Rescaling creatinine makes GFR estimation equations generally applicable across populations - validation results for the Lund-Malmö equation in a French cohort of sub-Saharan ancestry.

OBJECTIVES: To make glomerular filtration rate (GFR) estimating equations applicable across populations with different creatinine generation by using rescaled serum creatinine (sCr/Q) where sCr represents the individual creatinine level and Q the average creatinine value in healthy persons of the same population. METHODS: GFR measurements (mGFR, plasma clearance of 51Cr-EDTA) were conducted in 964 adult Black Europeans. We established the re-expressed Lund-Malmö revised equation (r-LMR) by replacing serum creatinine (sCr) with rescaled creatinine sCr/Q. We evaluated the r-LMR equation based on Q-values of White Europeans (r-LMRQ-white; Q-values females: 62 µmol/L, males: 80 µmol/L) and Black Europeans (r-LMRQ-Black; Q-values females: 65 µmol/L, males: 90 µmol/L), and the European Kidney Function Consortium equation (EKFCQ-White and EKFCQ-Black) regarding bias, precision (interquartile range, IQR) and accuracy (percentage of estimates within ±10 % [P10] and ±30 % [P30] of mGFR). RESULTS: Median bias of r-LMRQ-White/r-LMRQ-Black/EKFCQ-White/EKFCQ-Black were -9.1/-4.5/-6.3/-0.9 mL/min/1.73 m2, IQR 14.7/14.5/14.5/15.6 mL/min/1.73 m2, P10 25.1 %/34.8 %/30.3 %/37.2 % and P30 74.2 %/84.1 %/80.6 %/83.6 %. The improvement of bias and accuracy when using proper Q-values was most pronounced in men. Similar improvements were obtained above and below mGFR 60 mL/min/1.73 m2 and at various age and BMI intervals, except for BMI<20 kg/m2 where bias increased, and accuracy decreased. CONCLUSIONS: GFR estimating equations may be re-expressed to include rescaled creatinine (sCr/Q) and used across populations with different creatinine generation if population-specific average creatinine concentrations (Q-values) for healthy persons are established.

Development and validation of a new equation based on plasma creatinine and muscle mass assessed by CT scan to estimate glomerular filtration rate: a cross-sectional study.

Background: Inter-individual variations of non-glomerular filtration rate (GFR) determinants of serum creatinine, such as muscle mass, account for the imperfect performance of estimated GFR (eGFR) equations. We aimed to develop an equation based on creatinine and total lumbar muscle cross-sectional area measured by unenhanced computed tomography scan at the third lumbar vertebra. Methods: The muscle mass-based eGFR (MMB-eGFR) equation was developed in 118 kidney donor candidates (iohexol clearance) using linear regression. Validation cohorts included 114 healthy subjects from another center (51Cr-EDTA clearance, validation population 1), 55 patients with chronic diseases (iohexol, validation population 2), and 60 patients with highly discordant creatinine and cystatin C-based eGFR, thus presumed to have atypical non-GFR determinants of creatinine (51Cr-EDTA, validation population 3). Mean bias was the mean difference between eGFR and measured GFR, precision the standard deviation (SD) of the bias, and accuracy the percentage of eGFR values falling within 20% and 30% of measured GFR. Results: In validation population 1, performance of MMB-eGFR was not different from those of CKD-EPICr2009 and CKD-EPICr2021. In validation population 2, MMB-eGFR was unbiased and displayed better precision than CKD-EPICr2009, CKD-EPICr2021 and EKFC (SD of the biases: 13.1 vs 16.5, 16.8 and 15.9 mL/min/1.73 m2). In validation population 3, MMB-eGFR had better precision and accuracy {accuracy within 30%: 75.0% [95% confidence interval (CI) 64.0-86.0] vs 51.5% (95% CI 39.0-64.3) for CKD-EPICr2009, 43.3% (95% CI 31.0-55.9) for CKD-EPICr2021, and 53.3% (95% CI 40.7-66.0) for EKFC}. Difference in bias between Black and white subjects was -2.1 mL/min/1.73 m2 (95% CI -7.2 to 3.0), vs -8.4 mL/min/1.73 m2 (95% CI -13.2 to -3.6) for CKD-EPICr2021. Conclusion: MMB-eGFR displayed better performances than equations based on demographics, and could be applied to subjects of various ethnic backgrounds.

Prevalence, treatment and determinants of obstructive sleep apnoea and its symptoms in a population-based French cohort.

