NIR-LT had the highest sensitivity (99.67–99.67%) and accuracy (78.22–77.23%) for the determination of occlusal enamel caries according to examiners 1 and 2, respectively. LF method had the highest sensitivity (70.83–54.17%) and accuracy (66.34–59.41%) for determining occlusal dentin caries according to examiners 1 and 2, respectively. The ROC curve (Az) value ranged between 0.524 and 0.726 for the different methods tested. Most effective methods for the diagnosis of occlusal enamel and dentin caries were determined to be NIR-LT and LF pen methods, respectively. The present prospective clinical study showed that NIR-LT and LF-Pen were a reliable modality for the detection of occlusal enamel and dentin caries without ionizing radiation.The aim of this study was to compare the diagnostic performance of clinical visual examination (ICDAS II), digital periapical radiography (PR), near infrared light transillumination (NIR-LT), and laser fluorescence (LF) to microcomputed tomography (Micro-CT) which is the reference standard for the detection of non-cavitated occlusal enamel and dentin caries in third molar teeth. Potential participants were consecutively recruited. In this prospective study, 101 third molars of 101 patients were examined; the molars had non-cavitated occlusal caries which required extraction. ICDAS II, PR, NIR-LT and LF examinations were carried out by two blinded examiners. Reference standard was determined by micro-CT imaging seven days after extraction. Accuracy rate, sensitivity, specificity, predictive values and areas under receiver operating characteristic (ROC) curves (Az) were statistically analyzed. Nonparametric variables were subjected to the Kruskal–Wallis Test. Significance level was set as  Risk assessment and early diagnosis of adult caries and application of conservative and/or restorative treatment is essential . OcclusaIdeal diagnostic method for occlusal caries detection should be non-destructive, simple, fast, accurate, easily applicable, and cost effective. It should also be able to show the depth and extend of the caries lesion in order to enable early detection and early conservative intervention . Visual Today, it has been shown that fluorescence techniques and improved visual techniques supported by clinical studies are effective in the early diagnosis of occlusal caries, therefore it is no wonder that their popularity is increasing by the day . Porphyrin-vitro caries assessment [Microcomputed tomography (Micro-CT) is a non-invasive and non-destructive innovative technique that is used to visualize tooth structures in three dimensions with very high accuracy. Micro-CT replaced microscopic evaluation and is now considered as the gold standard method for sessment ,19. Recesessment ,18,19. Usessment .The majority of the studies in the previous literature regarding comparison of examination techniques in the detection of caries were carried out under in vitro conditions due to ethical concerns. However, it is not always an acceptable approach to defend the clinical applicability of the evaluation performed under in vitro conditions.Therefore, the aim of this study was to compare and evaluate the diagnostic accuracy of the initial occlusal caries lesions in third molars requiring extraction for different indications by using ICDAS II, PR, NIR-LT and LF methods under in vivo conditions with the gold standard micro-CT method. In addition, clinical application time and patient comfort analysis were also conducted for each method. The null hypothesis of the study was that the clinical performance of the evaluated methods in detecting non-cavitated occlusal caries was not statistically significantly different for caries at the enamel and dentin level at different depths.www.clinicaltrial.gov (Identifier: NCT05064566).This prospective clinical research protocol was approved by Mersin University Clinical Ethics Research Council in Turkey . Data was collected at Faculty of Dentistry, Mersin University. In this clinical trial, STARD statements (Standards for Reporting of Diagnostic Accuracy Studies) were followed  and the Only ASA status 1 (according to the American Anesthesiologists Association) healthy patients were included. The following inclusion criteria were used in the present research: (1) fully erupted permanent dentition, (2) absence of fixed prosthetic restoration, restorative material and orthodontic apparatus, (3) the patients aged at least 18 years, (4) at least one erupted third molar of the patient (third mandibular or third maxillary molar from each patient was included), (5) non-cavitated occlusal caries in the third molars, (6) absence of hypoplasia or hypomineralization of third molars, (7) third molars that required extraction for surgical, orthodontic and prosthetic reasons. Patients were asked to participate in this additional examination if clinical signs indicated an existing caries risk or activity and additional diagnosis was deemed necessary.Patients with ASA status 2–6 (according to the American Society