Hemodynamic , office BP, and autonomic variables  were measured at baseline and after the short-term intervention. 24 h-ambulatory BP monitoring was measured after acute and short-term protocols. Acute intervention: tDCS reduced BP, cardiac output, and increase high-frequency band of PI . Short-term protocol: tDCS did not change BP and cardiac output parameters. In contrast, central systolic BP (−12%), augmentation index (−31%), and pulse wave velocity (34%) were decreased by the short-term tDCS when compared to SHAM. These positive results were accompanied by a reduction in the low-frequency band (−37%) and an increase of the high-frequency band of PI (+62%) compared to SHAM. These findings collectively indicate that short-term tDCS concomitantly improves resting cardiac autonomic control and pulse wave behavior and reduces central BP in RHT patients, https://ensaiosclinicos.gov.br/rg/RBR-8n7c9p.Previously, we demonstrated that acute transcranial direct current stimulation (tDCS) reduced blood pressure (BP) and improved autonomic modulation in hypertensives. We hypothesized that acute and short-term tDCS intervention can promote similar benefits in resistant hypertensive patients (RHT). We assessed the impact of one (acute intervention) and ten (short-term intervention) tDCS or SHAM  sessions on BP, pulse interval (PI) and systolic blood pressure variabilities, humoral mechanisms associated with BP regulation, and cytokines levels. True RHT subjects ( Resistant hypertension (RHT) is a clinical condition defined as above-goal elevated blood pressure in a patient, despite optimal use of ≥3 antihypertensive classes of drugs (which includes a diuretic agent), administered at maximally tolerated doses . PatientTechnological devices were developed to treat RHT by inhibiting sympathetic activity, including activation of the carotid baroreceptors using electrical stimuli  and seleSince those studies using functional magnetic resonance imaging to assess the connection of the M1 area and autonomic nervous system were not found, it is already known that cortical motor areas, including M1, project directly to the reticular formation regions and the spinal cord –23, and We have previously demonstrated that an acute session of tDCS in M1 area tDCS promoted positive adjustments on cardiac autonomic control and reduced 24-hs blood pressure values of non-RHT patients . Here, wGiven this background, the purpose of the present clinical trial was to rigorously assess the effects of one  and ten  tDCS sessions on the blood pressure levels and neurohumoral mechanisms in RHT subjects. Considering that vagal activation seems to suppress pro-inflammatory cytokines production –28, we aThirteen resistant hypertensive volunteers from the Outpatient Hypertension Clinic of the University of Campinas  were screened for this study. This protocol was approved by the Ethical in Research Committee of the School of Medical Sciences, University of Campinas  and performed following the Declaration of Helsinki. All participants signed a written consent form before being included in the study . This study was registered at the Brazilian Registry of Clinical Trials (ReBEC) under Register Number: RBR-8n7c9p.stem.Patients were included after at least a 6-month screening protocol for diagnosing RHT and check the adherence to pharmacological and non-pharmacological therapy. Two ambulatory blood pressure monitoring (ABPM) were performed to exclude white-coat hypertension, and pill counts assessed lack of adherence. Patients with an adherence rate below 80% of the prescribed medication were excluded from our sample. We tested patients for: renal artery stenosis, pheochromocytoma, primary hyperaldosteronism , Cushing syndrome (by assessing cortisol and adrenocorticotropic hormone levels), and obstructive sleep apnea (classified as “high risk” according to Berlin questionnaire), to exclude secondary causes of hypertension. Thus, after patients were screened for possible causes of pseudo-RH, they were defined as those using ≥3 antihypertensive agents of different classes, including a diuretic .Other exclusion criteria were: clinically evident coronary artery or cerebrovascular diseases, significant impaired renal or liver function, myocardial infarction or peripheral vascular disease, use of pacemakers or other implanted electronic devices, and depression  .This study had a double-blind, randomized crossover with a placebo (SHAM) design. Participants were involved in the study for two protocols, as showed in 2, in the primary motor cortex, M1 region, for 20 min. Placebo (SHAM) sessions were constituted by the electrode positions and stimulation parameters identical to that used for anodal stimulus. The excitation stopped after a ramp-up and ramp-down period of the 30s each to provide an equivalent scalp sensation. Hemodynamic and autonomic measurements were conducted during the 20 min of SHAM and tDCS stimulation. (photoplethysmography). After the acute intervention, for 20 min, beat-to-beat photoplethysmography continued being assessed. Then, central hemodynamic variables were evaluated, and 24 h-ambulatory blood pressure measurements (ABPM) were started. After 1 week of “washout,” subjects were submitted to the same procedures, crossing the type of intervention (SHAM or tDCS).The participants were interviewed for their demographic characteristics and medication use on the first visit, assessed for body weight, height, and office blood pressure. On the second visit, applanation tonometry was performed to assess noninvasive central hemodynamic variables . After this procedure, subjects were assessed to 20 min of photoplethysmography with beat-to-beat signal  to evaluate hemodynamic and autonomic variables. Then, subjects participated in the first randomized stage of the protocol. An investigator not involved in the assessment, intervention, or statistical analysis conducted the randomization (1:1) of subjects and programmed the device for the tDCS or SHAM sessions. After device programming by this investigator, another researcher started the session, blinded to the type of intervention that the device was programmed. tDCS  was performed with anodal excitation, 0.06 mA/cmAfter 1 week of Protocol 1, the same subjects were enrolled in thirteenth visits over 3 weeks. The participants were interviewed for their medication use on the first visit, assessed for body weight, height, and office blood pressure. After 12 h of fasting, on the second visit, blood samples were collected (8:00–9:00 h a.m.) to analyze biochemical markers. After a standardized breakfast, subjects were assessed for 20 min of photoplethysmography with a beat-to-beat signal to evaluate hemodynamic and autonomic variables. Then, applanation tonometry was performed to assess noninvasive central hemodynamic variables and pulse wave analysis.On the third visit, subjects participated in the first randomized stage of the protocol. An investigator not involved in the assessment, treatment, or statistical analysis conducted the randomization (1:1) of subjects and programmed the device for the tDCS or SHAM sessions. After device programming by this investigator, another researcher started the session, blinded to the type of intervention that the device was programmed. tDCS and SHAM sessions were similar to the acute protocol and occurred between 8:00–12:00 h a.m. after patients took their usual antihypertensive medication. Such protocols were applied for 10 days.Thereby, patients received tDCS or Sham interventions on consecutive days from the third to the twelfth visit. On the thirteenth visit (24 h after the last tDCS session), patients were reassessed by biochemical markers, office blood pressure, hemodynamic and autonomic variables, as well as central blood pressure and pulse wave analyses. Immediately after the recording, 24 h-ABPM was carried out. After 1 week of “washout,” participants initiated the same experimental sequence performed with the crossing of subjects, i.e., those selected for Sham stimulation in the previous stage, tDCS was performed, and vice-versa.Office BP was measured using a certified digital sphygmomanometer  by a trained health professional, according to the European Society Hypertension (ESH) 2018 guidelines .Blood samples were collected by venipuncture in heparinized vacutainers after 12 hs fasting and immediately centrifuged at 4,000 rpm for 5 min to separate plasma. The TNF-α, IL-10, noradrenaline, and cortisol concentrations were determined in peripheral blood by the enzyme-linked immunosorbent assay (ELISA) technique using high detection sensitivity kits  with ranges between 15.6–1,000 pg/mL for TNF-α, and 7.8–500 pg/ml for IL-10. Intra- and inter-assay variations (%) were 4.2–5.2 and 4.6–7.4 for TNF-α, and 1.7–5.0 and 5.9–7.5 for IL-10. Noradrenaline ranges between 0.313 and 20 ng/mL, and cortisol ranged from 8.5 to 23.8 μg/dL. Intra- and inter-assay variations (%) were 5.5–8.4 for noradrenaline and 7.2–10.9 for cortisol.With patients in a sitting position, after 15 min of rest, continuous beat-to-beat blood pressure waves were obtained by a digital photoplethysmography device  for 20 min. A software program (BeatScope) used BP curves and patient data  to calculate systolic and diastolic BP (SBP and DBP), heart rate (HR), cardiac output (CO), and peripheral vascular resistance (PVR). The waveforms were simultaneously recorded on another computer equipped to acquire and convert the biological signals AT/MCA-CODAS . The sampling frequency of signals was 1,000 Hz.The stored data from photoplethysmography underwent a routine analysis  to provide pulse interval (PI) and systolic blood pressure (SBP) variability. Although the PI variability assessment may be considered may be less accurate than measuring heart rate variability by electrocardiogram, some studies have demonstrated the agreement between heart rate variability and PI variability , 32.Beat-to-beat BP was analyzed using a specialized algorithm for spectral data analysis , which automatically detects SBP and DBP waves. Pulse interval (PI) was calculated as the difference between the cycle's start and endpoints (t1-t0). The spectral power density of the SBP and the PI range were computed using the Fast Fourier Transform and the Welch method. To set the window length was established in 5 min.In the time domain, we analyzed: SDNN [standard deviation of normal-to-normal (NN) PI] and PI Variance ; RMSSD  and SBP Variance (variance of systolic blood pressure in short-time). The spectral bands evaluated for humans were defined as very-low-frequency (VLF: 0.007–0.04 Hz), low-frequency (LF: 0.04–0.15 Hz), high-frequency (HF: 0.15–0.4 Hz), and total power. The normalized values (nu) for the LF and HF bands