Background: Obstructive sleep apnoea (OSA) is associated with increased morbidity and mortality. Although the disorder has been well studied in selected high-risk populations, few data exist on its prevalence in the general population. We aimed to assess the prevalence and determinants of OSA in France. Methods: Data from participants of the French population-based CONSTANCES cohort aged 18-69 years at inclusion and being treated for sleep apnoea or screened for OSA in 2017 using the Berlin Questionnaire were analysed. Weighted analyses were performed to provide recent and representative results in the general population. Results: Among 20 151 participants, the prevalence of treated sleep apnoea was 3.5% (95% CI 3.0-3.9%). The prevalence of untreated subjects with a positive Berlin Questionnaire was 18.1% (95% CI 17.3-19.2%) for a total weighted prevalence of treated sleep apnoea or high risk of OSA of 20.9% (95% CI 20.0-21.9%). Regarding prevalence of OSA symptoms, it was 37.2% (95% CI 36.1-38.3%) for severe snoring and 14.6% (95% CI 13.8-15.5%) for hypersomnolence. In multivariable logistic regression analysis, male sex, age, previous cardiovascular events, smoking, low educational level, low physical activity and depressive symptoms were associated with having either treated sleep apnoea or a positive Berlin Questionnaire. Conclusion: In this large French population-based cohort, one in five participants had a high likelihood of OSA, whereas only 3.5% were treated for the disorder, suggesting major underdiagnosis in the general population. OSA diagnosis should be considered more often in people with risk factors such as depressive symptoms as well as unhealthy behaviours and socioeconomic conditions.

Comparison of 99mTc-DTPA and 51Cr-EDTA for glomerular filtration rate measurement with the continuous infusion method.

BACKGROUND: In late 2018, the production of 51Chromium-labelled ethylenediamine tetra-acetic acid (51Cr-EDTA), a validated and widely used radio-isotopic tracer for measuring glomerular filtration rate, was halted. Technetium-99m-diethylenetriaminepentaacetic acid (99mTc-DTPA) has been validated for GFR measurement with a single bolus injection, a procedure not suitable in patients with extracellular compartment hyperhydration. In such cases, a bolus followed by continuous infusion of the tracer is required. The aim of this study was to evaluate whether 99mTc-DTPA with the infusion protocol can replace 51Cr-EDTA for GFR measurement. METHODS: We conducted a prospective single centre study during February and March 2019. All patients referred for GFR measurement received both radiotracers simultaneously: 51Cr-EDTA and 99mTc-DTPA bolus and continuous infusion were administered concomitantly through the same intravenous route. Over four and a half hours, plasma and urine samples were collected to calculate urinary and plasma clearance. RESULTS: Twenty-two patients were included (mean age 63.4 ± 17.5 years; 68% men). Mean urinary clearance of 51Cr-EDTA and 99mTc-DTPA was 52.4 ± 22.5 mL/min and 52.8 ± 22.6 mL/min, respectively (p = 0.47), with a mean bias of 0.39 ± 2.50 mL/min, an accuracy within 10% of 100% (95% CI 100; 100) and a Pearson correlation coefficient of 0.994. Mean plasma clearance of 51Cr-EDTA and 99mTc-DTPA was 54.8 ± 20.9 mL/min and 54.4 ± 20.9 mL/min, respectively (p = 0.61), with a mean bias of - 0.43 ± 3.89 mL/min, an accuracy within 10% of 77% (95% CI 59; 91) and a Pearson correlation coefficient of 0.983. CONCLUSIONS: Urinary and plasma clearance of 99mTc-DTPA can be used with the infusion protocol to measure GFR.

New developments and future prospects in the field of glomerular filtration rate estimation / Actualités et perspectives dans l'estimation du débit de filtration glomérulaire

Glomerular filtration rate (GFR) is estimated from equations based on serum or plasma concentrations of endogenous markers (creatinine and/or cystatin C), and demographic data (age, sex, ± ethnicity). These equations are accurate at the population level, but often inaccurate at the individual level. The creatinine-based Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation published in 2009 (CKD-EPIcr-2009), and the CKD-EPI equation published in 2012 based on creatinine and cystatin C, were recalibrated in 2021 to remove their dedicated race correction factors for black American subjects. All creatinine-based CKD-EPI equations overestimate true GFR in subjects younger than 30 years. The Full Age Spectrum (FAS) equation, applicable across the entire age spectrum (pediatrics to old age), solved this problem, but remained suboptimal at low GFR values. The European Kidney Function Consortium (EKFC) equation published in 2021 was an improvement of the FAS equation, which also includes the Q factor (median creatinine in the general population). EKFC is applicable across the age spectrum and is efficient at low and normal GFR values. The new creatinine-based CKD-EPI equation (CKD-EPIcr-2021) underestimates GFR in Black Americans and overestimates it in non-Black Americans. In European and African subjects, CKD-EPIcr-2021 overestimates true GFR and should not be adopted. The EKFC equation, which performs well in this population, also performs well in European Black subjects and in African subjects, provided dedicated Q factors are used.