of Anesthesiologists) who were not healthy were excluded from the study. The following exclusion criteria were used in this research: (1) completely non-erupted permanent dentition, (2) fixed orthodontic apparatus, prosthetic restoration and filling material, (3) a maximum age of 18 years, (4) at least one third non-erupted molar teeth (non-erupted third mandibular or non-erupted third maxillary molar from each patient was excluded), (5) cavitated occlusal caries, (6) teeth with hypoplasia or hypomineralization, (7) third molars that have dental occlusion, function, caries-free and not required to be extracted for other reasons were excluded from the study.Sample size was calculated by using the G*Power test software. The study sample size was calculated as 40 patients considering that a small effect size of d = 0.614, an alpha level 0.05, a target power of 80% and two predictors were expected in the final model. Potential participants were consecutively recruited from December 2020 to April 2021, and they all provided informed consent for participation. In this prospective cohort study, 140 patients were examined; however, the final sample comprised of 101 third molars of 101 patients with non-cavitated occlusal caries requiring extraction in the sample. A total of 39 patients/third molars were excluded since patients did not show up for their extraction appointments or extensive damage occurred in their dental crowns during extraction. Finally, 101 patients with a mean age of 30.80 years (standard deviation 9.70) agreed to participate in the overall study. The final sample comprised of 101 third molars requiring extraction with non-cavitated but suspected occlusal caries from 101 patients. This study was divided into three sections as shown in in-vivo parts  and in-vitro micro-CT parts  of the study were conducted by two blinded independent observers who were not aware of the characteristics of teeth they observed in advance. A total of four different observers were employed in the in vivo and in vitro parts of the study and were unaware of each other’s examination results.Each of the A benchmarking examiner (K.K.) trained each of the observers by using 15 occlusal surfaces; however, no calibration procedures were performed. Afterwards, these teeth were not included in the study.For each clinical method, clinical procedural application time and comfort/pain analysis by using Visual Analog Scale (VAS) were evaluated by consensus. Clinical procedural application times for total time (from the beginning to the end of the procedure) were measured by using a stopwatch for each method. In addition, for each clinical technique, patients were also asked to score their feelings (in relation to comfort and pain) from absence of discomfort and pain to extreme discomfort and pain (between 0 and 10). Clinical visual examination of teeth was conducted under standard conditions by two observers . Accordi®, Planmeca, Helsinki, Finland) operated at 60 kVp and 7 mA with a size 2 (3 × 4 cm) photo-stimulable phosphor plate (PSP) detector . Image recording was set at 35μm pixel size and 16-bit color. Imaging was performed using standardized paralleling technique equipment with circular collimation  with a focus receptor distance of 20 cm and an image exposure time of 0.08 s and scanned with , stored and assessed by using built-in Romexis software . Pulpal root canal, dentine and enamel visibility were used as indicators of optimal image quality, determined by consensus. The presence of occlusal enamel or dentin caries was determined by using the classification suggested by Schaefer et al. [Digital intraoral periapical radiographs were exposed by using an X-ray unit  laser type 1 (780). The camera was focused on the occlusal surface at the correct focus-to-object distance and appropriate images were saved in the KID software (KaVo Integrated Desktop/version 2.4.1.6374). The stages of occlusal enamel and dentin caries were determined by using the criteria suggested by Schaefer et al.  as folloThe fissure probe type 2 DIAGNOdent Pen  was applied to the designated location and performed with rotational movements in order to examine all fissure walls to record the maximum value. Values between 0 and 99 were recorded for the examined tooth. Sound areas ranged between 0 and 13. Occlusal enamel caries was associated with values between 14 and 29 and dentin caries were associated with values ≥ 29 ,25.Micro-CT has been accepted as the gold standard method over time, replacing microscopic methods for in vitro caries assessment, as it provides reproducible results with high sensitivity and very high accuracy in tooth structures ,19. AfteAfter 1-week interval time, 45 patients were recalled in order to calculate the intra- and inter-observer reliability of each diagnostic method. These patients also consisted of patients who came to their appointments for other dental treatments. Evaluation of all examination methods was repeated independently. p < 0.05. The clinical performance of different