Elevated blood pressure (BP) is pervasive among patients that visit emergency departments (EDs) for their care.In this review article, we outline the current approach to the management of these individuals and highlight the crucial role emergency medicine clinicians play in reducing the morbidity associated with elevated BP.We highlight the critical importance of immediate treatment when elevated BP contributes to new or worsening end-organ injury but emphasize that such hypertensive emergencies are rare. For the vast majority of patients with elevated BP in the ED who do not have new or worsening end-organ injury from elevated BP, immediate BP reduction within the ED is not recommended or safe. Nonetheless, within weeks after an ED visit, there is a pressing need to improve the care of patients with elevated or previously undiagnosed hypertension. For many, it may be their only regular point of engagement with the healthcare system. To address this, we present novel perspectives that envision a new role for emergency medicine in chronic hypertension management—one that acknowledges the significant population-level gaps in BP control that contribute to disparities in cardiovascular disease and sets the stage for future changes in systems-based practice.Emergency medicine plays a key and evolving role in reducing morbidity associated with elevated BP. Of equal, if not greater importance, we then deliberate on assessment of patients with nonmarkedly elevated BP and the evolving, essential role that emergency medicine has in population-level hypertension management and in reducing long-term cardiovascular disparities that remain particularly pervasive in urban environments where poor BP control is common. We highlight our experience in Detroit, where hypertension directly contributes to a 1.5-fold increase in years of potential life lost due to heart disease in African Americans compared with non-Hispanic Whites under age 75 years.2–4 More than 145 million ED visits take place each year in the United States, and the estimated prevalence of elevated BP among these patients is close to 45%.5 In an analysis of 7 years of data from the Nationwide ED Sample (2006–2012), 165.9 million hypertension-related visits  occurred. During this same period, patients hospitalized declined while hypertension-related ED visits increased.6 Data from 2016 showed that approximately 1.2 million ED visits had a chief complaint of essential hypertension.7An estimated 33–50% of adults in the United States have hypertension, and approximately 41–50% of these adults do not have adequate BP control.9 Accordingly, nearly all patients that emergency clinicians see in the ED with elevated BP, including markedly elevated BP , are not experiencing an emergency that requires immediate intervention. Despite this, there is often an expectation on the part of patients and other providers, who send their patients to the ED based on a perceived acute risk associated with markedly elevated BP, that something will (or should) be done. Such expectations lead to wide variation in practice patterns.Based on their training, emergency medicine clinicians naturally focus on the identification and management of hypertensive emergencies for those patients with elevated BP. These critical conditions require rapid evaluation and treatment; however, such patients are rare overall, accounting for <2% of ED visits where high BP is noted.10Furthermore, existing guidelines provide few recommendations as to the management of those with markedly elevated BP absent a hypertensive emergency, leading to questions on who warrants diagnostic testing to look for end-organ injury, how much acute pain or anxiety may contribute to BP in the ED, when initiation or titration of antihypertensive medications is indicated, or how to manage patients with no reliable outpatient follow-up. Emergency clinicians continue to use outdated and incorrect diagnoses such as “hypertension urgency,” a term that implies the need for “something” to be done in the ED setting, despite lack of sound basis in the literature, including current international guidelines.12 Nevertheless, lower thresholds can be associated with hypertensive emergencies in the setting of rapid elevations from low-to-normal baseline BP. Furthermore, BP elevations >170/100 mm Hg can cause worsening target-organ injury in select patients. Elevated BP values in isolation, no matter how high they may be, do not by themselves define a hypertensive emergency unless the patient has concomitant acute organ injury for which immediate BP lowering will modify this injury. Thus, terms such as “hypertensive crisis,” which have been historically assigned to all patients with markedly elevated BP have little utility in contemporary practice. New or worsening end-organ injury occurs in the cerebrovascular, cardiovascular, ophthalmologic, hematologic, and renovascular systems.13 The most common hypertensive emergencies are stroke (ischemic and hemorrhagic) and acute heart failure leading to pulmonary edema. Hypertensive encephalopathy is a rare and poorly understood condition that may reflect direct adverse acute effects of markedly elevated BP on the brain.Hypertensive emergencies classically occur in patients with systolic BP (SBP) >220 mm Hg and/or diastolic BP (DBP) >120 mm Hg.14 Thus, while all hypertensive emergencies should be managed with intravenous (IV) antihypertensive therapy to achieve immediate BP reduction, few patients require such intervention. Beyond hypertensive emergency, IV antihypertensive therapy is only indicated for select patients with strict oral medication restrictions and patients abruptly withdrawing from beta-blockade or sympatholytic therapy. These latter patients may benefit from IV labetalol. Given the aforementioned variability in clinical practice, it is not surprising that the majority of IV medications given to achieve immediate BP reduction in the ED are done so inappropriately to patients without new or worsening end-organ injury that can be modified by rapid treatment.15Most ED patients with SBP ≥180 mm Hg or DBP ≥110 mm Hg have elevated BP without evidence of end-organ injury. These patients have no immediate indication for rapid BP lowering. Though a common concern among ED providers, hypertensive emergency is rare in patients with elevated BP in the ED.8 For time-sensitive conditions such as acute ischemic stroke, rapid BP lowering may be indicated when BP exceeds 185/110 mm Hg and thrombolytic or endovascular treatment is planned.16 Most acute ischemic stroke patients, however, are not candidates for thrombolytic or endovascular therapy, and BP lowering should be avoided. The ischemic penumbra lacks autoregulation of cerebral blood flow and is dependent on systemic perfusion pressure such that acute lowering may worsen ischemia.While specific symptoms such as acute dyspnea associated with hypertensive heart failure or chest pain concerning for an acute aortic syndrome may prompt immediate treatment before a full diagnostic evaluation, symptoms alone do not define hypertensive emergencies, and ongoing IV antihypertensive treatment should depend on additional diagnostic tests that confirm acute organ injury. For the large majority of ED patients, presenting clinical features are too nonspecific to prompt immediate IV antihypertensive therapy without confirmatory testing. 17 Likewise, biomarkers of cardiac injury (troponin) and stress (natriuretic peptides) should be obtained for patients with concurrent shortness of breath or chest pain, with the addition of computed tomography angiography of the thorax and abdomen when an acute aortic syndrome is suspected.Specific tests are indicated for all patients with suspected hypertensive emergency including a basic metabolic profile, complete blood count, urinalysis, electrocardiogram, and chest x-ray. Further workup of patients with markedly elevated BP should be symptom-based and aligned with each associated condition’s differential diagnosis. 17–19 Blood flow to cerebral, renal, and other vascular beds is tightly autoregulated to maintain constant perfusion,20 but this autoregulation becomes overwhelmed at extreme elevations in BP. Each individual’s BP threshold for a loss of autoregulation, however, is dependent on adaption of their vascular beds. In the typical normotensive patient, the brain maintains constant cerebral flow over a mean arterial pressure (MAP) range from 50 to 160 mm Hg.21 In patients with chronically elevated BP, the autoregulatory system shifts to the right to accommodate a persistently greater pressure load, leading to a higher set-point, which can far exceed an SBP of 220 mm Hg or MAP of 160 mm Hg. Because of the adaptation to chronically elevated BP, most thresholds and targets for treatment should be tailored to each patient. Published thresholds apply to large populations and are based upon expert opinion.Among the diagnoses encompassing the broader grouping of hypertensive emergencies, hypertensive encephalopathy represents the purest form of acute vascular injury from markedly elevated BP. In conditions such as intracerebral hemorrhage and aortic dissection, there is a critical need for immediate BP reduction, but their etiologies are not directly related to a loss of vascular autoregulation. In hypertensive encephalopathy, BP exceeds limits of autoregulation and directly injures the vascular endothelium, leading to cerebral vasodilation and retinal injury often accompanied by glomerular injury and thrombotic microangiopathy.17 Besides alterations in mental status, these patients often have seizures and visual changes.22 Imaging findings, which typically require magnetic resonance imaging to detect, include vasogenic edema in the posterior brain, especially in the occipital–parietal regions.23 Despite its distinct diagnosis, posterior reversible encephalopathy syndrome and general hypertensive encephalopathy share the same treatment strategy of rapid BP lowering with IV agents.With the advent of magnetic resonance imaging, a specific subset of hypertensive encephalopathy known as posterior reversible encephalopathy syndrome has emerged as an important diagnosis. While other etiologies for posterior reversible encephalopathy syndrome exist, such as renal disease, immunosuppressive therapy, erythropoietin use, and thrombotic thrombocytopenic purpura, acute, elevated BP is by far the most common cause.13 Following the ED management, inpatient BP reduction aims to reach a normal range gradually within 24–48 hours. For individual disease processes, additional guidelines exist to tailor BP management, and the optimal BP goal for immediate intervention may be greater than 25% of MAP. 24–27 Notably, we do not suggest the use of diuretics for emergent BP treatment. The BP-lowering effect of diuretics is unpredictable, and patients with hypertensive emergencies do not routinely have hypervolemia. The existing literature does not provide sufficient evidence to show that any specific IV antihypertensive agent is superior to another, though the dihydropyridine agents (nicardipine and clevidipine), as well as labetalol, are preferred agents in the setting of neurological hypertensive emergencies.28Current treatment for patients with hypertensive emergencies involves rapid BP reduction to reverse new or worsening end-organ injury and preventing further damage. The American College of Cardiology and the American Heart Association Task Force in their 2017 guidelines recommend reduction of the MAP by 25% within the first hour of treatment. This recommendation is based on evidence that the baseline right-shift in the cerebral autoregulation curve with chronic hypertension is understood to reset approximately 25% above the average MAP. However, it is important to remember that with acute BP elevation, an individual with a hypertensive emergency may be able to withstand greater BP drops as they are on the ascendant portion (as opposed to the plateau) of the autoregulation curve. In general, carefully titrated IV antihypertensive medications are the preferred initial treatment approach in order to limit the risk of cerebral hypoperfusion that may be caused reducing BP too quickly. Over the next 2–6 hours, further BP reduction should occur with the goal SBP 160 mm Hg and DBP 100–110 mm Hg.6 In 2012, just over 1 million ED visits had a primary diagnosis of hypertension, and almost 27 million ED visits were hypertension related.6 Thus, appropriate recognition and management of nonemergent BP elevations for patients with and without diagnosed hypertension should be a core function of emergency medicine clinicians.While hypertensive emergencies are rare, ED encounters with elevated BP are common and represent valuable opportunities to recognize and address chronic hypertension, particularly among difficult-to-reach patient populations. ED visits related to hypertension rose more than 5% annually from 2006 to 2012.33–36 Elevated SBP and DBP in the ED are both risk factors for incident cardiovascular disease, and the risk rises in a step-wise, dose-dependent fashion with increasing ED BP. The