Disruption in glutathione metabolism and altered energy production in the liver and kidney after ischemic acute kidney injury in mice.

Acute kidney injury (AKI) is a systemic disease that affects energy metabolism in various remote organs in murine models of ischemic AKI. However, AKI-mediated effects in the liver have not been comprehensively assessed. After inducing ischemic AKI in 8-10-week-old, male C57BL/6 mice, mass spectrometry metabolomics revealed that the liver had the most distinct phenotype 24 h after AKI versus 4 h and 7 days. Follow up studies with in vivo [13C6]-glucose tracing on liver and kidney 24 h after AKI revealed 4 major findings: (1) increased flux through glycolysis and the tricarboxylic (TCA) cycle in both kidney and liver; (2) depleted hepatic glutathione levels and its intermediates despite unchanged level of reactive oxygen species, suggesting glutathione consumption exceeds production due to systemic oxidative stress after AKI; (3) hepatic ATP depletion despite unchanged rate of mitochondrial respiration, suggesting increased ATP consumption relative to production; (4) increased hepatic and renal urea cycle intermediates suggesting hypercatabolism and upregulation of the urea cycle independent of impaired renal clearance of nitrogenous waste. Taken together, this is the first study to describe the hepatic metabolome after ischemic AKI in a murine model and demonstrates that there is significant liver-kidney crosstalk after AKI.

Derivation, External Validation and Clinical Implications of a deep learning approach for intracranial pressure estimation using non-cranial waveform measurements.

Importance: Increased intracranial pressure (ICP) is associated with adverse neurological outcomes, but needs invasive monitoring. Objective: Development and validation of an AI approach for detecting increased ICP (aICP) using only non-invasive extracranial physiological waveform data. Design: Retrospective diagnostic study of AI-assisted detection of increased ICP. We developed an AI model using exclusively extracranial waveforms, externally validated it and assessed associations with clinical outcomes. Setting: MIMIC-III Waveform Database (2000-2013), a database derived from patients admitted to an ICU in an academic Boston hospital, was used for development of the aICP model, and to report association with neurologic outcomes. Data from Mount Sinai Hospital (2020-2022) in New York City was used for external validation. Participants: Patients were included if they were older than 18 years, and were monitored with electrocardiograms, arterial blood pressure, respiratory impedance plethysmography and pulse oximetry. Patients who additionally had intracranial pressure monitoring were used for development (N=157) and external validation (N=56). Patients without intracranial monitors were used for association with outcomes (N=1694). Exposures: Extracranial waveforms including electrocardiogram, arterial blood pressure, plethysmography and SpO2. Main Outcomes and Measures: Intracranial pressure > 15 mmHg. Measures were Area under receiver operating characteristic curves (AUROCs), sensitivity, specificity, and accuracy at threshold of 0.5. We calculated odds ratios and p-values for phenotype association. Results: The AUROC was 0.91 (95% CI, 0.90-0.91) on testing and 0.80 (95% CI, 0.80-0.80) on external validation. aICP had accuracy, sensitivity, and specificity of 73.8% (95% CI, 72.0%-75.6%), 99.5% (95% CI 99.3%-99.6%), and 76.9% (95% CI, 74.0-79.8%) on external validation. A ten-percentile increment was associated with stroke (OR=2.12; 95% CI, 1.27-3.13), brain malignancy (OR=1.68; 95% CI, 1.09-2.60), subdural hemorrhage (OR=1.66; 95% CI, 1.07-2.57), intracerebral hemorrhage (OR=1.18; 95% CI, 1.07-1.32), and procedures like percutaneous brain biopsy (OR=1.58; 95% CI, 1.15-2.18) and craniotomy (OR = 1.43; 95% CI, 1.12-1.84; P < 0.05 for all). Conclusions and Relevance: aICP provides accurate, non-invasive estimation of increased ICP, and is associated with neurological outcomes and neurosurgical procedures in patients without intracranial monitoring.

A real-world observational study assessing relationships between excessive daytime sleepiness and patient satisfaction in obstructive sleep apnea.

