Kidney transplantation (KT) has become the standard of care for patients with end-stage renal disease. However, as atherosclerosis progresses with time on dialysis, it causes increasing difficulties in implanting the graft. This is a comparative study analyzing complications and graft survival of recipients with iliac revascularization before transplantation.Between January 2006 and December 2015, 1691 kidney transplants were performed at our institution. We retrospectively analyzed eighteen patients with peripheral arterial disease (PAD) with the necessity of vascular revascularization before kidney transplantation to protect the inflow to the renal graft and to optimizing blood supply to the extremities. The primary endpoint included patient survival and graft survival. The secondary endpoints evaluate perioperative and early postoperative complication rates after kidney transplantation.All patients enrolled in this study underwent two consecutive surgical procedures. No patient reported limb loss, and there was no additional perioperative morbidity or mortality related to the vascular procedure. Primary endpoints such as graft survival without dialysis and overall patient survival show 1-month survival of 100%, 1-year survival of 94.1%, and 5-year survival of 84.70%, respectively. One graft failure occurred 8 months after transplantation due to acute rejection, and there were two deaths over follow-up period due to myocardial infarction.Vascular repair before kidney transplantation is safe, and results are suggestive that it prolongs graft survival. These promising results should encourage other centers to address vascular repair before the transplantation to optimize blood supply to the extremity and the future graft. Although, the interpretation of our results must be cautiously because of the small and heterogeneous sample size, and the limitations of retrospective study design. Prospective trials with larger study populations are needed to confirm the results of this study and to identify significant differences. The number of patients with chronic kidney disease (CKD) has been increasing over the last decade . ChronicBesides patients refusing access to kidney transplantation, the only other option is to review the operative strategy defining indications for aorto-iliac reconstruction before or at the time of transplantation, , 10 to iThe aim of our retrospective observational single-center study was to evaluate graft function and graft survival as well as intra- and postoperative complication rates of kidney transplant recipients with peripheral arterial disease (PAD) where vascular revascularization was performed before kidney transplantation over 10 years.This study was a single-center retrospective observational study of 1691 consecutive patients undergoing deceased donor kidney transplantation between January 2006 and December 2015. We analyzed patient charts of all kidney transplant recipients to identify those patients with peripheral artery disease (PAD), diabetes mellitus, hypertension, history of coronary artery disease, and smoking. Other data, including clinical presentation, operative details, graft, and patient survival, were extracted from medical records.All patients receiving renal transplants were assessed preoperatively according to an established protocol that included a complete assessment of their vascular status based on medical history and physical examination. When atherosclerosis of the aorta, iliac, or femoral arteries was suspected, ankle-brachial pressure index (ABI) was measured, and axial computed tomographic scan (CT) of abdomen and pelvis was performed in case the ankle-brachial pressure index measurement detected any abnormality. The ABI measurements were grouped into four categories: normal (0.90–1.39), mild disease (0.70–0.89), moderate disease (0.40–0.69), and severe disease (0–0.39). Additionally, we analyzed the type of PAD presentation  and the level of PAD . Consequently, the indication for vascular reconstruction was defined by the transplant team and was based on vascular calcification, considering the risk of technical obstacles for renal transplantation caused by significant occlusive lesions. Patients with diffuse aorto-iliac atherosclerosis, type-C or -D aorto-iliac disease according to the Trans-Atlantic Inter-Society Consensus Document (TASC),  were conWe retrospectively analyzed patients with the necessity of vascular revascularization before kidney transplantation to protect the inflow to the renal graft and to optimizing blood supply to the extremities. Finally, data of 18 patients with vascular revascularization were available for complete analysis. The primary endpoint included patient survival and graft survival. The secondary endpoints evaluate perioperative and early postoperative complication rates after kidney transplantation.All study procedures adhered to the Declaration of Helsinki and were approved by the Institutional Ethics Committee (18–8023-BO). All patients provided written informed consent for kidney transplantation.All procedures were performed with general endotracheal anesthesia with continuous radial artery pressure monitoring and all recipients undergoing deceased donor kidney transplantation. Patients underwent kidney transplantation into the right or the left iliac fossa using an extraperitoneal approach. The vein was anastomosed to the external iliac vein in end-to-side manner. End-to-side anastomosis of renal artery was done to the external iliac artery. Lower pole arteries were always reconstructed and connected to arterial flow. Accessory arteries were reimplanted to the main renal artery in an end-to-side manner. Sutures of Prolene (6/0 or 7/0),  were used for vascular anastomoses. The ureter was reimplanted to the urinary bladder in standard Lich-Gregoir manner in all cases. A double-J stent  was routinely inserted into the ureter and removed 6 weeks after transplantation.All patients received triple-immunosuppression with calcineurin inhibitors, such as cyclosporine or tacrolimus, antimetabolic agents, and low-dose steroids. Perioperative antibiotic prophylaxis was a second-generation cephalosporin used routinely for patients undergoing simple renal transplantation or for those who had a prosthetic replacement. At our institution, intraoperative heparin is not given as intravenous, and, postoperatively, there was only prophylactic anticoagulation therapy.Postoperatively, patients were monitored for clinical , biological , and sonographic signs of complications at defined time points. Graft function was initially evaluated by urine production within the first 24 h after transplantation and by serum creatinine levels at defined time points.The presence of delayed graft function (DGF) was defined as the need for dialysis within the first week after surgery and/or failure of creatinine clearance to rise above 10 mL/min within the first 5 postoperative days irrespective of dialysis need, acute rejection, and immunosuppressant regimen at discharge.Any complication or need for intervention following surgery was noted. Postoperative complications were rated according to the Clavien-Dindo classification .Follow-up data were collected by our transplant program in cooperation with the Department of Nephrology of the University of Essen, Germany. Initially, patients were evaluated every 2 weeks until 3 months and every month thereafter until 6 months. After 6 months, the follow-up examination carried out every 3 months.Statistical analysis was performed using IBM SPSS Statistics version 24 . Graphs were created using SigmaPlot for Windows version 10.0 . Data were presented as mean (standard deviation) or median (range) as appropriate.n = 7), ever smoker (n = 8), coronary artery disease (n = 9), and hypertension (n = 14). The mean age of patients was 51.56 + / − 10.77 years. The indication for renal transplantation in all these patients was the progression of chronic renal insufficiency requiring long-term dialysis. All were recipients of their first kidney transplant, and in these patients, the artery of the transplanted kidney was implanted on the revascularization side. Baseline characteristics are presented in Table A total of 1691 patients underwent deceased kidney transplantation between January 2006 and December 2015 at our institution. According to the inclusion and exclusion criteria, data of 18 patients  with vascular revascularization were available for complete analysis. The reason for revascularization was, in all cases, iliac occlusive disease. These patients had multiple comorbid conditions including diabetes  before kidney transplantation, and all patients underwent elective repair. For this purpose, in five patients (27.78%), vascular prostheses were implanted , and in four patients (22.22%), common iliac arteries were stented. In three cases, stenosis of the iliac vessels was expanded using a transluminal angioplasty (16.67%); in two patients, endarterectomy procedures with bovine pericardium  patch  were performed; and, in two patients, angioplasty along with a stent implantation (11.11%) of the common iliac artery was conducted. Furthermore, one patient received an aorto-femoral bypass and one an aorto-bifemoral bypass (5.56%)  had one or more postoperative complications. One patient (5.56%) had elevated blood pressure values and thus a type-I complication during postoperative course. Two patients (11.11%) had type-IIIa complications . A total of six type-IIIb complications were documented, such as wound complications requiring surgery, ureter leakage with reimplantation and revisions in intubation anesthesia, new ureter implantations, and/or hematoma clearance under general anesthesia in three different patients (16.67%). Type IVa complications occurred in three patients. All of them required temporary, postoperative dialysis (16.67%). Details of complications according to Clavien-Dino classification are demonstrated in Fig. Regarding the documented endpoints, one patient (5.56%) was dialyzed again 82 months after kidney transplantation during follow-up. In another patient (5.56%), the kidney graft had to be removed 8 months following implantation caused by rejection, and the same patient died 29 months after the original transplant. Another patient died 44 months after kidney transplantation. Thus, a total of two deaths (11.11%) were recorded because of myocardial infarction.Graft survival without dialysis and overall patient survival show 1-month survival of 100%, 1-year survival of 94.1%, and 5-year survival of 84.70%, respectively. All survivor recipients have stable renal function in follow-up period. No patient developed signs of arterial infection or stenosis, and there was no need for secondary interventions.Patients with severe atherosclerosis account for 5.9% of all kidney transplant recipients . Selection of arterial anastomotic site and method of arterial anastomosis by careful preoperative and intraoperative examination are extremely important . As repoIn our study, the total number of patients with PAD and CKD was 59 (3.5%). However, only 18 patients (1.1%) underwent iliac revascularization before kidney transplantation. This demonstrates that only a limited number of patients with PAD and CKD received vascular revascularization before kidney transplantation. Furthermore, the optimal strategy for the timing of the aortic disease revascularization and kidney transplantation is unknown. Severe deterioration in the vascular status of patients listed for transplantation may be due to longer waiting times. Thereby, severe arteriosclerosis and peripheral arterial occlusive disease can represent contraindi-cations for kidney transplantation in rare cases. In our center, an extensive workup of the vascular status of patients is performed before putting them on the waiting list. Every patient is investigated by ABI and duplex sonography. Additionally, according to clinical symptoms and risk factors, we performed angiography, MR angiography, and CT scans. During the evaluation, we collected sufficient information about the peripheral vascular status to correct critical stenosis by interventional or operative therapy, as needed. For this reason, we rarely excluded patients for kidney transplantation (approximately 1–2 patients/year) because of extensive arteriosclerosis. Moreover, unintended simultaneous revascularization was extremely rare (3 patients) due to dissection of the intima following clamping.Postoperative kidney function showed a postoperative decrease in serum creatinine concentration, and none of the patients had a significant transient worsening of renal function. In the literature, postoperative kidney function after aorto-iliac repair based on creatinine values is described only by Pittaluga et al., demonstrating values of below 200 µmol/L (< 2.26 mg /dL) in 27 patients (87.1%) 1 month after kidney transplantation . ComparaPrimary endpoints such as graft survival without dialysis and overall patient survival show 1-month survival of 100%, 1-year survival of 94.1%, and 5-year survival of 84.70%, respectively. The interpretation of our results must be cautiously because of the small and heterogeneous sample size of study population. Early graft failure in previous studies ranges from 8 to 11% , 19. Losn = 12) of our patients. Pittaluga et al. [The Clavien-Dindo classification is applied as a simple tool to assess and report postoperative complications. However, this classification only categorizes postoperative complications into five grades, disregarding preexisting conditions and comorbidities. We registered complications in 66.66% (a et al.  describeMatia et al.  also desPatients with CKD who have PAD are at higher risk of cardiovascular mortality, –23 and cBased on our findings and other reports in the literature, we can state that vascular repair before kidney transplantation is safe, and results are suggestive that it prolongs graft survival. These promising results should encourage other centers to address vascular repair before the transplantation to optimize blood supply to the extremity and the future graft. Even though patients undergo two surgical procedures implicating postoperative complications, this strategy will increase overall patient survival and minimize graft loss. Optimal management of these patients is unknown. However, this study reflects our experience with this special patient population.The greatest limitation of this study’s results is the rarity that patients receive vascular revascularization before the kidney transplant. As a result, only a small number of patients could be included. The fact that all the indications for surgery were discussed by the interdisciplinary transplant team limits the selection bias to a certain extent.A comparison between a reconstruction group and a non-reconstruction group would likely be biased due to the different extent of PAD as non-reconstructive recipients had a mild ABI and fewer calcification than reconstructive patients did. For this reason, patients without vascular reconstruction or patients with emergency one-stage approach were not included in the further analysis.The patient collective used in the present study is small. However, on the basis of our experience, acceptable outcomes were attained. Although our results must be cautiously interpreted because of the small and heterogeneous sample size, and the limitations of retrospective study design, there is a clear trend that graft and in particular patient survival are superior if PAD patients receive iliac vascular revascularization before kidney transplantation. Prospective trials with larger study populations are needed to confirm the results of this study and to identify significant differences.


