kidney Transplant Candidates.

Background Exercise stress testing for cardiovascular assessment in kidney transplant candidates has been shown to be a feasible alternative to pharmacologic methods. Exercise stress testing allows the additional assessment of exercise capacity, which may have prognostic value for long-term cardiovascular outcomes in pre-transplant recipients. This study aimed to evaluate the prognostic value of exercise capacity on long-term cardiovascular outcomes in kidney transplant candidates. Methods and Results We retrospectively evaluated exercise capacity in 898 consecutive kidney transplant candidates between 2013 and 2020 who underwent symptom-limited exercise stress echocardiography for pre-transplant cardiovascular assessment. Exercise capacity was measured by age- and sex-predicted metabolic equivalents (METs). The primary outcome was incident major adverse cardiovascular events, defined as cardiac death, non-fatal myocardial infarction, and stroke. Cox proportional hazard multivariable modeling was performed to define major adverse cardiovascular events predictors with transplantation treated as a time-varying covariate. A total of 429 patients (48%) achieved predicted METs. During follow-up, 93 (10%) developed major adverse cardiovascular events and 525 (58%) underwent transplantation. Achievement of predicted METs was independently associated with reduced major adverse cardiovascular events (hazard ratio [HR] 0.49; [95% CI 0.29-0.82], P=0.007), as was transplantation (HR, 0.52; [95% CI 0.30-0.91], P=0.02). Patients achieving predicted METs on pre-transplant exercise stress echocardiography had favorable outcomes that were independent (HR, 0.78; [95% CI 0.32-1.92], P=0.59) and of similar magnitude to subsequent transplantation (HR, 0.97; [95% CI 0.42-2.25], P=0.95). Conclusions Achievement of predicted METs on pre-transplant exercise stress echocardiography confers excellent prognosis independent of and of similar magnitude to subsequent kidney transplantation. Future studies should assess the benefit on exercise training in this population.

Use of Atrial Strain to Predict Atrial Fibrillation After Cerebral Ischemia.

OBJECTIVES: This study sought to identify whether atrial strain could be used as an imaging biomarker to predict atrial fibrillation (AF). BACKGROUND: AF is found in up to 30% of cryptogenic cerebrovascular accidents (CVAs), which themselves account for 30% to 40% of ischemic CVA. METHODS: This observational study evaluated all patients who had an echocardiogram (transthoracic echocardiogram [TTE]) following presentation with cryptogenic CVA from 2010 to 2014. The TTEs were evaluated for reservoir strain (ƐR), contractile strain (ƐCt), and conduit atrial strain (ƐCd) using speckle tracking. Baseline clinical and TTE characteristics of patients who developed AF over 5 years of follow-up and those who did not were compared. The independent and incremental predictive value of atrial strain over established clinical models was assessed. Discriminatory cutpoints were defined using a Classification and Regression Tree (CART) analysis to identify patients at risk of developing AF. RESULTS: Of 538 patients, 61 (11%) developed AF, and this occurred within 2 years in 85% of patients. Patients who developed AF were older, had higher clinical risk scores, had higher LA volume, and had lower atrial strain than did those who did not develop AF. The area under the receiver-operating characteristic curve was 0.85 for ƐR, 0.83 for ƐCt, and 0.76 for ƐCd (all p < 0.001). The nested Cox regression model showed that ƐR (p = 0.03) and ƐCt (p < 0.001) demonstrated independent and incremental predictive value over the clinical risk. CART analysis identified ƐR ≤21.4%, ƐCd >10.4%, and CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology Atrial Fibrillation) score >7.8% as discriminatory for AF, with a 13-fold greater hazard of AF (p < 0.001) in patients with increased clinical risk and reduced ƐR. However, validation is needed for these strain cutoffs for detection of AF. CONCLUSIONS: Left atrial strain adds independent and incremental predictive value to current risk-prediction models for AF following cryptogenic CVA. Further studies should examine the implications of these findings for AF monitoring or empiric anticoagulation.

Association of survival time with transthoracic echocardiography in stable patients with heart failure: Is routine follow-up ever appropriate?