OBJECTIVES/BACKGROUND: To estimate prevalence and severity of excessive daytime sleepiness among patients with obstructive sleep apnea (OSA) who were prescribed treatment; assess perception and satisfaction of OSA-related care; describe relationships between excessive daytime sleepiness, treatment adherence, and patient satisfaction. PATIENTS/METHODS: A national population-based cross-sectional sample of US adults with clinician-diagnosed OSA was surveyed in January 2021 via Evidation Health's Achievement App. Patients completed the Epworth Sleepiness Scale, rated satisfaction with healthcare provider and overall OSA care, and reported treatment adherence. Covariates affecting excessive daytime sleepiness (average weekly sleep duration, treatment adherence, sleepiness-inducing medications, age, sex, body mass index, nasal congestion, smoking status, and comorbidities) were adjusted in multivariate regression models. RESULTS: In 2289 participants (50.3 % women; 44.8 ± 11.1 years), EDS was highly prevalent (42 %), and was experienced by 36 % of patients with high positive airway pressure (PAP) therapy adherence. Each additional hour of nightly PAP use was associated with improved sleepiness (a 0.28-point lower Epworth score; p < 0.001). Excessive daytime sleepiness was associated with lower patient satisfaction with healthcare providers and overall care (OR [95 % CI] 0.62 [0.48-0.80] and 0.50 [0.39-0.64], respectively; p < 0.0001), whereas PAP adherence was associated with higher patient satisfaction (OR [95 % CI] 2.37 [1.64-3.43] and 2.91 [2.03-4.17]; p < 0.0001), after adjusting for confounders. CONCLUSIONS: In a real-world population-based study of patients with OSA, excessive daytime sleepiness was highly prevalent and associated with poor patient satisfaction ratings. Better patient-centered care among patients with OSA may require interventions aimed at addressing excessive daytime sleepiness and treatment adherence.

The DES-OSA Score for Identifying Patients with Sleep Apnea: A Validation Study and Suggestions for Improvement.

BACKGROUND: The DES-obstructive sleep apnea (DES-OSA) score uses morphological characteristics to predict the presence and severity of obstructive sleep apnea syndrome (OSAS). OBJECTIVES: To validate DES-OSA scores on the Israeli population. To identify patients requiring treatment for OSAS. To evaluate whether additional parameters could improve the diagnostic value of DES-OSA scores. METHODS: We performed a prospective cohort study on patients attending a sleep clinic. Polysomnography results were examined independently by two physicians. DES-OSA scores were calculated. STOP and Epworth questionnaires were administered, and data on cardiovascular risk was extracted. RESULTS: We recruited 106 patients, median age 64 years, 58% male. DES-OSA scores were positively correlated with apnea-hypopnea index (AHI) (P < 0.001) and were significantly different between the OSAS severity groups. Interobserver agreement for calculating DES-OSA was very high between the two physicians (intraclass correlation coefficient 0.86). DES-OSA scores ≤ 5 were associated with high sensitivity and low specificity (0.90 and 0.27, respectively) for moderate to severe OSAS. In univariate analysis, only age was significantly correlated with the presence of OSAS (OR 1.26, P = 0.01). Age older than 66 years as a single point in the DES-OSA score slightly improved the sensitivity of the test. CONCLUSIONS: DES-OSA is a valid score based solely on physical examination, which may be useful for excluding OSAS requiring therapy. DES-OSA score ≤ 5 effectively ruled out moderate to severe OSAS. Age older than 66 years as an extra point improved the sensitivity of the test.

Biologic treatments for severe asthma: 4 year experience of a single medical center.

