PurposeThe accuracy of the diagnosis of hypertension increases by obtaining repeated blood pressure values. This can be achieved by obtaining multiple office blood pressure measurements (OBPM) or by home blood pressure measurements (HBPM) or using ambulatory blood pressure measurement (ABPM). A 24-hour ABPM is recommended as the preferred modality to diagnose hypertension by the latest guidelines. In this study, we evaluated the diagnostic accuracy achieved by four short-duration-ABPM (sABPM) protocols, i.e., two-hour, four-hour, six-hour, eight-hour compared to standard 24-hour ABPM.Materials and methodsWe performed a prospective diagnostic accuracy study in individuals attending the medicine outpatient department. Participants were >18 years, had systolic BP between 130 and 150 mmHg, and were not previously diagnosed as hypertensive. Initially, two OBPM values were taken, and then the ABPM apparatus was applied for 24 hours, which recorded BP at every 30 minutes while awake and at every 60 minutes while asleep. We used four sABPM values  and OBPM values as index tests, with awake ABPM cut-off of greater than or equal to 135/85 as the definition of hypertension. Analyses were conducted using the R Statistical language  on macOS Catalina 10.15.6.ResultBased on the 24-hour ABPM based reference standard definition, 76 (48.7%) individuals out of 156 were classified as hypertensive. The positive predictive value (PPV) of sABPM at two-hour, four-hour, six-hour, and eight-hour above the cut-off of 135/85 was 80.0%, 83.8%, 93.4%, and 94.8%, respectively. PPV increased from 83.8% to 93.4%, and the positive likelihood ratio (LR+) increased from 5.4 to 15.0 with an increase in the sABPM duration from four to six hours.ConclusionWe conclude that short-duration ABPM for six hours has a good diagnostic accuracy amongst hospital attendees. It can act as an intermediary approach between multiple OBPM and standard 24-hour ABPM in this population. Accuracy in making a diagnosis of hypertension depends upon obtaining repeated blood-pressure measurements. Traditionally these measurements are obtained by healthcare providers in clinics or office settings and, more recently, self-obtained at home. Either of these are fraught with limitations. While office blood pressure measurement (OBPM) requires multiple visits to the health facility for diagnosis, home blood pressure measurement (HBPM) requires possession of a well-calibrated instrument. OBPMs are rarely recorded as per the recommended protocol in real-world practices, and this method leads to an overdiagnosis due to white coat hypertension (WCH), which accounts for 30%-40% of patients with elevated office BP . Owing tDespite ABPM being a better diagnostic tool, and the reference standard for the diagnosis of hypertension, it has not gained popularity in clinical practice. In addition to its limited availability due to cost, there are logistic issues both for patients as well as providers for 24-hour usage. We hypothesized that a shortened-duration ABPM (sABPM) could be an intermediate strategy that retains the benefits of ABPM like the elimination of the white-coat effect and the ability to obtain multiple BP values. At the same time, sABPM can address practical problems like enabling the retrieval of equipment on the same day and avoiding nocturnal patient discomfort. Our four-part research question in PICO format for the current study was, among adults with newly diagnosed elevated blood pressure (P), is sABPM  (I), compared to 24-hour ABPM (C), accurate for diagnosis of hypertension(O).Design and ethicsWe performed a prospective diagnostic accuracy study to address our research question. The study design was approved by the institutional human ethics committee. Participants provided written informed consent for the study. The protocol of this study was not pre-published in a public registry.SettingThe study was carried out at the All India Institute of Medical Sciences, Bhopal. Patients who attend the medicine out-patient department (MOPD) have their blood-pressures obtained by para-medic staff at the reception using digital sphygmomanometers. Treating physicians evaluate this and previous values for the initiation of drug therapy. Office blood pressure measures (OBPM) obtained at each time point is an average of three values obtained one minute apart. Obtaining blood pressures prior to the consultation is a standard practice in this setting.ParticipantsWe screened adults (age 18 years or more) presenting to the MOPD for inclusion in the study. We sought to include individuals who had their systolic blood pressure between 130 and 150 mmHg and did not have any previous diagnosis of hypertension in the study. We excluded individuals who were pregnant, were on any blood pressure-lowering therapy, or had a past history of diabetes mellitus, ischemic heart disease, cerebrovascular disease, or chronic kidney or liver disease. This screening was done two days a week among all outpatient department (OPD) attendees on that particular day, beginning October 2019. The screening was continued till November 2020 (except between February and October 2020 due to the ongoing coronavirus disease 2019 (COVID-19) pandemic). All eligible participants were explained about the utility of ABPM for the diagnosis of hypertension, and consent was sought to collect baseline variables (demography and cardiovascular disease (CVD) risk factors) from their outpatient records and for using their ABPM derived blood-pressure data for current research. Eligible participants were advised to seek an appointment for ABPM, as only two recorders were available and a maximum of six recordings were possible in a week. Consent was obtained when participants reported for their ABPM appointment.ProceduresEligible and consenting participants were required to undergo a repeat OBPM on the day of their appointment. Participants were explained about the standard precautions such as not to smoke, or have any meals in the preceding one hour, or have any medication in the week preceding the appointment. OBPM was obtained using a digital sphygmomanometer  with participants sitting with feet, back, and arms well-supported. Thereafter, ABPM apparatus Schiller BR-102plus  was applied and programmed to record blood pressure values at every 30 minutes while awake (between 6 am and 10 pm) and at every 60 minutes when asleep (between 10 pm and 6 am) for next 24 hours. Usually, ABPM was applied in the forenoon, to ensure at least nine hours of continuous awake recordings. Participants were asked to return back the next day to remove the device and recorder. Blood pressure values were retrieved from the recorder through Medilog Darwin-2 software . sABPM-based index tests and the reference standard were both defined based on these values. The reference test was based on values downloaded in the software. The index test values were estimated based on the tabulation of values exported to Microsoft Excel  by an investigator (SU) who was unaware of the reference standard values.DefinitionsHypertension on ABPM and OBPM was defined as per EHS 2018 guidelines. These guidelines define hypertension depending on the method of blood-pressure measurement as 24-hour ABPM greater than or equal to 130/80 mmHg  and OBPM value of greater than or equal to 140/90 mmHg. Blood pressure values of the first hour is excluded from ABPM-based definitions. In the current study, hypertension based on 24-hour ABPM values was the reference standard. The average of ABPM-derived values obtained between the first and third hour constituted two-hour sABPM. Similarly, values between the first and fifth hours were four-hour sABPM; between the first and seventh hour were six-hour sABPM; between the first and ninth hour were eight-hour sABPM. We used four sABPM values  as index tests, with awake ABPM cut-off of greater than or equal to 135/85 as the definition of hypertension. OBPM values were used as another index test, with blood pressure greater than or equal to 140/90 defined as hypertension. We also performed an analysis using a method-independent definition of blood pressure of greater than 130/80mm Hg for both OBPM as well as ABPM for comparison. The interpretation of all index tests  was done blinded to the reference standard (24-hour ABPM). Since sABPM values were derived from the 24-hour ABPM recording, it eliminated any temporal bias between the index test and the reference standard. The presence of hypertension on an index test, but its absence on the reference standard  was defined as WCH. The absence of hypertension on an index test but its presence on a reference standard  was defined as MH.Statistical analysisAnalyses were conducted using the R Statistical language  on macOS Catalina 10.15.6 , epiR  and their 95% confidence intervals. Further, we used sABPM values on a continuous scale and performed a receiver-operating curve (ROC) analysis to determine the overall accuracy of the index tests.Of the 6320 OPD attendees, 156 individuals were included in the study  individuals were classified as hypertensive. As more blood pressure values are available, with a longer duration of recording, the proportion of individuals with WCH  is considerably reduced. However, the proportion of individuals with MH  is less affected  and 2.38 (95%CI 2.14 - 2.63), respectively. These positive likelihood ratios (LR+) correspond to a positive predictive value (PPV) of 67.5 and 69.3%, respectively. A lower OBPM threshold of 130/80 mmHg does not improve the diagnostic accuracy. The PPV of sABPM at two hours, four hours, six hours, and eight hours above a cut-off of 135/85 was 80.0%, 83.8%, 93.4%, and 94.8%, respectively. PPV increased from 83.8% to 93.4%, and LR+ increased from 5.4 to 15.0 with an increase in sABPM duration from four to six hours  for sABPM at four hours was 86.1%, at six hours was 90.2%; and at eight hours, it was 92.5% Figure . In the current study of adults, who had elevated SBP between 130 and 150 mmHg recorded during a hospital outpatient visit, without a previous diagnosis of hypertension, only about half of them truly had hypertension. Hypertension was more likely in men who also had a higher prevalence of smoking. Since individuals who are diagnosed as having hypertension need to be initiated on life-long therapies, accuracy measure of interest to the clinicians is a positive-predictive value. It is the proportion of true positives amongst all those who are positive on an index test. While this metric is only about 70% when we measure OBPM twice, it rises to above 90% with at least six hours of ABPM. The positive likelihood ratio is a related metric, and odds of a person truly having hypertension are increased by about 2.3 times with OBPM and up to 15 times with six hours of ABPM. Likelihood ratios can also be explained in terms of pre- and post-test probabilities. Given a pre-test probability of hypertension of 48%, as in the current study, two OBPMs increase the post-test probability to about 70%. On the other hand, six hours of ABPM increases the post-test probability to 93%. Higher post-test probabilities make clinicians more confident about the diagnosis for the initiation of useful life-long drug therapies. While a standard 24-hour ABPM is the reference standard for accurate diagnosis of hypertension, at least six hours of awake recordings will be needed to achieve reasonable accuracy in diagnosis.The context of the research inquiry philosophized here needs to be reemphasized before moving further. The authors were interested to check not only the concordance of sABPM to standard ABPM but also to classify correctly based on test results. Moreover, this inquiry is a little away from the conventional diagnostic accuracy studies in the sense that both the tests are fundamentally governed by the same rationale, and results may be considered as final for making clinical decisions by physicians. Hence, the predictive values of the tests may be given due emphasis. It becomes more pertinent when choosing the optimum duration of ABPM between two close values like six or eight hours. We argue that as hypertension is largely asymptomatic, with the potential for having serious implications at a later time and being treated effectively if diagnosed on time, a high NPV is desirable even if it is having a moderate PPV. The false positive  cases in this scenario are likely to be get benefitted/protected by complying/adopting the appropriate alterations in lifestyle. Yet, we can afford to lose a hypertensive  because of the reasons mentioned above. From this perspective, a six-hour ABPM (having the highest NPV) value seems the optimum