Le débit de filtration glomérulaire (DFG) est estimé à partir d'équations prenant en compte la concentration sérique ou plasmatique de marqueurs endogènes (créatinine et/ou cystatine C) et des données démographiques (âge, sexe, ± origine ethnique). Ces équations sont justes à l'échelle populationnelle, mais fréquemment inexactes à l'échelle individuelle. L'équation Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI), basée sur la créatinine, publiée en 2009 (CKD-EPIcr-2009), et l'équation CKD-EPI de 2012, basée sur la créatinine et la cystatine C, ont été recalibrées en 2021 afin d'éliminer leurs facteurs correctifs ethniques dédiés aux sujets Noirs américains. Toutes les équations CKD-EPI basées sur la créatinine surévaluent le DFG réel chez les sujets de moins de 30 ans. L'équation Full Age Spectrum (FAS), applicable sur tout le spectre d'âge (de la pédiatrie au grand âge), résolvait ce problème, mais restait suboptimale aux valeurs basses de DFG. L'équation European Kidney Function Consortium (EKFC) publiée en 2021 est une amélioration de l'équation FAS, qui inclut également le facteur Q (créatinine médiane en population générale). Elle est applicable sur tout le spectre d'âge, et performante aux valeurs basses et normales de DFG. La nouvelle équation CKD-EPI basée sur la créatinine (CKD-EPIcr-2021) sous-évalue le DFG chez les sujets Noirs américains et le surévalue chez les non-Noirs américains. Chez les sujets européens et africains, CKD-EPIcr-2021 surévalue le DFG réel et ne doit pas être adoptée. L'équation EKFC, qui est performante dans cette population, l'est aussi chez les sujets européens Noirs et les Africains, à condition d'utiliser des facteurs Q dédiés.

Optimal or standard control of systolic and diastolic blood pressure across risk factor categories in patients with chronic coronary syndromes.

AIMS: Guidelines have lowered blood pressure (BP) targets to <130/80 mmHg. We examined the benefit of intensive control for each BP component, vs. the burden of other modifiable risk factors, in patients with chronic coronary syndromes (CCS). METHODS AND RESULTS: The CLARIFY registry (ISRCTN43070564) enrolled 32 703 patients with CCS, from 2009 to 2010, with a 5-year follow-up. Patients with either BP component below European guideline safety boundaries (120/70 mmHg) were excluded, leaving 19 167 patients (mean age: 63.8 ± 10.1 years, 78% men) in the present analysis. A multivariable-adjusted Cox proportional hazards model showed a gradual increase in cardiovascular risk (cardiovascular death, myocardial infarction, or stroke) when the number of uncontrolled risk factors (active smoking, no physical activity, low-density lipoprotein cholesterol ≥100 mg/dL, and diabetes with glycated haemoglobin ≥7%) increased [adjusted hazard ratio (HR): 1.34; 95% confidence interval (CI): 1.17-1.52, 1.65 (1.40-1.94), and 2.47 (1.90-3.21) for 1, 2, and 3 or 4 uncontrolled risk factors, respectively, vs. 0], without significant interaction with BP. Although uncontrolled systolic (≥140 mmHg) and diastolic (≥90 mmHg) BP were both associated with higher risk than standard BP, standard BP was associated with higher risk than optimal control for only the diastolic component (adjusted HR: 1.08; 95% CI: 0.94-1.25 for systolic BP 130-139 vs. 120-129 mmHg and 1.43; 95% CI: 1.27-1.62 for diastolic BP 80-89 vs. 70-79 mmHg). CONCLUSIONS: Our results suggest that the optimal BP target in CCS may be ≤139/79 mmHg and that optimizing the burden of other risk factors should be prioritized over the further reduction of systolic BP.