BACKGROUND: Severe asthma affects up to 20,000 citizens of Israel. Novel biological therapies, which individually have been proven to reduce asthma morbidity in clinical trials, have become available in recent years. Comparative data among different drugs are scarce. OBJECTIVES: To describe and compare the clinical outcomes of biological therapies in severe asthma patients treated at Shamir Medical Center. METHODS: We conducted a cohort study based on a review of cases treated with monoclonal antibodies for severe asthma at our center. Data were extracted for demographics, eosinophil count, lung function (FEV1), exacerbation rate, and median dose of oral prednisone. Between-drug comparison was conducted by repeated measures ANOVA. RESULTS: The cohort included 62 patients receiving biological therapy. All biologic drugs were found to reduce exacerbation rate [F(1, 2) = 40.4, P < 0.0001] and prednisone use [F(1, 4) = 16, P < 0.001] significantly. ANOVA revealed no difference of efficacy endpoints between the different drugs. Eosinophil count was significantly reduced post-biologic treatment in the anti-interleukin-5 agents (P < 0.001) but not under treatment with omalizumab and dupilumab. CONCLUSIONS: All of the biological therapies were effective for improving clinical outcomes. None of the agents was clearly superior to any other. These data emphasize the need for severe asthma patients to be seen by pulmonary medicine specialists and offered, where appropriate, biological therapies.

Transitioning from hospital to home with non-invasive ventilation: who benefits? Results of a cohort study.

BACKGROUND: Non-invasive ventilation (NIV) is effective in a variety of acute respiratory illnesses in hospitalised patients. Home NIV is effective for stable patients with hypercapnia due to neuromuscular or chronic pulmonary disease. However, there are little data to guide which patients may benefit from NIV immediately following hospitalisation with hypercapnia. OBJECTIVE: To evaluate outcomes of patients with daytime hypercapnia at the end of an acute hospital admission. DESIGN: Retrospective cohort study. PARTICIPANTS: Entry into the cohort was by querying the hospital electronic medical system for consultations regarding NIV after discharge. Cases received NIV and controls did not. We extracted data on demographics, ICD-9 diagnoses and medications coded at admission, blood gas measurements and dates of discharge, first readmission and death. INTERVENTION: None. MAIN MEASUREMENT: Time from hospital discharge to mortality or readmission. KEY RESULTS: We identified 585 cases and 53 controls who survived to discharge at the index admission. Cases and controls were broadly similar in age and Charlson Comorbidity Index. In the whole cohort, cases treated with home NIV were at increased risk of death compared with controls (HR 1.88 95% CI 1.17 to 3.03). In multivariate Cox regression for all-cause mortality, poor prognostic factors were increasing age (HR 1.03 per year, 95% CI 1.02 to 1.04), cardiac failure (HR 1.31, 95% CI 1.01 to 1.67) and failure to attend NIV follow-up (HR 2.33, 95% CI 1.33 to 4.10). In contrast, chronic respiratory disease was associated with improved prognosis (HR 0.77, 95% CI 0.61 to 0.97) as was sleep apnoea (HR 0.44, 95% CI 0.23 to 0.83). Cases did not have different time-to-readmission compared with controls (HR 1.42 95% CI 0.99 to 2.02). CONCLUSION: Transitioning to home NIV after a hypercapnic hospitalisation may be useful in younger, co-operative patients with chronic respiratory disease. For older patients or those with cardiac failure, home NIV may not be beneficial and may potentially be harmful.

The Paradox of Pulmonary Vascular Resistance: Restoration of Pulmonary Capillary Recruitment as a Sine Qua Non for True Therapeutic Success in Pulmonary Arterial Hypertension.

Exercise-induced increases in pulmonary blood flow normally increase pulmonary arterial pressure only minimally, largely due to a reserve of pulmonary capillaries that are available for recruitment to carry the flow. In pulmonary arterial hypertension, due to precapillary arteriolar obstruction, such recruitment is greatly reduced. In exercising pulmonary arterial hypertension patients, pulmonary arterial pressure remains high and may even increase further. Current pulmonary arterial hypertension therapies, acting principally as vasodilators, decrease calculated pulmonary vascular resistance by increasing pulmonary blood flow but have a minimal effect in lowering pulmonary arterial pressure and do not restore significant capillary recruitment. Novel pulmonary arterial hypertension therapies that have mainly antiproliferative properties are being developed to try and diminish proliferative cellular obstruction in precapillary arterioles. If effective, those agents should restore capillary recruitment and, during exercise testing, pulmonary arterial pressure should remain low despite increasing pulmonary blood flow. The effectiveness of every novel therapy for pulmonary arterial hypertension should be evaluated not only at rest, but with measurement of exercise pulmonary hemodynamics during clinical trials.