were then calculated using the predefined formulae: LF (n.u.) = LF/ ×100 or HF (n.u.) = HF/ ×100. The ratio for the absolute values for the LF band of PI and HF band of PI (LF/HF) was also calculated as a representative of autonomic balance.The HF component of PI variability has been related to the efferent vagal modulation. However, the interpretation of the LF component of PI is more controversial since that includes the influences of sympathetic and parasympathetic modulation . Also, tApplanation tonometry was performed to assess noninvasive central hemodynamic variables and pulse wave velocity (PWV) using the SphygmoCor system . Consecutive measurements of the carotid and femoral artery pulse waves were electrocardiogram gated. The distance between the two sites was measured on the body surface to determine aortic PWV in meters/second (m/s). The total distance between the carotid and femoral arteries was used for measurement. The average measurements throughout 8 s (9–10 cardiac cycles) were calculated after excluding extreme values .After 20 sequential waveforms were acquired and averaged, a validated generalized mathematical transfer function was used to synthesize the corresponding central aortic pressure wave .The Augmentation Index (AIx), defined by the ratio between the pressure exerted by the reflected wave and the ejection wave, was evaluated . This in2 area) housed in saline-soaked sponges, an anodal stimulation in the M1 region was positioned in the C3 area  the cathode was placed in the supraorbital region. A current density of 0.06 mA/cm2 and an intensity of 2.0 mA were applied on the scalp during 20 min per active session. For placebo SHAM, the electrode positions and stimulation parameters were the same as those used for anodal stimulation. The stimulation stopped after a ramp-up and ramp-down period of the 30 s each to provide an equivalent scalp sensation. Thus, for SHAM stimulation, the device switched off automatically after the 30 s of stimulation. The device display remained, indicating the stimulation time, regardless of whether the active or SHAM current was provided. Previous work demonstrated that this type of blinding is effective at low stimulation intensities (The primary motor cortex region (M1) was chosen as the target for tDCS and was stimulated by a constant current stimulator . With a 5.0 ×7.0 cm electrode , and only records with more than 85% of total measures were analyzed. Those patients who had more than 25% of incomplete measurements should retake the exam. However, no patient had to be re-examined. The device was then set to obtain four blood pressure readings per hour (one every 15 min). The parameters measured were average 24-h, daytime and nighttime of systolic BP, diastolic BP, mean BP, and pulse pressure.*Power software to ANOVA (version 3.1.9.2.), based on the magnitude of the mean differences in systolic blood pressure levels among tDCS or SHAM sessions  of SHAM and tDCS conditions. Considering that the LF band of PI represents, at least partly, the influence of sympathetic modulation, this parameter was chosen as an independent variable for associations with cortisol levels and central blood pressure. As vagal activation has been related to a reduction in the inflammatory profile . Since the hemodynamic effects of tDCS in resistant hypertensive patients are not known, we tested its acute effects on blood pressure and associated variables. To begin to uncover it, we assessed the pulse moment-by-moment (plethysmography) at Baseline, During, and After tDCS or SHAM session, as observed in Next, we focused on autonomic modulation and investigated whether this regulatory mechanism can explain the observed effects of tDCS on blood pressure . As expeTo determine whether tDCS can extend its effects beyond 20 min post-stimulation, we evaluated 24-h blood pressure through ambulatory blood pressure monitoring (ABPM). At 24-h measurement, SBP, DBP, mean BP (MBP), and pulse pressure (PP) were reduced by tDCS. During the daytime, tDCS did not change these variables, except for PP values, which were reduced after tDCS. In the nighttime, tDCS reduced SBP, DBP, MBP, and PP . These rKnowing that acutely tDCS promotes blood pressure reduction and improved autonomic modulation, we tested whether short-term stimulation can promote similar benefits in these patients. To test this hypothesis, we submitted the resistant hypertensive patients to ten sessions of tDCS and SHAM stimulation .Despite the results observed in the acute protocol, ten sessions of tDCS did not change systolic, diastolic, mean blood pressures, pulse pressure, heart rate, cardiac output, and peripheral vascular resistance as compared with SHAM at the end of intervention .Regarding 24 h-ambulatory blood pressure measurements, after short-term tDCS intervention, we did not observe changes in 24 h, daytime, and nighttime of systolic, diastolic, and mean blood pressure. Pulse pressure values were reduced at daytime after tDCS when compared with baseline and SHAM at final moment .P = 0.0225] (P = 0.0320] (P = 0.0421]), AIx@HR75% [P < 0.0001]  [P = 0.0002], increased HF-PI (n.u.) [P < 0.0001], as well as decreased LF-HF-ratio [P < 0.0001], SBP Variance [P = 0.0018], and LF-SBP [P = 0.0012] vs. SHAM at the end of experiments.Given the blood pressure is regulated by the autonomic nervous system, we also investigated whether ten sessions of tDCS can improve cardiac and peripheral autonomic modulation. As can be seen in P = 0.0056; vs. Baseline: P=0.0033]  band and central SBP  (2) band and cortisol levels  (2) band and IL-10   LF-PI  LF- 0.0001] , and iii 0.0049] . Finally 0.0049]  . This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001 and National Council for Scientific and Technological Development (CNPq) [grant number #422979/2018-0]. BR and HM-J are fellowships from CNPq (BPQ) .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Resistant hypertension (R-HTN) implies a higher mortality and morbidity compared to non-R-HTN due to increased cardiovascular risk and associated adverse outcomes—greater risk of developing chronic kidney disease, heart failure, stroke and myocardial infarction. R-HTN is considered when failing to lower blood pressure below 140/90 mmHg despite adequate lifestyle measures and optimal treatment with at least three medications, including a diuretic, and usually a blocker of the renin-angiotensin system and a calcium channel blocker, at maximally tolerated doses. Hereby, we discuss the diagnostic and therapeutic approach to a better management of R-HTN. Excluding pseudoresistance, secondary hypertension, white-coat hypertension and medication non-adherence is an important step when diagnosing R-HTN. Most recently different phenotypes associated to R-HTN have been described, specifically refractory and controlled R-HTN and masked uncontrolled hypertension. Optimizing the three-drug regimen, including the diuretic treatment, adding a mineralocorticoid receptor antagonist as the fourth drug, a β-blocker as the fifth drug and an α1-blocker or a peripheral vasodilator as a final option when failing to achieve target blood pressure values are current recommendations regarding the correct management of R-HTN. Arterial hypertension (HTN), defined as office systolic blood pressure (BP) values ≥ 140 mmHg and/or diastolic BP values ≥ 90 mmHg, is known as the most important risk factor for cardiovascular (CV) diseases. Nowadays, the prevalence of HTN amounts to 1.13 billion people, or around 30–45% of the global population . The WorResistant hypertension (R-HTN), a severe form of HTN, has been intensively studied since the early 1960s, when it was first defined. R-HTN is considered when failing to lower BP below 140/90 mmHg despite adequate lifestyle measures and optimal treatment with at least three antihypertensive medications of different classes, including a diuretic, typically a blocker of the renin-angiotensin system (angiotensin converting enzyme inhibitor or angiotensin receptor blocker) and a long-acting calcium channel blocker (CCB), at maximum or maximally tolerated daily doses administered at the appropriate dosing interval [The 2018 European Society of Hypertension and European Society of Cardiology (ESH/ESC) Guidelines’ definition for R-HTN requires inadequate control of BP to be confirmed by ambulatory BP monitoring (ABPM) or home BP monitoring (HBPM) and adherence to therapy to be validated . After eDifferent R-HTN-associated phenotypes have been described. The 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline introduced two new concepts: controlled R-HTN and refractory R-HTN . ControlMost recently, a new R-HTN-associated phenotype was described—masked uncontrolled HTN, referring to patients receiving four or more antihypertensive medications and achieving an adequate office BP control, but with elevated out-of-office BP . Hence, Various physiological mechanisms are involved in maintaining normal BP values; hence, their dysfunction may lead to the development of HTN. R-HTN is broadly attributed to two underlying processes: the renin-angiotensin-aldosterone system and sympathetic nervous system activation.Aldosterone is the most important mineralocorticoid hormone produced in the zona glomerulosa of the adrenal cortex as a response to angiotensin II, increased levels of extracellular potassium and corticotropin activity. Aldosterone regulates the sodium and potassium balance by binding and activating the mineralocorticoid receptor in the distal tubule and collecting duct of the kidney. Increased aldosterone production induces salt retention and, consequently, fluid retention, thus promoting elevated BP values. The detrimental actions of aldosterone include endothelial dysfunction, sympathetic activation and oxidative stress. In vascular smooth muscle cells, aldosterone displays several extrarenal effects by activating the expression of genes involved in inflammation, calcification and fibrosis ,11,12. AEssential HTN is characterized by both impaired parasympathetic tone and increased sympathetic activation. Increased levels of the adrenergic neurotransmitters norepinephrine and epinephrine have also been found in normotensive patients with a family history of HTN . The symActivation of the adrenergic nervous system is involved in the development of vascular remodeling, endothelial dysfunction and arterial stiffness in hypertensive state . For a sIn recent years, new methodologies have been developed making it possible to employ genome-wide association studies (GWAS) for testing the correlation between thousands of common gene variants and common characteristics in samples from different populations. GWAS assume genetic expression and epigenetic analysis in different