duration for ABPM. Moving from six to eight hours offers no advantage in terms of NPV with little gain in PPV although the confidence intervals are largely overlapping.A few previous studies also had similar findings. A study by Sheps SG et al. found that as few as six hours of monitoring with two to three recordings per hour was associated with the most gain in the precision of the diagnosis, keeping awake ABPM as the reference . SimilarWith the ubiquitous availability of blood pressure devices, the diagnosis of hypertension is usually made with measurements obtained in the clinics, at home, or nearer home as in community-based screenings. It is important to understand that all these methods do have their limitations, especially if the diagnosis of hypertension is not made diligently. While ESH-2018 guidelines recommend that ABPM should be used for making an initial diagnosis of hypertension owing to its greater accuracy, limited availability of this device and practical difficulties in 24-hour recording preclude its usage. The findings of the current study emphasize the fact that multiple blood pressure readings are essential for a more accurate diagnosis. If an ABPM device is available, and 24-hour measurements are not feasible, at least six-hour recordings will be the next best option. If an ABPM device is not available, the limitation of OBPM should be recognized and multiple values should be obtained at or nearer home to at least limit the WCH effect of clinic-based values. These approaches improve the diagnostic certainty of hypertension. Individuals with WCH can be seen as having greater BP variability in clinic-based settings. This state should be recognized as having a greater risk of development of true hypertension on follow-up .Our study used robust diagnostic accuracy measures, in a population where there is real uncertainty in classifying individuals as having hypertension. There are, however, certain limitations in our approach. We used standard ABPM values obtained every 30 minutes as our index test. While obtaining more values in awake recording could have allowed us to maximize the utility of the ABPM device, it would have also resulted in greater patient discomfort. Our study population consisted of outpatient attendees, where the pre-test probability of having hypertension is greater. These results may not translate well in settings such as community-based settings, where the prevalence is lower. The shorter duration of ABPM does not significantly reduce the number of false negatives or individuals with masked hypertension. Missing out on masked hypertension remains a limitation with recordings that are either for a short duration or that preclude nocturnal values. We recognize the importance of nocturnal recordings on ABPM as having an important diagnostic and prognostic value, especially for the detection of masked hypertension.Short-duration ABPM for six hours has a good diagnostic accuracy as an index test. It can act as an intermediary approach between multiple OBPM measurements, which require repeated clinic visits by the patient and still do not eliminate the whitecoat effect significantly, and standard 24-hour ABPM, which has a component of patient discomfort and logistic issues. At the primary healthcare level, the use of sABPM can lead to better classification of individuals as hypertensive or non-hypertensive and improved confidence of clinicians in their diagnostics.


Background and Objectives: An inter-arm systolic blood pressure difference (IASBPD) is defined as a blood pressure (BP) disparity of ≥10 mmHg between arms. IASBPDs are associated with an increased risk of cardiovascular disease (CVD). Similarly, visceral fat accumulation (VFA) is clinically important because it is associated with higher cardiovascular disease risk. Accordingly, this study compared the body composition parameters of IASBPD individuals with individuals who did not express an IASBPD. Materials and Methods: The analysis included 104 patients. The blood pressures of all participants were measured simultaneously in both arms using automated oscillometric devices. Then patients were divided into two groups according to their IASBPD status: Group 1 (IASBPD− (<10 mmHg)); Group 2 (IASPPD+ (≥10 mmHg)). Body composition parameters were measured using bioelectrical impedance analysis. Results: In 42 (40%) patients, the simultaneously measured IASBPD was equal to or higher than 10 mmHg. The right brachial SBP was higher in 63% of patients. There were no differences between the groups in terms of demographic and clinical characteristics. Regarding the two groups’ body composition parameter differences, VFA was significantly higher in group 2 (p = 0.014). Conclusions: The IASBPD is known to be associated with an increased risk of cardiovascular events. Although the body mass indexes (BMIs) of the two groups were similar, VFA levels in those with a greater than 10 mmHg IASBPD were found to be significantly higher. This finding may explain the increased cardiovascular risk in this group. In the guidelines for the management of hypertension, it is recommended to measure blood pressure (BP) in both arms during the first hospital visit and use the arm with a higher value for follow-up measurements . As suchObesity is an important risk factor for metabolic and CVD . Body maOur study first identified the patients with an IASBPD ≥10 mmHg by simultaneously measuring blood pressures from both arms and then examined and compared the distribution of body composition parameters, specifically VFA, in patients with and without IASBPD.The study protocol was approved by the local Ethics Committee with code number OMU-KAEK-2019-839 on 12 December 2019. All participants provided written informed consent. This study was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.One hundred and four patients  who were assessed in the medical checkup clinic were included in the study. Patients with a thoracic aortic dissection, aortic aneurysm, syphilitic aortitis, aortic coarctation or Takayasu Disease, anatomic defects in both arms that would prevent blood pressure measurement, distinct edema, symptomatic heart failure (New York Heart Association class II–IV), nephrotic syndrome, and pacemaker were excluded from the study. The body composition parameters of both groups were measured using BIA and compared. Trained study nurses interviewed participants and collected data on current smoking habits, hypercholesterolemia, diabetes, and previous history of CVD. Heights and weights were measured, and BMIs were calculated. Blood samples were taken for routine evaluation.®; Omron Life Science, Kyoto, Japan) and are calibrated every 6 months. Measurements were simultaneously taken at the level of the brachial artery from both arms while patients were in a sitting position. After selecting the appropriate cuff, measurements were taken from both arms twice. If a greater than 10 mmHg difference was detected in the measurements made from the same arm, a third measurement was made, and the arithmetic mean of the values was recorded.Blood pressure (BP) measurements were performed simultaneously using two automatic oscillometric devices after a 5-min rest. The devices used for measurement have the same features (Omron M3The difference in BP between arms was expressed as the absolute difference. Absolute BP difference (| R − L |) was calculated to investigate the BP difference between the right and left arms regardless of which arm showed higher BP.®. Tanita Corp., Tokyo, Japan). Body composition parameter measurements were made after settling on the analyzer while standing upright with bare feet and light clothes. Physical activity states  other than the usual daily life activities of the participants were questioned. Height, age, gender, and physical activity information were entered in the BIA analyzer. Weight, BMI, total body fat, body muscle mass, total body water, bone mass, and visceral fat mass values were calculated automatically via the device’s unique software . The Tanita body composition analyzer tracks visceral fat (VF) and gives a range between 1 and 59. A rating between 1 and 12 indicates the healthy level of VF. A rating between 13 and 59 indicates the increased level of VF.After 12 h of fasting and adherence to the pre-measurement guideline recommendations , body composition parameters were measured using the bioelectrical impedance analysis method  and analytical methods (Shapiro-Wilk Test). For the normally distributed variables, the Student’s p > 0.05) . Regarding laboratory measurements, the lipid profile and renal functions were similar. The fasting blood glucose value of Group 2 was significantly higher than Group 1 . The basic demographic and laboratory features of the patients included in the study are shown in The patients included in the study were divided into two groups according to their IASBPD status (Group 1: IASBPD− (<10 mmHg), Group 2: IASBPD+ (≥10 mmHg). Sixty-two (60%) of the participants were included in group 1, and 42 (40%) were included in group 2. The basic demographic and clinical characteristics were similar between the groups. The mean BMI of the patients included in the study was 28.45 ± 5, and there was no significant difference in terms of BMI between the two groups (p < 0.001). Alternatively, there was no statistically significant difference between the study groups in terms of systolic, diastolic, and mean blood pressure values measured from the right and left arm (p > 0.05). The blood pressure measurement values of both groups are shown in The simultaneously measured IASBPD was equal to or higher than 10 mmHg in 40% of the patients. Right brachial SBP was higher in 64%, and left brachial SBP was higher in 36% of patients. The absolute inter-arm systolic, diastolic, and mean blood pressure differences of Group 2 were significantly higher than Group 1 (p = 0.014), while there was no statistically significant difference in other parameters. Body composition parameters of the patients included in the study are shown in When the body composition parameters of both groups were evaluated, the amount of visceral fat rate was higher in Group 2  followed for an average of 9.8 years, 55 patients (23%) had an IASBPD ≥ 10 mmHg. In this study, the IASBPD ≥10 mmHg was associated with cardiovascular events and all-cause mortality. In addition, there was a 5–6% increase in the mortality incidence for each 1 mmHg increase in systolic blood pressure between the arms . In anotThere is controversy concerning which obesity marker is a stronger predictor of CVD . In a reExcess body fat is accepted as a heterogeneous situation in which individuals with similar levels of BMI may not have similar metabolic and cardiovascular disease risks. Variations in body fat distribution may provide a potential explanation for this risk difference . The whiExperimental studies show that abnormal glucose metabolism impairs normal endothelial function, accelerates atherosclerotic plaque formation, and contributes to plaque rupture and thrombosis . StudiesHowever, only a few cross-sectional studies have evaluated associations between adiposity and IABPSD. A representative sample of 484 Finnish adults aged 25–74 years, people with IASBPD > 5 mmHg had higher BMI and arm circumference . People This study’s main limitations were small number of patients, unbalanced probands by gender and cross-sectional study design. Long-term prospective studies with higher patient numbers would provide more robust data and important additional endpoints associated with IASBPD and visceral fat accumulation.To the best of our knowledge, this is the first study to examine the relationship between IASBPD and body composition parameters. Increased CVD risk in patients with an IASBPD ≥10 mmHg can be explained by the high amount of visceral fat. In this context, a significantly higher detection of VFA in patients with an IASBPD ≥ 10 mmHg may help to explain this situation.As a result of our study, data suggesting an association between IASBPD and increased visceral fat were obtained. Visceral fat accumulation, which was easily measured by the BIA method, was significantly higher in patients with IASBPD. This finding might provide an explanation for the increased cardiovascular risk in this group based on prior studies. Thus, in the general population, the detection of visceral fat by a simple and low-cost method in routine examinations for selected individuals can contribute to the prevention of cardiovascular diseases. If the BIA methodology had a wide range of availabilities, it might be possible to use it as useful as BP measurement.