Pulmonary capillary recruitment and distention in mammalian lungs: species similarities.

Pulmonary arterial pressure rises minimally during exercise. The pulmonary microcirculation accommodates increasing blood flow via recruitment of pulmonary capillaries and, at higher flows, by distention of already perfused capillaries. The flow transition range between recruitment and distention has not been studied or compared across mammalian species, including humans. We hypothesised that the range would be similar. Functional pulmonary capillary surface area (FCSA) can be estimated using validated metabolic techniques. We reviewed data from previous studies in three mammalian species (perfused rabbit lungs and dog lung lobes, and exercising humans) and generated blood flow-FCSA curves over a range of flows. We noted where the curves diverged from the theoretical line of pure recruitment (Recruitment) and determined the flow where the curve slope equalled 50% that of Recruitment, or equalled that of a theoretical curve representing full capillary distention (Distention). The three mammalian species have similar flow ranges for the transition from predominantly recruitment to predominantly distention, with dogs having the highest transition point. Within the physiological range of most daily activity, the species are similar and accommodate increasing blood flow mainly via recruitment, with progressive distention at higher flows. This is highly relevant to pulmonary physiology during exercise.

Lung metabolomics after ischemic acute kidney injury reveals increased oxidative stress, altered energy production, and ATP depletion.

Acute kidney injury (AKI) is a complex disease associated with increased mortality that may be due to deleterious distant organ effects. AKI associated with respiratory complications, in particular, has a poor outcome. In murine models, AKI is characterized by increased circulating cytokines, lung chemokine upregulation, and neutrophilic infiltration, similar to other causes of indirect acute lung injury (ALI; e.g., sepsis). Many causes of lung inflammation are associated with a lung metabolic profile characterized by increased oxidative stress, a shift toward the use of other forms of energy production, and/or a depleted energy state. To our knowledge, there are no studies that have evaluated pulmonary energy production and metabolism after AKI. We hypothesized that based on the parallels between inflammatory acute lung injury and AKI-mediated lung injury, a similar metabolic profile would be observed. Lung metabolomics and ATP levels were assessed 4 h, 24 h, and 7 days after ischemic AKI in mice. Numerous novel findings regarding the effect of AKI on the lung were observed including 1) increased oxidative stress, 2) a shift toward alternate methods of energy production, and 3) depleted levels of ATP. The findings in this report bring to light novel characteristics of AKI-mediated lung injury and provide new leads into the mechanisms by which AKI in patients predisposes to pulmonary complications.

Thoracentesis under clopidogrel is not associated with excessive bleeding events: a cohort study.

BACKGROUND: Thoracentesis is a low-risk procedure for bleeding (approx. 2%). Data regarding safety of thoracentesis under treatment with clopidogrel is scarce, and current guidelines are not evidence based. We performed a retrospective study to evaluate the rate of bleeding complications of thoracentesis under clopidogrel in hospitalized patients. METHODS: Retrospective chart review of hospitalized patients undergoing thoracentesis with or without clopidogrel treatment. Demographic and clinical data, diagnostic ICD9 codes, and use of ultrasound were extracted. Bleeding endpoints were defined as hemothorax, drop of > 2 g/dL hemoglobin, or need for packed red cell transfusion. RESULTS: The study group comprised of 88 cases and 169 controls. Four bleeding complications were noted in the cases group, versus 5 in the control group (RR 1.53, 95% CI 0.4-5.5). CONCLUSION: Thoracentesis may be performed safely in patients receiving clopidogrel. Bleeding event rates are consistent with previous reports of thoracentesis in general.

Non-tuberculous, adenosine deaminase-positive lymphocytic pleural effusion: Consider immunoglobulin G4-related disease.