diagnostic methods was based on the accuracy rate, sensitivity (SE) (positivity in caries), specificity (SP) (negativity in caries), negative predictive value (NPV), and positive predictive value (PPV). The receiver operating characteristic (ROC) curves (Az) were calculated to show the distinguishing ability of a test ,28. VariRegarding the micro-CT examination, it was determined that from a total of 101 occlusal sites, 26 were intact (0), 6 had carious lesions in enamel outer half (E1), 21 had carious lesions located at the inner half of the enamel (E2), 21 had carious lesions located at dentin outer one third (D1), and 27 sites had carious lesions at dentin middle 1/3 (D2). NIR-LT had the highest SE (99.67–99.67%) and accuracy (78.22–77.23%) for determining enamel caries, while PR had the lowest SE (58.67–61.33%) and accuracy (62.38–61.39%) according to examiners 1 and 2, respectively. The LF (76–76%) and clinical visual examination (82.67–82.67%) methods had intermediate SE values for determining enamel caries according to examiners 1 and 2, respectively. LF method had the highest SE (70.83–54.17%) and accuracy (66.34–59.41%) for determining dentin caries, while clinical visual examination had the lowest SE (10.42–18.75%) and accuracy (54.46–57.43%) according to examiners 1 and 2, respectively. The NIR-LT (64.58–52.08%) and PR (33.33–33.33%) methods had intermediate SE values for determining dentin caries according to examiners 1 and 2, respectively. All diagnostic methods showed lower diagnostic performance when compared to the gold standard for diagnosing occlusal enamel and dentin caries with ROC curve (Az) values between 0.524 and 0.726. For each diagnostic technique, ICC was calculated from both readings of measurements between each observer (intra-observer) and repeated measurements among all observers (inter-observer). The ICC values changed from 0 (no agreement) to 1 (perfect agreement). High correlation was accepted for an ICC value of >0.75, good correlation was accepted for 0.74 > ICC > 0.60 value, fair correlation was accepted for 0.59 > ICC > 0.40 value and poor correlation was accepted for ICC value of less than 0.40. The ICC values showed a perfect consistency, indicating a high correlation for the clinical diagnostic methods within and between examiners . The consistency of two examiners and each clinical diagnostic method with the micro-CT method showed fair to good correlation .p < 0.05). The clinical application time of the clinical visual examination group was lower than that of the LF group (p < 0.05). The patient comfort score and clinical application time of the clinical visual examination group were lower than those of the NIR-LT group (p < 0.05). The patient comfort score and clinical application time of the PR group were higher than those of the LF group (p < 0.05). The clinical application time of the PR group was higher than that of the NIR-LT group (p < 0.05). The patient comfort score and clinical application time of the LF group were lower than those of the NIR-LT group (p < 0.05)  .Today, occlusal caries assessment and detection plays a vital role in routine dental clinical practice and is a prerequisite for appropriate treatment. In general, the stage in which caries can be diagnosed both visually and radiologically is the dentin demineralization stage. The size and boundaries of deep dentin caries can be easily determined by traditional methods. Due to the different morphological structures of the occlusal surfaces of the teeth, early detection of occlusal caries without cavitation by visual inspection may be very difficult. New techniques (NIR-LT and LF method) utilized for the diagnosis of early occlusal caries in third molar teeth might be more successful compared to conventional methods  in terms of diagnosis, application time and patient comfort. Therefore, the teeth sample included in the present study had no cavitation, their occlusal surfaces were intact and possible caries were at the initial level.This hypothesis of the present research was that all methods would reveal similar diagnostic results. However, it was determined that the NIR-LT method for enamel caries and the LF method for dentin caries were superior to other diagnostic methods in comparison to gold standard micro-CT technique. These results contradict the previous studies that attributed a significant benefit to radiography for the detection of caries on occlusal surfaces ,31,32. OThe use of micro-CT showed a significant jump in dental research including the validation of in vitro caries detection in permanent teeth ,36. The It was determined that clinical application of NIR-LT proved to be the most effective method in the detection of occlusal enamel caries which was indiscernible with the use PR assessment in most cases. In a previous in vivo study, visual inspection examiners observed most of the diagnosed caries lesions on occlusal surfaces in young adults . PR and p < 0.001) for PSP sensor [To the best of our knowledge, no previous comprehensive