We aimed to compare the benefit associated with strict vs. standard control of blood pressure with the potential benefit of controlling other modifiable risk factors in patients with chronic coronary syndromes (CCS).Our analysis conducted in nearly 20 000 patients from the CLARIFY registry (a prospective international cohort of patients with CCS) showed that the benefit associated with strict blood pressure (BP) control (BP < 130/80 mmHg) was marginal and only driven by the diastolic component of blood pressure, whereas having one or more uncontrolled other risk factors was associated with a gradually increasing risk, for all underlying BP levels.Patients with CCS should be treated to achieve BP <140/80 mmHg. However, our results suggest that optimizing the burden of other risk factors (lipid-lowering therapy, exercise, smoking cessation, diabetes control) may need to be prioritized before considering further reduction of systolic BP.

Cystatin C-Based Equation to Estimate GFR without the Inclusion of Race and Sex.

BACKGROUND: The accuracy of estimation of kidney function with the use of routine metabolic tests, such as measurement of the serum creatinine level, has been controversial. The European Kidney Function Consortium (EKFC) developed a creatinine-based equation (EKFC eGFRcr) to estimate the glomerular filtration rate (GFR) with a rescaled serum creatinine level (i.e., the serum creatinine level is divided by the median serum creatinine level among healthy persons to control for variation related to differences in age, sex, or race). Whether a cystatin C-based EKFC equation would increase the accuracy of estimated GFR is unknown. METHODS: We used data from patients in Sweden to estimate the rescaling factor for the cystatin C level in adults. We then replaced rescaled serum creatinine in the EKFC eGFRcr equation with rescaled cystatin C, and we validated the resulting EKFC eGFRcys equation in cohorts of White patients and Black patients in Europe, the United States, and Africa, according to measured GFR, levels of serum creatinine and cystatin C, age, and sex. RESULTS: On the basis of data from 227,643 patients in Sweden, the rescaling factor for cystatin C was estimated at 0.83 for men and women younger than 50 years of age and 0.83 + 0.005 × (age - 50) for those 50 years of age or older. The EKFC eGFRcys equation was unbiased, had accuracy that was similar to that of the EKFC eGFRcr equation in both White patients and Black patients (11,231 patients from Europe, 1093 from the United States, and 508 from Africa), and was more accurate than the Chronic Kidney Disease Epidemiology Collaboration eGFRcys equation recommended by Kidney Disease: Improving Global Outcomes. The arithmetic mean of EKFC eGFRcr and EKFC eGFRcys further improved the accuracy of estimated GFR over estimates from either biomarker equation alone. CONCLUSIONS: The EKFC eGFRcys equation had the same mathematical form as the EKFC eGFRcr equation, but it had a scaling factor for cystatin C that did not differ according to race or sex. In cohorts from Europe, the United States, and Africa, this equation improved the accuracy of GFR assessment over that of commonly used equations. (Funded by the Swedish Research Council.).

Performance of creatinine-based equations to estimate glomerular filtration rate in White and Black populations in Europe, Brazil and Africa.

BACKGROUND: A new Chronic Kidney Disease Epidemiology Collaboration equation without the race variable has been recently proposed (CKD-EPIAS). This equation has neither been validated outside USA nor compared with the new European Kidney Function Consortium (EKFC) and Lund-Malmö Revised (LMREV) equations, developed in European cohorts. METHODS: Standardized creatinine and measured glomerular filtration rate (GFR) from the European EKFC cohorts (n = 13 856 including 6031 individuals in the external validation cohort), from France (n = 4429, including 964 Black Europeans), from Brazil (n = 100) and from Africa (n = 508) were used to test the performances of the equations. A matched analysis between White Europeans and Black Africans or Black Europeans was performed. RESULTS: In White Europeans (n = 9496), both the EKFC and LMREV equations outperformed CKD-EPIAS (bias of -0.6 and -3.2, respectively versus 5.0 mL/min/1.73 m², and accuracy within 30% of 86.9 and 87.4, respectively, versus 80.9%). In Black Europeans and Black Africans, the best performance was observed with the EKFC equation using a specific Q-value (= concentration of serum creatinine in healthy males and females). These results were confirmed in matched analyses, which showed that serum creatinine concentrations were different in White Europeans, Black Europeans and Black Africans for the same measured GFR, age, sex and body mass index. Creatinine differences were more relevant in males. CONCLUSION: In a European and African cohort, the performances of CKD-EPIAS remain suboptimal. The EKFC equation, using usual or dedicated population-specific Q-values, presents the best performance in the whole age range in the European and African populations included in this study.

MRI-based kidney radiomic analysis during chronic lithium treatment.