BACKGROUND: The appropriateness of repeat transthoracic echocardiography (TTE) for stable heart failure (HF) is based on timing of the follow-up examination, but this lacks scientific support. We sought the association of routine follow-up TTE on survival and readmission in stable HF. METHODS: Patients with HF were selected from consecutive HF admissions from 2008 to 2012. Groups were divided into: no follow-up TTE; routine <1year with no change in status ("rarely appropriate"), ≥1year follow-up with no change in status ("maybe appropriate") and TTE due to change in clinical status ("appropriate"). Survival analysis was performed for the combined endpoint of HF readmission and death, and a separate analysis was performed for HF readmission, with death as a competing risk. RESULTS: Of 550 HF patients, 141 had a follow-up TTE, including 41 (29%) within 1year. The event-free time in years was similar between no TTE (1.10years [95%CI: 0.69, 1.49], routine TTE <1year (2.61years [95% CI: 1.08, 3.04], routine >1year (2.45years [95% CI: 1.37, 5.78]); all were greater than symptomatic patients (0.09years [95% CI: 0.02, 1.80]). HF readmission was independently associated with statins, renal disease, coronary angiography and NYHA class, but not follow-up TTE timing. There were no differences in the cumulative incidence for death between groups. There were no differences in change in management in routine TTE <1year and ≥1year. CONCLUSION: The distinction of appropriateness of routine repeat TTE in stable HF patients, based on testing <1 or ≥1year after index admission appears unjustified.

PTHrP-mediated hypercalcemia: causes and survival in 138 patients.

CONTEXT: Hypercalcemia is a common complication of cancer with PTHrP an important mediator. Literature on the underlying causes of PTHrP-mediated hypercalcemia, in both malignant and benign conditions, is limited to small case series and case reports. OBJECTIVE: The purpose of this study was to systematically identify a large series of cases of PTHrP-mediated hypercalcemia and to document differences in demographics and the clinical course between malignant and benign etiologies. DESIGN, SETTING, AND PATIENTS: This was a hospital-based, retrospective case series that identified subjects from 1999 to 2010 from the public hospital system in Queensland, Australia. Included subjects were 18 years and older and had persistent hypercalcemia with simultaneously elevated PTHrP. RESULTS: A total of 138 cases were identified. Solid organ malignancies made up 82.6% (n = 114) of cases, with squamous cell carcinoma (28.2% of total) and adenocarcinomas (27.5%) almost equally as common. Hematological malignancy and benign conditions made up 8.7% (n = 12) each. Squamous cell carcinoma of the lung was the single most commonly identified etiology (10.9%). Causes not previously identified included myxoid sarcoma, plasma cell leukemia, duodenal adenocarcinoma, metastatic Merkel cell carcinoma, and epithelioid hemangioendothelioma. Median survival was different among the groups (52 days [interquartile range, 21-132 days] for solid organ malignancy, 362 days [18-652 days] for hematological malignancy, and 906 days [16 days to undefined] for the apparently benign group; P < .0001). There were no differences in PTHrP among the groups. Although the mean corrected calcium level was lower in the benign group (3.03 mmol/L [2.80-3.29 mmol/L]) compared with that in the solid organ (3.11 mmol/L [2.89-3.46 mmol/L]) and hematological malignancy groups (3.60 mmol/L [3.01-3.79 mmol/L]) groups (P = .046), it was not a useful discriminator of etiology. CONCLUSION: PTHrP-mediated hypercalcemia is most frequently caused by solid organ malignancy, and it portends a poor prognosis. Although the solid organ malignancy group had the shortest survival, the hematological malignancy and apparently benign causes groups still had relatively short overall survival.

Defining pulmonary exacerbation in children with non-cystic fibrosis bronchiectasis.