study compared several techniques in terms of caries diagnostic ability and clinical application time and comfort/pain analysis (VAS). However, few studies evaluated these parameters for PR radiographic techniques ,40. The P sensor . AnotherIt should be noted that during periapical radiographic imaging of third molar teeth, malposition and posterior position of the teeth along with gagging reflex may cause longer times to be required in order to obtain the ideal image and high scoring for patient comfort .p < 0.001). In terms of patient comfort, the difference was statistically significant, except for clinical visual examination and LF and digital PR and NIR-LT relations (p < 0.001). When the methods were listed from the most comfortable one to the most uncomfortable, clinical visual examination was followed by the LF pen method, NIR-LT and PR technique. In regard to clinical application time, it was determined that the quickest method was the clinical visual examination followed by the LF pen method, NIR-LT and PR. The study findings suggested that patient comfort has a positive impact on shorter clinical application time.According to the study findings, rankings for discomfort and clinical application time were identical. The difference between all methods in terms of clinical application time was statistically significant  creates cross-sectional images of tooth structure by reflection and backscattering of light in an attempt to measure optical reflection with depth recording . A systeIn a meta-analysis in which diagnostic studies of proximal surface caries were systematically reviewed, authors reported that in vitro studies were frequently included in the literature (120), whereas clinical studies were in the minority (9). Bitewing radiography was determined to be more successful in detecting proximal caries . It was In a similar study conducted by Taşsöker et al.  in 2020,In the study conducted by Mortensen et al. in 2018, which determined the reference standard as ICDAS and evaluated the clinical performance of impedance spectroscopy, laser fluorescence and bitewing radiographs in detecting occlusal caries in premolar and molar teeth without fillings, the LF pen was determined to be especially useful in the absence of bitewing radiographs or when ionizing radiation should be avoided. The authors suggested that it might be used as a second opinion to visual inspection. However, in the present study, LF pen was determined to be effective in detecting occlusal dentin caries.Today, while the pandemic is slowing down due to the COVID-19 vaccine, dental clinics with high patient circulation are considered as high-risk areas for transmission. In addition, another important problem in routine clinics is the dental treatment expectations of COVID-19-positive patients . The useEarly intervention of caries is of paramount importance as treatment delayed due to misdiagnosis may lead to tooth loss. The resulting cavities are potential candidates for implant prosthetic rehabilitation . It is bWith the bad changes in eating habits, the possibility of having diabetes is increasing day by day in addition to the formation of caries. As is known, this pathology affects the oral microbiome, vascularization and healing processes, and salivary composition . As a muThe observers examined third molars. It is known that the occlusal surfaces are very different from other teeth in terms of morphology, quantity of enamel and dentin, and position in the mouth. The frequent occurrence of variations observed in the morphology of the occlusal surfaces in the study sample, and the fact that the majority of the sample consisted of malposed teeth might be a possible limitation of this study. In addition, only occlusal surfaces were evaluated as they were difficult to diagnose. However, advanced methods  analyzed for caries detection may also be used for interproximal caries which were out of this study’s scope. Interproximal caries results may be different from those obtained by this study. Another limitation of this study was that different pain thresholds of the patients were not taken into account. The pain thresholds measured by the digital pressure algometer and the responses of the patients according to the VAS scale were not evaluated. However, in the present study, the relative comfort of the methods was prioritized rather than the pain threshold of the patients. In addition, caries risk assessment form data that could not be obtained and analyzed from all patients who participated in the study due to clinical intensity.ICC values calculated for different clinic diagnostic methods showed high repeatability. This prospective clinical study showed that NIR-LT and LF-Pen are reliable modalities for the detection of occlusal enamel and dentin caries without using ionizing radiation. The most comfortable method with the shortest application time is the clinical visual examination method, whereas the most uncomfortable method with the longest application time is the PR method.