BACKGROUND: Lithium therapy during bipolar disorder is associated with an increased risk of chronic kidney disease (CKD) that is slowly progressive and undetectable at early stages. We aimed at identifying kidney image texture features as possible imaging biomarkers of decreased measured glomerular filtration rate (mGFR) using radiomics of T2-weighted magnetic resonance imaging (MRI). METHODS: One hundred and eight patients treated with lithium were evaluated including mGFR and kidney MRI, with T2-weighted sequence single-shot fast spin-echo. Computed radiomic analysis was performed after kidney segmentation. Significant features were selected to build a radiomic signature using multivariable Cox analysis to detect an mGFR <60 ml/min/1.73 m². The texture index was validated using a training and a validation cohort. RESULTS: Texture analysis index was able to detect an mGFR decrease, with an AUC of 0.85 in the training cohort and 0.71 in the validation cohort. Patients with a texture index below the median were older (59 [42-66] vs. 46 [34-54] years, p = .001), with longer treatment duration (10 [3-22] vs. 6 [2-10] years, p = .02) and a lower mGFR (66 [46-84] vs. 83 [71-94] ml/min/1.73m², p < .001). Texture analysis index was independently and negatively associated with age (ß = -.004 ± 0.001, p < .001), serum vasopressin (-0.005 ± 0.002, p = .02) and lithium treatment duration (-0.01 ± 0.003, p = .001), with a significant interaction between lithium treatment duration and mGFR (p = .02). CONCLUSIONS: A renal texture index was developed among patients treated with lithium associated with a decreased mGFR. This index might be relevant in the diagnosis of lithium-induced renal toxicity.

Adrenal ganglioneuromas: a retrospective multicentric study of 104 cases from the COMETE network.

OBJECTIVE: Adrenal ganglioneuromas are rare, differentiated, neuroblastic tumors that originate from the peripheral sympathetic nervous system. Because of their rarity, information is limited, derived from small cases series. Our objective was to characterize this tumor and provide help for its management. METHODS: A retrospective multicenter analysis of adrenal ganglioneuromas from 20 French centers belonging to the COMETE network and one Belgian center. RESULTS: Among the 104 cases identified, 59.6% were women (n = 62/104), median age at diagnosis was 29 years, with 24 pediatric cases. 60.6% (n = 63/104) were incidentalomas. Ganglioneuromas were non-secreting tumors in 90.8% of cases (n = 89/98), whereas the preoperative hormonal evaluation was indeterminate for 9.2% of patients (n = 9/98). CT imaging, performed on 96 patients, revealed large tumors (median diameter of 50 mm) with a non-contrast density > 10 Hounsfield units in 98.1% (n = 52/53) and calcifications in 64.6% of cases (n = 31/48). Increased uptake on 123I-MIBG scintigraphy and 18F-FDG-PET/CT was observed in 26.7% (n = 8/30) and 42.2% (n = 19/45) of the tumors, respectively. All 104 patients underwent surgery. No recurrence was observed among the 42 patients who had an imaging follow-up (mean 29.6 months, median 18 months (4-156)). CONCLUSION: Adrenal ganglioneuromas are large tumors, mostly nonfunctioning, without benign imaging features. Although the duration of follow-up was limited in our series, no recurrence was identified. A review of the literature confirms the absence of postoperative recurrence. Based on all available data, in the absence of special circumstances (genetic form, uncertain histological diagnosis), long-term follow-up is not necessary after complete surgery for patients with an adrenal ganglioneuroma.

Comparison of 51Cr-EDTA and 99mTc-DTPA for glomerular filtration rate measurement.

PURPOSE: The production of 51Cr-labelled ethylenediaminetetraacetic acid (51Cr-EDTA), a validated and widely used radio-isotopic tracer for glomerular filtration rate (GFR) measurement in Europe, was recently halted by the manufacturer. Technetium-99m-diethylenetriaminepentaacetic acid (99mTc-DTPA) clearance has so far mostly been restricted to assessment of separate renal function by scintigraphy, but scarcely used and validated for GFR measurement. We compared the performances of 51Cr-EDTA and 99mTc-DTPA for GFR and extracellular fluid measurement. METHODS: In a multi-centre prospective study, 51Cr-EDTA and 99mTc-DTPA were simultaneously injected into 88 patients, and their urinary and plasma clearances, as well as their volumes of distribution, were measured during seven 30-min periods after a 90-min equilibrium time. RESULTS: Mean age was 52.2 ± 14.5 years, 59% were men. Urinary clearances of 51Cr-EDTA and 99mTc-DTPA were 64.1 ± 27.6 and 66.1 ± 28.0 mL/min, respectively, with a mean bias of 2.00 ± 2.25 mL/min, an accuracy within 10% of 95% [95% CI 91-99], and a coefficient of determination (R2) of 0.994. Plasma clearances of 51Cr-EDTA and 99mTc-DTPA were 66.1 ± 25.8 and 68.1 ± 26.6 mL/min, respectively, with a mean bias of 1.96 ± 3.32 mL/min, an accuracy within 10% of 91% [95% CI 85-97] and a R2 of 0.985. Distribution volumes were 17.3 ± 4.6 L for 51Cr-EDTA and 16.6 ± 4.6 L for 99mTc-DTPA (R2 0.930). CONCLUSION: The accuracy and precision of 99mTc-DTPA clearance, compared to 51Cr-EDTA clearance, was excellent for both urinary and plasma clearance methods, despite an approximate 2 mL/min overestimation, showing that the tracer is a reliable alternative to 51Cr-EDTA for GFR measurement.