The diagnosis of Eustachian tube dysfunctions is essential for better understanding of the pathogenesis of chronic otitis media. A series of tests to assess tube function are described in the literature; however, they are methodologically heterogeneous, with differences ranging from application protocols to standardization of tests and their results.To evaluate the variation in middle ear pressure in patients with tympanic membrane retraction and in normal patients during tube function tests, as well as to evaluate intra-individual variation between these tests.p-values <0.05 as statistically significant.An observational, contemporary, cross-sectional study was conducted, in which the factor under study was the variation in middle ear pressure during tube function tests  in healthy patients and in patients with mild and moderate/severe tympanic retraction. A total of 38 patients (76 ears) were included in the study. Patients underwent tube function tests at two different time points to determine pressure measurements after each maneuver. Statistical analysis was performed using SPSS software, version 18.0, considering p = 0.012). The variation in pressure was not significant either for the sniff test or for the Toynbee maneuver at the two time points evaluated (p ≥ 0.05). Agreement between measurements obtained at the two different time points was weak to moderate for all tests in all three groups of ears, and the variations in discrepancy between measurements were higher in ears with moderate/severe tympanic retraction.Mean (standard deviation) age was 11 (2.72) years; 55.3% of patients were male and 44.7% female. The prevalence of type A tympanogram was higher among participants with healthy ears and those with mild retraction, whereas type C tympanograms were more frequent in the moderate/severe retraction group. An increase in middle ear pressure was observed during the Valsalva maneuver at the first time point evaluated in all three groups of ears (In this study population, the mean pressure in the middle ear showed significant variation only during the Valsalva maneuver at the first time point evaluated in the three groups of ears. Normal ears and those with mild retraction behaved similarly in all tests. The tested maneuvers exhibited weak to moderate intra-individual variation, with the greatest variation occurring in ears with moderate/severe retraction. The Eustachian tube (ET), or auditory tube, is the main structure responsible for equalizing pressure between the middle ear and the outside environment, ensuring ventilation of the air spaces of the temporal bone, and protecting the middle ear from nasopharyngeal secretions.The diagnosis of ET dysfunction is therefore essential for a better understanding of COM pathogenesis. Several tests of ET function have been described in the literature.9The present study sought to assess variation in middle ear pressure in patients with mild and moderate/severe TM retraction and healthy patients during ETF tests , as well as assess intra-individual variation in these tests in the three aforementioned patient groups.This was an observational, cross-sectional, contemporary study. The factor under study was variation in pressure within the middle ear during ETF testing in patients with mild TM retraction, moderate/severe TM retraction, or healthy TMs. The sample comprised 38 patients aged 8–18 years, recruited from the outpatient otolaryngology clinic of a tertiary care center from December 1, 2012, to March 31, 2013. Patients were allocated into three groups according to the severity of pars tensa retraction in the worse ear, using the modified Sadé and Berco (1976) classification proposed by Costa et al., as follows: group 1 – patients with normal TMs bilaterally (controls); group 2 – patients with mild TM retraction in at least one ear; and group 3 – patients with moderate or severe TM retraction in at least one ear.Inclusion criteria for the patient group were: age between 8 and 18 years; mild, moderate, or severe TM retraction in at least one ear; and intact TMs in both ears. The inclusion criteria for controls were: good overall health; same age range as participants in the patient group; current outpatient follow-up for adenoidectomy or adenotonsillectomy performed at least six months before recruitment; and normal TMs bilaterally. Exclusion criteria for patients and controls were: middle ear effusion; cleft lip and palate or other craniofacial abnormalities; Down syndrome; mucopolysaccharidoses; immunosuppression-related diseases; nasal or nasopharyngeal obstruction; inability to undergo audiometry, aural toilet, video otoscopy, or ETF tests; and refusal to participate.All patients underwent a thorough, targeted interview during the first study visit. Video otoscopy was performed and recorded. Findings were systematically described by a senior otologist using a dedicated form. All patients also underwent nasal endoscopy for assessment of nasopharyngeal obstruction. Pure tone and speech audiometry was also performed during first assessment of all patients and controls.Valsalva maneuver: the patient was asked to perform five consecutive Valsalva maneuvers. Middle ear pressure was measured and recorded immediately after each maneuver (VP1–VP5), during which time the patient was asked to refrain from speaking or swallowing.Sniff test: the patient was asked to inhale forcefully through the nose (mouth closed) five times consecutively. Again, middle ear pressure was measured and recorded immediately after each maneuver (SP1–SP5), during which time the patient was asked to refrain from speaking or swallowing.Toynbee maneuver: the patient was asked to swallow a sip of water while his or her nose was pinched shut by the investigator, five times consecutively. Middle ear pressure was measured and recorded immediately after each maneuver (TP1–TP5), during which time the patient was asked to refrain from speaking or swallowing.Assessment of ETF consisted of the following tests, which were performed with the Interacoustics AZ26 and AT235h impedance audiometers to measure middle ear pressure after each test maneuver. First, tympanometry was performed in both ears to record the baseline pressure in each ear prior to testing and ascertain its type of tympanogram, according to the Jerger (1970) classification. This was followed by the Valsalva maneuver, sniff test, and Toynbee maneuver, which were performed sequentially, first in the right ear and then in the left. During each test, middle ear pressure was measured five times consecutively as described below:Between each test, a 5-minute interval was enforced and the patient was instructed to drink water, in an attempt to return pressure to baseline values. Baseline pressure before each test was recorded as well .All of the aforementioned tests were performed at a second time point of assessment, 15–30 days after the first study visit. Results were described as corresponding to the first or second time point of assessment.α = 0.05, the minimum sample size was calculated as 12 controls and 24 patients with TM retraction (12 mild and 12 moderate/severe). Data were stored in a dedicated database in Excel. SPSS v. 18.0 for Windows was used for statistical analyses. Quantitative data were expressed as means and standard deviations, and categorical data, as absolute and relative frequencies. Analysis of middle ear pressure measurements was based on mixed-effects (fixed and random) models, taking into account intra-subject correlated observations, both for ears and for repeated measures. Categorical data were analyzed by means of a generalized estimating equations (GEE) model. The Bland–Altman method and intraclass correlation coefficients were used for assessment of agreement between measurements.To detect a difference in ETF measured by means of a quantitative variable with approximately normal distribution in the three study groups, with a statistical power of 80% and a significance level of This study was approved by the ethics committee of the Group of Research and Graduate Studies under No. 12-0432. An informed consent was signed for the anonymous use of patient data by the legal guardians of all participants. Treatment was not affected in any way whether patients provided or refused informed consent. As this study also used historical data for analysis, all authors signed an agreement for the confidential use of data.A total of 38 participants were assessed: 14 healthy controls, 12 patients with mild TM retraction in at least one ear, and 12 patients with moderate/severe TM retraction in at least one ear. Separate analysis of each ear revealed 36 healthy ears, 23 ears with mild retraction, and 17 ears with moderate/severe retraction. Mean age and standard deviation (SD) was 11 (2.72) years . Patient distribution according to sex was 55.3% male and 44.7% female.p = 0.002 and p < 0.001, respectively, chi-squared test).The prevalence of type A tympanogram was higher in groups 1 and 2, whereas type C tympanograms were most common in group 3, at both time points of assessment. There were significant differences among the three groups at the first and second time points of assessment (p = 0.012 (p [measurement]). Mean pressures (VP1–VP5) were different in each group, with p < 0.001 (p [group]). At the second time point of assessment, the trend toward pressures increasing from VBP during each of the five consecutive maneuvers (VP1–VP5) remained; however, due to the behavior of pressure measurements in group 3, p-values did not reach statistical significance (p [measurement] = 0.707). Again, mean pressures (VP1–VP5) were different in each group, as at the first time point of assessment (p [group] < 0.001). At the first time point of assessment with the Valsalva maneuver, there was a trend toward increasing middle ear pressures from baseline (VBP) during each of the five consecutive Valsalva maneuvers (VP1–VP5) in all three groups of ears, with p-values obtained at the first and second time points of assessment . Mean pressures (SP1–SP5) were different in each group at both time points (p < 0.001). At both time points of assessment with the sniff test, there was no trend toward decreases in middle ear pressures from baseline (SBP) during each of the five consecutive test maneuvers (SP1–SP5) in any of the three groups of ears, as represented by the p-values obtained at the first and second time points of assessment . Mean pressures (TP1–TP5) were different in each group at both time points (p < 0.001). At both time points of assessment with the Toynbee maneuver, there were no trends toward either decrease or increase in middle ear pressures from baseline (TBP) during each of the five consecutive test maneuvers (TP1–TP5) in any of the three groups of ears, as represented by the To assess the degree of agreement between the two time points of middle ear pressure measurement during the performance of ETF tests, scatter charts were plotted for each test and intraclass correlation coefficients (ICCs) were calculated. The ICCs were 0.65 for the Valsalva maneuver, 0.67 for the sniff test, and 0.63 for the Toynbee maneuver, which correspond to moderate agreement between the two time points of assessment across all three tests. Bland–Altman plots of agreement between middle ear pressures at the two time points of assessment showed poor replicability of results with all three test maneuvers.p = 0.018 for Valsalva maneuver; p < 0.001 for sniff test; and p = 0.005 for Toynbee maneuver). Apparently, the variances in the discrepancies between measurements obtained at the first and second time points of assessment were greater in the moderate/severe TM retraction group across all three ETF tests, as shown by the box plots below .vs. only 48% in patients with TM retraction.Swarts et al.e.g., how forcefully air is insufflated, and whether the patient swallows immediately after the maneuver). Although these variations may have occurred in the present study, particularly due to the lack of any increase in mean pressures in the moderate/severe retraction group after the Valsalva maneuver at time point 2, the findings are consistent with those reported in the literature, which suggests that the Valsalva maneuver is more effective than other tests.It is well known that the results of ETF tests may depend on how the test is performed .In the study population, mean pressures in the tympanic cavity tended to increase from baseline during the Valsalva maneuver, in all three study groups, only at the first time point of assessment. The expected changes in pressure during the sniff test and Toynbee maneuver did not occur in any of the three study groups at either time point of assessment. The normal ear and mild retraction groups behaved similarly between one another across all tests. The maneuvers studied herein exhibited weak to moderate intra-individual variation, demonstrating poor test replicability. Greater variation between measurements occurred among ears with moderate/severe TM retraction.The authors declare no conflicts of interest.