Proteinuria after kidney transplantation (KTx) has been a frequent problem due to several factors, high protein intake being one of them. Individualized nutritional intervention in the late post-KTx period can promote the improvement or the reduction of risks associated with the parameters of evaluation of kidney function, body composition, and quality of life in individuals submitted to KTx.This is a single-center, randomized and stratified clinical trial. The study will be conducted in a university hospital in northeastern Brazil with 174 individuals aged ≥19 years submitted to KTx and followed up for 12 months. Assessments will take place at 3-month intervals . The patients will be allocated to intervention and control groups by random allocation. The intervention group will receive individualized nutritional interventions with normoproteic diets (1.0 g/kg) after 60 days of KTx whereas the controls will receive the standard nutritional guidance for the post-KTx period. The primary efficacy variable is the change from baseline in log proteinuria assessed with the urinary albumin/creatinine ratio. Secondary efficacy variables include body composition, anthropometry, quality of life assessment and physical activity, lipid profile and glycemic control. Ninety-two subjects per group will afford 70% power to detect a difference of 25% between groups in log proteinuria. Primary efficacy analysis will be on the modified intention-to-treat population with between-groups comparison of the change from baseline in log proteinuria by analysis of covariance.The study will assess the effects of an individualized nutritional intervention on proteinuria 12 months after KTx.REBEC (RBR-8XBQK5). Nutritional interventions in all stages of kidney transplantation (KTx) play important roles in individual care and in preventing common comorbidities that may arise in the post-KTx period, such as obesity or malnutrition, hypertension, diabetes, cardiovascular diseases , and cliProteinuria is an indicator of kidney function and, when present, it is associated with a higher incidence of acute rejection, hypertension, graft dysfunction, cardiovascular risk, and long-term mortality , 4. ThisAlthough this perception exists, there are few studies that have assessed the impact of dietary protein in the late post-KTx period (> 6th week after surgery), making it difficult to construct guidelines for dietary recommendations for the nutritional management of these patients based on scientific evidence , 6. CurrIn the immediate post-KTx period (< 6th week after surgery), a high-protein (1.3 to 2.0 g/kg/day) and hypercaloric  diet should be recommended to meet the needs caused by the resultant metabolic stress after surgery and the use of high doses of immunosuppressive therapy . HoweverThe average weight gain after the first year of surgery is close to 5–10 kg or 5%–10% of the initial body weight , 14. LikThe patient’s quality of life and renal graft survival depend directly on post-KTx clinical care. Multiprofessional follow-ups help in the maintenance and early identification of abnormalities or signs of kidney function regression. Possibly, adequate intake of energy and protein in the diet could contribute to control lipid levels and to maintain the balance of micronutrients such as sodium, calcium, iron, potassium and phosphorus in the late post-KTx period that favors the maintenance of kidney function, especially in the reduction or prevention of proteinuria, decreasing the risk of complications, helping to maintain a favorable body composition, and improving the quality of life of patients undergoing KTx , 6, 10.Considering the scarcity of nutritional guidelines and the heterogeneity of experimental studies on dietary recommendations after KTx, this study aimed to evaluate the effect of an individualized nutritional intervention on the parameters of assessment of kidney function, body composition, and quality of life in individuals submitted to KTx followed for 12 months in a nephrology clinic at an university hospital in northeastern Brazil.This is a single center, stratified and randomized clinical trial to evaluate the efficacy of individualized nutritional intervention considering normal protein diet with consumption of 1.0 g/kg versus standard nutritional guidelines in chronic kidney disease patients submitted to KTx in the previous two months. The trial site will be the Onofre Lopes University Hospital/Federal University of Rio Grande do Norte (UFRN), Rio Grande do Norte, Brazil.Brazilian Clinical Trials Registry (REBEC) online platform, obtaining the registration RBR-8XBQK5 and UTN  U1111-1231-6000, linked to the World Health Organization (WHO).The study was submitted to and approved by the Research Ethics Committee of Onofre Lopes University Hospital/UFRN with authorization number 3,127,266 and registered with the CAAE: 02445018.7.0000.5292. Eligible patients will be informed verbally and in written about the objectives, procedures and potential risks of the study. Those agreeing to participate will be asked to sign an informed consent form. The clinical trial was registered on the The clinical trial groups will be evaluated at Time 0 (T0) or immediate post-KTX and every three months thereafter, until to complete 12-months post-KTx. At each study visit, the patients will be evaluated for kidney function and other biochemical parameters, food consumption, anthropometric measurements, body composition, and