OBJECTIVE: Immunoglobulin G4-related disease (IgG4-RD) is a recently described systemic disorder. Pleural effusion is considered an uncommon manifestation of the disease. We describe a case series of patients with IgG4-RD and clinically significant pleural effusions. METHODS: A retrospective analysis of patients with histologically proven IgG4-RD treated for pleural effusion in our clinic. RESULTS: We identified 4 male patients with pleural effusion caused by IgG4-RD. The effusions were lymphocytic exudates, with especially high protein concentrations. All patients had hyperglobulinemia, elevated serum immunoglobulin G (IgG) levels and elevated levels subclasses IgG1 and IgG4. In two patients, levels of adenosine deaminase (ADA) were measured in the effusion and were elevated (309 and 108 IU/L). Tuberculosis was excluded in both cases by pleural biopsy. Involvement of other organs by IgG4-RD was the rule, especially thoracic lymphadenopathy which was prominent in all patients. In all cases, effusion responded to corticosteroids therapy. One patient developed radiological findings compatible with rounded atelectasis during remission. CONCLUSIONS: IgG4-RD may cause an ADA-positive, lymphocytic exudate with a high protein concentration, characteristics resembling tuberculous effusion. Thoracic lymphadenopathy, hyperglobulinemia, and an increased total IgG, IgG1, IgG4 may suggest the diagnosis. Not previously described, IgG4-RD pleural inflammation may result in rounded atelectasis. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 225-230).

IPF patients are limited by mechanical and not pulmonary-vascular factors - results of a derivation-validation cohort study.

BACKGROUND: During cardiopulmonary exercise testing (CPET), Idiopathic Pulmonary Fibrosis (IPF) patients do not reach their direct maximum voluntary ventilation (MVV) and have deranged gas exchange. Their exercise limitation is therefore attributed to a pulmonary vascular mechanism. METHODS: We studied two cohorts (derivation and validation) of IPF patients with lung function testing and CPET. Maximal ventilation at exercise (VEpeak) was compared to direct MVV by Bland-Altman analysis. RESULTS: In the derivation cohort (n = 101), direct MVV over-estimated VEpeak by a factor of 1.51, driven by respiratory rate during MVV that was 1.99 times higher at rest as compared to VEpeak at exercise. The formula (FEV1 × 20.1) + 15.4 was shown to predict VEpeak (r2 = 0.56) in the derivation cohort. In the validation cohort of 78 patients, VEpeak was within a factor of 1.27 (6.8 l/min) of predicted according to the novel formula. According to the novel prediction formula the majority of patients (58%) in the entire cohort have VEpeak within 85% of their predicted MVV, which would indicate a mechanical respiratory limitation to exercise. CONCLUSION: Estimation of direct MVV performed at rest leads to significant over-estimation of the breathing reserve in IPF patients. This may lead to over-diagnosis of pulmonary vascular limitation in these patients. Expected maximal ventilation at exercise may be accurately predicted indirectly by an IPF-specific formula.

Pulmonary capillary surface area in supine exercising humans: demonstration of vascular recruitment.

In exercising humans, cardiac output (CO) increases, with minor increases in pulmonary artery pressure (PAP). It is unknown if the CO is accommodated via distention of already perfused capillaries or via recruitment of nonconcomitantly perfused pulmonary capillaries. Ten subjects (9 female) performed symptom-limited exercise. Six had resting mean PAP (PAPm) <20 mmHg, and four had PAPm between 21 and 24 mmHg. The first-pass pulmonary circulatory metabolism of [3H]benzoyl-Phe-Ala-Pro (BPAP) was measured at rest and at peak exercise, and functional capillary surface area (FCSA) was calculated. Data are means ± SD. Mean pulmonary arterial pressure rose from 18.8 ± 3.3 SD mmHg to 28.5 ± 4.6 SD mmHg, CO from 6.4 ± 1.6 to 13.4 ± 2.9 L/min, and pulmonary artery wedge pressure from 14 ± 3.3 to 19.5 ± 5 mmHg (all P ≤ 0.001). Percent BPAP metabolism fell from 74.7 ± 0.1% to 67.1 ± 0.1%, and FCSA/body surface area (BSA) rose from 2,939 ± 640 to 5,018 ± 1,032 mL·min-1·m-2 (all P < 0.001). In nine subjects, the FCSA/BSA-to-CO relationship suggested principally capillary recruitment and not distention. In subject 10, a marathon runner, resting CO and FCSA/BSA were high, and increases with exercise suggested distention. Exercising humans demonstrate pulmonary capillary recruitment and distention. At moderate resting CO, increasing blood flow causes principally recruitment while, based on one subject, when exercise begins at high CO, further increases appear to cause distention. Our findings clarify an important physiologic question. The technique may provide a means for further understanding exercise physiology, its limitation in pulmonary hypertension, and responses to therapy.