In the majority of cases, HK is associated with chronic kidney disease (CKD), or with the use of renin–angiotensin–aldosterone system inhibitors (RAASis) and/or mineral corticoid antagonists (MRAs). These drugs represent the mainstays of treatment in CKD, HF, diabetes, hypertension, and even glomerular diseases, in consideration of their beneficial effect on hard outcomes related to cardiovascular events and CKD progression. However, experiences in relation to the Randomised Aldactone Evaluation Study (RALES) cast a long shadow that extends to the present day, since the increased risk for HK remains a major concern. In this article, we summarise the physiology of K+ homeostasis, and we review the effects of dietary K+ on blood pressure and cardiovascular risk in the general population and in patients with early CKD, who are often not aware of this disease. We conclude with a note of caution regarding the recent publication of the SSaSS trial and the use of salt substitutes, particularly in patients with a limited capacity to increase K+ secretion in response to an exogenous load, particularly in the context of “occult” CKD, HF, and in patients taking RAASis and/or MRAs.Hyperkalaemia (HK) is one of the most common electrolyte disorders and a frequent reason for nephrological consultations. High serum potassium (K Indeed, hyperkalaemia prevention allows for the safer administration of life-saving drugs such as angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and mineralocorticoid receptor antagonists (MRA) [How many nights have nephrologists spent in the hospital to dialyse patients with life-threatening hyperkalaemia (HK)? The answer is many, since HK is one of the most common electrolyte disorders and a frequent reason for nephrological consultation. High serum potassium  , which cts (MRA) ,10,11,12However, the publication of the seminal RALES trial  was not + content. However, caution should be exerted in the contest of an increasing number of people with chronic clinical conditions such as CKD, often neglected by the patient and often treated with RAASis [The interest in MRAs has recently been revived by the development of nonsteroidal MRAs such as finerenone, which reduce both cardiovascular events and the risk of progression of renal function in diabetic subjects with CKD . An incrh RAASis . In thish RAASis ,15,19. Ch RAASis , particu+ load and the appropriate distribution of K+ across the cell membrane are vital for normal cellular function [+ load is mainly determined by changes in the excretion of K+ by the kidneys in response to intake levels [+; however, despite these homeostatic pathways, disorders of K+ homeostasis are common, especially in CKD patients [In brief, total-body Kfunction . Total-be levels . Under npatients .+ is the most abundant intracellular cation; approximately 98–99% of total K+ is within the cells, and changes in concentration between the intracellular and extracellular compartments have important clinical consequences [+ levels need to be closely regulated to maintain plasma K+ concentration within a narrow range, matching K+ intake with excretion and ensuring a proper distribution between fluid compartments [+ concentrations [Kequences ,21. Thusartments . The sli+ itself, among others. Long-term renal mechanisms to avoid total-body K+ overloads involve all segments of the nephron. However, the most sophisticated regulation process occurs in the aldosterone-sensitive tubule  [+ through ROMK and Max-K channels [+ flow into the urine are influenced by plasma K+ concentration, mineralocorticoid activity, distal sodium delivery, and tubular fluid flow rate (which is decreased in HF), among other factors [Cellular buffering is an immediate mechanism mediated by insulin, catecholamines (β-adrenergic tone), acid–base disorders, plasma tonicity, and plasma Kng duct) . In theschannels . The ele factors .+ secretion further when there is an exogenous load, HK can occur following even a modest increase in K+ intake [HK is common in patients with acute kidney injury or advanced CKD , especially if they are under RAASi treatment . As the adaptations that occur in the kidney  in CKD patients have a limited capacity to increase K+ intake .p = 0.76) [The results of the SSaSS trial were recently published in the New England Journal of Medicine . This st = 0.76) . Notably = 0.76) .+ content in the diet [+. These concerns are of critical importance in patients with known or “occult” CKD and those taking RAASi, bearing in mind that the global prevalence of CKD is estimated to be around 9.1% [These results serve to broaden the interesting ongoing debate regarding the beneficial effects of increasing Kthe diet ,23,24, ethe diet ,26; howethe diet . Moreoveund 9.1% , and thaund 9.1%  and patiund 9.1% .+; the number of participants with elevated K+ levels therefore remained essentially unknown, hindering extrapolating the results to the general population.Lastly, the SSaSS trial has significant limitations in terms of the absence of information on renal function and the exclusion of potential participants due to “serious kidney impairment”. Moreover, the study lacked serial measurements of plasma K+ on blood pressure have been well-described in the literature [+ are more pronounced in individuals who consume a high-sodium diet, suggesting that K+ influences salt sensitivity (K+ induces natriuresis) [+ depletion directly activates renin, angiotensin II, and endothelin-1 in the kidney independently of the RAAS system [+ may exert positive effects by decreasing the activity of the kidney’s sympathetic nervous system (attenuating the activity (increasing the turnover) of catecholamines). It has direct effects on vascular tone, mediated via endothelium-dependent vasodilation, and also increases endothelial nitric oxide activity, which in turn decreases arterial stiffness [+ significantly reduces the stiffness of vascular endothelial cells by changing the endothelial cell structure and increasing the release of nitric oxide. In contrast, high extracellular sodium and aldosterone prevent these changes [The beneficial effects of Kterature ,31,32. Tiuresis) ,34,35,36tiffness . Accordi changes .+ [+ intake and a lower incidence of cardiovascular disease [+ intake to better kidney outcomes may be even more pronounced [+ diet may lead to blood-pressure-independent protective effects such as anti-inflammatory, antifibrotic, and antioxidant effects, the improvement of endothelial function, and the prevention of atherosclerosis [+ intake on blood pressure and renal/cardiovascular outcomes are becoming increasingly evident from epidemiological, clinical, and experimental studies  [+ excretion >1.72 g/day (44 mmol/day) in patients with type 2 diabetes mellitus decreased the incidence of renal failure or cardiovascular events and at least halved the progression to stage 4 CKD [Regarding cardiovascular disease, the diet of our ancestors consisted mainly of vegetables, fruits, and game, providing small amounts of sodium and large amounts of K+ . This di disease ,36,38, aonounced . Furtherclerosis . Thus, t et al.) . As anotge 4 CKD .+ may not all be a direct consequence of increasing dietary K+; in some cases, they may result from a decrease in sodium intake [+ intake (of at least 3.5 and 4.6 g/day (90 and 120 mmol/day), respectively) [+ or salt substitutes  in patients with CKD (as well as in diabetic patients or patients with HF) is far from consistent.Nevertheless, the beneficial effects attributed to Km intake . This mam intake . Indeed,ctively) ,44, the + may also protect the kidney, and that patients with CKD may benefit from increasing dietary K+ [+ intake may be protective for cardiovascular health in the general population, a low K+ intake is often recommended in patients with decreased renal function and/or those with decreased RAAS activity due to the risk of HK and the fear of adverse serious events  patients [+ levels may be allowed in these patients. Furthermore, despite the assumption that high dietary K+ may predispose to HK, clear supportive evidence is lacking [The close relationship among blood pressure, cardiovascular disease, and CKD has led to the hypothesis that dietary Ketary K+ . Indeed,etary K+ . Althougs events . Indeed,hout CKD ,46,47. Wortality , some otpatients ,49. Henc lacking , and awa lacking .+ or the consumption of certain food groups related to K+ intake was associated with HK in a non-dialysis-dependent CKD (NDD-CKD) cohort and an HD cohort [+ intake was assessed by means of 3-day food records. The NDD-CKD cohort included 95 patients with an estimated median glomerular filtration rate of 23 mL/min/1.73 m2 (CKD G4), and the HD cohort (CKD G5D) included 117 patients. Somewhat surprisingly, the authors did not find an association between serum K+ and either dietary K+ or the consumption of selected food groups in NDD-CKD patients with HK (36.8%). Conditions associated with HK in multivariable analysis were diabetes mellitus and metabolic acidosis. Similarly, no association was found between serum K+ and either dietary K+ or the consumption of selected food groups in HD patients with HK (50.5%). The authors consequently concluded that dietary K+ is not associated with serum K+ or HK in either NDD-CKD or HD patients, and that, before restricting dietary K+, other potential clinical factors related to serum K+ balance should be considered. They also acknowledged significant limitations regarding the study’s ability to establish a cause–effect relationship: there may have been errors in assessing K+ intake and an inability to differentiate the sources of K+ in the diet [+ intake being associated with higher risk of HK and death [A recent study investigated in a cross-sectional analysis whether dietary KD cohort . Dietarythe diet . Another with HK .5%. The + are associated with better kidney outcomes in the overall population or in patients with early CKD [+ intake on CKD progression, possibly due to the study heterogeneity, the relatively low range of overall dietary K+ intake reported in different studies  in late stages of CKD [+, seem to absorb less K+ from their diets [Most observational studies have demonstrated that diets rich in Karly CKD . Howeveridelines ), and cos of CKD . Intriguir diets .