quality of life, as shown in The study will include individuals of both sexes aged 19 years and older who underwent KTx in the previous two months, with exclusively on oral feeding, and be literate or have a literate caregiver. The exclusion criteria will be patients with diagnosis of focal segmental glomerulosclerosis, systemic lupus erythematosus, IgA nephropathy, with multiple organ transplantation, with a history of recurrent transplantation due to chronic rejection, patients on immunosuppressive therapy of everolimus or sirolimus, and with hospital stay longer than 60 days after surgery.The primary and secondary efficacy variables defined for the study are described in The sample calculation was performed using the software Stata 15.1 , based on a published study of patients who had undergone KTx with a mean log proteinuria of 2.36 mg (standard deviation of 1.55) at 6 months, by the urinary albumin/creatinine ratio . To demoDiabetes mellitus. Two randomization lists, one for each stratum, will be generated from the randomization.com website  and tacrolimus concentrations.Wiener kits according to the methodology described by the manufacturer, using the CMD-800 biochemical analyzer . Further, PTH, 25(OH)D, basal insulin and tacrolimus concentrations will be measured by the chemiluminescence method with ABBOTT® kits, using the ARCHITECT i2000SR Immunoassay Analyzer .The urea, creatinine, uric acid, triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting glucose, glycated hemoglobin, total proteins, albumin, total calcium, phosphorus, sodium, potassium, magnesium, total alkaline phosphatase will be evaluated in blood samples using All biochemical analyzes will be performed at all the time points in the study .Dietary intake will be assessed using the 3-day food record method completed by the patient himself, if literate, or by a caregiver who follows their daily routine, for 3 consecutive days that include a weekend day. Information about the food consumed, the amount and details of the type of the preparation, the times and places of meals, and the consumption of vitamin, mineral, and food supplements, will be collected. In periods T0, T3, T6, T9, and T12 after KTx, all the patients will be instructed on how to fill in the requested information and, to facilitate collection, all of them will receive a manual of home measurements prepared by the authors with images of utensils and conventional measures of food. The 3-day food record annotation form was adapted to facilitate the filling of meal-related information, by including information in a “step by step” form for a better understanding by patients or companions .® 2.0 . Nutritional information from industrial food labels will also be included in the software database, as necessary, along with their nutrient composition obtained from the Brazilian food composition tables and the United States Department of Agriculture database, as appropriate [The analysis of the food records will be made in a qualitative way by observing the type and quality of the food consumed. The quantity of each food item and drink will be converted into grams or milliliters using a measurement chart for food consumed in Brazil. The foods will be converted into energy and nutrients using the Virtual Nutri Plusropriate –25. For Balmak® , calibrated with accuracy class III, with a minimum capacity of 1 kg, and a maximum capacity of 150 kg. Height will be measured using an anodized aluminum stadiometer with a rectangular cursor from Sanny® , with wall-fixation with screws, a scale from 50 to 211 cm, and a resolution of 0.1 cm. To measure the WC, an inelastic measuring tape from Sanny® , with an extension of 200 cm and an accuracy of 1 mm will be used. The HGS, used to verify a reduction in muscle function, will be assessed based on the measurement of isomeric contraction of the hand muscles through an analog manual dynamometer from Crown®, with a scale from 0 to 100 kg and a resolution of 1 kg. The measurement will be conducted in triplicates, with the highest value being adopted between repetitions.Anthropometric measurements such as weight, height, waist circumference (WC), and handgrip strength (HGS) will be collected. The current weight will be obtained using a digital platform scale from double-beam X-ray absorptiometry (DXA) method, performed by the LUNAR-GE® device . For this, the measurements of lean mass (LM% and LM Kg), fat mass (FM% and FM/kg), body fat (%BF), bone mineral content (BMC), and fat-free mass (Kg) will be conducted.Body composition will be assessed at T0, T6, and T12 months after KTx using the EGWSOP) [The presence of sarcopenia will be assessed through the recommendations of the European Group Working Sarcopenia Older People (EGWSOP) , consideMedical Outcomes Study 36-Item Short-Form Health Survey (SF-36) translated and validated into Portuguese and applied in three periods T0, T6, and T12 after KTx [qualipes.com.br [Participants in the case and control groups will be assessed for quality of life, using the generic questionnaire fter KTx . The inss.com.br  by the sSelf-Reporting Questionnaire (SRQ-20) [Considering that depression, anxiety, and other mental disorders can directly affect the quality of life of individuals, an interview will be conducted with the (SRQ-20) , which iInternational Physical Activity Questionnaire (IPAQ), translated and validated in Portuguese [In addition to the previous parameters, the levels