number needed to screen to prevent a single cardiovascular event was 151, but that decreases to 71 among patients with ED BP ≥140/90 mm Hg in the ED. ED BP is particularly informative when measured more than an hour after ED arrival and when it remains elevated over repeated measures,38 but even triage BP provides important information despite the potential for measurement error due to cuff size and patient positioning. Among ED patients discharged with home BP monitors, more than 88% of patients with a single ED triage BP ≥160/100 mm Hg had a mean home BP ≥135/85 mm Hg.39 Another 46% of patients with elevated BP in the ED met criteria for hypertension in follow-up based on home BP monitor, and it is notable that ED physician gestalt was less accurate than mean ED BP for elevated post-ED BP.40One of the primary issues that affect the management of nonemergent BP elevations in the ED is uncertainty around measurement accuracy. BP measurements over minutes to hours using appropriate cuff size and patient positioning can provide valuable information regarding BP variability, range, and trajectory, which can supplement clinic and home BP measurements to guide hypertension diagnosis and medication titration. Multiple studies have shown that BP remains elevated after ED discharge for many patients, and even when BP decreases after ED visits, it does not reach normotension.41–44 Thus, elevated BP in the ED should not be discounted or explained away by false attribution to pain or anxiety. Given that BP variability is a marker of vascular disease,46 patients with even temporarily elevated BP in the ED may be at increased cardiovascular risk and therefore benefit from future cardiovascular screening. Long delays in achieving BP control increase the risk of a major adverse cardiovascular event and death,47 and younger patients with less elevated BP stand to gain the most benefit from antihypertensive therapy.48Multiple studies have found no evidence for a relationship between ED BP and pain or anxiety.49–51 Therefore, instead of focusing on immediate BP reduction to “treat numbers,” the goals of ED care for asymptomatic elevated BP are to: (i) assess for new or worsening end-organ injury and confirm lack of hypertensive emergency,52 (ii) evaluate risk for persistently elevated BP after ED discharge (which is more likely in patients with persistently elevated BP over repeated measures performed using appropriate cuff size and patient positioning) with consideration of antihypertensive medication prescriptions for those unlikely to successfully follow-up, particularly patients without an established primary care relationship, and (iii) communicate findings with patients and, for those with an existing primary care relationship, with their clinicians with a goal of assuring close outpatient follow-up for repeat BP measurement and possible medication adjustment. Though somewhat more controversial given the nature of the specialty, emergency medicine clinicians may consider briefly addressing lifestyle changes, diet, and exercise, along with medication titration or new initiation of BP-lowering therapy as appropriate.There are no evidence-based thresholds at which asymptomatic but markedly elevated BP in the ED benefits from immediate reduction. While it is important to recognize elevated BP in the ED, rapid BP reduction can cause significant harm by impairing cerebral blood flow, and it has not been shown to improve clinical outcomes except in hypertensive emergencies.53 However, given the lack of any evidence that additional testing improves diagnostic accuracy beyond history and physical exam, performing such testing routinely in the ED testing is not recommended other than to facilitate other aspects of clinical care, especially new medication initiation.54Whether or not an assessment for end-organ injury should be pursued is also a matter of controversy. This can be accomplished in most instances by history and physical exam. Fundoscopic examination is an important component of the physical exam to detect pressure-related target-organ injury such as papilledema, cotton wool spots, hemorrhages, and exudate. Detection and documentation of less severe but established hypertensive retinopathy confirms that BP is likely chronically elevated, which is important information to share with patients. When uncertainty regarding target-organ injury remains, laboratory testing, electrocardiogram, and/or chest x-ray can be helpful.55 Therefore, recommendations for patients in clinic are generalized to the ED, with an emphasis on close outpatient follow-up, need for BP reassessment in 1–2 weeks by a primary care provider, and need to assess electrolytes in 1–2 weeks for patients prescribed an angiotensin-converting enzyme inhibitor or thiazide diuretic. There are no guidelines regarding optimal prescription duration in the ED setting. As in clinic settings, ED treatment should include guidance on lifestyle and medication adherence as well as risks, benefits, side effects, dosing frequency, and anticipated costs. First-line agents include thiazide diuretics, angiotensin-converting enzyme inhibitors, and calcium antagonists.10 For ED prescribing, dihydropyridine calcium antagonists are the safer calcium antagonists to prescribe, particularly in older patients and those with severe hypertension that may have undiagnosed ventricular dysfunction. Dihydropyridine calcium antagonists also are advantageous as they can be used with beta-blockers, whereas nondihydropyridine calcium antagonists should not be used. Other important prescribing considerations include patient age, sex, comorbid conditions, current medications, and preferences regarding side effect profiles. For example, older patients with clinical signs of edema or increased intravascular volume may benefit most from a diuretic, and evidence suggests that young Caucasian patients may respond best to an angiotensin-converting enzyme inhibitor as monotherapy.56BP medications can be safely started or titrated in the ED, although there are currently no ED-specific guidelines.10 Recommended treatment is a combination drug therapy with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker combined with a calcium channel blocker or thiazide diuretic.58Another important consideration is race in antihypertensive medication selection. African American patients have higher risk of treatment resistant hypertension and are more likely to require more agents for adequate control. To this end, current guidelines promote the use of dual drug antihypertensive drug therapy.10 Additionally, clinicians should consider factors such as poor primary care follow-up, geriatric patients, or patients at greater risk for adverse outcomes from elevated hypertension such as African American patients in making ED prescribing decisions. Prescribing antihypertensive medication in the ED setting is effective and can be done safely.55 Additional resources include mobile health follow-up and engagement, home BP monitor, and community health workers.59–61Our recommendations are consistent with the 2013 American College of Emergency Physicians’ (ACEP) clinical policy which, based on expert opinion and panel consensus, states that in order to gradually lower BP and/or facilitate chronic BP management, “emergency physicians may choose to initiate hypertension treatment for markedly elevated BP” (defined as SBP ≥180 mm Hg and/or DBP ≥110 mm Hg based on expert opinion). The 2017 ACC/AHA guidelines similarly note that prompt management of very high BP is important to limit the risk of target-organ damage.10 adds to the importance of identifying and addressing elevated BP in the ED, particularly for ED patients without access other sources of care.62 While there is considerable evidence linked to long-term outcomes that guide non-ED assessment and management of nonemergent BP elevations, evidence to inform ED care is still evolving. The 2013 ACEP clinical policy writing group articulated this noting significant gaps in evidence regarding ED hypertension screening, management of nonemergent elevated BP, antihypertensive medication initiation or titration, and timing of follow-up to improve short- and long-term outcomes while minimizing risks of adverse events.The 2017 ACC/AHA guidelines revising the diagnosis threshold for hypertension and goal BP to 130/80 mm Hg among high-risk patients63 For patients with BP 130–139/85–89 mm Hg, ESC/ESH guidelines recommend lifestyle change and consideration of drug treatment, particularly if patients have high cardiovascular risk. For patients ≤80 years who have BP ≥140/90 mm Hg, drug treatment is indicated. For patients >80 years, ESC/ESH guidelines recommend drug treatment for SBP ≥160 mm Hg. If patients tolerate treatment to maintain BP <140/90 mm Hg, further lowering targets a DBP <80 mm Hg and SBP based on age . For patients with known coronary artery disease, therapy is targeted to maintain BP <130/80 mm Hg.63 Both guidelines have similar recommendations for BP measurement, lifestyle modifications, and recommended medications. Both recommend strong consideration for single-pill combination antihypertensive medications.64While the ACC/AHA guidelines have traction in the United States, the 2018 European Society of Cardiology (ESC)/European Society of Hypertension (ESH) guidelines have noted differences in defining hypertension and targets for treatment. The ESC/ESH guidelines define hypertension as ≥140/90 mm Hg and target treatment based on age and risk.65 the role of ED care in hypertension and other chronic conditions EDs must evolve to meet these needs.66 More than individual patient care, the ED can play an important role in population health through identification of undiagnosed hypertension and recognition of uncontrolled hypertension, particularly for patients without reliable access to primary care, many of whom are underinsured or racial minorities.62 Hypertension affects more than half of all non-Hispanic black adults in the United States, with greater severity and earlier onset than in other populations.67 Hypertension is the most important risk factor for cardiovascular disease among non-Hispanic black adults in the United States, with a more than 30% population attributable risk for cardiovascular disease and 69% population attributable risk for stroke for those less than 60 years of age.53 In this age group, a patient’s stroke risk triples for each 10 mm Hg increase in SBP.53 Because every patient who presents to the ED has a BP obtained, there is significant opportunity to intercede and reduce risk. However, nothing exists in isolation, and to be effective, hypertension-related initiatives in the ED must be part of a bigger, systems-based effort aimed at improving outcomes. Much like the success of human immunodeficiency syndrome screening efforts from the ED, one can easily envision population health programs that seek to capture patients with elevated or undiagnosed hypertension in the ED and ensure effective linkage to care through directed referral and set appointments. With the support of the Centers for Disease Control and Prevention, such efforts are already underway in EDs located in Detroit and involve, among other things, community health workers who serve to engage patients and provide care continuity beyond the index encounter.As outpatient visits for primary care continue to decline, and hypertension-related ED visits continue to rise,10 Understanding the anticipated BP-lowering effect using tools like the therapeutic intensity score can be used to give providers feedback regarding their prescribing practices and help guide emergency medicine clinicians who seek to do more than simply refer patients on to the next station of care.68 The therapeutic intensity score provides a quantifiable estimate of the anticipated impact of antihypertensive therapy, particularly in the setting of multiple antihypertensive medications.As mentioned, initiation and titration of antihypertensive therapy can be done from the ED, but there is reluctance to do so on the part of emergency medicine clinicians. Yet, this is a relatively simple and potentially highly effective strategy that ED clinicians can use to improve the BP control of their patients. It is also a simple strategy to overcome clinical inertia or the “bystander effect.” The 2017 ACC/AHA guidelines recommend maximizing the dose of antihypertensive medication and then adding addition medication.With the steady increase in ED visits and the high proportion of patients with elevated BP, the opportunity for recognition and interventions is shifting from the realm of outpatient medicine and becoming incorporated into the practice of emergency medicine. These opportunities require emergency medicine physicians to be familiar with the definitions of hypertension, the distinction between nonemergent hypertension and hypertensive emergencies, and the treatment for all BP elevations. The ED can serve as a critical partner in systems-level efforts to reduce the morbidity associated with poor hypertension control, particularly in underserved communities.