There is scant data on the role of hyperuricaemia, gout and allopurinol treatment in chronic kidney disease (CKD). Therefore, our aim is to investigate the possible associations between hyperuricaemia, gout, prescription of allopurinol and renal outcomes in patients with CKD.The retrospective cohort study involved 1123 Royal Brisbane and Women’s Hospital (RBWH) patients, enrolled in the CKD.QLD registry from May 2011 to August 2017. Patients were divided into two uric acid categories, with uric acid ≤ 0.36 mmol/L and > 0.36 mmol/L. Association of delta estimated glomerular filtration rate (eGFR) with gout, allopurinol treatment and hyperuricaemia were analysed.Patients with an entry urate > 0.36 mmol/L were older, had higher body mass index (BMI) and worse baseline kidney function. Proportion of patients with gout, hyperuricaemia and allopurinol treatment increased with advanced CKD stages. Age-adjusted analysis revealed a significant association between serum urate level and delta eGFR, with no significant association between gout, treatment with allopurinol and delta eGFR. Furthermore, neither gout nor the prescription of allopurinol had a significant effect on the time to renal death (composite end point of kidney replacement therapy or death).Hyperuricaemia seemed to be independently associated with faster CKD progression or renal death. This was not observed with gout or prescription of allopurinol. Furthermore, allopurinol was not associated with decreased incidence of cardiovascular events. These data suggest that hyperuricaemia is likely the effect and not the cause of CKD or CKD progression. Chronic Kidney Disease (CKD) is a global health issue . The proThe association between the diagnosis of gout and the prescription of urate lowering therapy on renal outcomes is not well characterised. The effects of one of these drugs, allopurinol, include improved endothelial function and arterial wave reflection . Small pCKD.QLD is a state-wide collaborative multidisciplinary research and practice program that was established in 2011 . It invoThe study was approved by the following Human research ethics committee; Royal Brisbane and Women’s Hospital, Queensland Health—HREC/15/QRBW/294 and the Medical research ethics committee, University of Queensland—2011000029. The study has been approved with subsequent protocol amendments and extensions.To investigate the association between hyperuricaemia, diagnosis of gout, prescription of allopurinol and renal outcomes, we performed a retrospective cohort study involving 1123 patients from the CKD.QLD registry from the Metro North Hospital and Health Service. The patients were followed from 1st of May, 2011 to 31st of August, 2017. Patients below the age of 18 and those who had been commenced on KRT prior to May 2011 were excluded from this study.p value < 0.05 was regarded as statistically significant.SPSS software was used to analyse the univariate and multivariate association between serum uric acid levels, diagnosis of gout, prescription of allopurinol and renal outcomes. The patient cohort was described as means as well as percentages. The concept of delta estimated glomerular filtration rate (eGFR) was used as the metric of progression of kidney disease. Delta eGFR was calculated by subtracting the latest eGFR (CKD EPI) from the initial eGFR (CKD EPI) and then dividing that by the time in years between the two data points. Chi square analysis between the groups based on presence or absence of hyperuricaemia, diagnosis of gout and prescription of allopurinol were compared to the comorbidities to ascertain an association between these variables. T tests were used to determine the significance of the association between serum uric acid levels, diagnosis of gout, prescription of allopurinol and the delta eGFR. Kaplan Meier analysis with log rank test and Cox proportional hazard modelling were used to determine the association between the above variables and time to renal death. The term renal death was defined as the onset of kidney replacement therapy or death. This was done for two reasons. Firstly, there was a large number of patients who died during the follow up and secondly, deaths are a competitive factor for end stage renal failure. The onset of renal death or patient death was subsequently used as an endpoint. Kaplan Meier analysis was also used to determine the association between the prescription of allopurinol and the time to new cardiovascular events during the follow up time. A A total of 1123 patients were analysed. The patients were followed up for a total of 7 years. The median follow-up was 2070 days and the range was 2404 days. The median age of the cohort was 70 years with an interquartile range of 21. There were 546 (49%) females and 577 males (51%). One hundred twenty-six patients (11%) progressed to end stage renal failure requiring KRT. In this cohort, there was a total of 274 deaths. Of these deaths, 41 were attributed to renal failure, 53 to sepsis, 40 to cardiac causes, 40 to cancer, 15 to respiratory causes, 14 to stroke and 60 to others and unknown causes.There were 775 patients with a serum uric acid level greater than 0.36 mmol/L (reference range 0.18–0.36 mmol/L). Their baseline characteristics are summarised in Table Multivariate analysis was performed controlling for age, diagnosis of gout and prescription of allopurinol. This analysis showed a significant correlation between initial urate levels and delta eGFR. Additionally, a more extensive multivariate analysis involving comorbidities such as cardiovascular risk factors, initial eGFR and age still revealed a significant association between initial serum uric acid levels and delta eGFR Table b.There were 210 patients with a diagnosis of gout. Baseline characteristics between patients with and without a diagnosis of gout are summarised in Table 2 vs 30.5 kg/m2; p < 0.01), worse kidney function at time of consent , higher serum uric acid levels  and higher proportions of diabetes mellitus (p = 0.04), dyslipidaemia (p < 0.01) and hypertension (p < 0.05); (Table 2/year (std dev: 6.9) compared to 2.4 ml/min/1.73m2/year (std dev: 7.6) in patients who were prescribed allopurinol (p = 0.8). On multivariant analysis, age, diagnosis of gout and allopurinol prescription were not associated with delta eGFR  commenced KRT during the study period and 59 (28.5%) died  . There was no significant difference in the time to death in patients with prescription of allopurinol, with mean days of 2788 compared to 2590 (log rank p = 0.3). Moreover, there was no significant difference in the time to death in patients with a diagnosis of gout, with mean days of 2761 in patients without diagnosis of gout compared to 2606 days in patients with a diagnosis of gout (log rank p = 0.3).In this study, there was an association between the rate of progression of CKD, including subsequent renal death, and serum uric acid levels. There was no association between the diagnosis of gout or prescription of allopurinol and progression to renal death. The presence of hyperuricaemia on CKD.QLD registry entry was associated with faster progression to renal death. However, it is important to note that the patients with hyperuricaemia had worse baseline kidney function as well as a higher incidence of cardiovascular risk factors such as dyslipidaemia and diabetes, which could have contributed to faster CKD progression. Importantly, on multivariate analysis there was still an association between serum uric acid levels and renal outcomes after adjusting for the diagnosis of gout, prescription of allopurinol, age and entry eGFR.At present, the literature on the effect of serum uric acid levels, allopurinol prescription and the diagnosis of gout on renal outcomes is inconclusive. Some studies reported that raised serum uric acid levels accelerated progression of CKD . HoweverIn our study, prescription of allopurinol was not associated with worsening renal outcomes. We also analysed the impact of allopurinol in patients with hyperuricaemia. However, even after focusing on allopurinol use in patients with hyperuricaemia, we could not identify an association between allopurinol prescription and renal outcomes. Others report similar findings. Siu and colleagues  used a rThe third relationship we explored was the effect of the diagnosis of gout on progression of kidney disease. We hypothesised that given the occurrence of clinical manifestations from hyperuricaemia, diagnosis of gout may be associated with faster progression of CKD. Our results did not support this hypothesis. There was no significant change in the renal outcomes. There was also no significant association with time to renal death in patients with diagnosis of gout in this CKD cohort. Interestingly, the literature looking at this issue is scarce. Most of the literature has been focused on exploring the prevalence of CKD in patients with a diagnosis of gout, with no studies exploring the rate of kidney deterioration.The strengths of our work include the use of delta eGFR to quantify the effect of the three interlinked variables on the progression of kidney dysfunction in CKD. This allowed a quantitative design of evaluation. Moreover, there was a relatively large number of patients included in the study. Furthermore, incorporating the diagnosis of gout, hyperuricaemia, and prescription of allopurinol to analyse the renal outcomes reduces loss of the sentient uric acid variables. However, there were several limitations to this study. Firstly, this study was a single centre study and this limits the generalisability of our findings. It would be hard to compare the findings of our study with other centres containing different environmental and socioeconomic profiles. Secondly, we lacked data on adherence patterns. This is especially important in evaluating the association between allopurinol prescription and kidney function deterioration. Thirdly, the threat of residual confounding factors cannot be excluded in a non-randomised study using registry-based retrospective data and this could explain some of the discrepancies in our results compared to other studies. Fourthly, the delta eGFR values were low with a high standard deviation. This could be due to the number of patients whose renal function improved over the course of the follow up period which could have affected our results.In summary, we undertook a retrospective cohort study investigating the relationships between hyperuricaemia, allopurinol prescription, diagnosis of gout and renal outcomes We observed an increased prevalence of hyperuricaemia and gout with more advanced stages of CKD. Moreover, we identified an association between hyperuricaemia and faster CKD progression, as well as reduced time to renal death. However, we did not observe an association between prescription of allopurinol, diagnosis of gout and renal outcomes Moreover, prescription of allopurinol was not associated with decreased incident cardiovascular events in the CKD cohort. These data suggest that the hyperuricaemia is likely the effect and not the cause of CKD. Randomised control trial evidence with a longer follow up remains the gold standard to clarify the effect of allopurinol and uric acid lowering therapies on renal outcomes in a CKD cohort.