RATIONALE: Exacerbations in non-cystic fibrosis (CF) bronchiectasis are associated with worsening lung functions and quality of life. A standardized definition of exacerbation could improve clinical care and research. OBJECTIVE: To formulate a clinically useful definition of pulmonary exacerbation for pediatric non-CF bronchiectasis. METHODS: A cohort of 69 children with non-CF bronchiectasis was prospectively followed for 900 child-months. The changes in clinical, systemic, and lung function parameters from 81 exacerbations were statistically evaluated using conditional logistic regression, receiver operating characteristic, sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) to formulate a definition of a pulmonary exacerbation. Formation of major and minor criteria was statistically based and models were developed. MEASUREMENTS AND MAIN RESULTS: Wet cough and cough severity (score ≥ 2) over 72-hr were the best predictors of an exacerbation with area under the curve (AUC) of 0.85 (95% CI 0.79-0.92) and 0.84 (95% CI 0.77-0.91), respectively. Sputum color, chest pain, dyspnea, hemoptysis, and chest signs were significant though minor criteria. Inclusion of serum C-reactive protein, amyloid-A, and IL6 to the definition improved its specificity and PPV. Our final combined model consisted of one major with one investigatory criterion (PPV 91%, NPV 72%); two major criteria (PPV 79%, NPV 91%); or one major and two minor criteria (PPV 79%, NPV 94%). CONCLUSIONS: Pulmonary exacerbation in children with non-CF bronchiectasis can be validly predicted using a standardized assessment of clinical features, with additional systemic markers improving predictive values. This definition potentially facilitates earlier detection (leading to appropriate management) of exacerbations.

Free cortisol method comparison: ultrafiltation, equilibrium dialysis, tracer dilution, tandem mass spectrometry and calculated free cortisol.

BACKGROUND: Free cortisol (FC) can be calculated from measurements of total cortisol and binding proteins or measured after mechanical separation of unbound and bound fractions by equilibrium dialysis or ultrafiltration. FC can then be measured indirectly by 3H-cortisol dilution or directly by immunologic or tandem mass spectrometry assays. METHODS: We compared FC measured with ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC MS/MS) with 3H-cortisol dilution in ultrafiltrates and dialysates and also with calculated FC (Coolens equation). An adult FC reference interval was established. RESULTS: The UHPLC MS/MS and 3H-cortisol dilution methods were non-linearly related (Cusum linearity test p<0.001) but well correlated (R2=0.984). FC calculated with Coolens equation agreed with the UHPLC MS/MS method. Impurity of 3H-cortisol and non-specific adsorption were excluded as causes on non-linearity. Ultrafiltration was linearly related to equilibrium dialysis, simpler to perform and more repeatable. A gender non-specific FC reference interval of 2.1-19.1 nmol/L was established. CONCLUSIONS: In view of the non-linearity between measuring techniques and the variability of reported reference ranges, care should be exercised in adopting a reference range. The ultrafiltration UHPLC MS/MS method we described is robust and suitable for use in a routine laboratory.

Characterising adrenal function using directly measured plasma free cortisol in stable severe liver disease.

BACKGROUND & AIMS: Adrenal insufficiency (AI) has been reported in patients with advanced liver disease. Diagnosing AI is problematic owing to controversies in using total serum cortisol as a measure of adrenal function. No published data exist on directly measured plasma free cortisol (PFC) in patients with liver disease. METHODS: This prospective study compared serum total and measured plasma free cortisol to evaluate adrenal function in clinically stable cirrhotic patients and healthy controls. Cortisol levels were measured at baseline and following 250 µg corticotrophin. AI was defined by total cortisol increments (delta cortisol) of less than 250 nmol/L, or a peak total cortisol under 500 nmol/L after cosyntropin. We used a peak plasma free cortisol concentration of 33 nmol/L as the threshold for AI. RESULTS: Forty-three consecutive patients and 10 healthy controls were studied. Cirrhotic patients had significantly lower peak (526 vs. 649 nmol/L, p=0.004) and delta total cortisol (264 vs. 397 nmol/L, p = 0.002) responses compared to healthy controls. However, basal plasma free cortisol was higher in patients (10.9 vs. 6.4 nmol/L, p = 0.03), and there were no differences in peak plasma free cortisol (p = 0.69) between the two groups. The prevalence of AI using total cortisol criteria was 58% compared to 12% using free cortisol (p<0.001). CONCLUSION: In patients with stable severe liver disease, a significant discrepancy exists between the rates of diagnosis of AI using the total and free cortisol criteria. We would advise caution in the interpretation of adrenal function testing using total cortisol measurements in this group.