tissues, and this way, thousands of genes and pathways with potential biological relevance may be discovered. However, the results for BP phenotypes are scarce as the gene variants explain only 2.2% of BP variation and are, thus, not applicable for clinical implementation . MoreoveThe classification of R-HTN has become much easier after the new definition of R-HTN was published in the 2018 ESH/ECS guideline . When asWhite-coat uncontrolled HTN—in patients with office BP above goal, but out-of-office BP measured by ABPM or HBPM are below target values;Masked uncontrolled HTN—in patients with adequate office BP control, but with elevated out-of-office BP measured by either ABPM or HBPM;Sustained uncontrolled HTN—in patients whose BP values are elevated at both office and out-of-office measurements.According to the definition, elevated values of office BP are not sufficient for establishing the diagnosis of R-HTN, and the inadequate control of BP needs to be confirmed by ABPM and, if not available, HBPM in patients whose adherence to therapy has been confirmed . These tUncontrolled R-HTN—in patients with office BP ≥ 140/90 mmHg and/or 24-h ambulatory BP ≥ 130/80 mmHg, taking three or more antihypertensive medications of different classes, including a diuretic, and usually a long-acting calcium channel blocker and a blocker of the renin-angiotensin system blocker at maximal or maximally tolerated doses;Controlled R-HTN—in patients with office BP < 140/90 mmHg and/or 24-h ambulatory BP < 130/80 mmHg, taking at least four antihypertensive medications of different classes.Another HTN classification based on BP control and number of antihypertensive medications is the following  and non-prescription drugs  . HoweverAfter excluding pseudoresistance and drug-related HTN, screening for secondary causes of HTN is essential. Screening for this type of HTN should be guided by clinical findings as, in most situations, curative treatment of secondary HTN does not imply the normalization of BP values, especially if the disease had evolved for a long period of time and, thus, led to possible vascular or organ damage.Once a patient was diagnosed with R-HTN, a set of nonpharmacological, pharmacological and, if needed, device-based strategies can be applied in order to obtain optimal control of BP.Nonpharmacological measures are commonly recommended as they are the cornerstone for both preventing and treating HTN. We will discuss below several lifestyle factors that influence BP values.Obesity is, undeniably, one of the most evident and yet neglected problems of public health. The number of obese adults was estimated at 500 million in 2016, with an alarming increasing trend among children. It is estimated that by 2030, the epidemic of “globesity” will amount to approximately 1.5 billion people .Even if the pathophysiological mechanisms that link obesity to BP are complex, the key element might be the distribution of body fat. Vague was the first to raise this issue back in 1956, when finding the correlation between metabolic and CV complications and the phenotype of obesity—android or gynoid . Since t2 and 4.5 cm waist circumference in men and 1.3 kg/m2 and 2.5 cm in waist circumference in women, the systolic BP increases with 1 mmHg [Studies also demonstrated that there is an almost linear correlation between body mass index and BP values. With every 1.7 kg/mh 1 mmHg .2 doubles the risk of true R-HTN [2. Even if the BP-lowering effect appears in early stages of weight loss, the long-term effects being more attenuated, persevering in weight loss is extremely important [The National Health and Nutrition Examination Survey (NHANES) and the Spanish ABPM Registry demonstrated that a body mass index above 30 kg/mmportant . HoweverOne of the most important measures in reducing BP values is, undeniably, sodium restriction, given the fact that hydro-saline retention is involved in the pathophysiology of HTN. The 2018 ESH/ECS Guidelines recommend a daily sodium intake limited to 5 g per day . In contThe Dietary Approaches to Stop Hypertension (DASH) diet was designed as a 11-week program in 459 individuals with mild and untreated HTN who were randomly assigned to one of three types of diet. The first one—the DASH diet—was based on fruits, vegetables and low-fat dairy products with reduced saturated and total fat, the second was based on fruits and vegetables rich in potassium and fiber, while the third one was based on a typical American diet (the control diet). Each diet accounted a total sodium intake of about 3 g per day. The DASH diet lowered BP by 6/3 mmHg, while the fruits and vegetables diet lowered BP by 3/1 mmHg . In addiPhysical activity has been consistently studied and shown to reduce both systolic and diastolic BP, being beneficial for preventing and treating HTN as well as lowering CV risk and mortality. There are multiple types of physical activities, such as dynamic or aerobic exercises  and isometric or resistance exercises , and each of these showed BP-lowering properties. When hypertensive patients perform 90 to 150 min of aerobic exercise per week, they can register a reduction of BP values by 5–8 mmHg, whereas when performing an isometric resistance exercise over the course of 8–10 weeks, the systolic BP can be reduced by 4–5 mmHg . The benOther lifestyle measures that are found to be helpful in reducing BP values are: limiting alcohol consumption to less than 14 units per week in men and less than 8 units per week in women, avoiding binge drinking, avoiding excessive caffeine, smoking cessation and having a healthy sleep pattern with at least six hours of sleep per night .Beyond lifestyle measures, the psychosocial factors play an important role in treating HTN, mainly because they may influence adherence and/or persistence to therapy. Psychosocial stress, anger, anxiety and especially depression are common in adults and are frequently associated with the development of HTN, hence affecting the individual health and the quality of life . A meta-All hypertensive patients require drug therapy in addition to lifestyle measures to achieve an adequate BP control. We will discuss below the pharmacological strategies that should be applied in a stepwise manner in order to achieve therapeutic success in R-HTN .When treating R-HTN assuring that the diagnostic criteria have been fulfilled alongside with optimal nonpharmacological measures is essential. Therefore, the treatment of R-HTN includes at least three antihypertensive medication of different classes, including a diuretic, and usually a blocker of the renin-angiotensin system and a CCB, at maximum or maximally tolerated daily doses and at the appropriate dosing interval. Note that when HTN is associated with atrial fibrillation or heart failure, the initial triple therapy may be different. Additionally, adherence to treatment must be improved  .Thiazide-like diuretics  are considered the first-line diuretics in R-HTN having a longer half-life when compared to thiazide diuretics (hydrochlorothiazide), which translates into a better control of BP .2, it is advisable to use thiazide or thiazide-like diuretics, whereas in patients with eGFR below 30 mL/min/1.73 m2, loop diuretics  are preferred. Even though hydrochlorothiazide is the most prescribed thiazide diuretic, switching to chlorthalidone might be a better choice due to its longer acting effect , its higher efficiency and superiority in preventing CV events and left ventricle hypertrophy [When choosing the appropriate diuretic, one must take into account the estimated glomerular filtration rate (eGFR). In patients with eGFR higher than 30 mL/min/1.73 mertrophy ,42. Elecertrophy .When target BP values cannot be obtained with the three-drug regimen, a fourth medication needs to be added. Therefore, given the fact that mineralocorticoid receptor blockade is extremely important in hypertensive patients, mineralocorticoid receptor antagonists are one of the front-runner medication classes for treating R-HTN ,5.The PATHWAY-2 study (Prevention and Treatment of Hypertension with Algorithm Based Therapy) included patients with uncontrolled R-HTN taking optimal treatment with at least three antihypertensive medication of different classes who were randomized to a double-blinded, four-way cross-over comparison of 3 months each of placebo, spironolactone (25 or 50 mg), bisoprolol (5 or 10 mg) and doxazosin modified release (4–8 mg) . Spirono2, as it may lead to deterioration of renal function and hyperkalemia. Studies show that potassium binders such as patiromer are extremely efficient in patients with R-HTN and chronic kidney disease by enabling patients to continue the treatment with spironolactone with a lower risk of hyperkalemia [Even though spironolactone is very useful in treating R-HTN, it has certain limitations and contraindications. It should not be used in patients with eGFR lower than 45 mL/min/1.73 mPATHWAY-2 included several sub-studies aimed to explore the underlying causes of R-HTN, including the role of aldosterone and excess fluid retention as important mediator of treatment resistance. The first sub-study demonstrated the relation between the baseline aldosterone-renin ratio and baseline renin level and the BP response to spironolactone . The secThe fourth therapeutic option consists of adding a cardio-selective β-blocker or a combined α- and β-blocker, especially if the basal heart frequency is above 70 beats per minute, and in case they are not already part of the treatment for a different pathology such as heart failure with reduced ejection fraction, atrial fibrillation, or coronary artery disease. The 2018 ESH/ECS guideline favors the use of bisoprolol as it was shown in the PATHWAY-2 study ,46. HoweIn case β-blockers are ineffective, contraindicated or not tolerated, central α-2 agonists such as clonidine, rilmenidine or moxonidine can be considered. A patch form of clonidine is preferred because of a lower risk of rebound after discontinuation or non-adherence . More reRarely, if there is a specific contraindication to β-blockers, a non-dihydropyridine calcium channel blocker can be added .The fifth therapeutic option consists of adding a new therapeutic class with a more potent antihypertensive effect, but also with greater side effects.The first option would be α1-blockers such as doxazosin. The starting dose for doxazosin is 1 mg per day, preferably in the evening in order to minimize the risk of orthostatic hypotension and/or syncope, especially in older adults. The dose can increase every one or two weeks until a maximum dose of 16 mg per day, although many patients only need 4 to 8 mg per day in order to obtain adequate control of BP. The α1-blockers may be considered in patients