In this study, we applied a composite index of neutrophil-lymphocyte * platelet ratio (NLPR), and explore the significance of the dynamics of perioperative NLPR in predicting cardiac surgery-associated acute kidney injury (CSA-AKI).st and December 31th 2019, participants were prospectively derived from the ‘Zhongshan Cardiovascular Surgery Cohort’. NLPR was determined using neutrophil counts, lymphocyte and platelet count at the two-time points. Dose-response relationship analyses were applied to delineate the non-linear odds ratio (OR) of CSA-AKI in different NLPR levels. Then NLPRs were integrated into the generalized estimating equation (GEE) to predict the risk of AKI.During July 1n = 658, 26.9%), stage 2–3 . Compared with non-AKI patients, both preoperative and postoperative NLPR were higher in AKI patients . Such an effect was a ‘J’-shaped relationship: CSA-AKI’s risk was relatively flat until 1.0 of preoperative NLPR and increased rapidly afterward, with an odds ratio of 1.13 (1.06–1.19) per 1 unit. Similarly, patients whose postoperative NLPR value >11.0 were more likely to develop AKI with an OR of 1.02. Integrating the dynamic NLPRs into the GEE model, we found that the AUC was 0.806(95% CI 0.793–0.819), which was significantly higher than the AUC without NLPR .Of 2449 patients receiving cardiovascular surgery, 838 (34.2%) cases developed CSA-AKI with stage 1 (Dynamics of perioperative NPLR is a promising marker for predicting acute kidney injury. It will facilitate AKI risk management and allow clinicians to intervene early so as to reverse renal damage. Acute kidney injury (AKI) is a complicated and multifactorial clinical syndrome, which is characterized by a sudden decrease in renal function. Cardiac surgery is the second commonest reason for AKI behind sepsis . It was Preoperative inflammation is commonly encountered in patients receiving cardiac surgery. It can be caused either by heart infection (such as infectious endocarditis) or other chronic infectious diseases (COPD). In clinical practice, the neutrophil to lymphocyte ratio (NLR) is an easily effective and low-cost biomarker of inflammatory status ,6. PreviThis study was designed as a prospective cohort study based on the ‘Zhongshan Cardiovascular Surgery Cohort’. This cohort was established in 2009 and contained nearly 30,000 subjects with complete demographic and clinical records. We recruited patients who underwent cardiac surgeries in 1 July 2019 to 31 December 2019. The inclusion criteria of participants were as follows: (1) aged over 18 years, (2) underwent cardiac surgery, (3) did not receive renal replacement therapy (RRT) before surgery, and (4) had completed renal and cardiac data. We further excluded those who were under 18 years old, received the heart transplant and RRT, or took less than one serum creatinine (SCr) test. This study was approved by the Institutional Committee of Zhongshan Hospital (B2017-039). Participants were given informed consent prior to recruiting, and their identity information was replaced as a unique code during analysis.Patients’ demographics were collected through a structured questionnaire. Clinical data with timestamps were extracted from the electronic medical records (EMR). We selected thirty-seven factors for analysis. They were divided into five groups in chronological order: (1) demographics and comorbidity: age, gender, body mass index (BMI), hypertension, diabetes, unstable angina pectoris (UAP), and myocardial infarction (MI) within the last 3 months; (2) preoperative cardio-renal function [within 24 h of admission to hospital]: cardiac surgery history, coronary angiography, New York heart association (NYHA) grade, left ventricular eject fractions (LVEF), pulmonary artery pressure (PAH), SCr, blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), serum uric acid (SUA) and proteinuria; (3) perioperative blood routine test [within 24 h of admission]: glucose, albumin, hemoglobin, peripheral blood cell counts including erythrocyte, total leukocyte, neutrophil, lymphocyte and platelet; (4) intraoperative factors: cardiopulmonary bypass (CPB), surgery type, aortic cross-clamp time (ACCT), ultrafiltration volume and blood transfusion; (5) postoperative factors : APACHE II score, Euro score and blood routine test. Moreover, we also retrieved the preoperative medication data for patients with higher NLPR to evaluate the effect of antibiotic use on AKI occurrence.According to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) criteria [It was calculated at two-time points: on admission and within 1 h at ICU. Cardiac surgery was typed into the valve, coronary artery bypass grafting (CABG), aorta, valve + CABG, valve + large vessels and others.m = 5, maxit = 5). Student’s t test and Wilcoxon test were applied to compare the distributional difference of continuous variables. Pearson test and Fisher’s exact test were applied to compare the proportional difference of categorical variables (‘gmodels’ package). Given the prior hypothesis of the dose-response relationship, we used restricted cubic splines with three knots at the 10th, 50th and 90th centiles to flexibly model the association of neutrophil count, lymphocyte count, platelet count, and NLPR with CSA-AKI incidence . Non-linearity was tested by using a likelihood ratio test comparing the model with only a linear term against the model with linear and cubic spline terms. Bounded with the median value, we used a logistic model to calculate odds ratios (ORs) for each 1/10 unit increase in predict variables. Moreover, the generalized estimating equation (GEE) was applied for multivariate analysis, which combined the time-dependent indicators of leukocyte counts and NLPR (‘geepack’ package). We applied the purposeful selection of covariates [p < 0.05 as the criterion for statistical significance.Statistics were conducted by using R 3.6.1 software (R core team). Continuous variables are presented as mean ± standard deviation or median with inter-quartile range (IQR). Categorical variables were expressed in numbers and percentages (‘Hmisc’ package). Missing data were found in less than 10% of the records, mainly focusing on NYHA grade, BMI, and albumin. We imputed the missing value by the methods of multiple imputations . The average age was 57.2 ± 12.8 years old, and male patients accounted for 59.2% (n = 1449). According to KDIGO classification, 838 (34.2%) patients developed AKI after surgery. Of them, 658 patients located in Stage-1, and another 131 and 49 cases were Stage-2 and Stage-3, respectively. The rate of AKI-RRT was 1.2% (n = 30). Of the 2618 enrolled participants who underwent cardiac surgeries, 2449 patients met the inclusion criteria and were comprised of formal analysis , p < 0.001), and NLPR , p < 0.001) were higher in AKI patients. Lymphocyte , p < 0.001) and platelet , p < 0.001) counts were negatively associated with AKI risk. Due to the posttraumatic stress response after surgery, blood cell counts changed a lot. While patients with a higher postoperative NLPR still had an increased risk of developing AKI , p < 0.001).The blood analysis was summarized in 9). It then increased after that (p for non-linearity <0.001). The OR per 1 unit increase was 0.76 (95% CI 0.61–0.95) below 3.2*109, and 1.11 (95% CI 1.04–1.17) above 3.3*109. The risk of CSA-AKI was relatively flat until around the median of lymphocyte, platelet, NLPR. It then started to increase rapidly afterward. The median of preoperative NLPR was 1.0. Above the median, the OR per 1 unit increase was 1.13 (95% CI 1.06–1.19). In comparison, no significant association was found below the median (OR 1.22 95% CI 0.63–2.38). Similarly, we observed such a ‘J’ shape curve between postoperative NLPR and AKI. The OR increased along with the NLPR increase after surgery below the median of 11.0 (OR 1.02 95% CI 1.01–1.03). Then we classified the NLPR value into five groups (In e groups . Comparen = 82) had ever used antibiotics before cardiac surgery. The incidence of AKI in patients receiving antibiotic treatment was 32.9%, significantly lower than that without antibiotics . The aOR was estimated as 0.44 (95% CI 0.26–0.76). Subgroup analysis revealed that patients in the second-highest NLPR group (2.00–2.99) could benefit more from antibiotic treatment .We further retrieved the medication data, especially the antibiotic use, in 365 patients whose preoperative NLPR was over 2.0 . Of themZ = 4.081, p < 0.001).We combined the NLPR values in two-time points to predict CSA-AKI occurrence . ConsideThe present study provides the first report for integrating the dynamics of NLPR at two-time points into the prediction model and described the dose-response relationship of NLPR and AKI risk. Previous studies also identified that NLPR was associated with AKI in sepsis  and abdoet al. found that a distinct population of primed neutrophils in circulation had a high expression of adhesion and activation markers [Neutrophils and lymphocytes play essential roles in the innate immune system and adaptive immune system, respectively . At the  markers . Additio markers . During  markers . SubstanCardiovascular surgery involves a series of renal injury pathways. It includes hypoperfusion, ischemia-reperfusion injury, neurohumoral activation, inflammation and oxidative stress . CPB areIn this study, we creatively incorporated platelets into traditional NLR and the new indicator was used to quantify the effect of inflammation on AKI. After integrating the dynamic NLPRs into multiple predictive models, we found that the AUC was up to 0.806, higher than the AUC without NLPR. It will facilitate AKI risk classification management and allow clinicians to intervene AKI in early-stage. While the model’s specificity was superior to sensitivity. It suggests that NLPR could be most effectively used to exclude AKI. For high-risk patients, further testing (SCr or novel biomarkers) is necessary to stratify their AKI risk. Notably, we found that the incidence of AKI in patients receiving antibiotic treatment was significantly lower than that without antibiotics. This phenomenon may be related to blocking certain inflammatory processes by antibiotics. Vancomycin and ceftriaxone have been proved to be potentially nephrotoxic. However, these antibiotics are still the first-line antibiotic for the infection after heart surgery. Subgroup analysis revealed that the application of nephrotoxic antibiotics could reduce the risk of CSA-AKI. However, cardiac surgeons and nephrologists should reach a consensus and weigh up the pros and cons of nephrotoxic antibiotics.Still, our study has several limitations to be declared. Firstly, this study was designed as a single-center study. And it would be better to follow-up the patients and describe the relation between NLPR and long-term kidney recovery. Secondly, we did not compare it with C-reactive protein and monitor the related cytokine expression, such as interleukin (IL)-8, myeloperoxidase, and IL-6. However, our pilot study showed that NLPR had a highly positive correlation to procalcitonin and lactic acid. In future studies, a large-scale cohort and multi-omics analysis are needed to verify the predictive value of NLPR in CSA-AKI incidence.In conclusion, the dynamics of perioperative NPLR is a promising and noninvasive marker relating to acute kidney injury during the perioperative period. Protective strategies should be implemented for those who had initially increased NLPR. It will facilitate AKI risk management and allow clinicians to intervene early so as to reverse renal damage.Click here for additional data file.