+ management in CKD, and this group recently published the conclusions of their Kidney Disease Global Outcomes (KDIGO) controversy conference [+ to the normal range” [+ supplements, with analysis of the change in estimated glomerular filtration rate, and secondary outcomes such as 24 h blood pressure and albuminuria [+ homeostasis, and to cast light on the risk/benefit ratio of treatment with K+ supplements in CKD.A multidisciplinary group of researchers and clinicians met in October 2018 to identify evidence and address controversies relating to Knference . The autl range” ,56. Theyuminuria . These i+ levels. Indeed, as documented in a recent pooled analysis of 13,171 patients with diabetes mellitus and CKD G3 and G4 enrolled in the FIGARO-DKD and FIDELIO-DKD studies, the serum levels of K+ increased by 0.2 mmol/L among patients treated with finerenone [+ > 5.5 mmol/L) when finerenone was added to maximal dose of ARB/ACEi was observed [+ levels, casting further questions on the optimal therapeutic strategy in a specific subgroups of patients to ameliorate renal and cardiovascular outcomes, and prevent the occurrence of HK.Future studies should also evaluate nutritional intervention in light of the concomitant use of drugs that modulate the RAASi, such as ACE-I, ARBs, MRA, and/or sodium-glucose transporter 2 inhibitors (SGLT2i), beta blockers, or diuretics. Indeed, recent evidence supports the use of finerenone on top of maximal ACEi/ARB tolerated doses in diabetic patients to reduce the risk of both cardiovascular and renal outcomes at the cost of a small but statistically significant increase in serum Knerenone . As compobserved . In this+ delivered by the salt substitute in this study. Third, the bioavailability of inorganic K+  is not necessarily equivalent to that of K+ derived from a fruit- or vegetable-rich diet, as we already know from the strikingly different intestinal bioavailability of phosphate from inorganic  versus plant-derived phosphate sources [+, other nutrients , protein (with lower phosphate bioavailability), higher fiber content , or alkali  in plant-based or adapted “healthy” diets may have contributed to the outcomes of different studies [+ [+ content is rapidly evolving due to the potential pleiotropic benefits deriving from a fundamentally vegetarian or Mediterranean-adapted diet [+ [+ enriched salts or diets are suggested in light of the potential interaction with impaired renal function and/or excretion and the risk of HK.Several important gaps in knowledge remain even after the publication of the SSaSS trial, and, as previously mentioned, a note of caution is advised. First, previous association studies do not prove causality. Second, the effects of lower sodium cannot be separated from those of the higher K sources ,58. The  studies ,59,60,61udies [+ ,61. As wudies [+ ,61, the ted diet . Lastly, diet [+ ; however+ supplementation increases the tubular phosphate reabsorption capacity in rats and increases serum phosphate in healthy individuals [+, phosphate, and fibroblast growth factor-23 [+ kills rapidly, whereas phosphate kills slowly [Lastly, studies have shown that Kividuals ,62, indiactor-23 . Both phactor-23 . Thus, ns slowly ,65.Globally, 850 million people have CKD, and it is projected that by 2040, it will be the fifth leading cause of death in the world . Moreove+ intake , the evidence is still blurred and scarce, especially in elderly CKD patients and patients with HF who are taking RAASis and/or MRAs. As explained above, adaptations that occur in the kidneys and gastrointestinal tract in CKD patients result in a limited capacity to increase K+ secretion when there is an exogenous load or inhibition of the RAAS system.Despite advances in our knowledge of the potential benefits of increasing K+ binders with better safety profiles and tolerability, such as patiromer or sodium zirconium cyclosilicate [+ content and without proper K+ and/or renal function monitoring, may extend further the “long shadow” of the RALES trial. Broadcasting and encouraging global public health policies on the beneficial use of salt substitutes rich in K+ without appropriate warnings may not be desirable. In this regard, food manufacturers are increasingly substituting KCl in food products so as to reduce the sodium chloride content [+ [Fortunately, the development of new RAASis and/or MRAs such as finerenone ,68, and silicate , may mitsilicate . Moreovesilicate . Neverth content , and warntent [+ , such as


What is the association of uric acid–lowering therapy with the development of new onset chronic kidney disease (CKD)?2 and no albuminuria, there was no beneficial association between initiating uric acid–lowering therapy and the incidence of CKD. Uric acid lowering–therapy was associated with a significantly higher risk of new-onset CKD.In this cohort study of 269 651 patients with estimated glomerular filtration rate of at least 60 mL/min/1.73 mThese findings do not support the initiation of uric acid–lowering therapy as a means to prevent the development of CKD. This cohort examines the association of initiating uric acid–lowering therapy with the incidence of chronic kidney disease among patients receiving care at US Department of Veterans Affairs health care facilities. Uric acid is a waste metabolite produced from the breakdown of purines, and elevated serum uric acid levels are associated with higher risk of hypertension, cardiovascular disease, and mortality and progression of chronic kidney disease (CKD). Treatment of hyperuricemia in patients with preexisting CKD has not been shown to improve kidney outcomes, but the associations of uric acid–lowering therapies with the development of new-onset kidney disease in patients with estimated glomerular filtration rate (eGFR) within reference range and no albuminuria is unclear.To examine the association of initiating uric acid–lowering therapy with the incidence of CKD.2 or greater and no albuminuria treated at US Department of Veterans Affairs health care facilities from 2004 to 2019. Clinical trial emulation methods, including propensity score weighting, were used to minimize confounding. Data were analyzed from 2020 to 2022.This cohort study included patients with eGFR of 60 mL/min/1.73 mNewly started uric acid–lowering therapy.2, new-onset albuminuria, and end-stage kidney disease.The main outcomes were incidences of eGFR less than 60 mL/min/1.73 m2  and incident albuminuria  but was not associated with the risk of end-stage kidney disease . In subgroup analyses, the association of uric acid–lowering therapy with worse kidney outcomes was limited to patients with baseline serum uric acid levels of 8 mg/dL or less.A total of 269 651 patients were assessed . Among these, 29 501 patients (10.9%) started uric acid–lowering therapy, and 240 150 patients (89.1%) did not. Baseline characteristics, including serum uric acid level, were similar among treated and untreated patients after propensity score weighting. In the overall cohort, uric acid–lowering therapy was associated with higher risk of both incident eGFR less than 60 mL/min/1.73 mThese findings suggest that in patients with kidney function within reference range, uric acid–lowering therapy was not associated with beneficial kidney outcomes and may be associated with potential harm in patients with less severely elevated serum uric acid levels. Uric acid is a purine metabolite that has numerous deleterious physiologic effects, including vascular smooth muscle cell proliferation, inhibition of nitric oxide production, endothelial dysfunction, and oxidative stress.7 These could translate to harmful organ effects, potentially explaining the association of elevated urate levels with all-cause mortality, ischemic stroke, myocardial infarction, and congestive heart failure in observational studies.12 Additionally, higher uric acid level is associated with hypertension,14 which could potentially explain a putative deleterious effect on the kidneys, in addition to direct effects on kidney structures.17 The association of elevated urate level with progression of preexisting CKD has been documented,23 but the casual link between kidney function and uric acid level is complex, as decreased kidney function itself can result in hyperuricemia. Higher urate level was also associated with a higher incidence of CKD in previously healthy individuals in a meta-analysis,24 but individual observational studies have shown disparate results.28Chronic kidney disease (CKD) affects more than 10% of the US general population, and it is estimated that approximately 850 million people worldwide are affected by kidney diseases.30 but the effects of urate lowering on the incidence of new-onset CKD are less clear. We examined the association of uric acid–lowering therapy with the incidence of various kidney outcomes in a large cohort of US veterans with no preexisting CKD. We hypothesized that lowering urate levels is independently associated with a lower incidence of new-onset kidney disease.A causal effect of uric acid on CKD could be proven by demonstrating an impact of therapeutic urate lowering on kidney outcomes. Recent clinical trials of urate lowering in patients with existing CKD did not document a reduction in CKD progression,STROBE) reporting guideline for observational studies.This cohort study was approved by the institutional review boards of the Memphis and Long Beach VA Medical Centers, with exemption from informed consent because there was minimal risk for cohort participants. This report follows the Strengthening the Reporting of Observational Studies in Epidemiology  pharmacy  in our primary analyses.We analyzed data from the Therapeutic Interventions in Chronic Kidney Disease (TRI-CKD) study, a retrospective cohort study of 3 562 882 US veterans with estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 mpharmacy . Among t31 We identified medications obtained outside VA pharmacies from non-VA medication files in CDW. We defined baseline medication use as the presence of at least 1 outpatient prescription for at least 30 days during the 365 days preceding the baseline date. We extracted information about comorbidities from the VA Inpatient and Outpatient Medical SAS Data sets, using International Classification of Diseases, Ninth Revision (ICD-9) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic and procedure codes and Current Procedural Terminology (CPT) codes, as well as from Centers for Medicare & Medicaid Services (CMS) data files, and defined prevalent comorbid conditions based on the presence of at least 1 inpatient code or at least 2 outpatient codes recorded prior to the baseline date. We calculated the Charlson Comorbidity Index score using the Deyo modification for administrative data sets.32 We collected information about relevant laboratory characteristics from the VA