with concomitant benign prostatic hyperplasia [α-methyldopa is frequently used in pregnancy HTN, but it can also be useful in R-HTN. The starting dose is 250 mg, once daily, preferably in the evening for one or two weeks to minimizing the effect of sedation and to monitor tolerance. Then, the doses can be slowly increased until a maximum dose of 2 g per day .If BP is still uncontrolled with the aforementioned medications, hydralazine can be another option. Doses less than 150 mg per day decrease the risk of developing drug-induced lupus-like syndromes. Another major disadvantage of hydralazine is that the direct arterial vasodilation determines the activation of the sympathetic nervous system with subsequent tachycardia and hydro-saline retention . Thus, hSince the activation of the sympathetic nervous system is one of the key mechanisms for the development and progression for both essential HTN and R-HTN, there has been an emerging need to create a series of device-based therapies to disrupt this mechanism and, thus, control BP.The purpose of renal sympathetic denervation is to ablate the sympathetic nerves that are localized close to the renal arteries by radiofrequency or ultrasound waves emitted by an endovascular catheter and, therefore, interrupt the sympathetic activation. This therapy was evaluated in patients with R-HTN taking 4–5 antihypertensive drugs by three studies called SYMPLICITY . It was first used in a human feasibility trial (SYMPLICITY HTN-1) and then in a larger randomized prospective study (SYMPLICITY HTN-2) and showed a reduction in office BP and a good safety profile when using this device ,55. HoweSince then, the Renal Denervation for Hypertension (DENER-HTN) Trial showed a statistically significant reduction in daytime ambulatory systolic BP (–5.9 mmHg) in hypertensive patients on a three-drug regimen randomized to renal sympathetic denervation, when compared to patients taking four antihypertensive medications without renal denervation .Recently, catheters have been re-designed to allow complete circumferential renal nerve ablation. SPYRAL-OFF MED Pivotal trial is a prospective, sham-controlled, randomized trial that uses this type of catheter and evaluates renal sympathetic denervation independently of antihypertensive drugs. This trial showed significant BP reduction (–4.7 mmHg in 24-h ambulatory BP and –6.6 mmHg in office BP) after 3 months of follow-up . AlthougRadiofrequency from renal sympathetic denervation can be replaced with ultrasound, as new research demonstrated—Paradise Renal Denervation System, ReCor Medical. This technique also showed a reduction of BP in its own proof-of-concept trial .The carotid baroreceptor activation reflex is triggered by a rapid pressure within the carotid body, which leads to a reduction of sympathetic signals to the vessels, heart and kidneys, and hence, to the reduction of BP. There are two types of devices that evaluate baroreceptor activation therapy: an implantable pulse generator (Rheos and BAROSTIM NEO systems) and an endovascular device (MobiusHD).The Rheos system consists of a battery-powered implantable pulse generator that electrically activates the carotid baroreflex. Although the Rheos Pivotal Trial showed no superiority of baroreceptor activation therapy for reducing BP compared to medical therapy after a six-months follow-up, more than half achieved a systolic BP less than 140 mmHg .The central arteriovenous anastomosis assumes unloading the arterial vascular bed into the venous system. The ROX Coupler utilizes a stent-like nitinol device that is placed through the anastomosis that has been created between the femoral artery and vein and demonstrated efficacy in lowering BP . HoweverThe identification of new molecules to lower BP and CV risk is a continuous concern of the pharmaceutical industry. Notwithstanding a large spectrum of new therapeutic agents used in HTN, it seems difficult to create efficient and competitive molecules that go beyond the clinical phases of studies.Several studies evaluated the antihypertensive effect of the association between angiotensin-converting enzyme inhibitors and neutral endopeptidase inhibitors. The first class of drugs inhibit the angiotensin-converting enzyme leading to a decrease of angiotensin-II, thus improving vasoconstriction and reducing sodium retention. The second class of drugs prevents the degradation of natriuretic peptides into metabolites and promotes vasodilation, increases sodium excretion and displays antihypertrophic and antifibrotic properties. Their effect on BP is synergic and the protection of organ damage is superior. The biggest problem when combining these two classes is the growing number of patients with angioedema because both angiotensin-converting enzyme inhibitors and the neutral endopeptidase inhibitors are involved in the degradation of bradykinin. The Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial compared the antihypertensive effect of omapatrilat versus enalapril and although the antihypertensive effect was superior, angioedema appeared more frequently with the first (2.17% versus 0.68%) . These oAs discussed before, the mineralocorticoid receptor antagonists have proved their efficiency in controlling BP. At this moment, among the novel nonsteroidal mineralocorticoid receptor antagonists, dihydronaphthyridine finerenone BAY94-8662) has accumulated the most evidence. Finerenone is distributed in both cardiac and renal tissues, and it was initially developed for the treatment of heart failure with reduced ejection fraction and mild to moderate chronic kidney disease . Fineren2 has accA functional renin-angiotensin system exists inside the brain and controls the cardiac functions and the body fluid homeostasis . AminopePatients with R-HTN present a higher mortality rate compared to non-R-HTN patients due to increased CV risk and its associated adverse outcomes—greater risk of developing chronic kidney disease, heart failure, stroke or myocardial infarction. Excluding pseudoresistance, secondary and white-coat hypertension is crucial when diagnosing R-HTN. Ensuring adherence to lifestyle measures and drug regimen is an important factor in achieving adequate BP control and avoiding unnecessary intensification of treatment. Optimizing the three-drug regimen, switching to a more potent diuretic, adding a mineralocorticoid receptor antagonist as the fourth drug, a β-blocker or combined α- and β-blocker as the fifth drug and an α1-blocker or a peripheral vasodilator as a final option when failing to achieve target BP values, are current recommendations that regard the correct management of R-HTN. Until the approval of new medications, we must optimize the usage of the existing ones by combining them more rationally and in optimal doses, in order to improve adherence to treatment and, thus, control BP. Device-based therapies such as renal sympathetic denervation and carotid baroreceptor activation therapy show promising results but need further studies to confirm their efficacy and safety in clinical practice.


Median follow-up was 88.1 months . When race was removed from MDRD, 39.9% of patients in CKD G1/2 were reclassified to CKD G3a, 72.6% of patients in CKD G3a would be reclassified to CKD G3b, and 54.1% and 36.4% of patients would be reclassified from CKD 3b to CKD G4 and CKD G4 to CKD G5, respectively (p < 0.0001). Comparing the CKD-EPI formula against the MDRD in our cohort, we found that 8.2%, 18.8%, and 11.4% of patients were reclassified from CKD G1/2 to CKD G3a, CKD G3a to G3b, and CKD G3b to CKD G4 respectively. Overall median time to progression to CKD G5 was 137.4 (131.9–142.8) months in patients who were not reclassified and 133.6 (127.6–139.6) months for patients who were reclassified by MDRDrace removed(p < 0.288). Concerns of inequitable access to healthcare have elicited calls to review race-corrected eGFR equations. A substantial number of individuals would have their CKD stage reclassified should have the MDRDrace removed equation be adopted en masse on an AA-only population. The discrepancy is highest at the 45–59 and >60 ml/min/1.72 min2 ranges. This will have tremendous impact on our center's approach to pharmacological dosing, referral system, best practices, and outcome surveillance. Comprehensive review of the current “race-corrected” eGFR will require a multifaceted approach and adjunctive use of noncreatinine-based approach.The widely used Modification of Diet in Renal Disease (MDRD) formula adapts a 1.212 multiplier for individuals who are identified as African Americans (AAs) or Blacks, which leads to a higher GFR estimation. As it stands, AAs have a lower prevalence of chronic kidney disease (CKD) but higher incidence of end-stage renal disease (ESRD) compared with Whites. Many hypotheses have been postulated to explain this paradox, but the imprecision of the GFR estimation with race-adaptation could be contributory. We performed a single-center, longitudinal, retrospective study on a cohort of outpatient AA patients using the MDRD and MDRD Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function, present for more than 3 months, with adverse implications on health. Equations that determine the estimated filtration rate (eGFR) are used universally to determine the CKD stage and guide clinical decision-making, including appropriate drug dosing, dialytic therapies, or listing for kidney transplantation. African Americans (AA) have lower prevalence of CKD  but highWhile studies have observed a higher serum creatinine in AA with CKD , the assThe rationale for the use of race as a coefficient in eGFR equations is that it mitigates bias and improves performance of the equation on the population from which it is derived , 7. HoweAccurate staging of CKD is critically important in medical care and tremendous impact in raising awareness for the individual patient and implementation of key primary and secondary preventive measures such as control of hypertension, the use of renin-angiotensin-aldosterone inhibition, sodium-glucose-transporter inhibitor therapy, and proper medication dosing .The use of race does not account for heterogeneity within racial groups. Therefore, the use of a race coefficient in the estimation of diagnostic biological measures is inherently flawed and devoid of a strong scientific premise and lacks precision . The incA cross-sectional study involving 2225 AA patients showed that 33.4% of them would be hypothetically reclassified to a more severe CKD stage if the race multiplier was removed from the CKD-EPI equation . In an a2) in people who are reclassified by the correction removal.The objective of this study is to determine the impact of removing the race correction from the MDRD and