Blood pressure (BP) shows a seasonal variation with higher levels at lower temperatures. Many hypertensives, however, report on BP disturbances rather in association with acutely changing weather conditions than with absolute temperatures. To date, the impact of changing meteorological parameters on hypertensive episodes remains elusive. We performed a retrospective time series regression analysis on 203,703 patients in three hospitals in Germany between 2010 and 2018, of whom 7362 patients were admitted for hypertensive disease. Numbers of daily admissions for hypertension were associated with metereological data obtained from three nearby weather stations. Data comprised temperature , athmospheric pressure, and precipitation. Changes of these parameters were calculated over a two and three day period. There was an inverse correlation between maximal daily temperature and the number of admissions for hypertensive disease, which remained significant both after adjustment for seasonality and week day in a spline model and in a constrained distributed lag model. A decrease of maximal temperature by 5 °C was associated with a 3% increase of risk for admission for hypertension and vice versa. There were no significant effects of precipitation and athmospheric pressure on the number of admissions. With regard to all observed metereological parameters, neither the change within two, nor within three days was consistently associated with the number of daily admissions. High temperatures are associated with lower numbers of hypertensive episodes requiring hospital admission. In contrast to the subjective perception of many hypertensive patients, however, acutely changing weather conditions are not associated with a higher risk of hypertensive emergency. Daytime BP is increased in winter, whereas there is an elevation of nighttime BP in summer6. The elevation of BP in wintertime is primarily attributable to low daytime temperatures. In contrast, the summertime elevation of nighttime BP is an indirect consequence to higher nighttime temperatures: It is considered to be related to poor sleep quality in warm summer nights6. The seasonal variation of BP is a global phenomenon affecting both sexes, all age groups, normotensive individuals, and hypertensive patients4.Many hypertensive patients report on blood pressure (BP) disturbances in times of changing weather conditions. So far, however, there is only data on the association of absolute temperatures and hypertension. Thus, BP shows a seasonal variation with lower levels at higher environmental temperatures and higher levels at lower temperatures8. A recent study analyzed 74 million deaths in 13 countries and estimated that 7.7% of overall mortality was attributable to environmental temperature exposure9. High BP occurs more frequently in winter than in summer10. A likely physiological explanation is subcutaneous vasoconstriction leading to an increased total peripheral resistance and central blood volume.Low and high temperatures are associated with increased cardiovascular mortality12. Hospitalizations for hypertensive crises are less frequent during summer-time high temperatures. Low temperatures and thereby wintertime are associated with a higher number of hospitalizations. This phenomenon is of clinical relevance, since the decline of BP in summer may be associated with orthostatic symptoms and may thereby necessitate a reduction of antihypertensive medication. In contrast, an up-titration may be required in winter A consensus statement by the European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability summarized the current evidence on the seasonal variations of BP and provides recommendations for adjustment of antihypertensive treatment1.Two studies have investigated the impact of ambient temperatures on hospitalization rates for hypertensionHence, a change of weather conditions induces compensatory vegetative reactions. It is conceivable, that these reactions are perceivable for some "meteorosensitive" subjects. Whereas the depicted evidence for seasonal long-term effects of temperature on BP is robust, the effects of short-term changes of metereological parameters on BP are unknown. Moreover, it remains elusive, whether such acute changes of temperature or athmospheric pressure are associated with an increased risk of hospitalization for hypertension. If so, there would be a clinical need to acutely adjust hypertensive treatment. Therefore, data on this topic are urgently required. The present work associates weather parameters from three meteorological stations in the Ruhr-region of Germany with the incidence of hospitalizations for hypertension in three large hospitals of this region. It examines for the first time, whether short-term changes of metereological parameters within three days predict an increased incidence of admissions for hypertension.max, Tmin and Tmean; °C), R (mm in 24 h) and mean P (hPa). Changes of these parameters from one day to the other were calculated as Δd2T, Δd2R and Δd2P as well as changes within three days as Δd3T, Δd3R and Δd3P. Moreover, the daily temperature amplitude Trange (Tmax − Tmin) and the maximal temperature amplitude between two days Trange_max  were calculated. Thus, there were eighteen meteorological datasets comprising data for each of the 3287 days in the observation period. The metereological data are available on request from the “Deutsche Wetterdienst” (www.dwd.de), the data on daily numbers of admissions for hypertension are available from the corresponding author on reasonable request.Data on average daily ambient temperatures (T), precipitation  and athmosperic pressure (P) for the observation period of January 1st 2010 to December 31st 2018 was obtained from the National Reference Institution (“Deutscher Wetterdienst”). Parameters were measured at three meteorological stations . These meteorological stations were located closest to the participating hospitals with a distance of < 25 km each. Meteorological parameters comprised maximal, minimal and mean daily temperature (Thttps://recht.nrw.de/lmi/owa/br_text_anzeigen?v_id=74120170406111640601). The local ethical committee of Ruhr-University Bochum decided that there was no need for ethical approval, since there was no personalized data (registration number 21-7424-BR). Data obtained from the three hospitals contained only numbers on daily admissions and numbers of diagnoses. Data did not obtain any additional personal information like age, gender, etc., either. Every hospital in Germany has to publish such data sets on numbers of patients and diagnoses on an annual basis as individual quality reports in order to make its competences and focuses transparently available. The study thereby followed the Declaration of Helsinki.We performed a systematic retrospective multi-center analysis using an electronic data extraction approach to identify subjects, who were admitted to hospital for hypertensive disease. Three hospitals in two cities  of the central Ruhr-region in Germany participated in the project. All hospitalizations for hypertensive diseases in these hospitals were extracted in a day-by-day manner using the diagnosis coded at discharge and submitted to the health insurance. Briefly, all subjects with a diagnosis related group (DRG) code "I10" or “I11” between 2010 and 2018 were identified. These DRGs comprise admissions for “hypertension” and “hypertensive emergency” and “hypertensive heart disease”. Thus, we included only patients, who attended the hospital for the primary diagnosis of hypertension. Admission for alternative diagnoses with hypertension as a comorbidity was an exlcusion criterion. Daily numbers of admissions in the three hospitals were added to an overall sum of hospitalizations. According to the local code of medical ethics, an ethics approval was not necessary  there should be. The number of knots determines the number of end-to-end cubic curves. The more degrees of freedom, the more flexible the function is. Seven splines per year provide a a balance between adequate seasonality control without competing with the variable of interest to explain the short term variable of interest. We primarily used 62 knots [(Number of years × 7) − 1] and afterwards changed the number of knots as sensitivity analysis.p < 0.05. These statistical calculations constitute a state of the art approach to investigate changes of metereological parameters on clinical endpoints and has been performed in analogous studies in the past15. Calculations were done with freely available software R16.In order to take delayed effects into account we used a distributed lag model (sevens days) as part of a sensitivity analysis. In the distributed lag model (DLM) the series of the weather parameter is shifted foreward in time an re-fitted with the previous adjusted model. The lag time was increased from 0 to 7 days and the lag effects were adjusted for each other by entering the 0- to 7-day shifted series simultaneously in the model. Statistical significance was evaluated using partial Wald test with a significance level set to The local ethical committee of Ruhr-University Bochum checked the project and decided that an ethical approval was dispensable (registration number 21-7424-BR).From January 2010 to December 2018, there were an overall number of 203,703 patients admitted to the internal medicine emergency rooms of the three hospitals. The mean number of daily admissions were 62 ± 26 per day with a minimum of 12 and a maximum of 137. 