LabChem files33 and we calculated eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.34 We collected information about proteinuria, including urine protein to creatinine ratio, urine albumin to creatinine ratio (UACR), and urine dipstick protein, from the DSS National Data Extracts Laboratory Results file and the VA LabChem file in the CDW. Since UACR is the preferred method for defining and staging CKD, we converted urine protein to creatinine ratio and urine dipstick protein to UACR values using the conversion equations by Sumida et al35 and categorized all available UACR values as less than 30 mg/g  or 30 mg/g or greater .We collected data on demographic and socioeconomic characteristics, comorbidities, medications, vital signs, and laboratory characteristics corresponding to each patient’s baseline date through the VA Corporate Data Warehouse (CDW). We used race and ethnicity categories as reported in the VA CDW, including African American, Hispanic, White, and other, which included those who self-identified as Asian, American Indian, Pacific Islander, and other without further specification. Race and ethnicity data were included because they have known associations with kidney outcomes and are thus considered confounders. We collected information about prescribed medications from the Decision Support System National Data Extracts’ outpatient and inpatient pharmacy files, including the date of dispensation, the dose, and the number of pills, as well as from Medicare Part D files for those eligible for such coverage.We used an incident new user design to define treatment exposure. We defined exposure as the de novo initiation of any chronic oral uric acid–lowering therapy  following the first measurement of serum uric acid level and throughout the entire follow-up period. Chronic new users were defined as patients receiving a first-time outpatient prescription of uric acid–lowering therapy covering at least 30 days, preceded by the lack of any prescriptions of urate lowering agents during the previous 365 days while having a record of VA pharmacy enrollment during the same period. We defined controls as patients who did not receive uric acid–lowering therapy but had at least 1 serum uric acid level measured.2 and of new-onset albuminuria. Both of these had to be measured twice with at least 90 days between the 2 measurements, with the outcome date corresponding to the date of the first measurement. For the incidence of eGFR less than 60 mL/min/1.73 m2, we also specified that the values had to be at least 25% lower than the baseline eGFR.36 We also examined end-stage kidney disease (ESKD), defined as the initiation of kidney replacement therapy  and identified from the US Renal Data System.37 We considered all-cause death as a competing risk, identified from the VA Vital Status Files.38 Patients were followed up until the occurrence of any of these outcomes, last recorded VA encounter date, or end of follow-up .Our coprimary outcomes were the incidences of new-onset eGFR less than 60 mL/min/1.73 mWe examined the association of urate-lowering therapies (vs no therapies) with the outcomes of interest using a target trial emulation with an intention-to-treat–like design. We used the intention-to-treat principle from randomized trials (the treatment exposure at cohort entry is carried forward irrespective of future treatment status) to model a trial in which patients initiating de novo urate-lowering therapy are compared with untreated comparators who are included  within the same 180-day calendar period. We described actual exposure to uric acid–lowering therapy in the treated group by calculating the proportion of days covered . Treated patients started follow-up on the date of receiving the first de novo prescription, while untreated patients entered follow-up on an assigned date randomly chosen based on the start of follow-up dates in the treatment exposure group, occurring after the measurement of a first serum uric acid level but before the occurrence of a potential outcome or censoring date, with the exclusion of patients whose randomly assigned entry dates fell outside of these dates.39 with mortality as the competing event. We accounted for differences between baseline characteristics using propensity scores (PSs) calculated from logistic regression models, using as variables the 180-day baseline time period, patient baseline age, sex, race, ethnicity, marital status, insurance type, baseline use of medications , comorbidities , body mass index, systolic and diastolic blood pressure, baseline eGFR, and serum uric acid level. Owing to the presence of extreme PSs  overall and stratified by treatment status, incorporating the competing risk of death. We examined the association of uric acid–lowering treatment (vs no treatment) with the events of interest in competing risk regression models using the Fine and Gray method,Analyses were conducted using Stata MP statistical software version 17.1 (StataCorp) and SAS statistical software version 9.4 (SAS Institute). Analyses were conducted in 2020 to 2022.We identified 269 651 patients in our primary analytical cohort. The mean (SD) age was 57.4 (12.5) years, and 252 171 patients (94%) were men. The sample included 49 932 African American patients (19%), 25 274 Hispanic patients (9%), and 203 643 White patients (77%). A total of 66 276 patients (25%) had diabetes . Of 29 52 , 68 759 patients (25.5%) experienced incident albuminuria , and 531 patients (0.2%) experienced incident ESKD . Event rates and unadjusted subhazard ratios (SHRs) for all 3 outcomes were higher in patients initiating urate lowering therapy  and incident albuminuria  but was not associated with ESKD  experienced an incident eGFR less than 60 mL/min/1.73 m therapy . In the ith ESKD . Associafarction . The assfarction . Resultsfarction .2, albuminuria, or ESKD. Contrary to our hypothesis, we found that uric acid–lowering therapy  was associated with a higher incidence of new-onset CKD and showed no association with incident ESKD. In subgroup analysis, the association of uric acid–lowering therapy with unfavorable kidney outcomes was limited to patients with baseline serum uric acid levels of 8 mg/dL or less, while the same associations were not significant in patients with serum uric acid levels greater than 8 mg/dL. These results do not support a direct benefit of urate lowering on the development of new-onset CKD, and support the results of recent large randomized clinical trials30 that found no benefit of allopurinol in delaying progression of established CKD. Our study is notable for its large size, national representativeness, and availability of comprehensive information on a broad array of clinical data.In this large national cohort study of US veterans, uric acid–lowering therapy was not associated with improved kidney outcomes, including the incidence of eGFR less than 60 mL/min/1.73 m45 but 2 large randomized clinical trials examining reducing uric acid in patients with type 1 diabetes and in patients without diabetes found that treatment of hyperuricemia did not result in improved progression of preexisting kidney disease.30 The impact of urate-lowering therapies on the incidence of new-onset CKD has been less well studied in clinical trials. While some have suggested that uric acid lowering is beneficial in preventing the development of CKD,47 the quality of these trials has been low; hence, their results are not conclusive.Elevated serum uric acid can be lowered using readily available therapies; hence, the impact of uric acid level on various clinical outcomes can be studied in clinical trials using such treatments. Smaller trials have suggested benefits from lowering serum uric acid levels in patients with preexisting kidney disease,48 We used a robust definition of incident CKD, which is less likely to be affected by transient elevations of serum creatinine, but acute kidney injury events could potentially contribute to the development of CKD, thus explaining our findings.Our findings of higher risk of incident CKD and albuminuria in patients with less severe elevations of serum uric concentration treated with urate lowering therapy may appear surprising, as we hypothesized that the lowering of uric acid levels would be beneficial owing to the detrimental effects of uric acid on various metabolic and cardiovascular processes. While it is possible that the higher risk associated with urate-lowering therapy was due to residual confounding, we cannot exclude the possibility that the administration of allopurinol (the uric acid–lowering agent used in most of our cohort) could also be deleterious. Allopurinol has a known potential to cause acute allergic reactions and could cause acute kidney injury by inducing acute interstitial nephritis.Our study has several limitations that should be considered when interpreting its results. We examined mostly US veteran men; hence, it is unclear if our results apply to women or nonveterans in general. Our study is observational and retrospective and therefore prone to confounding. While we accounted for major known confounders of the development of kidney disease, residual confounding remains possible, such as the doses of various potentially nephrotoxic medications or the severity of cardiovascular disease or other comorbidities. We used data collected from multiple hospitals during an extended period. While all of the hospitals currently use the isotope-dilution mass spectrometry traceable method to measure serum creatinine, we cannot ascertain when all these hospitals made the transition to this method, which may have resulted in misclassification of presence or absence of CKD. In our attempt to examine treated and untreated patients with comparable characteristics, we excluded a large number of patients, thus limiting the external validity of our findings to patients with characteristics similar to those included in our analyses.2, albuminuria, or ESKD. Uric acid–lowering therapy was associated with a higher risk of new-onset CKD, including both the development of eGFR less than 60 mL/min/1.73m2 and new-onset albuminuria, in patients with baseline serum uric acid levels of 8 mg/dL or lower. The causal effect of uric acid–lowering therapies, and especially allopurinol, in patients with no preexisting CKD needs to be examined in properly powered randomized clinical trials. Short of such trials, the preponderance of existing evidence does not support the administration of uric acid–lowering therapies as a means to prevent the development of CKD.This cohort study found that uric acid–lowering therapy was not associated with beneficial kidney outcomes, including the incidence of eGFR less than 60 mL/min/1.73 m