Background: Tacrolimus is routinely monitored using trough concentrations, however, recent data have suggested that area under the curve (AUC) provides better correlation with toxicity and efficacy. Area under the curve is cumbersome to measure, but studies have demonstrated that surrogate time points such as 2-hour concentrations are well correlated with AUC. Methods: This is a single center, retrospective study of adult kidney transplant recipients with 2-hour tacrolimus concentrations measured over three years post-transplant. The primary outcome was to determine the difference in serum creatinine (Scr) in those with 2-hour tacrolimus concentrations greater than 20 ng/mL versus those less than or equal to 20 ng/mL. Results: A total of 150 kidney transplant recipients were included. The mean Scr and glomerular filtration rate were 1.49 ± 1.01 mg/dL and 59 ± 23.2 mL/min/1.73 m2, respectively, for the entire cohort. The rate of donor specific antibody formation was 2% and 8% experienced biopsy-proven rejection. The rate of cytomegalovirus viremia was 2% and BK viremia was 13%. There was no significant difference in kidney function over 36 months for the groups specified a priori. Conclusions: Long-term outcomes of maintaining tacrolimus 2-hour concentrations over 20 ng/mL is favorable with minimal opportunistic infections. Tacrolimus (FK) is a calcineurin inhibitor most commonly used in immunosuppressive regimens after kidney transplantation . It has At our institution, we have implemented routine trough and C2 therapeutic drug monitoring for immediate-release tacrolimus. The bioavailability of tacrolimus is low, ranging from 17–23% [This is a single center, retrospective, observational cohort study of adult kidney transplant recipients at the University of California San Diego Health System between 2009 and 2012. Patients met the inclusion criteria if they were 18 years or older, kidney transplant recipients, and were receiving immediate-release tacrolimus for immunosuppression. Patients were excluded from this study if they were multi-organ transplant recipients, re-transplant recipients, receiving cyclosporine, sirolimus, or employing calcineurin minimization strategies. This study was approved by the institutional review board on 16 September 2014 for project #140932X. The standard of care at UC San Diego Health System is for all patients to receive thymoglobulin induction, unless patients have concurrent hepatitis C (HCV) or human immunodeficiency virus (HIV) infection. Patients are stratified into the high risk group as opposed to the low risk group if the patient had any of the following criteria: panel reactive antibodies (PRA) ≥20%, positive donor specific antibodies (DSA), if kidneys are from donors after cardiac death (DCD), if delayed graft function (DGF) or slow graft function (SGF) is observed, or if the patient is African American. Patients are initiated on immediate-release tacrolimus at 0.1 mg/kg/day, which is administered in a fasting state, starting on post-operative day 0 up to day 3, depending on their risk level. Patients had a target trough of 10–13 ng/mL from days 0–45, tapered down to 8–10 ng/mL thereafter. If patients were deemed to be high risk, a higher trough target of 13–16 ng/mL was used from days 0–45, tapered down to 10–13 ng/mL from days 45–90, then further tapered down to 8–10 ng/mL thereafter. The in-house tacrolimus assay used during the time of the study was a chemiluminescent micro particle immunoassay.Methylprednisolone is initiated during surgery, and gradually tapered, as described in our protocol. Mycophenolate is initiated prior to discharge. Cytomegalovirus (CMV) risk is stratified based on the donor and recipient CMV serostatus and type of induction agent used. Valganciclovir prophylaxis is prescribed for six months if high risk, three months if moderate risk, and acyclovir is prescribed for three months if low risk. Surveillance for CMV includes monitoring polymerase chain reaction (PCR) every 3–6 months thereafter as needed. BK viremia is monitored monthly until three months and then on an as needed basis. Patients are counseled and educated on the importance of taking tacrolimus on an empty stomach as well as the need for them to have both a tacrolimus trough and C2 drawn on the same day. Laboratory staff are trained to draw the tacrolimus trough, and advise patients to return for the tacrolimus C2 90–120 minutes after they have taken their dose. The following variables were collected at baseline (at time of discharge from transplant admission): age, gender, race, date of transplant, type of transplant (living or deceased donor), comorbidities prior to transplantation, indication for kidney transplant, and type of induction therapy received at time of transplant. Additional variables were collected at baseline and at six month intervals up to 36 months: weight, serum creatinine (Scr), urine protein to creatinine ratio (UPC), BK PCR, CMV PCR, tacrolimus daily dose, trough concentrations, C2, prednisone (Pred) dose, mycophenolate (MMF) dose, and whether the patient was receiving any cytochrome P450 inhibitors or inducers . If a trough and/or C2 concentration was not available at the exact time point, the closest trough and/or C2 concentration around that time point was used. If none were available, then the data point was omitted. If the patient underwent a biopsy , the biopsy date, biopsy result, Scr, tacrolimus dose, trough concentration, and C2 prior to biopsy were collected. If DSA was measured, the date and result were collected. Glomerular filtration rate (GFR) was estimated using the CKD-EPI Creatinine Equation . The priFor the primary analysis, the Scr was compared between patients with tacrolimus C2 greater than 20 ng/mL and those with tacrolimus C2 less than or equal to 20 ng/mL. Based on a previous study from our institution, the average Scr value at one-year post transplant was 1.48 ± 0.49 mg/dL . In ordeDuring the study period, a total of 254 patients were screened, and 150 patients met the inclusion criteria with approximately 50% of subjects having follow up at three years .Baseline demographics are shown in A summary of the immunosuppression regimen is listed in Over the first 12 months, the majority of C2 concentrations were greater than 20 ng/mL 72–89%, . After tKidney function in terms of SCr for the respective tacrolimus C2 groups are shown in The overall rate of DSA formation was low and is summarized in A summary of the opportunistic infections is listed in 2 with a rate of decline of approximately 1 mL/min/1.73 m2 per year.The primary objective of our study was to determine if patients receiving higher levels of immunosuppression as defined by a tacrolimus C2 greater than 20 ng/mL had improvements in kidney function over a 3-year period. We were not able to detect a statistically significant difference in kidney function between the groups. However, we found overall that our cohort of patients had a low rate of antibody formation, acute rejection, and incidence of CMV viremia, while the incidence of BK viremia was similar to the national averages. The 3-year graft function was good, as measured by an average SCr of 1.49 mg/dL and GFR of 59 mL/min/1.73 mA higher proportion of patients had C2 concentrations >20 ng/mL, reflecting adequate absorption likely a result of fasting administration of tacrolimus. Studies have found that co-administration of tacrolimus with food can result in a decrease in Cmax ranging from 65–77%.  TacrolimAlthough early pharmacokinetic studies of tacrolimus suggested that trough concentrations may be predictive of toxicity and efficacy ,4,5,6, lThe national average incidence of rejection post-transplant is approximately 10% at 12 months and 16–18% at 36 months, depending on whether the kidney transplant was from a deceased or live donor ,24. Our Improved tacrolimus exposure through increased AUC/drug levels might increase incidence of calcineurin-inhibitor (CNI) toxicity and opportunistic infections. National average rates of CNI toxicity are difficult to compare, as most studies assessed CNI toxicity rates of both cyclosporine and tacrolimus combined. We documented a low rate of CNI toxicity, 3.8%, for subjects who had for cause kidney biopsies. The incidence of CMV viremia was shown to be approximately 5.8% in kidney transplant patients with a mean follow up of 33.6 months in one study , and appAlthough the addition of C2 monitoring may have slight increases in cost and complexity for patients, based on our results, it allows for increased immunosuppression without added risk of CNI toxicity or opportunistic infection, suggesting the utility of such a monitoring strategy.There are several limitations of this study. The study was retrospective and observational in nature, describing standard of care treatment. Patients may have obtained their C2 or trough level at the incorrect time point, though our patients and laboratory staff have been well trained to minimize this source of error. The number of C2 concentrations reported for each patient was less than expected with attrition leading to loss of power to detect a difference in kidney function. Additionally, the C2 concentration of 20 ng/mL was used based on prior pharmacokinetic studies, suggesting a peak to trough ratio of 2, however, we did not specifically evaluate other C2 concentrations as measures of efficacy. Immunosuppression was individualized in this study. Measurement of C2 concentrations and DSA as well as the decision to perform a kidney biopsy were done for cause rather than per protocol. Our findings are biased, since higher risk patients had more interventions made. Contamination bias may have been introduced if patients switched between immunosuppression profiles at different time points . Laboratory measurement errors from interferences and lot-to-lot variability of the immunoassay used may also affect the accuracy of the measurement. Finally, attrition of patients may have introduced bias in either direction, data may be reflective of survivors or adherent patients or alternatively, subjects at greater risk who were followed more closely. Of note, the results found in this study apply to the immediate-release version of tacrolimus only. There are currently two other formulations of tacrolimus on the market, tacrolimus extended-release capsules  and tacrolimus extended-release tablets , also known as LCP-Tacro ,31,32. TFurther studies are warranted to examine the relationship between monitoring tacrolimus using combined C2 and trough concentrations and graft outcomes in larger samples and additional transplant populations.Tacrolimus 2-hour concentrations greater than 20 ng/mL were not associated with an improvement in long-term graft outcomes. However, many patients were able to achieve these 2-hour concentrations without increased risk of CNI toxicity or opportunistic infection. Further research is required to determine the appropriate target 2-hour concentration to optimize long term graft outcomes.