CKD-EPI on CKD staging and analyze the progression to CKD 5  of Nephrology AA patients from a large academic medical center located in Central Brooklyn was performed. Our center serves a predominantly AA community that has been subject to widespread disparate health outcomes . The racFor all patients, the laboratory measurement of serum creatinine was performed using the Beckman Coulter AU2700 system . Serum creatinine was analyzed by the kinetic alkaline picrate methodology which is traceable to the reference method based on isotope dilution-mass spectrometry (IDMS). GFR was estimated according to the MDRD abbreviated formula , 19.2Stage G1/2: −60–89 ml/min/1.73 m2Stage G3a: 45 to 59 ml/min/1.73 m2Stage G3b: 30 to 44 ml/min/1.73 m2Stage G4: 15 to 29 ml/min/1.73 m2 [Stage G5: less than 15 ml/min/1.73 m2 We used the 2012 KDIGO Clinical Practice Guideline for the Evaluation and Management of CKD, which classifies estimated GFR in the following ranges:2) = 175 × (SCr/88.4)−1.154 × age−0.203 × 1.212 (if the patient is AA) × 0.742  [MDRD: eGFR (ml/min/1.73 mrace removed: eGFR = 175 × (SCr/88.4)−1.154 × age−0.203 × 0.742 MDRDCr/κ, 1)α ×  max−1.209 × 0.993Age × 1.018  ×  1.159 (if AA) [CKD-EPI: eGFR = 141 ×  min (S (if AA) .race removed: eGFR = 141 × min α × max−1.209 × 0.993Age × 1.018 CKD-EPIThe following equations are used:2.Past medical history of hypertension, diabetes mellitus, congestive heart failure, stroke, coronary artery disease, and dyslipidemia and etiology of CKD and laboratory data were extracted from the EHR which is populated during in-person medical visits. The body mass index (BMI) was measured by calculating the individual's weight divided by the square of the height and expressed as kg/m2.The observation period of each patient was defined as the time period from the first registered measurement of serum creatinine until CKD G5, defined as eGFR <15 ml/min/1.73 m2 test. The Kaplan–Meier method was used to describe the progression to CKD G5. The log-rank test was used to compare between groups [Continuous variables are presented as mean ± SD. Comparison of continuous variables between stages of CKD were performed using one-way ANOVA or the Kruskal–Wallis test, depending on the underlying distribution. Categorical and nominal data were compared using the Χn groups . All com327 AA patients were analyzed. The mean age of the cohort was 61.9 ± 14.2 years. 60% of patients were female, and 57.5% had a diagnosis of diabetes mellitus. Body mass index (BMI) was evenly distributed across all groups. Over 90% of patients had a diagnosis of hypertension across all eGFR categories .race removed, CKD EPI, and CKD EPIrace removed are applied, with the number of patients in CKD G3b almost doubling at the expense of the earlier stages in MDRDrace removed compared to MDRD.Median follow-up was 88.1 months . race removed was applied, 39.9% of patients in CKD 1/2 were reclassified to CKD G3a, 71.8% of patients in CKD G3a would be reclassified to CKD 3b, and 54.1% and 36.4% of patients would be reclassified from CKD G3b to CKD G4 and CKD G4 to CKD G5, respectively (p < 0.0001) (p < 0.0001) (When MDRD 0.0001) . When th 0.0001) .race removed and found that CKD stage reclassification is less severe but remained significant with 22.6%, 46.5%, and 38.3% of patients reclassified from CKD G1/2, G3a, and G3b, respectively (p < 0.0001)  .race removed. The Kaplan–Meier curves for the end point of reaching eGFR <15 ml/min/1.73 m2 (CKD G5) in patients with different stages of CKD who were not reclassified by MDRDrace-removed and those who were reclassified are depicted in Figures p < 0.288). Advanced age was a significant predictor of progression to CKD G5  to stage G3b (eGFR between 30 and 44 ml/min/1.73 m2)  . In a sts cutoff .race removed , but it underestimates GFR in higher GFR ranges  . In reco removed , and sho2, the 4-variable MDRD equation without correction for race classified the highest proportion of participants under the age of 40 years (7.8%) as having reduced eGFR [2, in comparison with a median bias of 1.9 (95% CI 0.8 to 4.5) ml/min/1.73 m2 when the race factor was discarded [In a cohort of 533 healthy Black Africans using a cutoff of 75 ml/min/1.73 mced eGFR . In 2001ced eGFR . Howeverced eGFR . This stiscarded . It shouiscarded , 32. In iscarded .race removed and CKD-EPIrace removed reclassified over 49.5% and 30.6% of our AA patients to a higher stage of CKD, respectively, in comparison with their conventional counterparts. This partially explains the seemingly paradoxical observation that although AA patients present with more advanced CKD stage than Whites, AAs on hemodialysis have a lower mortality than their White counterparts probably because once they are recognized within the healthcare system as dialysis patients, and eGFR becomes a less important determinant of healthcare resource [In this study, the exclusion of race in both MDRDresource . Other fresource .2 has inherent biases. Thus, our results do not inform the biological impact of removing the race correction in eGFR formulas but highlight the disparate classification that informs clinical decision-making paradigms in our center such as referral to specialists, eligibility for kidney transplantation, and other social and disability support.Our study has the following limitations: we did not have mGFR, and as such, our comparison of various eGFR equations is not validated against a gold standard. Another major limitation is the absence of proteinuria data. As well, the definition of AA is a heterogenous one as our patient cohort comprises mainly Black individuals who derived their ancestry from the Caribbean . As wellIn conclusion, the removal of race multiplier factor in eGFR formulas is highly impactful on CKD epidemiology and management. The identification of an adjunctive noncreatinine-based novel biomarker remains a critical unmet medical need.


The pulse arrival time (PAT), the difference between the R-peak time of electrocardiogram (ECG) signal and the systolic peak of photoplethysmography (PPG) signal, is an indicator that enables noninvasive and continuous blood pressure estimation. However, it is difficult to accurately measure PAT from ECG and PPG signals because they have inconsistent shapes owing to patient-specific physical characteristics, pathological conditions, and movements. Accordingly, complex preprocessing is required to estimate blood pressure based on PAT. In this paper, as an alternative solution, we propose a noninvasive continuous algorithm using the difference between ECG and PPG as a new feature that can include PAT information. The proposed algorithm is a deep CNN–LSTM-based multitasking machine learning model that outputs simultaneous prediction results of systolic (SBP) and diastolic blood pressures (DBP). We used a total of 48 patients on the PhysioNet website by splitting them into 38 patients for training and 10 patients for testing. The prediction accuracies of SBP and DBP were 0.0 ± 1.6 mmHg and 0.2 ± 1.3 mmHg, respectively. Even though the proposed model was assessed with only 10 patients, this result was satisfied with three guidelines, which are the BHS, AAMI, and IEEE standards for blood pressure measurement devices. However, in the case of noninvasive blood pressure (NIBP) measurement using a cuff, blood pressure cannot be continuously measured. In the invasive blood pressure measurement method, blood pressure can be measured continuously. However, it is used only for patients with acute dysfunction failures, who are in a critical condition in an intensive care unit (ICU), and the blood pressure is measured by inserting a cannula into the artery3.There are two types of methods used to measure blood pressure: invasive and noninvasive. In the commonly used noninvasive method, blood pressure is measured through the pulse sound generated when the blood vessels in the forearm are compressed by injecting air into the cuff5. These were developed based on the known relationship between blood pressure and pulse arrival time (PAT). Therefore, blood pressure can be continuously estimated by continuously measuring changes in the PAT7. Proença et al. expressed the relationship between PAT and blood pressure using a nonlinear equation8, and Whong and Poon estimated the relationship between blood pressure, PAT, and heart rate through linear regression9. PAT can be measured through the time difference between the R-peak of the ECG and the systolic peak of the PPG; however, this difference is not easy to calibrate because it changes according to the physiological characteristics and pathological conditions of each individual. This may result in a decrease in accuracy or a problem with the reliability of estimating blood pressure for a completely new patient group rather than a verified patient group10. Meanwhile, several research groups have continuously estimated blood pressure using machine learning algorithms via features extracted from ECG and PPG signals. Chen et al. proposed a blood pressure estimation method using a genetic algorithm-mean influence value-support vector regression (GA-MIV-SVR). They extracted various features, including features related to PAT from ECG and PPG signals, and finally selected features to predict systolic blood pressure (SBP) and diastolic blood pressure (DBP) using mean influence value rankings. The obtained prediction performance satisfied the AAMI  standard (Error: 3.3 ± 5.5 mmHg for SBP and 1.2 ± 2.0 mmHg for DBP)4. Furthermore, Sharifi et al. proposed a multiadaptive regression spline (MARS) method based on ECG and PPG signals. They predicted SBP, DBP, and mean blood pressure with high predictive accuracies of − 0.3 ± 9.1 mmHg, − 0.1 ± 5.2 mmHg, and − 0.2 ± 4.6 mmHg, respectively11. Kachuee et al. extracted the heart rate, PPG features, and PAT features from ECG and PPG through feature engineering and used them to continuously estimate blood pressure, considering changes in PAT according to individual physiology5. They showed that DBP can be accurately estimated using a support vector machine method.Many research groups have proposed a blood pressure measurement algorithm based on electrocardiography (ECG) and photoplethysmography (PPG) for noninvasive and continuous blood pressure measurementsThe aforementioned studies estimated blood pressure using features extracted by conducting a complex feature engineering process. In this paper, we used the morphological differences of ECG and PPG signal as a novel feature that includes information on PAT and avoids the complex preprocessing task. Furthermore, we propose an artificial neural network algorithm capable of continuously and noninvasively estimating blood pressure based on these morphological differences between ECG