Whether the association between systolic blood pressure (SBP) and risk of cardiovascular disease is monotonic or whether there is a nadir of optimal blood pressure remains controversial. We investigated the association between SBP and cardiovascular events in patients with diabetes across the full spectrum of SBP.A cohort of 49 000 individuals with diabetes aged 50 to 90 years between 1990 and 2005 was identified from linked electronic health records in the United Kingdom. Associations between SBP and cardiovascular outcomes  were analyzed using a deep learning approach.Over a median follow-up of 7.3 years, 16 378 cardiovascular events were observed. The relationship between SBP and cardiovascular events followed a monotonic pattern, with the group with the lowest baseline SBP of <120 mm Hg exhibiting the lowest risk of cardiovascular events. In comparison to the reference group with the lowest SBP (<120 mm Hg), the adjusted risk ratio for cardiovascular disease was 1.03  for SBP between 120 and 129 mm Hg, 1.05 (0.99–1.11) for SBP between 130 and 139 mm Hg, 1.08 (1.01–1.15) for SBP between 140 and 149 mm Hg, 1.12 (1.03–1.20) for SBP between 150 and 159 mm Hg, and 1.19 (1.09–1.28) for SBP ≥160 mm Hg.Using deep learning modeling, we found a monotonic relationship between SBP and risk of cardiovascular outcomes in patients with diabetes, without evidence of a J-shaped relationship. This study investigated the shape of the association between blood pressure and future risk of cardiovascular outcomes in a cohort of 49 000 patients with diabetes using a validated deep learning causal model .In contrast to conventional statistical approaches, the T-BEHRT model showed no evidence of a J-shaped pattern.Patients in the lowest systolic blood pressure category of <120 mm Hg had the lowest risk of future cardiovascular disease.This study extends the lower, the better paradigm of hypertension to patients with diabetes and provides further reassurance about the role of intensive blood pressure lowering in this growing patient population.1 Observational studies conducted in low-risk groups have suggested that the association between elevated BP and risk of major cardiovascular disease (CVD) is log-linear.3 However, the association in patients with pre-existing cardiometabolic disorders is less well understood.Blood pressure (BP) reduction is a well-known primary and secondary preventive strategy for cardiovascular events in addition to diabetes.4 Another study similarly found a J-shaped pattern in patients with diabetes, with the nadir of risk between 135 and 139 mm Hg.5 This apparent discontinuous relationship has found some support from conventional meta-analyses of randomized controlled trials. For instance, one study concluded that BP lowering increased the risk of cardiovascular death in trials of patients with diabetes when average SBP was <140 mm Hg at baseline.6 However, previous observational studies, which implemented conventional statistical models are prone to issues of reverse causation and uncontrolled confounding,4 and tabular meta-analyses of trials, which have provided the best level of evidence to date, are vulnerable to the ecological fallacy.7In people with diabetes, reports have been inconsistent in their conclusion about the nature of the association between systolic blood pressure (SBP) and risk of CVD. Although in a cohort of patients with diabetes free of known CVD, the risk of CVD increased continuously with higher SBP, and in the same study when diabetic patients with or without prior CVD were considered, the relationship was J-shaped with the lowest observed risk of cardiovascular events among those with SBP between 130 and 139 mm Hg.10As a consequence, the shape of the association between SBP and cardiovascular endpoints in patients with pre-existing diabetes remains contentious. Recently, better access to rich, longitudinal electronic health records (EHRs) in line with the development of deep learning models for causal inference have provided a new opportunity to overcome issues of uncontrolled confounding that low-dimensional expert-driven statistical approaches are prone to. Methods combining deep learning modeling for rich EHR data utilizing automatic feature extraction and confounding adjustment as well as semiparametric statistical modeling for mitigation of selection biases have shown promising results in several works utilizing semisynthetic and routine clinical EHR data.In this study, we leveraged such novel deep learning methods to re-evaluate the relationship between SBP and cardiovascular events in a sample of 49 000 UK patients with diabetes.https://cprd.com/data-access).Requests to access the dataset from qualified researchers trained in human subject confidentiality protocols may be sent to the Clinical Practice Research Datalink (CPRD) organization , and the Office of National Statistics . We included people between 50 and 90 years of age with at least 1 BP measurement taken between the years 1990 and 2005. Consistent with previous studies on BP, the study entry  was defined as the date of the first BP measurement in this time period.15 We identified individuals as having diabetes at study entry using validated phenotyping methods; full list of codes for identifying diabetes are available in Table S1.16 Consistent with previous epidemiological studies, patients with heart failure before study entry were excluded from the study.1We used prospectively collected EHR data from CPRD, which has been validated for epidemiological research.The Transparency and Openness Promotion and the Reporting of Studies Conducted Using Observational Routinely-Collected Data reporting guidelines were followed for this cohort study. CPRD Independent Scientific Advisory Committee of UK (protocol: 16_049R) gave the approval for this work.12 The European Society of Cardiology guidelines recommend 3 BP measurements measured 1 to 2 minutes apart with BP recording as the average of the last 2 BP readings.17 In CPRD, the general practice staffs follow the same approach but a single BP measurement is recorded from each visit.12 We excluded the SBP values <50 and >300 mm Hg as suggested by the previously published phenotyping methods to exclude outlier measurements.18 All analyses were conducted with exposure status calculated as mean of SBP measurements in the first 12 months after study entry . For example, for a hypothetical individual with 4 measurements in the first 12 months following study entry, the exposure would be the mean value of the 4 measurements. Patients who had a cardiovascular event or left the study during this baseline exposure period were removed from the analyses. Patients were categorized into 6 exposure categories of SBP: <120 mm Hg (reference), 120–129 mm Hg, 130–139 mm Hg, 140–149 mm Hg, 150–159 mm Hg, and ≥160 mm Hg.SBP was the exposure variable and was derived from CPRD measurement data. In CPRD, BP measurement is recorded by general practice staff during an in-person visit or consultation.International Classification of Diseases, Tenth Revision (ICD-10) codes  as reported previously.11 Follow-up period started 12 months after study entry; this feature of study design was implemented in order to avoid conducting inference within the exposure period (first 12 months after study entry). Thus, events that occurred between 12 and 120 months after study entry  were captured for analysis .The primary outcome was fatal or nonfatal CVD, defined as a composite of ischemic heart disease (IHD), incident heart failure, stroke, and cardiovascular death. Secondary outcomes were components of the primary outcome: (1) IHD, (2) incident heart failure, and (3) stroke. All outcomes were identified by Read codes (primary care) and 9 For each of these comparisons, T-BEHRT was first trained to jointly predict exposure category (propensity score) and risk of outcome with 5-fold cross-validation implemented for training and testing.19 The T-BEHRT model incorporated all recorded diagnoses and medications in medical history prior to study entry in addition to baseline smoking status —identified by last known status in the 12 months before baseline—and sex.For the deep learning approach, we used Targeted Bidirectional Electronic Health Records Transformer (T-BEHRT) for risk ratio (RR) estimation of association between SBP and cardiovascular outcomes with SBP of <120 mm Hg considered as reference group.20 RR and 95% CI were derived from this post hoc estimation procedure. More details and implementation of the T-BEHRT approach can be found in the Supplemental Methods section .Initial estimates were computed on patients from test set of each of the 5 iterations. Second, equipped with these initial estimates, the T-BEHRT model updated risk estimates utilizing doubly-robust post hoc estimator, Cross-Validated Targeted Maximum Likelihood Estimation, to further mitigate biases.21 Smoking status  was identified by last known status in the 12 months up to baseline. To comply with standard epidemiological research, we conducted imputation before inputting data to LR models. Multiple imputation using chained equations was used to impute missing variables BMI, high-density lipoprotein, total cholesterol, triglycerides, and smoking status; 25 imputations were conducted. For the LR, an estimate for the RR was obtained utilizing direct standardization.22 We calculated RR as the average across the test sets of k-fold cross-validation (k=5) and calculated 95% CI over the 5 runs.23 Additionally, the crude RR was also calculated as the average risk of the outcome in a particular exposure group divided by the average risk of the same outcome in the reference exposure group.To compare against the T-BEHRT, logistic regression (LR) models were implemented to investigate the relationship between SBP and outcomes in individuals with diabetes. The exposure, SBP group was included as a categorical variable. The model was adjusted for age, sex, smoking status at baseline, body mass index (BMI), antihypertensive use at baseline, high-density lipoprotein, total cholesterol, triglycerides, atrial fibrillation, and chronic kidney disease. Baseline BMI, total cholesterol, high-density lipoprotein, and triglycerides were calculated as the average of measurements in the 12 months before baseline. Antihypertensives were identified by British National Formulary codes.In addition, to check that findings of our binary regression models were not simply due to unaccounted informed censoring during follow-up, a Cox proportional hazards model was implemented with the same predictors as for the LR model. As is done traditionally for Cox proportional hazards modeling, censoring and time of cardiovascular event data were used for the modeling. The proportional hazards assumption was tested by plotting Schoenfeld residuals.As a sensitivity analysis, to check that the impact of more complete adjustment of covariates, we extended our adjustment of the LR model with the following additional variables: insulin use at baseline, mean of measured values of hemoglobin A1c in the 12 months up to study entry, and duration of diabetes at baseline. As a measurement, hemoglobin A1c measurements were missing for 45.1% of patients in our cohort. Multiple imputation using chained equations was used to impute missing variables hemoglobin A1c, BMI, high-density lipoprotein, total cholesterol, triglycerides, and smoking status; 25 imputations were conducted.5 Third, we conducted stratified analysis of the primary outcome additionally by baseline antihypertensive use. Fourth, to assess the possible impact of reverse causation, we excluded individuals who had cardiovascular events in the first 12 and 24 months of the follow-up period (24 and 36 months after study entry). Fifth, we repeated analysis without excluding patients who had an event in the first 12 months after study entry.Several additional sensitivity analyses were conducted using the T-BEHRT model. First, we conducted analyses stratified by sex  and age (≤75 and 75 years of age) analyses. Second, since