Hospital integration among rural districts to concentrate medical resources is one of the main projects of the Japanese government. In advance of this, we experienced hospital integration and screening for chronic kidney disease as definitive risk for end‐stage kidney disease and cardiovascular mortality. After that, high‐risk patients have been appropriately referred from generalists to nephrologists and/or cardiologists without acute deterioration of renal function or cardiac sudden death. Consequently, the concentration of medical resources among such districts is recognized as a major project of the government, which recently designated hospitals for integration.Chronic kidney disease (CKD) is a definitive and common risk factor for not only development of ESKD and requiring chronic dialysis, but also cardiovascular and all‐cause mortality.2 to more than 30 mL/min/1.73 m2. If a subject did not have AKI, he or she was regarded as possibly having CKD.Along with hospital integration in April 2019, we developed a screening system using electronic medical records and establish an algorithm to detect CKD. Among retrospectively obtained data from April 2018 to December 2019, 61 588 creatinine measurements and 40 973 dipstick proteinuria tests were performed in 12 335 men and 9756 women with a mean age of 48 ± 23 (±SD) years. Each participant's worst results for estimated glomerular filtration rate (eGFR) and proteinuria were evaluated. The sequential data from individual patients sometimes contained transient elevations of serum creatinine. CKD is diagnosed based on reduced eGFR persisting for 3 months.2 that is CKD stage 4 or worse  and publicly registered at UMIN‐CTR (#UMIN000039020). Serum creatinine levels were measured as part of routine clinical practice and health check‐ups in Kamisu Saiseikai Hospital, not specifically for this clinical research.1https://www.mhlw.go.jp/content/10800000/000551037.pdf. Accessed June 1, 2020.Website Available from: 2BelloAK, HemmelgarnB, LinM et al Impact of remote location on quality care delivery and relationships to adverse health outcomes in patients with diabetes and chronic kidney disease. Nephrol Dial Transplant. 2012;27(10):3849–55.227593853GoAS, ChertowGM, FanD, McCullochCE, HsuCY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351(13):1296–305.153856564LeveyAS, de JongPE, CoreshJ et al The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int. 2011;80(1):17–28.211508735ChenTK, KnicelyDH, GramsME. Chronic kidney disease diagnosis and management: a review. JAMA. 2019;322(13):1294–304.31573641Figure S1Click here for additional data file.Supplementary MaterialClick here for additional data file.


Our aim was to conduct a post participation survey of respondent experiences with in-home remote patient monitoring via telehealth for blood pressure monitoring of women with postpartum hypertension. We hypothesized that the in-home remote patient monitoring application will be implemented with strong fidelity and have positive patient acceptability.This analysis was a planned secondary analysis of a non-randomized controlled trial of telehealth with remote blood pressure patient monitoring for postpartum hypertension compared to standard outpatient monitoring in women with a hypertension-related diagnosis during pregnancy. In collaboration with survey experts, we developed a 41-item web-based survey to assess 1) perception of quality of care received, 2) ease of use/ease to learn the telehealth program, 3) effective orientation of equipment, 4) level of perceived security/privacy utilizing telehealth and 5) problems encountered. The survey included multiple question formats including Likert scale responses, dichotomous Yes/No responses, and free text. We performed a descriptive analysis on all responses and then performed regression analysis on a subset of questions most relevant to the domains of interest. The qualitative data collected through open ended responses was analyzed to determine relevant categories. Intervention participants who completed the study received the survey at the 6-week study endpoint.Sixty six percent of respondents completed the survey. The majority of women found the technology fit easily into their lifestyle. Privacy concerns were minimal and factors that influenced this included age, BMI, marital status, and readmissions. 95% of women preferred remote care for postpartum follow-up, in which hypertensive type, medication use and ethnicity were found to be significant factors in influencing location of follow-up. Most women were satisfied with the devices, but rates varied by hypertensive type, infant discharge rates and BMI.Postpartum women perceived the telehealth remote intervention was a safe, easy to use method that represented an acceptable burden of care and an overall satisfying method for postpartum blood pressure monitoring.ClinicalTrials.gov identification number: NCT03111095 Date of registration: April 12, 2017. Hypertensive disorders are one of the most common complications of pregnancy in the United States. Approximately 10% of pregnancies are affected nationwide . While gBlood pressure (BP) decreases within 48 h following delivery and increases 3–6 days postpartum , 4, 5. TACOG defines telehealth as “technology-enhanced health care framework that includes services such as virtual visits, remote patient monitoring, and mobile health care.”  This tecThe objective of this study is to assess patient perspectives and experiences regarding daily postpartum blood pressure monitoring via telehealth with remote patient monitoring. Of great contribution to this study is the self-administered questionnaire (SAQ). It is more detailed than previous studies which have evaluated patient’s perspectives and experiences regarding remote monitoring for postpartum hypertension. Additionally, at the time of our study there was no validated survey to evaluate areas of interest related to remote monitoring. This survey was designed to ascertain overall opinions and to also specifically query, burden of care, ease of use and satisfaction separately. Furthermore, this is the first study to our knowledge which will analyze patient opinion by hypertension type, healthcare utilization, medication use and infant/maternal factors. In turn, this SAQ has the potential to guide future survey studies for telehealth with remote patient monitoring for blood pressure monitoring of women with postpartum hypertension. Last, the questionnaire could also be useful for investigators in other specialties who are studying remote patient monitoring for blood pressure surveillance, if adapted to reflect their study.Our hypothesis was that intervention participants would find the remote blood pressure monitoring equipment to be easy to use, a secure way to submit health data, not overly burdensome and an overall satisfying way to receive postpartum care of their hypertension.We conducted a cross-sectional, post-participation web-based survey study to assess 1) perception of the quality of care received, 2) ease of use/ease to learn the telehealth program, 3) effective orientation of the equipment, 4) level of perceived security/privacy utilizing telehealth and 5) problems encountered using the health equipment devices.Inclusion criteria for the parent intervention study and subsequently this survey were women admitted for delivery of their neonate with any of the following hypertensive diagnoses: chronic hypertension, gestational hypertension, preeclampsia or eclampsia. At six-weeks postpartum the study equipment was returned and an online self-administered questionnaire (SAQ) was distributed to each intervention participant who had completed the study. The SAQ was sent to the email address they had identified at time of enrollment through Qualtrics Survey Service . Participants received a package of diapers at enrollment as well as a $15 gift card at the conclusion of the intervention study period at 6 weeks postpartum. Participants provided written informed consent. The study was approved by the University of Wisconsin Institutional Review Board (IRB # 017–003 approved 03/21/2017).All methods were performed in accordance with the relevant guidelines and regulations (Declaration of Helsinki).The survey was developed in in a collaborative effort between the experts at the University of Wisconsin Survey Center and our team of women’s health physicians. It included 41questions which assessed: 1) perception of the quality of care received, 2) ease of use/ease to learn the telehealth program, 3) effective orientation of the equipment, 4) level of perceived security/privacy utilizing telehealth and 5) problems encountered using the health equipment devices. The survey included 4-point Likert-type scale items . Additional items pertained to demographics; time required for vital sign submission (1–15 min); dichotomous Yes/No responses; and open-ended questions. The open-ended questions encouraged written responses on individuals’ personal experience of equipment , and suggestions for improvement. Questions included 1) Please tell us more about the problems you have had regarding the tablet, 2) BP cuff, 3) scale, and 4) Please tell us anything you can think of that would make using the health devices a better experience for you.Types of hypertension were divided into chronic hypertension, gestational hypertension, preeclampsia without severe features and all other preeclampsia which included preeclampsia with severe features, HELLP and eclampsia. Healthcare utilization was assessed by Emergency Room (ER) visit or readmission, length of initial hospital stays and length of initial postpartum stay. Maternal demographics were collected including insurance type, age, marital status, and race and medication use, specifically medications prior to delivery, medications at discharge and increase or initiation of medications after discharge. Finally, infant parameters included NICU admission, gestational age at delivery and discharge of mother and infant together.Statistical analysis of the quantitative survey responses included both descriptive statistics and two forms of logistic regression. All quantitative survey questions were analyzed to assess the breadth of results. Logistic regression was