and PPG signals. The previous machine learning methods for blood pressure estimation separately trained the models for both SBP and DBP. However, the proposed algorithm is a combined deep CNN–LSTM network-based multitasking learning architecture model that can predict SBP and DBP simultaneously by considering the morphological features of the ECG and PPG signals, along with temporal features.2) and the mean squared error, which are the indicators used to evaluate the performance of the regression model  mmHg and 70.8 (56–92) mmHg on average, respectively  and , respectively. Besides, the mean absolute difference (MAD) was 1.2 for SBP and 1.0 for DBP, which was satisfied with the A grade of IEEE standard  signals in the MIMIC database. The ABP signal is invasively obtained through a catheter or cannula inserted into a blood vessel, which is mainly used to monitor the BP of patients in the ICU patient. That is, the proposed model was trained using the value of invasive BP to estimate the accurate BP non-invasively, which is closer to the value of invasive BP. In addition, since the proposed method does not have reinforcement learning, it does not receive feedback or provide additional learning via cuff BP during actual use. In other words, invasive BP and non-invasive BP are not used for learning together. Therefore, the estimated BP through the proposed model is the invasive BP, and it will not necessarily be the same as the measure BP through the standard cuff-based device.For training and testing the proposed model, we randomly extracted the dataset during 48 s from each patient. For assessment of overfitting due to the small sample size, we extracted the same size of dataset during other 48 s in a different time interval and the longer dataset during the time interval of the 80 s to 800 s. The performance of the proposed model using these two datasets in the different time intervals was evaluated based on the three standards for BP measurement Table . The acc15. The estimation algorithms of BP using PAT are based on the relationship between the pulse pressure and PAT. The pulse pressure is controlled by SBP and DBP. Therefore, to precisely predict BP, a model need to be trained with consideration of SBP and DBP simultaneously. The combined deep CNN–LSTM architecture-based multitasking model developed in this study outputs both SBP and DBP simultaneously using a single model. This can lead to better performance compared to that when training separately for each factor because the common representative factors of SBP and DBP are extracted while the ECP and PPG difference signals pass through a shared layer23. It was shown that the prediction performance of the proposed model is greater than that of the models developed in previous studies.Most previous studies have trained and used individual models to predict SBP and DBP. Besides, other studies developed the CNN-LSTM models to predict SBP and DBP, which separately trained the CNN-LSTM model for estimation of each BP value24. This is called autocorrelation, and a regression model with autocorrelation in which the error of the predicted value of the model is affected by the error of adjacent observation values may not be completely reliable. Therefore, the Durbin–Watson test was performed to test the autocorrelation between the observed values and the predicted values of the proposed model, and it was confirmed that the independence of error was satisfied through the d-statistics adjacent to 2 for both prediction errors of SBP and DBP25.The error histograms of the proposed model showed a normal distribution form, and it was statistically confirmed that the mean errors converged close to zero and satisfied the normality Fig. C,D. In g12. Besides, the AAMI guidelines require that the average difference between the true and predicted values should be less than 5 mmHg, and the standard deviation for 85% of the true values should be less than 8 mmHg13. In the validation on 10 patients, the model proposed achieved an accuracy that satisfied both of these guidelines. These standards are for the performance evaluation of the upper-arm cuff measuring BP. Therefore, we validated the proposed model using the IEEE standard, which is suitable to evaluate the wearable and cuffless BP measurement device. The IEEE standard evaluates the performance using MAD accuracy, in which if MAD is over 4 mmHg, it would get the A grade. This standard proposes to report the performance of the BP measured for each patient before and after the calibration14. However, the BP estimation using a neural network does not need to calibrate according to the subject, because the neural network can extract the machine learning features with consideration of individual characteristics according to the subjects such as weight, age, gender, and so on26. Solely, it might need the calibration if it estimates BP during the long-term of 6–12 months11.The BHS guideline evaluates the accuracy of the sphygmomanometer’s prediction of SBP in four grades from A to D according to the cumulative percentage of the predicted SBP within 5, 10, and 15 mmHg of the errors. Here, A is the most accurate, and the accuracy decreases toward D27. Accordingly, it is not known whether the accuracy of our proposed model decreases or increases when estimating blood pressure using long-term data from weeks to months. Second, the generalizability of the model was not verified. In this study, the data of ICU patients from PhysioNet were used. Although the signals were simultaneously measured, a missing signal or a signal of poor quality was removed from the dataset. For example, in some PPG signals, any fluctuated waves were not observed during the randomly extracted interval, and in some ABP signals, meaningless values such as − 2,147,483,648 or the zero states were observed. Accordingly, the number of samples used for verification of the proposed model was 7400, and the number of patients was 10, and thus the applicability of the model to many patients has not been verified. All guidelines for evaluating the accuracy of BP measurements require a minimum number of subjects that must be verified through the models or devices. The assessment guidelines we used also required a minimum number of subjects; BHS guidelines and AAMI standard require the report for over 85 subjects, and IEEE standards require over a total of 45 subjects in all phases. Even though the result we have shown in this study was satisfied with three of the guidelines, it might be due to the small number of patients. In other words, when our proposed model is tested for over 85 patients, the results could be different. Therefore, our proposed model needs to be assessed by more subjects. In conclusion, if the generalizability of the model is validated and optimized through more data, it can be applied to medical devices requiring long-term monitoring, including patient monitors and implantable cardiac devices such as the Holter ECG monitoring system. Especially, the proposed simpler algorithm would be more utilized when applied to a mobile system.There are several limitations to our proposed model. First, the accuracy of long-term monitoring was not verified. For LSTM models, the accuracy may vary depending on the measurement time of the data used29. Whole signals were measured from ICU patients, and especially, ABP signals were obtained through invasive methods. Among the data of 57 patients , the data that did not include ECG, PPG, and ABP, or data containing missing signals were not used. Finally, the ECG, PPG, and ABP data of 48 patients  receiving intensive care were used for prediction, and the average age of the patients was 69.9 (21–92) years. Patients had one of 13 diseases, including bleeding, respiratory failure, congestive heart failure/pulmonary edema, brain injury, sepsis, angina, postoperative valve, postoperative coronary artery bypass graft, cord compression, trauma, renal failure, myocardial infarction, and cardiogenic shock. Each signal was acquired with a sampling frequency of 125 Hz for different recording times, but the average recording time was 42.7 (10.5–77.4) h.In this study, we used ECG, PPG, and ABP signals measured simultaneously in PhsioNet’s Multi-parameter Intelligent Monitoring for Intensive Care (MIMIC) Databasen + 1) sequences were generated from the ECG, PPG, and ABP signals based on the detected R-peak (n) of the ECG to include two cycles. Zero padding was applied based on the maximum R–R sequence to compensate for the difference in the data length of the generated R–R sequence due to the change in the R–R interval according to time.Simultaneously measured signals collected from the PhysioNet database were randomly extracted from each patient to obtain 6000 samples (48 s). Some extracted signals have zero values or unusable values, which are meaningless values such as − 24,975,832 or do not change according to time. These signals were removed or interpolated based on adjacent data points. To remove motion artifacts and solve the baseline wandering problem, a bandpass filter of 2 Hz to 20 Hz was applied to the ECG signal, and a bandpass filter of 0.5 Hz to 20 Hz was applied to the PPG signal. After extracting the R-peak from the filtered ECG, R(n-1) − RDBP Fig. .Figure 331 with a learning rate of 0.01 and a decay rate of 0.00002 was used as the model optimization function. The model was trained 1000 times with a batch size of 28; however, the optimal model with hyperparameters was selected as the final model through early stopping.Eighty percent of the total dataset was used to train the model and 20% to evaluate the model performance. Furthermore, 10% of the training data was used for validation to prevent the model from overfitting the training dataset. The mean squared error was used as the error function for the output result, and Adam (Adaptive Moment Estimation)32, along with the value of R2 and mean squared error19 used in the performance evaluation of the regression model. The prediction performance was verified using the BHS12 and AAMI13 standards, which are the blood pressure monitor certification standards for upper-arm cuff validation13. Besides, the possibility of grafting the proposed model into medical devices was assessed using IEEE standard, which is the guideline for evaluation of the wearable, cuffless blood pressure monitoring devices14. Even though these three standards require the minimum number of patients for assessment, we didn’t follow them strictly; we validated the proposed model to only 10 patients (see the “The accuracy of SBP and DBP predicted by the proposed model was evaluated through the root mean squared error and the mean absolute errorsee the “’ sectionSupplementary Information.