7362 patients were admitted for hypertensive disease between 2010 and 2018. The mean number of daily admissions for hypertensive disease was 2 ± 2 (range 0–14).d2T, Δd2R, Δd2P).The mean temperature between 2010 and 2018 was 10.5 ± 6.8 °C. The maximal temperature was 36.7 °C (in July 2015 and August 2018). The mean daily temperature amplitude was 9.4 ± 4.7 °C, the maximal temperature amplitude between two days was 26.8 °C. The highest amplitudes occurred between March and April (> 21 °C). The mean daily precipitation was 2.3 ± 4.7 mm. Mean atmospheric pressure was 997.9 ± 8.7 hPa. From 2010 to 2018 the mean daily temperature increased from 8.9 to 11.5 °C. Except for 2018 (1.7 mm), mean daily precipitation was rather constant over the observation period (Ø 2.4 mm). Figure mean, Tmax, Tmin, Trange, Trange_max and the number of admissions for hypertensive disease . The association of daily maximum temperatures and the ratio of admissions for hypertension/ overall admissions is illustrated by Fig. Correlation analysis showed a significant correlation between Tse Table . All Spemax and hospital admissions for hypertension remained significant. The findings of this model are presented in Table In a second step we analyzed the association of metereological parameters and daily admissions for hypertensive disease in an adjusted model accounting for seasonality and long-term effects (spline-model). After adjustment of the naive Poisson model for seasonality, long-term effects and weekday as confounders, only the association between Tmax and the number of daily admissions for hypertension . Thus, the risk for admission to hospital for hypertension decreases by 3% per 5 °C increase of Tmax. Vice versa, the risk for admission is increased by 3% with a 5 °C decrease of Tmax.There was a significant inverse association of Tmean and Trange , which did not reach, however, statistical significance. A decrease of Tmin was not statistically significantly associated with an increasing risk of hospital admissions for hypertension .There were analogous trends for TNeither atmospheric pressure, nor precipitation had a significant effect. There was no effect of interday changes of any of these parameters either. These results did not change significantly after adding weather parameters as confounders in the models: Thus, e.g. the findings for temperature effects remained significant after controlling for athmospheric pressure and precipitation.mean the RRcumulative is 0.602 with an 95% CI of 0.387–0.938, for Tmax the RRcumulative was 0.671 per 5 °C increase with an 95% CI of 0.462–0.973. This means that the cumulative effect of increasing temperature after a 7 day lag period is a risk decrease up to 40% per 5 °C increase.Potentially delayed effects were calculated with constrained distributed lag models (DLM) as part of the sensitivity analysis. The protective effect of increasing temperature was reproducible in the DLM. Per 5 °C increase of T13 After reducing the number of knots from 62 to 40 as well as after increasing the number from 62 to 75 the protective effect of Tmax in the adjusted model remained. However for Tmean and Tmax the effect in the lag model was no longer significant.The sensitivity analysis also included changing the amount of control for seasonality and long term trends by changing the number of knots in the spline based approach as proposed by Bashkaran et al.6. The present study constitutes the first systematic analysis of the association of short-term weather changes and hospitalizations for hypertension. Our findings show that neither a change of temperature, athmospheric pressure, nor rainfall within two or three days is associated with the incidence of hospital admissions for hypertension. The analysis comprises a period of nine years and more than 200,000 patients in the emergency rooms of three large hospitals. The observed nine years cover both years with outstandingly warm summers (e.g. 2015 and 2018) and cold winters (e.g. 2010–2012). Thus, the findings may be regarded as rather representative for a middle European region.Many patients with hypertension report that they perceive short-term weather changes by increasing BP. This subjective view, however, has never been investigated in an adequate scientific manner. Whereas there is robust evidence for long-term, seasonal effect of changing temperatures on BP, these data are lacking for short-term changes of weather conditionsThe study did not examine BP itself. Instead, the daily incidence of hospital admissions for hypertension was analyzed as a surrogate parameter of severe hypertensive episodes. In fact, some of the hospitalizations may have taken place primarily for diagnostic reasons, e.g. an exclusion of secondary causes of hypertension. Since these diagnostics usually take place in an outpatient setting, however, it may be assumed that the majority of cases indeed represent hypertensive emergencies. Moreover, admissions for diagnostic reasons are unlikely to be affected by weather conditions. Hence, the study does not exclude a potentially mild effect of changing meteorological parameters on BP. It does exclude, however, that short-term changes are associated with substantial increases of BP necessitating hospitalization.24. In 1961 there was a highly ranked study showing that BP in men is lower in summer than in wintertime3. This finding was confirmed e. g. in the PAMELA cohort, a population-based study in Ontario, Canada, and elderly individuals in the Three-City Study11. This finding is supposed to be primarily mediated by peripheral vasoconstriction in colder temperatures. Our data confirm that the long-term changes of metereological parameters translate into a higher hospitalization rate for hypertension in wintertime.Our study supports the clinical relevance of previous findings on the association of absolute temperatures and BP6.This central finding was consistent in both mere correlation analysis and all applied adjusted models accounting for seasonality, week day, athmosperic pressure, precipitation as well as in the lag model. In order to assess the quantity of this effect, we analyzed the assocation of a 5 °C decrease of maximal temperature on hospital admission. This decrease was associated with a 3% increase of risk for admission, whereas a 5 °C increase lowered the risk by 3%. The correlation between mean and minimum daily temperatures with the number of hospital admissions lost statistical significance in the adjusted models. The maximal daily temperature is usually reached during daytime, whereas minimal temperatures occur at nighttime. Nighttime temperatures, however, are likely to have a lower effect on BP, since they affect the sleep period with people being inside. As described above, there is a summertime elevation of nighttime BP, which is considered to be related to poor sleep quality in warm summer nights25. Our study and the majority of previous investigations found no correlation of atmospheric pressure with BP changes2.Atmospheric pressure is the most objective weather parameter because it is independent of outdoor or indoor activities. The association of atmospheric pressure and BP has been investigated before with conflicting findings. Thus, a significant inverse relationship between atmospheric pressure and systolic BP has been described for hypertensive patients in individual reports26. The investigation covered a period of two years in the city of Novi Sad. The overall number of admissions for hypertension was 264 and thereby substantially lower than in the present investigation (n = 7362). In contrast, a study in Ontario, Canada, found that cold temperatures (1st percentile compared to the temperature with minimum risk of morbidity) were associated with a 37% increase in hypertension-related hospitalizations whereas no significant association with hot temperatures was observed12. Accordingly, an investigation in New York reported that summer-time high temperatures were associated with reduced risk of hypertension-related hospital admissions27. Unfortunately, it did not evaluate any possible effects from cold temperatures. None of these studies, however, evaluated the effects of short-term metereological changes on BP or hospital admissions.To date, there are only three studies that have investigated the impact of temperature on hypertension-related hospitalizations. A recent Serbian study found no association between three weather parameters  and hospitalizations for hypertensionOur study investigated the effects of short-term changes of metereological parameters on hospital admissions for hypertension for the first time and exruled a significant association. On the one hand, this might be intriguing, since the subjective perception of changing weather is frequently stressful. This stressful perception could indeed have led to an increase in sympathetic tone. On the other hand, it may be questioned, in how far subtile changes in temperature or athmospheric pressure may elicit a clinically relevant effect on the autonomic nervous system. Our data disprove that this psychological phenomenon has a substantial impact on vasomotor tone leading to an increased risk of hospitalization for hypertension. Moreover, many patients decide to attend a hospital only in case of long-lasting complaints. Hence, resolution of a potential short-term increase on BP might have prevented the need for hospitalization. Even if so, however, the present large-scale data exclude clinically relevant hypertensive adverse events in context of short-term weather changes.Our study is limited by the lack of data on BP itself. Data on BP cannot be derived from a DRG based case extraction. This approach, however, allows to investigate a very high number of subjects. Moreover, it allows to analyze the clinical relevance of potentially changing BP in terms of a "harder" cardiovascular endpoint, namely the need for hospitalization for substantially increased BP values.The present analysis constitutes the first investigation on the association between acute changes of weather parameters and hypertension-associated hospitalizations. It shows that short-term changes in weather do not increase the risk for hypertensive emergencies. It supports, however, the seasonal long-term association of low temperatures with a higher risk of hospitalization and vice versa.The findings of our investigation may be of practical clinical relevance. On the one hand, physicians should inform hypertensive patients about a potential need of an intensified medication in colder seasons and should encourage them to check their BP eventually. On the other hand, they can inform them that acute changes in weather conditions will have little effect on their BP.