Reduction of exposure to tacrolimus trough level variability is associated with better graft survival after kidney transplantation.

PURPOSE: High tacrolimus trough drug level variability was found to be associated with reduced graft survival. The primary goal of this study was to find whether reduction of exposure to high tacrolimus trough level variability in patients in which previously had high variability was associated with better graft survival. METHODS: All tacrolimus drug level values in patients that underwent kidney transplantation at our center between 2006 and 2015 were collected. Exposure to variability was calculated using a time-weighted coefficient of variability (TWCV). Time-dependent univariate and multivariate Cox proportional hazard models were used to analyze the primary outcome of graft survival and to determine a cutoff value for TWCV as a predictor of this outcome. RESULTS: A total of 878 patients were included in the study with a median follow-up of 1263 days. TWCV above 25% was significantly associated with reduced graft survival (HR3.66, 95% CI 2.3-5.8, p < 0.001). Of the 480 patients (54.7%) who had a cumulative TWCV of > 25% at a certain time during the follow-up, 110 (22.9%) later returned to a cumulative TWCV of less than 25%. Reduction of TWCV to values below 25% was associated with a hazard of graft loss that was not different from patients who had cumulative TWCV of less than 25% during the entire follow-up period (HR 1.81, 95% CI 0.71-4.62, p = 0.218 and HR 1.08, 95% CI 0.39-2.99, p = 0.780) in univariate and multivariate analyses, respectively. CONCLUSIONS: Monitoring TWCV can help detect the high-risk patients. Interventions intended to reduce variability on long-term graft survival may have a positive effect on graft survival.

Metabolomics assessment reveals oxidative stress and altered energy production in the heart after ischemic acute kidney injury in mice.

Acute kidney injury (AKI) is a systemic disease associated with widespread effects on distant organs, including the heart. Normal cardiac function is dependent on constant ATP generation, and the preferred method of energy production is via oxidative phosphorylation. Following direct ischemic cardiac injury, the cardiac metabolome is characterized by inadequate oxidative phosphorylation, increased oxidative stress, and increased alternate energy utilization. We assessed the impact of ischemic AKI on the metabolomics profile in the heart. Ischemic AKI was induced by 22 minutes of renal pedicle clamping, and 124 metabolites were measured in the heart at 4 hours, 24 hours, and 7 days post-procedure. Forty-one percent of measured metabolites were affected, with the most prominent changes observed 24 hours post-AKI. The post-AKI cardiac metabolome was characterized by amino acid depletion, increased oxidative stress, and evidence of alternative energy production, including a shift to anaerobic forms of energy production. These metabolomic effects were associated with significant cardiac ATP depletion and with echocardiographic evidence of diastolic dysfunction. In the kidney, metabolomics analysis revealed shifts suggestive of energy depletion and oxidative stress, which were reflected systemically in the plasma. This is the first study to examine the cardiac metabolome after AKI, and demonstrates that effects of ischemic AKI on the heart are akin to the effects of direct ischemic cardiac injury.

Step oximetry test: a validation study.