Despite significant advances in the management of heart failure (HF), further improvement in the outcome of this chronic and progressive disease is still considered a major unmet need. Recurrent hospitalizations due to decompensated HF frequently occur, resulting in increased morbidity and mortality rates. Past attempts at early detection of clinical deterioration were mainly based on monitoring of signs and symptoms of HF exacerbation, which have mostly given disappointing results. Extensive research of the pathophysiology of HF decompensation has indicated that hemodynamic alterations start days prior to clinical manifestation. Novel technologies aim to monitor these minute hemodynamic changes, allowing time for therapeutic interventions to prevent hemodynamic derangement and HF exacerbation. The latest noticeable advancements include assessment of lung fluid volume, wearable devices with integrated sensors, and microelectromechanical systems-based implantable devices for continuous measurement of cardiac filling pressures. This manuscript will review the rationale for monitoring HF patients and discuss previous and ongoing attempts to develop clinically meaningful monitoring devices to improve daily HF health care, with particular emphasis on the recent advances and clinical trials relevant to this evolving field. Heart failure (HF) is a common clinical syndrome with detrimental effects at the individual patient and society levels ,2. OveraHF is characterized by a progressive course of disease accompanied by recurrent exacerbations leading to high hospitalization and rehospitalization rates, which account for a substantial part of the disease load ,13,14,15The pathophysiological process of ADHF incites days to weeks prior to the development of noticeable signs and symptoms ,26,27. IUnderstanding the time course of progression to ADHF, it has been hypothesized that interventions to achieve an euvolemic status prior to overt clinical manifestation may prevent HF exacerbation events ,32. Sevep = 0.032). There was no difference in mortality or HF admission between HTM and NTS, but the length of stay in the hospital was six days shorter for the HTM arm [In the Trans-European Network-Home-Care Management System trial (TEN-HMS), 426 patients with recent HF-related hospitalizations were randomized into three monitoring options: home telemonitoring (HTM), monthly nurse telephone support (NTS), or usual care (UC). Home telemonitoring  was reviewed by a care manager at a linked medical reference center to facilitate prompt intervention when needed. Patients randomized to HTM or NTS had significantly lower mortality rates at 240 days post hospitalization compared with UC  is a wearable necklace-shaped device that monitors electrocardiography (ECG) and calculates stroke volume, cardiac output, and thoracic fluid index (TFI) using chest bioimpedance. In a pilot study to predict HF events, 20 patients with New York Heart Association class I-IV HF symptoms underwent daily home monitoring with The CoVa™ Monitoring System. The TFI volatility, defined as the standard deviation of the TFI determined over five days divided by the average TFI over the same 5-day period, was recorded. This study showed an increase of ≥40% in TFI volatility before 100% of the HF events and an 8% reduction in stroke volume before 60% of ADHF events. These findings suggest that a multisensory system has the potential to predict HF hospitalizations .p = 0.01) reduction in 9 months rehospitalization in the ambulatory ReDS monitoring group [The Remote Dielectric Sensing (ReDS) vest , measures the lung fluid content using a focused electromagnetic beam similar to radar technology . When cong group .Whole-body bioimpedance (WBBI) allows the non-invasive measurement of body composition for the assessment of various clinical conditions. This technology works by sending a small electrical current throughout the entire body and measuring its impedance. WBBI was first introduced by Hoofer then revised by Nyboer and validated by Lukaski ,55,56,57This sensor uses the piezoelectric effect and converts changes in pressure into electrical signals . VibratiWe increasingly observe inflation in complex wearable monitoring devices . NumerouThe LINK-HF (Multisensor Non-invasive Remote Monitoring for Prediction of Heart Failure Exacerbation) multicenter study has examined the accuracy of a wearable multisensor remote monitoring patch  for the prediction of ADHF rehospitalization. This disposable patch is attached to the chest and is able to collect continuous ECG, skin impedance, body temperature, and activity level data. Utilizing artificial intelligence to generate a personalized baseline model-based alerts, the system forecasted ADHF with a 76% to 88% sensitivity and an 85% specificity . This stp = 0.013) [Cardiac implanted electronic devices (CIEDs) are indicated in numerous HF patients. Alongside the competence to monitor rhythm disturbances and sleep-disordered breathing, several studies have examined whether CIED’s remote monitoring capabilities could facilitate early warning of ADHF development. In the IN-TIME trial (implant-based multiparameter telemonitoring of patients with heart failure), HF treatment was modified according to home-monitored variations in the electrocardiogram, such as ventricular extrasystoles or tachyarrhythmias, and patient activity level. At one year of follow-up, 63 (18.9%) of 333 monitored patients vs. 90 (27.2%) of 331 in the control group developed the composite outcome of death, HF hospitalization, worsening NYHA class, or worsening self-assessment  . However= 0.013) .A unique feature of selected CIEDs is the capability to perform intrathoracic impedance monitoring, to some extent, similar to the non-invasive devices already described ,82. In tNotably, previous studies have demonstrated that an increase in filling pressure may precede HF decompensation by three weeks or even more . These fThe CardioMEMS   is a wirp = 0.0002) compared to the control group. No major complications related to the sensor implantation or any sensing failure were observed. During the entire follow-up period (mean of 15 months), the treatment group had a 37% reduction in HF-related hospitalizations compared with standard care alone [p < 0.0001) reduction in admissions for HF compared with the nonmonitored period [The CardioMEMS HF Sensor Allows Monitoring of Pressures to Improve Outcomes in NYHA Functional Class III Heart Failure Patients (CHAMPION) trial has investigated the use of CardioMEMS sensor implanted in the PA. Five hundred and fifty HF patients with NYHA Class III and a previous admission for HF in the prior year were recruited. On top of standard care and after implementing the CardioMEMS sensor in both groups, in the treatment group, physicians could monitor the PA pressure and adjust treatment accordingly, while in the control group, no PA pressure-guided adjustment of treatment was performed. After six months of follow-up, there was a significant reduction in hospitalization for HF in the treatment group ). The rate of all-cause hospitalization was also lower following sensor implantation , p < 0.0001)). Subgroup analyses including ejection fraction, sex, race, cause of cardiomyopathy, presence/absence of implantable cardiac defibrillator, or cardiac resynchronization therapy found no significant interaction between any of these variables and the prespecified outcomes, indicating consistent benefits on HF hospitalization using the CardioMEMS system in various patient cohorts [To assess the generalizability of the CardioMEMS system, a larger study involving 1200 participants was conducted, with a special focus on subgroup diversity defined by sex, race, and ejection fraction. The rate of HF-related hospitalizations was significantly lower after 12 months of follow-up compared with the year before implantation  0.43 . Importantly, the trial was conducted during the COVID-19 pandemic and prespecified COVID-19 impact analysis found significant improvement in the treatment group prior to the pandemic  [The recent 1022 participants, GUIDE-HF (hemodynamic-guided management of HF) trial tested if the benefits of PA monitoring extended beyond NYHA functional class III to patients with NYHA Functional class II and IV. The primary endpoint of all-cause mortality and HF hospitalization or unplanned hospital visit was not met in the hemodynamic-guided management compared to controls  .The Cordella System is another wireless PA pressure sensor. In one study, the Cordella device was implanted in 30 patients without complications or sensor failure. At 90 days, there was a mean difference of 2.7 mmHg between the Cordella sensor and Swan-Gantz catheter measurements  .Whereas CardioMEMS and other PA sensors measure right-sided pressures, left-side filling pressure measurements may provide additional important information regarding the patient’s tendency for pulmonary congestion. In animal models, an increase in left atrial (LA) pressure significantly correlated with pulmonary congestion, and reversal of pressure elevation resulted in normalization of lung permeability. In addition, many factors contribute to a mismatch between PA and LA pressure, including elevated pulmonary vascular resistance, advanced HF, acute HF, and pulmonary hypertension . These dThe HeartPOD  is a system that allowed direct LA pressure using an implantable sensor lead connected to a subcutaneous module. The sensor was implanted in the LA transvenously through the interatrial septum . In a laA novel LA pressure sensor that is currently being investigated is the V-LAP system . The V-LAP system is a wireless sensor that uses a MEMS pressure transducer and is implanted in the interatrial septum under angiographic and echocardiographic guidance . In precEarly detection and intervention in HF patients to prevent clinical HF decompensation and subsequent hospitalization may provide significant health and financial advantages. In contrast to previous monitoring methods, novel technologies have been developed to target the initial aspects of the pathophysiological cascade of HF decompensation. Invasive and non-invasive methods have remarkably advanced cardiovascular medicine, taking advantage of recent developments in MEMS, big data, artificial intelligence, and wearable sensors. There is a growing body of evidence supporting a potential clinical benefit from monitoring devices for the management of HF, mainly with PA pressure monitoring.