antihypertensives can dilute associations, we repeated our main analysis with patients who had not taken antihypertensives after study entry.https://github.com/deepmedicine). Please see the Major Resources Table in the Supplemental Material.All data processing, data imputation, and analyses were undertaken in the programming language, Python. The programming code for the T-BEHRT model is found as an open-source package on the Deep Medicine research group codebase . Descriptive statistics of the cohort according to the baseline SBP are shown in Table Table S3). The median follow-up duration was 7.3 years. A total of 16 378 (33.4%) patients had cardiovascular events in the follow-up period, and 12 797 (26.1%) patients were censored . Event rates are provided in the Supplemental Material (Table S4).A total of 49 000 patients with diabetes were included in this study . However, for stroke, the crude and adjusted LR models estimated that <120 mm Hg SBP demonstrated lowest risk similar to the T-BEHRT model. The adjusted Cox proportional hazards approach found that SBP between 130 and 139 mm Hg exhibited the lowest risk of all secondary outcome investigations. In sensitivity analysis of primary and secondary outcomes using an LR model with additional adjustment variables, the trends were almost identical to those captured by the main adjusted LR approach (Table S5).By contrast, the crude, LR, and the Cox proportional hazards models depicted a J-shaped pattern with all models capturing a nadir of risk at SBP between 130 and 139 mm Hg  with 34 000 patients.Conventional statistical models are usually implemented in observational studies with curated, low-risk cohorts relatively free of multimorbidity at baseline. By ensuring the cohort is healthy, statistical models may only require a handful of established confounding variables to sufficiently provide adjusted and trustworthy estimates. However, in cohorts like ours with high baseline BMI and a host of underlying conditions—including some cardiovascular in nature indicating prevalent multimorbidity—conventional approaches with expert selected confounders and regression modeling might be insufficient for capturing complex interactions and confounding.1 evidence of heterogeneity of treatment effects in patients with diabetes has been controversial. In particular, a tabular meta-analysis of randomized trials in patients with diabetes has suggested that BP lowering might increase the risk of cardiovascular death when SBP is <140 mm Hg. While not directly analyzing BP lowering, our observational study, on the contrary, provides evidence that SBP maintains a log-linear relationship with cardiovascular outcomes across a wide range of baseline SBP categories in patients with diabetes.Our work implementing deep causal modeling addresses these issues and fills some of the gaps in this research of SBP and cardiovascular outcomes. With T-BEHRT modeling, our research found no evidence of the J-shaped association between SBP and primary and secondary outcomes. While a recent individual-participant data meta-analysis of randomized evidence has indirectly dismissed the existence of a J-shaped in patients with or without prior CVD,4 The weak associations might be due to 2 main reasons. First, as recently shown by trial evidence, the relative effect of BP lowering on cardiovascular outcomes was half as strong in people with diabetes as those without diabetes.26 This might be due to the fact that part of the effect of BP lowering on CVD outcomes is mediated through prevention of diabetes; a pathway that might not be relevant to people with pre-existing diabetes.27 Second, our cohort included patients with several comorbidities and use of several medications. While all these attributes are typical in diabetes patients (and a suitable case for complex models such as T-BEHRT), they could lead to attenuation of true associations with CVD as compared to associations in lower risk cohorts.28 This is supported by our sensitivity analyses, where exclusion of patients with use of antihypertensives at baseline or during follow-up led to stronger relationship between SBP and risk of CVD.We note in our cohort of high-risk patients, relatively modest associations were observed using the T-BEHRT approach. This, however, was also the case in our conventional modeling and comparable with previous research.26 Together, they support the lower the better paradigm of SBP in patients with diabetes.These results have important implications for cardiovascular research. Our analysis provides some clarity concerning the relationship between SBP and cardiovascular events in patients with diabetes. Hence, while our investigation on its own is insufficient for recommending revisions of hypertension guidelines, our work rather functions as independent analyses complementing the findings of the individualized patient data meta-analysis of randomized evidences.Our first strength is CPRD allows us access to a host of rich diagnosis, medication, and measurements variables. Also, we leveraged phenotyping methods validated for CPRD. Unlike previous studies of SBP and cardiovascular events that have excluded older individuals, patients between 50 and 90 years of age were included in this work. Exclusion based on baseline attributes was limited; only those with heart failure were excluded at baseline.Second, deep learning feature extraction was used to automatically adjust for confounding variables and latent interactions in our input data. We also implemented conventional statistical approaches enabling direct comparison of T-BEHRT to established methods in the study of SBP and cardiovascular outcomes. We showed that by using superior adjustment methods, we can more effectively model the association in observational data, thereby rejecting the J-shaped argument.29 case ascertainment of diabetes might have misclassifications . Measurement errors are a natural issue with EHR data, especially that of BP, but we have attempted to mitigate these issues in the case of SBP data by taking an average of multiple measurements over the course of 12 months following baseline. However, we are unable to make any direct inference about the relationship in particular patient groups such as those with white coat hypertension.This study also has several limitations. EHR data might have some level of measurement error or misclassification. Despite endorsement of the validity and reliability of physician diagnoses in the CPRD dataset, especially concerning studies of cardiovascular disorders,9 When data are sparse or limited (finite sample), the doubly-robust estimation, with known benefits for finite-sample estimation, more accurately estimates RR than the variants without utilization of doubly-robust estimation.20 Furthermore, when positivity (overlap) between exposure groups is limited, the T-BEHRT model fares better than other benchmark models.22 Specifically, in our study of patients with cardiometabolic multimorbidity, where the traditional LR model insufficiently captures confounder relationships, deep learning modeling in tandem with semiparametric methods can be appropriately implemented for robust RR estimation. Further testing to assess model estimation accuracy is needed for settings in which the exposure is poorly defined  or when the outcome is categorical or continuous. Future confirmatory investigations on additional data sources would be invaluable for studying the association from different perspectives.T-BEHRT framework typically requires high-dimensional longitudinal data. The T-BEHRT estimator can function optimally with access to multiple EHR modalities  and associated temporal annotation . Furthermore, as previously reported, when such rich data are provided, the unsupervised learning component (masked EHR modeling) of the T-BEHRT model works well in reducing bias in estimation.Our deep learning approach functions in the binary outcome framework as opposed to the time-to-event framework, which would be a more optimal framework for analyses where time-dependent bias is likely. Specifically, failure to carefully consider censoring in cohort can bias downstream estimation of the association. However, even though deep learning for survival analyses has been explored in the risk prediction setting, methodological issues in estimation of hazard ratios using nonlinear, deep learning models have limited pursuits of survival modeling for population-level association estimation. Hence, methodological studies would be necessary to develop and demonstrate the utility of deep learning-driven survival models for EHR, which could be applied to investigate the studied association and other challenging questions. Lastly, as is the case for all observational studies, our model is unable to overcome the challenge of fully taking account of unmeasured confounding and when this is of concern, alternative study designs such as randomized controlled trial might be required.Using large-scale, linked EHR, our investigation utilizing a deep learning model concluded that patients with diabetes in the lowest category of SBP of <120 mm Hg exhibited the lowest cardiovascular risk. This was in contrast to expert-dependent conventional approaches that have largely defended the paradoxical nonlinear J-shaped association between SBP and cardiovascular end points in those with diabetes. This difference is likely explained by the deep learning model’s ability to more comprehensively capture known and latent confounders in routine EHR, thus reducing the potential of important confounders being missed out. In light of a recent meta-analysis of trials demonstrating that BP lowering medications reduces the risk of cardiovascular events in patients with diabetes regardless of baseline BP, our investigation provides complementary evidence against a causal link between low BP and risk of CVD in this population. Together these lines of evidence support the lower, the better paradigm of BP management. In terms of methodological insights, our work demonstrates that where complex confounding might be at play, conventional modeling is more likely to fall short of delivering well-adjusted estimates of risk. In such scenarios, models such as T-BEHRT, which are capable of automatically capturing known and latent confounding in minimally processed, rich EHR provide a worthwhile alternative for minimizing biases. Future research applying and testing such data-driven deep learning methods in high-risk cohorts would be beneficial for disentangling the nuances of risk and protection in patients with pre-existing conditions.S. Rao and K. Rahimi conceived the study concept and designed the study. K. Rahimi and S. Rao acquired and curated the data. S. Rao conducted the data analysis and analysis visualizations. M. Nazarzadeh contributed to data analysis. S. Rao wrote the initial draft of the article. K. Rahimi is the guarantor for the study. All of the authors contributed to the revisions of the article and had full access to the data.This work was supported by grants from the British Heart Foundation , , and ; United Kingdom Research and Innovation (UKRI) Global Challenges Research Fund ; Oxford National Institute of Health Research (NIHR) Biomedical Research Center (to K. Rahimi), Novo Nordisk grant (to M. Mamouei), and the Oxford Martin School (OMS), University of Oxford (to K. Rahimi). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. The views expressed are those of the authors and not necessarily those of the OMS, the BHF, the GCRF, the NIHR, or the Department of Health and Social Care.None.Supplemental MethodsTables S1–S5Figures S1–S4Major Resources Table