performed on a subset of questions specifically addressing the domains 1) ease of use, 2) burden of care, 3) satisfaction and 4) privacy. We wanted to determine if any relationships existed between these specific four domains and types of hypertension, health care utilization and demographic characteristics of the respondents.p-value were reported for each independent variable to assess which independent variables were significantly associated with the dependent outcome of each question of interest. When dealing with scale variables such as the ones we have, research shows that it is more appropriate to use an ordered logistic model rather than OLS regression by either failing to demonstrate significance of certain variables or underestimate the effect of variables in the model  eased the burden of having to not go out in the snow for appointments with my newborn!! -Patient 1And,In terms of “I personally really enjoyed using this product, I didn't want to be in the hospital any more than I had to … I am very satisfied and happy to have gotten the chance to take this device home, it made me feel safer.” – Patient 2satisfaction with remote blood pressure monitoring the analysis showed that women with other forms of preeclampsia found the devices more enjoyable to use  as did women with chronic hypertension . Overall satisfaction rates were higher with women with all other forms of preeclampsia  and who started on medications after discharge . The higher the maternal BMI the lower the overall level of satisfaction reported with the devices . Narrative comments from open-ended questions also imply overall satisfaction. Examples include,Lastly, for “I don't think I would have been as well cared for with traditional office visit Medicare. My pressures were especially high just after discharge...which happened to be over weekend. I was distracted caring for my new baby and wouldn't have called the doctor on the weekend and certainly wouldn't have gone into a clinic or the emergency department with my new baby. So, my preeclampsia would have gone untreated without this technology. Thank you for this program! Even while pregnant as my pressures rose and my edema worsened, I felt my providers were dismissive of my concerns about a possible preeclampsia diagnosis...in retrospect, I am so disappointed in my obgyn office for not making this diagnosis during pregnancy and feel sure that they would have neglected to monitor and treat this disease postpartum as well. It is only because of this program that I received such excellent monitoring and care.Again, thank you!” – Patient 3And,“I felt empowered, informed and safe. The nurses at telehealth made me feel like I mattered and were very informative. They even asked me questions about my recovery and my baby which made it much more personal. This program saved me a lot of stress and grief. I would recommend this to all women in my situation.” – Patient 4And,The nurses and staff were all phenomenal in staying in touch if any concern arose. I felt so much better having these devices after pregnancy to monitor my vitals and get them under control.” – Patient 5“Regarding suggestions for improvements, several respondents noted problems associated with the design of equipment .However, they most frequently noted problems with Bluetooth syncing and cellular data connectivity. These problems resulted in an inability for the Bluetooth enabled data collection devices to reliably sync the patient’s clinical data to the tablet for transmission to clinicians. In these instances, respondents submitted data through text messaging, or phone calls which accomplished the need to submit data but at the expense of privacy, increased effort and time.“Sometimes the BP cuff wouldn't register with the device and I'd either have to repeat the test or text the information to the study coordinator. It gave me a lot of trouble at first. We had to unpair and then pair the machines. After that, it still happened, but much less often.” – Patient 6For example, And,“It wasn't difficult, but it was an extra step and a little less privacy having to send my weight in texts.” – Patient 7Some respondents noted poor cellular data connectivity issues which at times resulted in the inability to transmit the synced data to the clinician. In these instances, when able, the respondent’s home internet service was connected, and cellular data turned off.The monitor would yell at me “Good morning, it is time to take your vitals” if I didn’t do it right at 9am. It would continue to do this every two minutes until I did take my vitals. This was frustrating for a new mom as some of the times I was feeding my newborn and other times I had just gotten to go back to sleep after a crazy night. There was no way to silence this alarm or turn the volume down on it. I had to call a clinician to have her change my alarm settings for it to stop yelling at me...it would have been nice to have more control over this part myself.– Patient 8Finally, respondent comments stress the importance of having an intervention compatible with the busy and ever shifting lifestyle that comes with a new baby. One particular annoyance was the scheduling of data collection  at 9 am.“Also, sitting through the blood oxygen monitoring when I didn't have a device to take the measurement was a waste of time--I was forced to sit through the tablet go through the motions of the oximeter instead of skipping ahead to the next step.” – Patient 9In the same way, mothers wanted more flexibility in system navigation. For example, Again, this point was specifically important for new mothers.“It would be nice if you had a "submit these vitals?" option at the end that you had to accept so that if something was off or incorrect, you could redo that portion. My toddler stepped on the scale while I was trying to weigh myself a few times and it submitted both her weight alone once and my weight combined with her weight a second time. It would have been nice if I could have cancelled those weights and redone them without having to go back through the whole touch screen system after they were incorrectly submitted.” – Patient 10Finally, a few respondents noted that it would be helpful to have access to a history of their data submissions to self-monitor over the course of the intervention.The results of this study confirm our hypothesis that remote blood pressure monitoring was generally accepted by postpartum women with a hypertensive disorder as an easy to use, secure system that was overall satisfying and did not represent an undue burden of care. These findings are also congruent with earlier studies , 20, 21 Our findings are the first to delineate specific groups who may be more amenable to this intervention. Younger respondents found less mental energy levels was required to use the devices, which may be expected as younger individuals may be more adept at using technology. The differences in ease of use metrics, in regards to marital status may also be due to variations in patient ages between married and unmarried groups although that analysis was not performed in this study due to the sample size limitations. Furthermore, respondents who had a postpartum ER visit or readmission felt most confident in using remote blood pressure technology. Our results suggest, women with conditions making them at increased risk of complications will feel secure and have broad adoption with engagement in remote monitoring.This study also demonstrated that most respondents feel secure using remote blood pressure monitoring and that privacy and security concerns did not appear to be influenced by type of hypertension .While there are certain groups that may find more benefit or satisfaction from remote blood pressure monitoring than others, these results indicate that most women will find value in this system regardless of demographic characteristics, hypertension type and medication use. This supports that from a patient perspective, remote blood pressure technology is likely to be acceptable to women when offered as an alternative to traditional hospital/clinic-based blood pressure surveillance for any individual who requires additional postpartum blood pressure surveillance as identified by ACOG.Limitations of this study include the fact that it performed at a single site with a relatively homogenous population and small sample size. Furthermore, although the results indicate the respondents preferred telehealth to standard outpatient blood pressure monitoring, the study did not include a control group in which satisfaction rates and burden of care metrics were also assessed. Additionally, the lack of a control group does introduce the risk of volunteer bias into the results. Specifically, individuals who participate in a remote blood pressure monitoring program may have fewer privacy concerns that the general population and be more adept at technology. We acknowledge that the associated baseline variables used in our analysis were exploratory and we did not adjust for multiple comparisons so some findings of significance may be due to chance. Last, although the Genesis Touch Monitor came equipped with language settings other than English, due to financial restraints, a limitation of the study is that it was limited to English speaking participants. However, upon completion of the intervention study, we transitioned to a no-cost remote blood pressure monitoring program for postpartum hypertension in which all women affected by a hypertensive disorder of pregnancy are in invited to participate free of charge.Future directions include conducting a larger multicenter study with more patient diversity to validate the findings of this study. In the interim, this study indicates that telehealth with remote blood pressure monitoring has high rates of acceptance among respondents who view it as a secure way to submit protected health information and reduce the burden of care associated with postpartum blood pressure monitoring. As technology continues to advance, telehealth monitoring may represent an important method of data collection regarding postpartum blood pressure trends, improve compliance with blood pressure recommendations, and reduce readmission rates to ultimately improve maternal health.