How did the volume and characteristics of patients initiating treatment for incident kidney failure change early in the COVID-19 pandemic, and were these changes associated with race, ethnicity, or socioeconomic status?In this cross-sectional study of 127 149 US adults with incident kidney failure during the first 4 months of the pandemic , the number of patients initiating treatment for incident kidney failure declined by 30%, with Black patients and patients living in counties with high COVID-19 mortality initiating treatment with significantly worse levels of kidney function when compared with prior years.These results suggest that declines in the number of patients with incident kidney failure may indicate delayed treatment initiation or changes in care delivery during the pandemic. This cross-sectional study examines the volume of US adults initiating treatment for incident kidney failure across racial, ethnic, and socioeconomic groups during the first 4 months of the COVID-19 pandemic. Persons with kidney failure require treatment  for survival. The burden of the COVID-19 pandemic and pandemic-related disruptions in care have disproportionately affected racial and ethnic minority and socially disadvantaged populations, raising the importance of understanding disparities in treatment initiation for kidney failure during the pandemic.To examine changes in the number and demographic characteristics of patients initiating treatment for incident kidney failure following the COVID-19 pandemic by race and ethnicity, county-level COVID-19 mortality rate, and neighborhood-level social disadvantage.This cross-sectional time-trend study used data from US patients who developed kidney failure between January 1, 2018, and June 30, 2020. Data were analyzed between January and July 2021.COVID-19 pandemic.Number of patients initiating treatment for incident kidney failure and mean estimated glomerular filtration rate (eGFR) at treatment initiation.P < .001) and initiating hemodialysis treatment with an arteriovenous fistula . The mean (SD) eGFR at initiation declined from 9.6 (5.0) mL/min/1.73 m2 to 9.5 (4.9) mL/min/1.73 m2 during the pandemic (P < .001). In stratified analyses by race/ethnicity, these declines were exclusively observed among non-Hispanic Black patients . There were significant declines in eGFR at initiation for patients residing in counties in the highest quintile of COVID-19 mortality rates , but not for patients residing in other counties. The number of patients initiating treatment for incident kidney failure was approximately 30% lower than projected in April 2020.The study population included 127 149 patients with incident kidney failure between January 1, 2018, and June 30, 2020 . Compared with the pre–COVID-19 period, in the first 4 months of the pandemic , there were significant decreases in the proportion of patients with incident kidney failure receiving preemptive transplantation (1805 [2.1%] pre–COVID-19 vs 551 [1.4%] during COVID-19; In this cross-sectional study of US adults, the COVID-19 pandemic was associated with a substantially lower number of patients initiating treatment for incident kidney failure and treatment initiation at lower levels of kidney function during the first 4 months, particularly for Black patients and people living in counties with high COVID-19 mortality rates. The early months of the pandemic disrupted the provision of health care services unrelated to COVID-19 infection, with widespread reductions in hospitalizations and office visits for both discretionary and emergent services.11 Additionally, the pandemic was accompanied by severe financial insecurity for low-income communities who disproportionately experienced loss of employment and health insurance coverage.13 This economic disruption exacerbated unmet social needs , which, among patients with CKD, are associated with more rapid declines in kidney function and faster progression to kidney failure.19For people with kidney failure, kidney replacement therapy—including dialysis and kidney transplantation—is essential for survival. For patients with chronic kidney disease (CKD), missed routine care could result in faster progression to kidney failure, suboptimal treatment initiation, or urgent dialysis initiation during a hospitalization without vascular access in place, all of which are more common among racial and ethnic minority (particularly Black) patients.To date, there has been little information about how the pandemic factors into initiation of kidney failure treatment and on the distribution of demographic characteristics of patients with incident kidney failure initiating treatment. We examined changes in the numbers and characteristics of patients with incident kidney failure initiating treatment between January 2018 and June 2020. We stratified analyses by race and ethnicity, county-level COVID-19 mortality rate, and neighborhood socioeconomic disadvantage.20 The CMS 2728 form is completed irrespective of insurance coverage, treatment modality, or citizenship, and includes detailed sociodemographic characteristics, clinical information, and patients’ primary mailing address. We geolocated incident patients to US Census block-groups using ArcGIS spatial mapping software version 10.5.1 (ESRI). Brown University’s institutional review board and the Centers for Medicare & Medicaid Services (CMS) Privacy Board approved the study protocol and waived the need for informed consent owing to use of deidentified data. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies.We conducted a cross-sectional time-trend study of the changes in the number of patients with incident kidney failure initiating treatment and estimated glomerular filtration rate (eGFR), a measure of kidney function, from March 1 to June 30, 2020. The study population included all patients who developed and initiated treatment for incident kidney failure—hereafter referred to as patients with incident kidney failure—from January 1, 2018, to June 30, 2020, and who lived in the 50 US states or the District of Columbia. We used data from the Renal Management Information System Medical Evidence Form (CMS 2728), a national census of all patients with incident kidney failure initiating long-term dialysis or receiving a preemptive kidney transplantation.22 To identify whether a patient lived in a county with high COVID-19 mortality, we used daily, county-level cumulative COVID-19 deaths and publicly available 2020 US Census Bureau annual county population estimates.24To determine neighborhood socioeconomic disadvantage, we linked the CMS 2728 data to the 2018 Area Deprivation Index (ADI) at the census block-group level. The ADI is an area-level measure of disadvantage based on 17 metrics of income, education, employment, and housing quality.28 We estimated the difference between observed and expected kidney failure incidence based on historical trends to capture changes in incidence associated with the COVID-19 pandemic.The primary outcomes were: (1) the monthly number of patients initiating treatment for kidney failure, which included both incident dialysis patients and those receiving preemptive kidney transplantation; and (2) eGFR at the time of treatment initiation. We calculated eGFR using serum creatinine values reported on the CMS 2728 using a modified Chronic Kidney Disease Epidemiology Collaboration formula excluding the race term.We also assessed changes in sociodemographic and clinical characteristics of patients with incident kidney failure. Sociodemographic characteristics included age, sex, race and ethnicity, health insurance coverage, and employment status. Race and ethnicity information was collected by the dialysis provider or transplantation facility based on patient self-report at treatment initiation and classified as non-Hispanic White, non-Hispanic Black, Hispanic/Latino, or other. Clinical characteristics included primary cause of kidney failure , treatment setting and modality , and, for hemodialysis patients, vascular access type (catheter or arteriovenous fistula).To stratify by neighborhood socioeconomic disadvantage, we identified individuals living in neighborhoods in the top quintile of ADI, which reflects economic conditions for populations living in the most disadvantaged neighborhoods. We calculated county-level COVID-19 mortality rates by dividing the number of COVID-19 deaths from March 1, 2020, through June 30, 2020, by the county’s 2020 annual estimated population. More information about data sources is presented in eTable 1 in the 2 tests to compare the sociodemographic and clinical characteristics of patients with incident kidney failure during the first 4 months of the COVID-19 pandemic (March to June 2020) to incident patients in the same 4-month time period in 2018 and 2019. We limited our comparisons to the same months before and during COVID-19 because of the seasonality of kidney failure incidence.29 We used t tests and Pearson χ2 tests to compare changes in eGFR, measured as continuous and categorical  variables, respectively. P values were 2-tailed and α < .05 was considered statistically significant.We used Pearson χ32To estimate the expected number of patients with incident kidney failure had the COVID-19 pandemic not occurred, we fitted a Poisson regression model using weekly counts of patients with incident kidney failure in the prepandemic period (January 2018 through February 2020), adjusting for linear time trend and seasonality using weekly fixed effects. We estimated counts of patients with incident kidney failure overall and separately for each racial or ethnic group. We then calculated change in kidney failure incidence during the pandemic, defined as the difference between the estimated and observed numbers of patients with incident kidney failure, and relative differences between estimated and observed patient counts. To assess disparities in the number of patients with incident kidney failure and kidney function at initiation, we stratified our analyses by patient race and ethnicity, residence in a county in the highest quintile of COVID-19 mortality rates, and residence in a socioeconomically disadvantaged neighborhood.P < .001), received a preemptive transplantation , and initiated hemodialysis treatment with an arteriovenous fistula . There were significant increases in the proportion of patients who were non-Hispanic Black , Hispanic/Latino , initiating with home dialysis , and initiating hemodialysis treatment with a catheter .In the pre–COVID-19 period (March through June of 2018 and 2019), 88 223 patients initiated treatment for incident kidney failure  . During P < .001) (P < .001) and significant increases in the proportion who were non-Hispanic Black.Among non-Hispanic White patients, there were significant increases in the proportion who had Medicare insurance (28 022 [59.9%] pre–COVID-19 vs 11 623 [61.2%] during COVID-19) and among Hispanic/Latino patients, there were significant increases in the proportion who were uninsured  . In the  < .001)  and coun < .001) , there w2, which declined to 9.5 (4.9) mL/min/1.73 m2 during the pandemic (P < .001) , with significantly more initiating treatment with eGFR lower than 5 mL/min/1.73 m2  , but no significant difference for patients residing in lower-COVID-19 counties. ( < .001) . Unlike  < .001) . There w < .001) . There wounties. .The substantial overlap between observed and estimated number of patients with incident kidney failure by week indicates that the Poisson model fit the data well and provides reliable estimates for the first 4 months of the pandemic  among Black patients with CKD.38Our findings suggest that during the pandemic patients with incident kidney failure initiated treatment with statistically lower eGFR levels than pre–COVID-19. The relationship between eGFR at treatment initiation, optimal timing of treatment initiation, and outcomes remains unclear, and some patients may initiate treatment earlier than is optimal. It is possible that the observed decline in eGFR is not clinically meaningful, although it will be critical to evaluate the long-term outcomes of individuals initiating treatment with lower eGFR levels during the pandemic. Furthermore, this decline was exclusively seen in non-Hispanic Black patients. The Chronic Kidney Disease Epidemiology Collaboration equation widely used to measure kidney function includes a modifier for Black race, thereby systematically raising eGFR for Black individuals by 16%.41 Other policy reforms to expand eligibility and access to social safety net programs  may mitigate unmet social needs and prevent disease progression.43Our study has several implications for policy and practice. First, it remains critical to maintain continuity of care and improve care delivery for people with CKD. For example, the Advancing American Kidney Health Initiative and CMS have prioritized increasing home dialysis and transplantation as a central strategy in improving kidney care. Improving access to care and reducing disparities for people with kidney disease are national priorities, but our findings suggest that the early months of the COVID-19 pandemic were associated with lower rates of treatment initiation for this high-risk population with social risk factors. Second, state and federal policies may play a critical role in dually reducing cost-related barriers to care and unmet social needs. For example, in states that have not done so, expanding Medicaid eligibility could facilitate access to care for low-income patients with incident kidney failure and reduce kidney failure incidence.Our study has several limitations. First, it is possible that data reported by dialysis facilities and transplantation clinics during the first half of 2020 is incomplete. Data after June 2020 were not available, and continued evaluation of changes in treatment initiation later into the pandemic is important. Second, our analysis is unable to examine specific mechanisms to explain reduced treatment initiation or account for the discontinuation of dialysis or competing risk of death, whether due to untreated kidney failure, COVID-19, or another cause. Third, because area-level population estimates are not yet available for 2020, we were unable to calculate changes in the rate of kidney failure incidence and instead modeled counts of incident patients.This cross-sectional study of US adults identified substantial declines in the number of patients with incident kidney failure initiating treatment in the first 4 months of the COVID-19 pandemic, and found patients initiated treatment with significantly lower kidney function. Initiation of kidney replacement therapy with worsened kidney function was particularly evident among Black patients and those living in counties with higher COVID-19 mortality rates. This suggests that the COVID-19 pandemic was associated with delayed treatment for kidney failure, a life-threatening condition that disproportionately impacts socially disadvantaged populations in the US. The implications of these findings for disparities in CKD warrant further investigation.