Asthma is a heterogeneous condition where biomarkers may be of considerable advantage in diagnosis and therapy monitoring. However, the changes in asthma biomarkers and immunoglobulin E (IgE) over the course of life has not been extensively investigated.To study longitudinal changes in type‐2 inflammatory biomarkers, IgE, and clinical outcomes, and the association between these changes, in young asthmatics.n = 253) were examined at baseline and at a follow‐up visit, 43 [23–65] (median [range]) months later. Subjects were analyzed using the multi‐allergen tests Phadiatop and fx5 (ImmunoCAP) and grouped based on the baseline allergen‐specific IgE antibody (sIgE) concentration: <0.10, 0.10–0.34, and ≥0.35 kUA/L. The relationship between changes  in type‐2 biomarkers  and FEV1/forced vital capacity (FVC)], and Asthma Control Test [ACT]) score were determined.Asthmatics , whereas ACT score had increased . A significant decline in lung function was seen in subjects with sIgE ≥ 0.10 kUA/L, but not in those with undetectable sIgE (<0.10 kUA/L). Furthermore, tIgE and sIgE declined over time  whereas FeNO% and B‐Eos count were not significantly changed. In univariate analysis, significant negative correlations between ∆B‐Eos count and ∆FeNO%, on one hand, and changes in lung function, on the other hand, were seen, and multivariate analysis showed an independent relationship between ΔFeNO%, and ΔFEV1 (p < 0.05) and ΔFEV1/FVC% (p < 0.01). Sex‐specific analysis showed that the independent association between ΔFeNO%, and ΔFEV1 remained only in females (p = 0.005), and there was a significant interaction with sex (p = 0.02).At follow up, FEV1 in females.In young asthmatics, IgE levels declined over 43 months, whereas FeNO and B‐Eos remained unchanged. In spite of improved asthma control, an accelerated lung function decline was seen in patients with detectable sIgE at baseline, and the decline correlated with changes in type‐2 biomarkers. Particularly, the increase in individualized FeNO associated independently with decline in FEV Based on the Minimally Invasive Diagnostic procedures in allergy, Asthma, or food hypersensitivity Study (MIDAS) cohort, we have profiled clinical outcomes and inflammatory biomarkers in relation to allergen‐specific IgE antibody levels (sIgE) in young asthmatics.22.1The MIDAS asthma cohort was recruited from primary and specialist care facilities in Uppsala, Sweden.2.2Dermatophagoides pteronyssinus, Dermatophagoides farinae, Cladosporium herbarum, cat, dog and horse; Phadiatop), and one with a mix of six food allergens .IgE antibodies were analyzed using two different multiallergen tests, one with a mix of nine aeroallergens  was measured using a Masterscope spirometer . Recommendations from the American Thoracic Society were followed.1 and FEV1/forced vital capacity (FVC) ratio were calculated on the basis of the Global Lung Function Initiative (GLI) reference valuesForced expiratory volume in 1 second (FEV2.52 gas of 200 ppb. The percent of predicted FeNO (FeNO%) was calculated using recently developed models, separate for males and females but with children and adults in the same models, adjusted for age and height,FeNO measurements were performed in accordance with the American Thoracic Society/European Respiratory Society recommendations,2.6t‐tests (for continuous variables) and chi‐square tests  were used for the univariate analyses performed for describing the asthmatic subjects at baseline and follow‐up visits. The GLI reference values took both between‐subject and age‐ and height‐related variability into account. We analyzed longitudinal changes  in inflammatory  and clinical variables  between the two visits, based on paired t‐test. Longitudinal changes in proportions were analyzed by chi‐square test. Further, we investigated the changes over time of these variables in relation to sIgE concentrations of either Phadiatop or fx5 at baseline, by dividing the asthmatics into three groups: elevated (≥0.35 kUA/L), detectable (0.10–0.34 kUA/L), and undetectable (<0.10 kUA/L) sIgE. Atopy was defined by the presence of either Phadiatop or fx5 above 0.10 kUA/L. We performed correlation analyses between the Δ values of different biomarkers, sIgE, and clinical outcomes, using Pearson's test. Zero values of sIgE concentrations were replaced with the value 0.005 before log transformation. Multiple linear regression models with ΔFEV1, ΔFEV1/FVC, ΔACT, and ΔmAQLQ as dependent variables were constructed for estimating coefficient factors. Independent variables were ∆B‐Eos count, ∆FeNO% (or ∆FeNO), ∆tIgE (or ∆IgE to Phadiatop and fx5), and the analyses were further adjusted for gender, change in age (months), weight, smoking, pet ownership, asthma medication, and ongoing allergen immunotherapy (AIT) at follow‐up. The influence of sex on the association between Δ values of inflammatory biomarkers and clinical outcomes was investigated by interaction analysis. A p value < 0.05 was considered statistically significant and p < 0.10 indicated a trend.All statistical analyses were performed using STATA/IC 13.1 (StataCorp LP). If continuous variables had a distribution skewed to the right , a geometric mean with a 95% confidence interval was used for descriptive statistics, and logarithmic transformation was performed before further analyses. Unpaired 2.7The Uppsala Regional Ethical Review Board approved the study (registration numbers 2009/349 and 2012/420) and all subjects and, when appropriate, their legal guardians gave written informed consent.33.1p = 0.032). A slightly larger proportion of atopic asthmatics (IgE antibody levels ≥ 0.10 kUA/L) was found at baseline compared to follow‐up (87.7% vs. 83.3%), but the difference was not significant (p = 0.210). Almost all (99%) of the atopic asthmatic subjects reported allergic symptoms to either furry animals or pollen (data not shown). A larger proportion of the asthmatic subjects who were lost to follow‐up were males and current smokers  but not in the group with undetectable sIgE (<0.10 kUA/L)  Table . Further3.31/FVC was noted.In unadjusted analyses, the longitudinal changes in type‐2 biomarkers and tIgE intercorrelated significantly with each other Table . In contn = 253), an independent relationship was observed between the changes in FeNO%, and FEV1/FVC (p < 0.01) and FEV1 (p < 0.05), respectively. Furthermore, these associations were also observed in a model including only asthmatics with sIgE levels ≥0.10 kUA/L (n = 224) .We further investigated the relationship between the change in inflammatory variables and IgE antibodies, and lung function using different multiple linear regression models adjusted for confounding factors . When analyzing the whole asthma population (1/FVC (p = 0.071) and FEV1 (p = 0.094). In similar models again, but with baseline values of the type‐2 biomarkers as independent variables, no significant associations were seen with changes in lung function. No significant associations between changes in type‐2 biomarkers, and changes in mAQLQ and ACT score as dependent variables, were noted in any of the above model variants. For the above multivariate analyses, replacing ΔtIgE with ∆sIgE concentrations to Phadiatop and fx5 did not change the results (data not shown).In similar models using absolute FeNO instead of FeNO%, the independent association between change in FeNO and lung function was markedly weakened: FEV3.4We divided the analyzed population into females and males and performed univariate analyses. A significant decline in IgE antibodies to fx5 was observed in both males and females, whereas IgE to Phadiatop and total IgE were significantly decreased only in females. Lung function was the only clinical outcome that was significantly changed over time in both females and males  but not males , whereas the association between ∆FeNO% and ∆FEV1/FVC became nonsignificant for both sexes. Furthermore, a significant interaction (p = 0.02) with sex was found for the relation between changes in FeNO% and changes in FEV1. When repeating the multiple linear regression analysis in asthmatics with sIgE levels ≥0.10 kUA/L and stratified according to sex, the independent association between changes in FeNO% and FEV1 remained in females (p = 0.002), and a similar interaction with gender was seen (p = 0.02).In sex‐specific analyses, a negative association between ∆FeNO% and ∆FEV4This study describes the longitudinal changes of clinical and inflammatory variables in young asthmatics over a median of 43 months. Despite improved asthma control, lower prevalence of recent asthma attacks at follow‐up, and the fact that the asthmatic subjects used more medication, they were characterized by a small reduction in lung function. This lung function decline was only seen in patients with detectable sIgE levels at baseline. Furthermore, an independent association between an increase in individualized FeNO and lung function decline was shown within this population of relatively well‐controlled asthmatic subjects.A/L). This could not be shown in a previous study with a shorter follow‐up period of 6 months.The longitudinal data of type‐2 biomarkers revealed an increase in absolute FeNO. However, it is well‐known that FeNO values increase in parallel with somatic growth and plateaus after puberty.Aging may generally be related to a decline in tIgE. In a recent large population‐based study of adults, a reduction in tIgE with increasing age was observed regardless of the age at baseline,A/L) but not in patients with undetectable sIgE.A/L for ruling out IgE sensitization used in this study contrasts with clinical routine where a higher cut‐off level of 0.35 kUA/L or a wheal diameter for skin prick test greater than 3 mm is commonly used for defining atopy. However, a lower cut‐off of >0 mm for skin prick tests seems to increase the sensitivity for identifying IgE sensitization, applicable though primarily in epidemiological studies.Another important observation derived from the stratification into different sIgE groups was that a significant reduction in lung function over time was seen in the elevated and detectable sIgE groups but was absent in the group with undetectable sIgE. This finding is supported by our recent study, highlighting the presence of clinically significant type‐2 inflammation in patients with low but detectable sIgE levels  but not in subjects with undetectable sIgE. An independent association between increase in individualized FeNO and lung function decline was seen in female asthmatics. Our findings suggest that exhaled NO signals for inflammatory mechanisms closely related to accelerated lung function decline independent of IgE levels and B‐Eos count.In conclusion, in this cohort of young asthmatics followed over a median of 43 months, IgE was reduced, but B‐Eos and FeNO remained unchanged during the observation period. An accelerated lung function decline was seen in subjects with detectable sIgE levels (≥0.10 kUMagnus Borres is an employee of Thermo Fisher Scientific, and Kjell Alving has received research material from the same company and from Hemocue. None of the other authors declare conflict of interest.