What is the association between blood pressure and mortality in Mexican adults and how does it vary with other characteristics such as diabetes?In this cohort study of 133 613 Mexican adults aged 35 to 74 years with high levels of adiposity and uncontrolled diabetes, blood pressure was most strongly associated with death from vascular and kidney disease, and the absolute excess mortality rates associated with elevated blood pressure were much higher in individuals with diabetes.The results reinforce the need for more widespread use of blood pressure–lowering medication in Mexico, particularly for individuals with diabetes. This cohort study of Mexican adults aged 35 to 74 years examines the association of elevated blood pressure with excess mortality rates, particularly for individuals with diabetes. Elevated blood pressure is a major cause of premature death, but there is little direct evidence demonstrating this association in studies of Hispanic populations.To assess the association between blood pressure and cause-specific mortality in a large cohort of Mexican adults with a high prevalence of uncontrolled diabetes.A total of 159 755 adults aged 35 years or older from 2 districts in Mexico City were recruited to this cohort study between April 1998 and September 2004 and followed up until January 2018. The present analyses focused on 133 613 participants who were aged 35 to 74 years and had no history of chronic disease besides diabetes.Blood pressure.Cox regression, adjusted for confounders, yielded mortality rate ratios (RRs) for deaths of participants occurring between ages 35 and 74 years.1c ≥9%) and 6548 (4.9%) had undiagnosed diabetes. Systolic blood pressure (SBP) was associated with vascular mortality between ages 35 to 74 years, with each 20 mm Hg lower usual SBP associated with 35% lower vascular mortality , including 48% lower stroke mortality  and 32% lower ischemic heart disease mortality . These RRs were broadly similar in those with and without diabetes. Compared with those without diabetes and SBP less than 135 mm Hg at recruitment, the vascular mortality RR was 2.8  for those without diabetes and SBP of 155 mm Hg or greater, 4.7  for those with uncontrolled diabetes and SBP less than 135 mm Hg, and 8.9  for those with uncontrolled diabetes and SBP of 155 mm Hg or greater. Lower SBP was also associated with decreased kidney-related mortality , decreased mortality from infection , and decreased mortality from hepatobiliary disease , but not decreased neoplastic or respiratory mortality. SBP was more informative for vascular mortality than other blood pressure measures .Of the 133 613 participants , 16 911 (12.7%) had self-reported previously diagnosed diabetes (including 8435 [6.3%] with uncontrolled diabetes, defined as hemoglobin ABlood pressure was most strongly associated with vascular and kidney-related mortality in this Mexican population, with particularly high absolute excess mortality rates among individuals with diabetes. The findings reinforce the need for more widespread use of blood pressure–lowering medication in Mexico, particularly among those with diabetes. Since most of these studies were completed, however, vascular mortality has decreased in many countries while obesity (a key determinant of blood pressure) and diabetes have increased.6 Moreover, most previous prospective studies have been conducted in high-income countries, so the extent to which their findings are generalizable to other countries with different health care systems and risk factor distributions is unclear.Elevated blood pressure is a major cause of death and disability. Using evidence from 2 large meta-analyses of prospective studies8 Using updated data from the Mexico City Prospective Study, the main aim of this study was to assess the association between blood pressure and 16-year cause-specific mortality in this Mexican population and in particular to examine how the association differed among those with and without diabetes.We previously found that, among 150 000 Mexican adults recruited into a prospective study between 1998 and 2004, diabetes was more strongly associated with mortality than was expected based on studies done in other populations.9 Trained nurses recorded sociodemographic and lifestyle factors, current medications, and medical history. Seated SBP and diastolic blood pressure (DBP) were measured 3 times  to the nearest 1 mm Hg using a standard mercury sphygmomanometer. Weight, height, waist circumference, and hip circumference were measured, and a 10 mL blood sample was collected. Hemoglobin A1c was measured from the buffy coat sample using validated high-performance liquid chromatography methods10 on HA-8180 analyzers (Arkray Inc) with calibrators traceable to International Federation of Clinical Chemistry and Laboratory Medicine standards.11 Ethics approval was granted by the Mexican Ministry of Health, Mexican National Council of Science and Technology, and the University of Oxford (United Kingdom). All participants provided written informed consent. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.From 1998 to 2004, households within 2 districts of Mexico City  were visited systematically, and all residents aged 35 years or older were invited to join the study; 159 755 residents agreed to participate.From June 2015 to February 2019, a median (interquartile range [IQR]) follow-up length of 15.5 (14.3-18.3) years, 10 144 surviving participants (7100 [70.0%] women) were revisited in their homes and agreed to participate in a resurvey. During this visit, seated blood pressure was measured 3 times using an automated upper arm blood pressure monitor .International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10).12 Study clinicians then reviewed and, if necessary, recoded the underlying cause of death . The single underlying cause of death was then used for prospective analyses (detailed in the following section). Vascular deaths were categorized as ischemic heart disease (IHD), stroke, and other vascular causes  prior diagnosis of angina, heart attack, stroke, cancer, chronic kidney disease (CKD), cirrhosis, or emphysema to reduce the risk of reverse causality bias . Participants who had missing or extreme values of any covariate data were also excluded. Remaining participants were then classified into 6 baseline SBP categories . The main analyses were limited to participants aged 35 to 74 years at recruitment and to deaths occurring before age 75 years. However, additional supplementary analyses are provided for those aged 75 to 84 years (and deaths at ages 75 to 84 years) .8 These confounders were specified a priori based on their known associations with blood pressure and with vascular mortality in other populations. In figures, mortality rate ratios  for each group are shown together with group-specific 95% CIs (including for the reference group with RR of 1.0).13 Separate RRs at levels of each confounder were estimated by inclusion of the relevant interaction terms in the regression models (while holding other confounders constant).Cox regression was used to estimate the associations between SBP (in the above 6 groups) and particular causes of death. Analyses were adjusted for age-at-risk, sex, location (2 districts), education , smoking , alcohol intake , leisure-time physical activity , anthropometry , and diabetes status  by the regression dilution ratio for SBP, which was conservatively estimated to be 0.76) .15To assess the strength of the association of SBP with cause-specific mortality, baseline SBP was then included in the model as a continuous variable, with RRs estimated for each 20 mm Hg lower SBP. However, because such analyses will underestimate the association of long-term “usual” blood pressure with risk because of regression dilution bias,1c <9% vs ≥9%), did separate analyses within each strata of the main confounders, and estimated the RRs separately for deaths occurring within 5 years, between 5 and 10 years, and 10 years or more after recruitment. Comparative analyses of DBP were also performed. Finally, to compare the strength of association of different blood pressure indices recorded at baseline with vascular mortality rates, the relative “informativeness” of a given blood pressure index  was estimated from the age-adjusted and confounder-adjusted χ2 statistic relating it to cause-specific mortality.1We then estimated the association between blood pressure and mortality separately for participant cohorts with and without previously diagnosed diabetes. For analyses of vascular mortality, we further separated those with diabetes according to glycemic control  and R version 3.5.3 . All Of the 159 755 potential study participants, 8135 (5.1%) were excluded because of a prior history of chronic disease and a further 8883 (5.6%) were excluded because of missing or extreme values. Among the remaining participants, 133 613 (93.6%) were aged between 35 and 74 years at recruitment   and 7461During a median (interquartile range) follow-up among survivors of 15.5 years (14.7-16.7), 2508 participants died from vascular causes between ages 35 and 74 years, including 574 (22.9%) from stroke, 1406 (56.1%) from IHD, and 528 (21.1%) from other vascular causes. For stroke, IHD, and the composite of all other vascular causes of death , the association of SBP with mortality was continuous and log-linear throughout the range studied . Across The proportional reduction in the vascular mortality rate associated with a 20 mm Hg lower usual SBP was greater at younger than at older ages but, for a given age, was broadly similar in those with and without previously diagnosed diabetes . Each 20Because individuals with diabetes had much higher death rates than those without diabetes, the absolute excess vascular mortality associated with higher blood pressure was greater among those with diabetes  . ClassifAt any given age, the associations between SBP and vascular mortality were similar for men and women , mid–blood pressure , and mean arterial pressure , a single measurement of SBP was found to be the most statistically informative for stroke, IHD, and vascular mortality , particularly among those with diabetes. The lack of any identifiable threshold level of blood pressure below which there was not a lower mortality risk also supports the most recent recommendations made by the European Society of Cardiology and European Society of Hypertension to reduce the treatment target level of blood pressure from below 140 mm Hg to below 130/80 mm Hg in most patients.27 From a global health perspective, the findings from this large previously understudied Hispanic population provide further support for the proposition that the association of blood pressure with cardiovascular disease risk is largely generalizable between different populations, a key assumption made by the Global Burden of Disease investigators when estimating the risks associated with elevated blood pressure and disability adjusted life-years lost worldwide.4A key feature of the present study that distinguishes it from most previously studied populations is the high prevalence of obesity and uncontrolled diabetes in this Mexican population at recruitment.The major strengths of the present study included the large population studied and prolonged duration of follow-up , the ability to exclude individuals with history of major chronic diseases, and the availability of information on a wide range of potential confounders. A further strength was the availability of repeat measurements of blood pressure in a sample of survivors at about 15 years after the baseline assessment, which allowed for an assessment of regression to the mean in blood pressure and appropriate correction for regression dilution bias.14 The chief limitation of the current study was the lack of any information on nonfatal vascular events. In addition, the present study relied on causes of death listed on the death certificate. However, almost all deaths in Mexico are certified by a doctor and the overall accuracy and quality of certification of causes of death in Mexico is high.28 Moreover, the validity of the attributed causes of death on the death certificates is supported by the specificity of the associations identified; by contrast with the associations seen with vascular causes of death, SBP was unrelated to major nonvascular causes of death (including deaths from neoplastic and respiratory causes). Finally, although the 2 study districts were not representative of Mexico as a whole, prospective studies of nonrepresentative cohorts of individuals can provide reliable evidence about the associations of risk factors with disease that are widely generalizable.29This study did have limitations. By adopting a somewhat conservative approach, ie, estimating the regression dilution ratio at the midpoint of the follow-up period, we may have undercorrected for regression dilution bias. Previous studies have reported that most of the long-term regression to the mean occurs shortly after the initial measurement.Consistent with previous reports from high-income populations, the present study showed that blood pressure was strongly associated with both vascular and kidney-related mortality in this Mexican population with high levels of adiposity and diabetes. These findings suggest that medications to lower blood pressure should be used more widely in Mexico, especially among individuals with diabetes.