We investigate the association between health-enhancing physical activity and the quality of life in patients with non-dialysis chronic kidney disease. We performed data analysis on 1618 of 2238 patients from 2011 to 2016, obtained from the KoreaN Cohort Study for Outcome in Patients with Chronic Kidney Disease (KNOW-CKD). Health-related quality of life was measured using the Korean version 1.3 of Kidney Disease Quality of Life short-form questionnaire. Health-enhancing physical activity was defined as 150 min of moderate-intensity or 75 min of vigorous-intensity aerobic physical activity throughout the week. Propensity score matching analysis and linear regression was performed to estimate the effect of health-enhancing physical activity on health-related quality of life. The estimate of average treatment effects was 2.60 in the kidney component summary score, 4.45 in the physical component summary score, and 4.24 in the mental component summary score. In all component summary scores and most of their subscales, health-enhancing physical activity showed a significant association with health-related quality of life. Subgroup and sensitivity analyses also showed robust results. This study suggests that health-enhancing physical activity elevated quality of life in patients with non-dialysis chronic kidney disease. The results can contribute to encourage physical activity in patients with chronic kidney disease. Chronic kidney disease (CKD) is an emerging public health problem globally . It is wThe World Health Organization (WHO) has recommended guidelines for physical activity for an individual’s healthy life and better QoL ,9. Healthttp://www.clinicaltrials.gov, accessed on 6 December 2021). A total of 2238 patients were enrolled between 2011 and 2016 from a tertiary care hospital in Korea. Patients with heart failure ; or liver cirrhosis (Child-Pugh class 2 or 3); or previous maintenance dialysis or organ transplantation; or inability or unwillingness to provide written consent; or history of current malignancy; or pregnancy; or a single kidney were excluded at enrollment. The detailed study design, methods, and protocols have been previously described [The KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD) is a nationwide prospective cohort study in Korea which includes patients with non-dialysis CKD from stages 1-5 (NCT01630486 at 2). Blood pressure was measured using an electronic sphygmomanometer in the clinic after 5 min of seated rest. In addition, 10 mL of a blood sample, first-voided urine sample, and a 24-h urine was collected from all the patients for biochemical analyses. The collected samples were sent to the central laboratory  for measurement of the complete blood count and blood chemistries. Serum creatinine level was measured by the isotope dilution mass spectroscopy (IDMS)-traceable method.Baseline demographic details and clinical data of the entire study population, including age, sex, smoking history, cause of CKD, economic status, educational level, comorbidities, and medications were surveyed by a well-trained research coordinator. Height, weight, and circumferences of waist and hip were also measured. BMI was calculated by dividing the initial body weight (kg) by height squared  was used to evaluate HRQoL. The KDQOL-SF comprises a kidney disease component summary (KDCS) and the Medical Outcome Study Short Form-36 Health Survey (SF-36) including a physical component summary (PCS) and a mental component summary (MCS). KDCS is an arithmetic mean of kidney disease-targeted scales which includes 11 subscales: (1) symptom/problems, (2) work status, (3) sexual function, (4) physician encouragement, (5) effects of kidney disease, (6) cognitive function, (7) sleep, (8) patient satisfaction, (9) burden of kidney disease, (10) quality of social interaction, (11) social support. The PCS and MCS each contain four subscales: (1) physical function, (2) role physical, (3) bodily pain, (4) general health, (5) emotional well-being, (6) role-emotional, (7) social function, and (8) energy/fatigue. The former four subscales are summarized in the PCS, and the latter four subscales are summarized in the MCS. Responses to each question of the questionnaire were converted to equivalent scores, and each scale ranged from 0 to 100, with higher numerical scores indicating better HRQoL in that subscale.Estimated glomerular filtration rate (eGFR) was calculated using the four-variable Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation . HEPA wat-test for normally distributed data and the Mann–Whitney U test for non-normal distribution data were used to compare the clinical characteristics between the groups. The Chi-square test and Cochran–Armitage trend test were used to compare the categorical variables . We applied a simple imputation method for missing data using the ‘MICE’ package [p-values < 0.05 were considered statistically significant.A student’s  package , because package . The sta package  and comp package . All sta2 and 509 (31.5%) patients had diabetes mellitus. Patients with higher education (above high school) were 1287 (79.6%), and most patients (82.8%) were married. A high prevalence of hypertension (95.7%) in this study population was observed. We compared the clinical characteristics between HEPA (patients who performed HEPA) and non-HEPA (patients who did not perform HEPA) groups, and significant differences in clinical characteristics were observed between the two groups. The HEPA group had a higher proportion of males and higher employment status than the non-HEPA group. The ratio of divorced or widowed subjects was higher in the non-HEPA group. In addition, a higher level of eGFR and a lower proportion of current smokers was observed in the HEPA group. The difference in the level of hemoglobin between the two groups was statistically significant; however, there was no difference in clinical practice. Age, body mass index, waist-hip ratio, serum albumin, serum uric acid, fasting glucose, C-reactive protein, protein to creatinine ratio, high-density lipoprotein, triglycerides, mean ankle-brachial pressure index, and bone mineral density of the total spine did not show any statistically significant difference between the groups. All component summary scores of HRQoL was higher in the HEPA group than in the non-HEPA group. The detailed data are summarized in Among a total of 1618 patients, the mean age was 52.3 years, and the number of females was 605 (37.4%). The median baseline eGFR was 48.0 mL/min/1.73 mWe constructed linear regression models to estimate the beta coefficients of HEPA on HRQoL, and the covariates were selected based on the outcomes of the univariate analysis and clinical significance. HEPA showed a statistically significant effect on all component summary scores even after adjusting for independent variables that could affect the quality of life. Beta coefficients (CI) of HEPA were 2.560 (1.496–3.624) for KDCS, 4.058 (2.517–5.599) for PCS, and 4.193 (2.529–5.857) for MCS in the fully adjusted linear regression model. Most subscales including symptoms/problem lists, sexual function, effects of kidney disease, sleep, the burden of kidney disease, quality of social interaction, social support, physical function, role-physical, bodily pain, general health, emotional well-being, role-emotional, social function, and energy/fatigue were significantly associated with HEPA in linear regression. The most powerful effects of HEPA on the subscales of the component summary scores were on sexual function  in KDCS, general health  in PCS, and energy/fatigue  in MCS. The detailed results were summarized in To control the influence of confounding variables, we performed propensity score matching analysis. Covariates were selected based on the results of the univariate analysis and the clinical significance. A full matching method was applied to ensure a balance between the covariates, and the covariate balancing was performed based on the average treatment effect on control (ATC) and average treatment effect on treated (ATT). The matching results of covariate balance are visualized in After obtaining covariate balance, we estimated the ATT, and average treatment effect (ATE) with non-parametric bootstrapping techniques . Estimates of the treatment effect of HEPA on all subscales and component summary scores are shown in Γ value of 1.4, at which the statistical significance disappears. It indicates that the improvement in HRQoL by the propensity score matching analysis becomes statistically insignificant when the odds to be assigned to the HEPA group are increased by 140% or more due to unobserved factors. However, these statements assume that the impact of unobserved variables on HRQoL is powerful, which rarely is the case.We performed a sensitivity analysis to evaluate the robustness of the increase in HRQoL due to HEPA in case of deviation from the conditional independence assumption, which is an important assumption in propensity score matching analysis. The sensitivity analysis showed a Both early and advanced CKD groups showed statistically significant relationships between HEPA and HRQoL a–c in liHEPA for patients with non-dialysis CKD was associated with all component summary scores of HRQoL in both linear regression and propensity score matching analysis. Propensity score matching was applied to minimize the effect of confounders, and the sensitivity analysis also showed robust and consistent results. Our study reveals the clinical effectiveness of HEPA in improving the HRQoL of patients with non-dialysis CKD.HRQoL is the assessment tool for QoL, which focuses on the effect of health status, and its importance in patient care is increasing. Patients with end-stage renal disease have a lower HRQoL score compared to that of the general population ,17. KDOQImproving HRQOL is an important goal to maintain health. HRQoL is affected by various factors including economic status , maritalWe hypothesized the probable mechanism of the impact of HEPA on HRQoL. Although there are many hypotheses, the identification of exact mechanism of HEPA’s influence on HRQoL is still challenging. Neuroendocrine dysfunction might induce lethargy and depressive mood in CKD, and adequate physical activity has an effect on the neuroendocrine system . It coulOur study has many strengths, including a prospective observational design, robust data collection, and a large study population. We also used robust statistical methods, including minimized omitted variable bias with multiple imputation methods and basic statistical assumptions to ensure unbiased and consistent results. These strengths make our analyses reliable. Despite many strengths, our study also has a few limitations. First, we could not explain the exact causal relationship between HEPA and HRQoL as seen in all observation studies. However, observational studies are powerful tools to assess the epidemiologic relationships, and we capitalized on complimentary analytic methods for a robust evaluation of the effect of HEPA and relevant clinical outcomes . Second,Our findings emphasize the importance of HEPA associated with HRQoL in patients with non-dialysis CKD. HEPA recommended in the CKD population could improve the patients’ HRQoL and might improve their health and disease prognosis. A further follow-up study is required to determine the recommended amount of individualized physical activity for patients with non-dialysis CKD.