Determinants of Kidney Function and Accuracy of Kidney Microcysts Detection in Patients Treated With Lithium Salts for Bipolar Disorder.

Objectives: Early kidney damage during lithium treatment in bipolar disorder is still hypothetical. We aimed at identifying the determinants of a decreased measured glomerular filtration rate (mGFR) and the accuracy of kidney MRI imaging in its detection. Methods: In this cross-sectional cohort study, 217 consecutive lithium-treated patients underwent mGFR and kidney MRI with half-Fourier turbo spin-echo and Single-shot with long echo time sequences. Results: Median age was 51 [27-62] years, and median lithium treatment duration was 5 [2-14] years. 52% of patients had a stage 2 CKD. In multivariable analysis, the determinants of a lower mGFR were a longer lithium treatment duration (ß -0.8 [-1; -0.6] ml/min/1.73 m2 GFR decrease for each year of treatment), a higher age (ß -0.4 [-0.6; -0.3] ml/min/1.73 m2 for each year of age, p < 0.001), albuminuria (ß -3.97 [-6.6; -1.3], p = 0.003), hypertension (ß -6.85 [-12.6; -1.1], p = 0.02) and hypothyroidism (ß -7.1 [-11.7; -2.5], p = 0.003). Serum lithium concentration was not associated with mGFR. Renal MRI displayed renal microcyst(s) in 51% of patients, detected as early as 1 year after lithium treatment initiation. mGFR and lithium treatment duration were strongly correlated in patients with microcyst(s) (r = -0.64, p < 0.001), but not in patients with no microcysts (r = -0.24, p = 0.09). The presence of microcysts was associated with the detection of an mGFR <45 ml/min/1.73 m2 (AUC 0.893, p < 0.001, sensitivity 80%, specificity 81% for a cut-off value of five microcysts). Conclusion: Lithium treatment duration and hypothyroidism strongly impacted mGFR independently of age, especially in patients with microcysts. MRI might help detect early lithium-induced kidney damage and inform preventive strategies.

Acute Stress Cardiomyopathy: Heart of pheochromocytoma.

Stress cardiomyopathy (SCM) is a syndrome characterized by transient regional systolic dysfunction of the left ventricle in the absence of angiographic evidence of coronaropathy. This abnormality is associated with high levels of catecholamines. Stress cardiomyopathy is also called Takotsubo (TS) cardiomyopathy. Pheochromocytoma crisis can occur spontaneously or can be precipitated by manipulation of the tumor, trauma, certain medications or stress for example during non-adrenal surgery. The main drugs leading to pheochromocytoma crisis include D2 dopamine receptor antagonists, noncardioselective ß-adrenergic receptor blockers, tricyclic antidepressants and related neurotransmitter uptake blockers, sympathomimetics, certain peptide and steroid hormones and several agents used during induction of anesthesia. Patients can develop symptoms of heart failure associated with tachyarrhythmia, cardiogenic shock with hypotension and collapse, or apparent acute coronary syndromes. This review describes pathophysiology, epidemiology, diagnosis criteria and management of SCM.

Adrenergic receptors and cardiovascular effects of catecholamines.