Access to kidney transplantation is limited to more than half of the Mexican population.A fragmented health system, gender, and sociocultural factors are barriers to transplant care. We analyzed kidney transplantation in Mexico and describe how public policies and sociocultural factors result in these inequities.Kidney transplant data between 2007 to 2019 were obtained from the National Transplant Center database. Transplant rates and time spent on the waiting list, by age, gender, health system, and insurance status, were estimated.During the study period 34,931 transplants were performed. Recipients median age was 29 (IQR 22–42) years, 62.4% were males, and 73.9% were insured. 72.7% transplants were from living-donors. Annual transplant rates increased from 18.9 per million population (pmp) to 23.3 pmp. However, the transplant rate among the uninsured population remained low, at 9.3 transplants pmp. In 2019, 15,890 patients were in the waiting list; 60.6% were males and 88% were insured. Waiting time to transplant was 1.55 (IQR 0.56–3.14) years and it was shorter for patients listed in the Ministry of Health and private facilities, where wait lists are smaller, and for males. Deceased-organ donation rates increased modestly from 2.5 pmp to 3.9 pmp.In conclusion, access to kidney transplantation in Mexico is unequal and restricted to patients with medical insurance. An inefficient organ procurement program results in low rates of deceased-donor kidneys. The implementation of a comprehensive kidney care program, recognizing kidney transplantation as the therapy of choice for renal failure, offers an opportunity to correct these inequalities. In 1984 legislation on organ and tissue donation and transplantation was passed by the Mexican congress, followed by the creation of the National Transplant Registry in 1988, to promote and coordinate tissue and organ transplantation in the country . These cHowever, because of the fragmentation of Mexico’s health system, access to kidney transplantation among the uninsured population remains limited to patients who could afford the cost of transplantation and maintaining immunosuppressive therapy . SimilarIn this report, we describe the inequities in organ donation and access to kidney transplantation in Mexico, and how current public policies and sociocultural factors may influence or exacerbate these inequities.Kidney transplant data from 2007 to 2019 were obtained from the National Transplant Center’s (CENATRA by its Spanish acronym) kidney wait list file , kidney n = 34,919) were kidney-alone transplants whereas 12 were combined kidney-pancreas transplants.Between 2007 and 2019, 35,107 transplants were performed; after excluding 126 patients with missing information and 50 patients < 3 years old, 34,931 transplants were included in the analysis. Median age among recipients was 29 (IQR 22–42) years; they were largely male (62.4%), and over 91.4% of the transplants were performed in the 15–64 age group; the majority  transplants were from living-donors (LD), and 9508 (27.2%) from brain death deceased-donors (DD); 3092 (8.9%) originated from living-unrelated donors (LURD). In 20 0.1%) cases the organ origin was unknown. The largest proportion (73.9%) of transplant recipients were patients with health care insurance, and over half of all transplants were performed at the Mexican Institute of Social Security (IMSS by its Spanish acronym), the largest dialysis and kidney transplant provider in Mexico  increased gradually from 18.9 pmp in 2007 to 23.3 pmp in 2019. The rise was driven mainly by the increase in the rate of DD transplants and the rate of LURD transplants , and the proportion of recipients of DD kidney transplants was significantly lower , in comparison with the uninsured population. On the contrary, the proportion of transplants from LURD was two-fold higher  in patients with health care insurance in comparison with uninsured patients. This was especially remarkable in private transplant facilities, where LURD represented 20.2% of all the transplants performed in this setting, in comparison to 6.4% in public facilities (p = 0.0001).Transplantation practices differed between insured and uninsured patients and between health systems. Insured patients were older (29 years (IQR 22–43) vs 27 years (IQR 20–40), On December 31, 2019, the cumulative kidney transplant waiting list had 17,081 candidates, of whom 16,487 patients were listed on the deceased-donor waiting list between 2007 and 2019. We excluded 34 patients from the analysis; in 20 cases because of missing information, and 15 cases because they were < 3 years old, leaving a total of 15,890 for the analysis. Their median age was 36 (IQR 27–49) years, and 9631 (60.6%) were males. Sixty-three percent were in the 30–64 age group. The largest proportion of listed patients belonged to IMSS patients (81.1%), followed by the Ministry of Health (12.4%), and the Institute for Social Security of Civil Servants (ISSSTE by its Spanish acronym) (3.4%).The annual number of listed patients increased significantly in the study period, from 138 cases in 2007 to 3, 660 patients in 2019 Fig. a, mainlyDuring the study period 9508 DD transplants were performed, representing 59.8% of the patients listed in the same time period; waiting time was available in 9362 cases. Median waiting time to transplant was 1.55 (IQR 0.56–3.14) years. Waiting time varied significantly by insurance status, health care system, and gender. Uninsured patients spent less time in the wait list, in comparison with patients with health care insurance.p = 0.0001). IMSS patients waited longer, 2.46 (IQR 1.03–4.70) years to get transplanted, in comparison with the Ministry of Health patients , and with private patients . The median waiting time to transplant was shorter in males than in females (1.51 (IQR 0.51–3.04) years vs 1.61 (IQR 0.62–3.31) years, p = .001). The highest deceased-donor transplant rates (pmp) were reported in Mexico City (22.4), Guanajuato (13.8), Sonora (13.5), San Luis Potosí (12.9), and Nuevo León (12.1), Table  LD and 5522 16.6%) DD. Overall, LD were largely females , while males represented the largest proportion  of DD. The largest proportion (49.3%) of DD kidneys were retrieved at the Ministry of Health facilities, followed by IMSS (36.0%), and private facilities (10.7%). The number of DD, aged 1–91 years, with at least one kidney retrieved increased 82.3%, from 272 in 2007 to 496 in 2019. However, deceased-organ donation rates increased modestly from 2.5 pmp in 2007 to 3.9 pmp in 2019. Average annual donation rate was 3.2 pmp  was implemented in 2003 to provide publicly subsidized health insurance to over half of the Mexican population not covered by social security . HoweverSimilar to a previous report in the Mexican population , we founagilizar (to speed up). Patients who don’t have enough economic and intellectual resources to facilitate their access to transplant candidacy, are seldom transplanted [An additional barrier to transplantation is the bureaucratic nature of the Mexican public health care system. As described by Crowley-Matoka, similar to activities outside the health sector, successfully navigating the health care system in Mexico requires the ability to deploy a combination of favors, personal connections, and political pressure, locally described by the verb splanted . In addisplanted , 27, 28.domestication and feminization of organ donation in Mexico [As described a decade ago, kidney transplantation in Mexico continues to be a family affair . Over 60n Mexico . Althougn Mexico , 29.Kidney transplantation from DD organs represented 27% of all kidney transplants performed in the study period. Although DD kidney transplantation rates increased from 4.6 pmp in 2007 to 7.2 pmp in 2019, they remained among the lowest rates in Latin America, in comparison with Uruguay (42.3 pmp), Argentina (24.6 pmp), and Brazil (23.4 pmp) . As expeBecause of Mexico’s multi-tiered health care system, deceased-organ retrieval and allocation is also fragmented. In addition to CENATRA, there are 32 state coordinating centers and 553 programs (each with their own waiting list) licensed to practice organ and tissue transplantation . The resThis scheme has led to substantial discrepancies in access to DD transplantation and has increased the gap between the insured and uninsured populations. Patients listed in public health care systems with large waiting lists, like IMSS, must wait longer than those listed in the Ministry of Health and private facilities, where wait lists are significantly smaller. To circumvent this barrier, IMSS or ISSSTE patients who can afford private transplantation or who have the skills to negotiate their listing in the Ministry of Health facilities, “migrate” to these programs where they can get a kidney transplant faster . Once trFinally, although the national transplant registry has been in operation for 32 years, reports on patient and graft survival are missing. Reports on outcomes come from single-center reports . Kidney Our study has a number of limitations. Because of the lack of CENATRAS’ reports on patient and graft survival, and to the absence of a national dialysis registry, we could not assess the accountability and transparency of kidney transplantation in Mexico. Time spent on the waiting list was estimated from the date of listing to the date of transplant, and not from the date of starting dialysis. Likewise, transplant rates were estimated per million population, and not to the relative size of the prevalent dialysis population. We could not identify the donor-recipient kinship, although it is known that Mexican women are more likely to be donors, a decision probably driven by economic dependency. Finally, since insurance status is not included in the CENATRA database, the uninsured transplantation rates were estimated by the number of patients transplanted at the Ministry of Health facilities. Since a small proportion of insured patients manage to get transplanted in these settings, this could lead to an overestimation of the results among the uninsured transplant population.Although our results describe serious disparities in organ donation and access to kidney transplantation in Mexico based on insurance status and gender, other factors such as patient’s preferences, transplant literacy, and bureaucratic barriers imposed by the public health care system cannot be ascertained by our study. However, since the reporting of any organ procurement and transplantation is mandatory by federal law, we consider our results as representative of transplant care at the national level.In conclusion, we found serious inequities in access to kidney transplantation in Mexico, which remains restricted largely to patients with public or private health insurance. Uninsured patients  continue to bear the expenses of transplant surgery and immunosuppressive therapy, restricting their opportunities to access transplantation, and increasing the likelihood of financial ruin. Bureaucratic barriers imposed by the public health system, aggravate the access to kidney transplant to those who most need it. An inefficient and unequal deceased organ procurement and allocation system is largely responsible for the lower rates of deceased organ donation and transplantation. Finally, the absence of reports on patient and graft survival, together with the lack of a dialysis registry, raises concerns about the accountability and transparency of kidney transplantation in Mexico.To correct these problems, Mexico needs a strategy to establish a national comprehensive kidney care program as outlined by the International Society of Nephrology . The ext