Chronic kidney disease (CKD) is accompanied by increases in circulating fibroblast growth factor 23 (FGF23) and aldosterone levels. Here, we tested the hypothesis that aldosterone may be one of the driving forces behind increased FGF23 secretion in CKD.Using data from a prospective study in humans, a retrospective study in dogs and cats, and an experimental study in 5/6-nephrectomized mice, we analyzed the relationship between circulating FGF23 and serum aldosterone levels in CKD across four species. To assess the effects of acute inhibition of aldosterone signaling on circulating FGF23, we acutely treated mice with established CKD with the mineralocorticoid receptor blocker canrenone (50 mg/kg iv/sc), and measured intact FGF23 before and 24 h as well as 72 h after start of administration of the drug.rS = 0.57, p = 0.0368; dogs: rS = 0.66, p = 0.0019; cats: rS = 0.75, p = 0.0003; mice: rS = 0.49, p = 0.0004). Injection of canrenone in mice with established CKD did not lead to changes in FGF23 levels within 24 h, but reduced FGF23 in all mice at 72 h.We found a tight positive association between circulating intact FGF23 and serum aldosterone in human, canine, and feline CKD patients, as well as in experimental murine CKD (humans: Aldosterone may drive enhanced FGF23 secretion in CKD, possibly explaining the tight positive association between circulating intact FGF23 and aldosterone in human, canine, and feline CKD patients as well as in experimental CKD models. Aldosterone is the body’s main mineralocorticoid hormone. Its production in the adrenal gland is triggered by potassium, angiotensin II, and, to a lesser extent, adrenocorticotropin . As part3  (Fibroblast growth factor 23 (FGF23) is a 32 kD proteo-hormone mainly secreted from bone cells, reducing phosphate reabsorption from urine by the downregulation of sodium phosphate co-transporters in proximal renal tubular epithelium . In addi(OH)2D3] , 2004. I(OH)2D3] . FGF23 m(OH)2D3] . It is cReciprocally to declining renal function, FGF23 levels continue to rise stage-dependently in CKD patients. In advanced CKD stages, circulating intact FGF23 can be increased 1,000-fold above normal . Elevatein vivo  mice. In addition, we tested the hypothesis that aldosterone may be a direct driving factor of increased FGF23 secretion in CKD in a mouse study.2) into 5 different groups: G2 , G3a , G3b , G4 , and G5 . Renal injury in most patients was caused by glomerulonephritis of different causes . Renal Damage in the rest of the patients was caused by atypical hemolytic-uremic syndrome (1), diabetic glomerulosclerosis (1), p-ANCA associated systemic vasculitis (1), cysts (1), and amyloidosis (1).The human study was approved by the Ethical Committee of the Medical University of Vienna on November 17, 2016 (#2006/2016), and each patient provided written consent for the use of the serum for this study. We prospectively collected serum from 16 patients with various stages of chronic kidney disease (CKD stage 2–5), who underwent a diagnostic kidney biopsy. Each patient received a full set of routine lab work including electrolytes, creatinine, aldosterone, and intact FGF23  measurements. Overall, 16 Caucasian study participants were included in the analysis . Both geThe retrospective study in cats and dogs was approved by the Institutional Ethics and Animal Welfare Committee of the University of Veterinary Medicine Vienna, and all owners signed a general consent form allowing the later use of non-used samples. Client-owned dogs and cats with or without CKD were retrospectively recruited from the patient population referred to the Teaching Hospital of the University of Veterinary Medicine Vienna. Unused blood samples after routine blood sampling of dogs and cats were collected and stored at –80°C. Serum samples of eligible patients fulfilling the inclusion criteria of the study were later analyzed for intact FGF23 and aldosterone. The diagnosis of CKD IRIS  stage ≥ 2 was made based on the presence of a history of polyuria and polydipsia, azotemia, and urine specific gravity < 1.030 in dogs and urine specific gravity < 1.035 in cats over at least 3 months. Dogs and cats were assigned to IRIS stages 2–4 for CKD based on plasma creatinine concentrations . Dogs and cats presented with non-renal diseases without impact on parathyroid function, and those with diseases with possible impact on renal function, but normal plasma creatinine values were assigned to the IRIS stage 0/1 group. All animals in IRIS stage 0/1 had plasma creatinine and urine specific gravity in the normal range. Dogs and cats < 1 year of age, and those diagnosed with acute kidney injury, primary parathyroid diseases, suspected recent acute-to-chronic kidney disease transition, and animals receiving corticosteroids or angiotensin-converting enzyme (ACE) inhibitors were excluded from the study. Overall, 1 intact male, 22 neutered males, 21 neutered female cats and 11 intact male, 5 neutered male, 11 intact female, and 8 neutered female dogs were included in this study.ad libitum access to food and water. CKD was surgically induced via 5/6-Nx under isoflurane anesthesia as previously described . All experiments were performed in 14–16-weeks old male C57Bl/6 mice. Mice were kept at 24°C with a 12/12-h light/dark cycle and had escribed . Buprenoescribed . 5/6-Nx escribed . In ShamTo test the putative FGF23-stimulating role of aldosterone signaling in this disease model, 5/6-Nx mice with established CKD (12 weeks postsurgery) received a single iv injection at 0 h for the 24 h time point or two sc injections at 0 and 48 h for the 72 h time point with the aldosterone receptor blocker canrenone . Blood for measurement of circulating intact FGF23 was taken from the submandibular vein immediately before and 24 or 72 h after start of canrenone treatment.Serum creatinine was measured on a Hitachi 911 autoanalyzer (Roche), and on a Cobas c111 analyzer (Roche) in dogs, cats and mice, respectively. Serum intact FGF23 in all species was analyzed using an immunoassay detecting intact FGF23 across many species . This assay has previously also been validated in cats and dogs . Serum iP < 0.05 were considered significant.Statistics were computed using Prism 8.4 . The data were analyzed by Spearman’s rank correlation analysis to reduce the effects of outliers, followed by linear regression analysis. Serum levels of FGF23 before and after treatment with canrenone were compared using Wilcoxon test. rS = –0.53, p = 0.0372), as well as with plasma creatinine in canine and feline CKD patients and in 5/6-Nx mice 2D3 lowering effect of FGF23 might indirectly stimulate renin expression in the kidney. To the best of our knowledge, short-term intervention studies examining the effects of RAAS inhibition on circulating FGF23 in CKD patients do not exist. Therapeutic use of RAAS inhibitors to lower blood pressure and to prevent further loss of renal function is common in CKD  underlying enhanced FGF23 secretion in CKD.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by the Ethical Committee of the Medical University of Vienna. The patients/participants provided their written informed consent to participate in this study. The animal study was reviewed and approved by the Ethics and Animal Welfare Committee of the University of Veterinary Medicine Vienna. Written informed consent was obtained from the owners for the participation of their animals in this study.JR, MP, OA, RO, IB, and RE conceived and designed the studies. JR, MP, OA, and RE performed the experiments, collected the samples, and analyzed the data. JR, MP, IB, and RE wrote the manuscript. All authors discussed and reviewed the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.