INTRODUCTION: Step climbing is a potentially useful modality for testing exercise capacity. However, there are significant variations between test protocols and lack of consistent validation against gold standard cycle ergometry cardiopulmonary exercise testing (CPET). The purpose of the study was to validate a novel technique of exercise testing using a dedicated device. METHODS: We built a step oximetry device from an adapted aerobics step and pulse oximeter connected to a computer. Subjects performed lung function tests, a standard incremental cycle CPET and also a CPET while stepping on and off the step oximetry device to maximal exertion. Data from the step oximetry device were processed and correlated with standard measurements of pulmonary function and cycle CPET. RESULTS: We recruited 89 subjects (57 years, 50 men). Oxygen uptake (VO2) was 0.9 mL/kg/min (95% CI -3.6 to 5.4) higher in the step test compared with the gold standard cycle CPET, p<0.001. VO2 in the two techniques was highly correlated (R=0.87, p<0.001). Work rate during stair climbing showed the best correlation with VO2 (R=0.69, p<0.0001). Desaturation during step climbing correlated negatively with diffusion capacity for carbon monoxide (r=-0.43, p<0.005). No adverse events occurred. CONCLUSIONS: The step oximetry test was a maximal test of exertion in the subjects studied, achieving slightly higher VO2 than during the standard test. The test was safe to perform and well tolerated by the patients. Parameters derived from the step oximetry device correlated well with gold standard measurements. The step oximetry test could become a useful and standardisable exercise test for clinical settings where advanced testing is not available or appropriate.

Combining Acute Kidney Injury with Gastrointestinal Pathology: A Clue to Acute Oxalate Nephropathy.

Acute oxalate nephropathy (AON) is an increasingly recognized cause of acute kidney injury (AKI). Herein, we present two cases of biopsy-proven acute oxalate nephropathy in patients with gastrointestinal malabsorption, coincidentally both stemming from cholangiocarcinoma. The first is a 73-year-old male who presented with syncope and was found to have severe, oliguric AKI in the setting of newly diagnosed, nonresectable cholangiocarcinoma. The second is a 64-year-old man with remote resection of cholangiocarcinoma who presented after routine laboratory monitoring showed significant AKI. Temporary dialysis was required in both cases before renal recovery occurred. Together, these cases should increase physicians' suspicion of AON in the presence of malabsorption. By doing so, the workup of oxalate nephropathy can be expedited with prompt initiation of treatment.

Tacrolimus Levels Are Not Associated with Risk of Malignancy in Lung Transplant Recipients.

BACKGROUND Lung transplant (LTx) recipients suffer from high rates of malignancy. Exposure to immunosuppressive medication such as tacrolimus has been proposed as a risk factor for tumorigenesis. We hypothesized that chronically high levels of tacrolimus would be associated with risk of malignancy. MATERIAL AND METHODS The study was performed in a transplant center in Israel, with a nested case-control design. Cases were LTx recipients who were diagnosed with any solid or hematological malignancy except non-melanoma skin cancer. Controls were tumor-free during their entire follow-up after LTx and had at least the same follow-up time as their matched case. Controls were matched to cases by age and type of transplant received (single/double). Tacrolimus levels were extracted and analyzed for median drug level and also integrated over time (area under the curve - AUC-tacrolimus). RESULTS We reviewed 412 LTx recipients in our registry. Thirty-nine cases of malignancy were diagnosed and 160 controls were matched, giving a crude tumor incidence rate of 26/100 000/year. Lung cancers were the commonest diagnosis. Cases and controls were well matched by age, smoking status, and LTx type. Median tacrolimus levels were 11.0 ng/ml and 11.3 ng/ml in cases and controls, respectively (p=0.88). The median log (AUC-tacrolimus) was 9.4 in the cases and 9.5 in the controls (p=0.59). CONCLUSIONS In this nested case-control study, exposure to tacrolimus was similar in tumor cases and non-tumor controls. These data, based on a cohort with modest size, suggest either that tumorigenesis in LTx recipients is unrelated to tacrolimus exposure or that levels in these patients are above an unknown threshold at which the dose-response effect is saturated.