CKD has a high prevalence worldwide, mainly due to its main etiologies—diabetes and hypertension. It has high cardiovascular morbidity and mortality, with traditional risk factors such as atherosclerosis, hypertension, diabetes, smoking, and left ventricular hypertrophy being common. Nontraditional cardiovascular risk factors, such as anemia, hyperparathyroidism, chronic inflammation, and microalbuminuria, are also well studied. Prolactin is a hormone not only related to lactation but also being considered a uremic toxin by some authors. It accumulates with loss of renal function, and it is associated with cardiovascular outcomes in both normal renal function population and CKD population. The purpose of this narrative review is to raise the main common aspects of CKD, prolactinemia, and cardiovascular risk. Chronic kidney disease (CKD) has high and increasing prevalence in the general population, mainly because the main causes of kidney failure are diabetes mellitus (DM) and hypertension, very common diseases. CKD has high morbidity and is associated with increased cardiovascular mortality, with 5 to 10 million annual deaths worldwide [The so-called traditional cardiovascular risk factors such as DM, hypertension, smoking, left ventricular hypertrophy (LVH), and peripheral vascular disease are very prevalent in this population . HoweverCKD patients have elevated prolactinemia when compared to the general population, and those with high hormone have higher cardiovascular mortality compared to those with normal prolactinemia . FurtherThe aim of this review was to raise the main points regarding prolactin, cardiovascular risks, and CKD.2, with or without renal damage markers  [Chronic kidney disease (CKD) is characterized by progressive and irreversible loss of renal function. It is defined by at least one of the following for more than 3 months: glomerular filtration rate less than 60 mL/min/1.73 mCKD has increasing prevalence worldwide, estimated at 10% of population, being more common in women when dysfunction is mild, and more common in men when dysfunction is severe . Its maiThe CKD classification was established in 2012 by the National Kidney Foundation and published in the Kidney Disease Improving Global Outcomes—KDIGO 2013 guidelines. It is widely used for assessment, risk stratification, and follow-up of CKD patients . For exaCKD is a progressive and silent disease, presenting signs and symptoms only in advanced stages. Therefore, its early diagnosis is very important because, in addition to avoiding a rapid progression to final stages, it is possible to reduce its morbidity and mortality .Besides high morbidity, CKD also has high mortality. Even those patients in renal replacement therapy (RRT) also have high death rates, much higher than certain types of cancer . Due to At all stages, regardless of type of treatment or CKD etiology, cardiovascular disease is the leading cause of death in these patients . Both re2 increased mortality due to all causes in 18%, 57%, and 214%, respectively [In a large meta-analysis study in which 1,234,182 CKD patients were compared with controls with normal estimated GFR, having estimated GFR reduction to 60, 45, and 15 mL/min/1.73 mectively .In the central pathogenesis of heart disease in CKD patients are arterial and myocardial remodeling . As a coTherefore, traditional cardiovascular risk factors such as hypertension, LVH, DM, smoking, dyslipidemia, and metabolic syndrome are very prevalent in this population and are widely studied . HoweverFor example, vascular calcification is observed even in young adults on dialysis, who do not have associated hypertension, smoking, or dyslipidemia . It is aAnother nontraditional cardiovascular risk factor common in CKD patients is anemia. Low hemoglobin levels and relative erythropoietin deficiency lead to increased cardiac output, reduced myocardial oxygen supply, oxidative stress, and cardiomyocyte apoptosis. Therefore, anemia is a risk factor for the development and progression of LVH, heart failure, and mortality .Elevated albuminuria (above 30 mg in 24-hour urine) is also a risk factor associated with cardiovascular disease, regardless of presence or absence of diabetes. Although the mechanism by which albuminuria is associated with cardiovascular disease is not well understood, it appears to be a sign that vasculature, particularly the endothelium, is damaged. For example, in diabetic patients, the degree of coronary endothelial dysfunction appears to be higher in those with moderately increased albuminuria .In addition to the nontraditional factors mentioned above, prolactin (PRL) also stands out. This hormone accumulates in the blood with loss of renal function and is associated with cardiovascular outcomes, being considered a uremic toxin .Prolactin (PRL) is a polypeptide hormone synthesized and secreted by lactotrophic cells of the anterior pituitary gland. The main role assigned to PRL is to stimulate proliferation and differentiation of breast cells needed for lactation by acting on its transmembrane receptor .big prolactin, 45–60 kDa) or macro , both corresponding to less than 20% of the total circulating PRL [The size of PRL is heterogeneous in terms of circulating molecular forms. The predominant form in healthy individuals and patients with hyperprolactinemia is monomeric, with a molecular weight of 23 kDa. It can also be dimeric , and ultrasensitive C-reactive protein were significantly higher in patients with elevated PRL, demonstrating that hyperprolactinemia is associated with preclinical atherosclerosis and metabolic abnormalities [In a study with rats, it was demonstrated that different plasma PRL levels have opposite effects: slightly high PRL causes decrease in blood pressure (BP) caused by increased nitric oxide (NO) production, whereas higher hormonal elevations lead to increased BP associated with heart failure due to decreased NO production , 38.Another interesting cardiovascular effect described in association with hyperprolactinemia is peripartum cardiomyopathy (PPCM). PPCM is a rare disease associated with late pregnancy or the postpartum period, marked by severe systolic dysfunction leading to reduced ejection fraction and symptoms of heart failure . It has An interesting study in patients undergoing endarterectomy found that both fibrotic layer and atherosclerotic plaque macrophages had PRL receptors. In the same study, it was also shown that PRL receptor expression was associated with the atherosclerotic lesion stage—more unstable plaques showed higher receptor expression. Thus, the study raised the hypothesis that PRL has a modulatory effect on atherogenesis .A cohort study evaluating 3,929 individuals  aged 20–81 years for 10.1 years  showed, after multivariate analysis, positive association of serum PRL levels with cardiovascular mortality, being the first study to report this positive association [Another more recent cohort study evaluating prolactinemia and incidence of cardiovascular risk found no association between them, but it should be noted that patients with elevated prolactin (above 30 mg/dL) were excluded  and men (8.0 mg/dL) . In thisKidneys play an important role in endocrine regulation, not only producing hormones such as erythropoietin and renin, but also acting on the metabolism of others such as insulin, cortisol, and prolactin. Therefore, CKD patients have numerous endocrine dysfunctions, with changes in feedback loops, reduced transport of protein-bound hormones, and reduced metabolism and hormone elimination .Regarding to PRL in patients with renal dysfunction, its accumulation occurs by several mechanisms. One of the main mechanisms is reduction in its metabolism . AnotherThus, hyperprolactinemia in these patients becomes very prevalent, ranging from 30% in CKD early stages to 65% in those on hemodialysis . In a stEven with a greatly increased prevalence of CKD, the clinical diagnosis of hyperprolactinemia in this population is difficult. Signs and symptoms of elevated PRL are confused with some manifestations of CKD itself such as oligomenorrhea, amenorrhea, decreased libido, erectile dysfunction, infertility, and osteoporosis. Galactorrhea and gynecomastia are suggestive signs but have limited sensitivity for diagnosis in this population .Dialysis therapies, such as conventional hemodialysis and peritoneal dialysis, do not normalize prolactinemia levels . This isAn interesting cohort evaluating 457 nondialysis CKD patients and 173 hemodialysis patients assessed endothelial function, arterial stiffness, cardiovascular outcomes, and prolactinemia. In nondialysis patients, it was observed a 27% increased risk of cardiovascular events for each 10 ng/mL PRL elevation, as well as a correlation with arterial stiffness. In those on hemodialysis, cardiovascular and all-cause mortality increased by 12% and 15%, respectively, with each 10 ng/mL PRL increase, as well as correlation of prolactinemia with pulse wave velocity [Renal transplantation and consequent improvement in glomerular filtration result in normalization of serum PRL levels . In a stChronic kidney disease is quite prevalent worldwide, with high cardiovascular mortality. Despite the high prevalence of hyperprolactinemia in this population, there is uncertainty about implications of this condition in patients with CKD, especially with regard to cardiovascular effects. Some authors suggested that prolactin could be a uremic toxin but until now it cannot be concluded whether hyperprolactinemia is a cardiovascular risk factor or only an intermediate in a major pathophysiological pathway. Further studies are needed because if causality between hyperprolactinemia and cardiovascular mortality is demonstrated in CKD patients, this could be a potential therapeutic target.