Activation of the sympathetic nervous system is responsible for the body's "fight or flight" reaction. The physiological responses to the activation of the sympathetic nervous system and adrenal medulla are mediated through the action of the endogenous catecholamines norepinephrine (or noradrenaline) and epinephrine (or adrenaline) on adrenergic receptors. Adrenergic receptors belong to the superfamily of G protein-coupled receptors (GPCR). Adrenoceptors are divided into alpha1, alpha2, beta1, beta2 and beta3 receptors. Norepinephrine stimulates both subtypes of α receptors and ß1 receptors. Epinephrine stimulates all subtypes ofα and ß adrenoreceptors. α1 adrenergic receptors, coupled to stimulatory Gq proteins, activate the enzyme phospholipase C and are mainly found in the smooth muscle cells of blood vessels and urinary tract, where they induce constriction. α2 receptors are coupled to inhibitory Gi proteins, that inactivate adenylyl cyclase, decreasing cyclic adenosine monophosphate (AMP) production. They are mainly found in the central nervous system, where their activation results in a decreased arterial blood pressure. ß1 adrenoreceptors predominate in the heart, activate the Gs-adenylyl cyclase -cAMP-protein kinase A signaling cascade, and induce positive inotropic and chronotropic effects. ß2 adrenoreceptors are distributed extensively throughout the body, but are expressed predominantly in bronchial smooth muscle cells. ß2 adrenergic receptors activate adenylyl cyclase, dilate blood vessels and bronchioles, relax the muscles of the uterus, bladder and gastrointestinal duct, and also decrease platelet aggregation and glycogenolysis. ß3 receptors can couple interchangeably to both stimulating and inhibiting G proteins. They are abundantly expressed in white and brown adipose tissue, and increase fat oxidation, energy expenditure and insulin-mediated glucose uptake. This review details the regulation of cardiac and vascular function by adrenergic receptors.

Long-term outcomes of chronic coronary syndrome worldwide: insights from the international CLARIFY registry.

AIMS: Over the last decades, the profile of chronic coronary syndrome has changed substantially. We aimed to determine characteristics and management of patients with chronic coronary syndrome in the contemporary era, as well as outcomes and their determinants. METHODS AND RESULTS: Data from 32 703 patients (45 countries) with chronic coronary syndrome enrolled in the prospective observational CLARIFY registry (November 2009 to June 2010) with a 5-year follow-up, were analysed. The primary outcome [cardiovascular death or non-fatal myocardial infarction (MI)] 5-year rate was 8.0% [95% confidence interval (CI) 7.7-8.3] overall [male 8.1% (7.8-8.5); female 7.6% (7.0-8.3)]. A cox proportional hazards model showed that the main independent predictors of the primary outcome were prior hospitalization for heart failure, current smoking, atrial fibrillation, living in Central/South America, prior MI, prior stroke, diabetes, current angina, and peripheral artery disease. There was an interaction between angina and prior MI (P = 0.0016); among patients with prior MI, angina was associated with a higher primary event rate [11.8% (95% CI 10.9-12.9) vs. 8.2% (95% CI 7.8-8.7) in patients with no angina, P < 0.001], whereas among patients without prior MI, event rates were similar for patients with [6.3% (95% CI 5.4-7.3)] or without angina [6.4% (95% CI 5.9-7.0)], P > 0.99. Prescription rates of evidence-based secondary prevention therapies were high. CONCLUSION: This description of the spectrum of chronic coronary syndrome patients shows that, despite high rates of prescription of evidence-based therapies, patients with both angina and prior MI are an easily identifiable high-risk group who may deserve intensive treatment. CLINICAL REGISTRY: ISRCTN43070564.

Risk of Ascending Aortic Aneurysm in Patients With Autosomal Dominant Polycystic Kidney Disease.

In recent years, simple renal cysts have been associated with an increased risk of aortic aneurysms. There is little data regarding aortic dilation in patients with autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to compare Sinuses of Valsalva (SoV) and tubular ascending aorta diameters in ADPKD patients with matched controls. From 2008 to 2016, 61 consecutive ADPKD patients who had an echocardiogram performed in our institution were matched 1:1 with controls for sex, age, blood pressure, and ß-blocker therapy use. SoV and tubular ascending aorta were measured at end-diastole, using the leading-edge to leading-edge convention. Paired t Tests were used for quantitative variables and McNemar-tests for qualitative variables. The mean age of patients was 56 ± 12 years, 54% were men, 38% received ß-blockers, and mean systolic and diastolic BP were 137 ± 25 and 78 ± 19 mm Hg. SoV diameters were significantly larger in ADPKD patients than in controls (36.4 ± 4.1 vs 34.0 ± 3.7 mm, p <0.0001). The Z-scores (normalized for sex, age, and body surface area) were significantly higher in ADPKD patients, both for SoV and tubular ascending aorta. Moreover, aortic aneurysms, as defined by a Z score >2 standard deviations, were present in 27 ADPKD patients (44%) versus 9 controls (15%, p <0.001). In conclusion, there is an increased prevalence of aortic aneurysms in ADPKD patients as compared with controls matched for common confounding factors for aortic dilation.

Usefulness of Magnetic Resonance Imaging in the Diagnosis of Juxtaglomerular Cell Tumors: A Report of 10 Cases and Review of the Literature.

Juxtaglomerular cell tumors (JCTs), a rare but potentially curable cause of hypertension, are difficult to diagnose because they may be missed or misidentified as a cyst by computed tomography (CT). Their magnetic resonance imaging (MRI) pattern has not been well described. We report the clinical, biological, and radiologic features of 10 patients with JCTs. Eight were women, and median age was 24.5 years. All had severe hypokalemic hypertension related to marked secondary hyperaldosteronism. Median plasma renin and aldosterone concentrations were 392 (minimum-maximum [min-max], 70.5-4,800) mIU/L and 1,490 (min-max, 671-2,492) pmol/L, respectively. Plasma prorenin concentration was 835.5 (min-max, 133-6,546) mIU/L. Median tumor size was 17.5mm. On CT, JCTs were spontaneously isodense, with little enhancement after contrast media injection. On MRI, JCTs were iso- (7/10) or hypointense (3/10) on T1-weighted images (WIs). On T2-WIs, JCTs were hypointense (2/10), isointense (4/10), or heterogeneously hyperintense (4/10). A thin peripheral "pseudo-capsule" (hypointense on T2-WIs) was observed in 6 of 10 cases. Contrast enhancement was low, slightly heterogeneous, and delayed. On diffusion-WIs, tumors were hyperintense with a restricted apparent diffusion coefficient. When hypertension with secondary hyperaldosteronism remains unexplained after CT, MRI of the kidney should be considered, especially for young women.

Extracellular Fluid Volume Is an Independent Determinant of Uncontrolled and Resistant Hypertension in Chronic Kidney Disease: A NephroTest Cohort Study.

Background Hypertension is highly prevalent during chronic kidney disease ( CKD ) and, in turn, worsens CKD prognosis. We aimed to describe the determinants of uncontrolled and resistant hypertension during CKD . Methods and Results We analyzed baseline data from patients with CKD stage 1 to 5 (NephroTest cohort) who underwent thorough renal explorations, including measurements of glomerular filtration rate (clearance of 51Cr-EDTA) and of extracellular water (volume of distribution of the tracer). Hypertension was defined as blood pressure ( BP ; average of 3 office measurements) ≥140/90 mm Hg or the use of antihypertensive drugs. In 2015 patients (mean age, 58.7±15.3 years; 67% men; mean glomerular filtration rate, 42±15 mL/min per 1.73 m2), prevalence of hypertension was 88%. Among hypertensive patients, 44% and 32% had uncontrolled (≥140/90 mm Hg) and resistant (uncontrolled BP despite 3 drugs, including a diuretic, or ≥4 drugs, including a diuretic, regardless of BP level) hypertension, respectively. In multivariable analysis, extracellular water, older age, higher albuminuria, diabetic nephropathy, and the absence of aldosterone blockers were independently associated with uncontrolled BP . Extracellular water, older age, lower glomerular filtration rate, higher albuminuria and body mass index, male sex, African origin, diabetes mellitus, and diabetic and glomerular nephropathies were associated with resistant hypertension. Conclusions In this large population of patients with CKD , a lower glomerular filtration rate, a higher body mass index, diabetic status, and African origin were associated with hypertension severity but not with BP control. Higher extracellular water, older age, and higher albuminuria were independent determinants of both resistant and uncontrolled hypertension during CKD . Our results advocate for the large use of diuretics in this population.

[Measurement and estimation of glomerular filtration rate]. / Mesure et estimation du débit de filtration glomérulaire.

Glomerular filtration rate is the best quantitative marker of renal function. It allows diagnosis and classification of severe chronic kidney disease into five stages. Theoretically, the measurement of glomerular filtration rate is based on the calculation of urinary clearance of exogenous substances such as chromium 51-labeled inulin or ethylenediaminetetraacetic acid ([51Cr]-EDTA). In practice, glomerular filtration rate is most often estimated from equations derived from plasma creatinine. This article reviews the range of methods used to measure or approximate glomerular filtration rate and attempts to describe recent developments in this area, including those related to plasma creatinine assay methods, creatinine and cystatin C concentration-derived estimations. Measurement of glomerular filtration rate by the clearance of exogenous tracers is also discussed.