of physical activity of the patients will be assessed using the full version of the rtuguese . The IPADiabetes mellitus entered as stratification variable, and study group as independent variable. For secondary efficacy variables, in those measured in an interval scale, the change from baseline will be compared between groups with the same method. For those variables that are related to patient sex , sex will be included as independent variable. For variables measured in ordinal scales, only the values observed in the last valid observation will be considered and will be compared between groups with the Wilcoxon-Mann-Whitney U test. No multiplicity correction of p-values will be applied to the secondary variables.The study will be analyzed by the modified intention-to-treat method, whereby all randomized patients who had at least one post-baseline measurement of proteinuria will be included in the primary analysis population. Data will be presented descriptively by means and standard deviations, or with absolute and relative frequencies, according to the respective scale of measurement. The difference between the groups in the change from baseline in the primary efficacy variable will be tested by analysis of covariance with a multiple linear regression model, with the baseline value entered as covariate, Statistical analyses will be performed using Stata 15.1 . Tests with two-sided p values < 0.05 will be considered statistically significant.The study started recruiting patients on May 1, 2019 and is expected to end on December 31, 2022.The main clinical relevance of this randomized trial is to provide information on the impact of an individualized nutrition intervention with a defined amount of protein intake on the 25% reduction in proteinuria levels in the late post-KTx period. In addition, this study will allow to evaluate other relevant parameters related to metabolic and quality of life outcomes, since this study raises the hypothesis that this balanced diet may improve parameters of body composition, lipid and glucose profiles, as well as quality of life of patients in the post-KTx.Patients with KTx in the present clinical trial will undergo an individualized nutritional intervention for 12 months after surgery. This period of nutritional intervention was selected based on previous studies, which demonstrated that protein intake is associated with maintenance of kidney function in the first year post-KTx –32. HoweA study conducted by Deetman et al. , includiThus, due to the lack of data with high quality of evidence on the influence of dietary intervention on post-KTx, there are no guidelines or recommendations for a specific nutritional intervention in the late post-KTx period . In addiThe primary efficacy variable evaluated will be proteinuria as it is a recognized marker of kidney injury , 38. PosFurthermore, research indicates that post-KTx proteinuria can be controlled through the diet . A nutriTherefore, as the reduction in proteinuria may favor better kidney function, as well as a longer graft survival and reduced mortality, the present study will use proteinuria as a primary efficacy variable in order to assess whether the intervention individualized nutrition may have an antiproteinuric effect post-KTx. And, thus, assess whether the patient can benefit in guaranteeing the success of KTx and a better quality of life.The present clinical trial was concerned with outlining exclusion criteria that could be possible biases in the assessment of the benefit of individualized nutritional intervention in the management of proteinuria in the late post-KTx period. Among the exclusion criteria are focal segmental glomerulosclerosis, systemic lupus erythematosus and IgA nephropathy, which are underlying diseases recognized for developing recurrent proteinuria after KTx due to deposition of immune complexes in the kidneys that lead to progressive renal failure –48; multOne of the possible limitations of this protocol will be the impossibility of blinding, which may imply risks of bias. To reduce these risks, in this study, standardized measurements and tests of anthropometric assessments, quality of life and laboratory tests will be adopted. In addition, to reduce the potential for confounding due to the variability of the measures evaluated, the same nutritionist will carry out the nutritional intervention protocol.Given the above, the results of this study may serve as a basis for food education and nutrition actions in the late post-KTx period. Since the consumption of a controlled diet in the post-KTx may represent a benefit in the maintenance of kidney function in the long term, reducing tendencies towards negative reflexes, such as proteinuria, overweight and imbalance in lipid and glucose profile, thus collaborate with the improvement of renal graft survival and quality of life of KTx patients.S1 Checklist(DOC)Click here for additional data file.S1 Appendix(DOCX)Click here for additional data file.S1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file.


Orthostatic hypotension (OH) is one of the most common autonomic dysfunctions, with high prevalence in populations of elderly, hypertensive, diabetic, or Parkinson’s patients. Evidence is emerging that OH co-occurs with postprandial hypotension (PPH); a greater prevalence of PPH than of OH is reported for Parkinson’s disease patients. OH is diagnosed by measuring the blood pressure changes associated with postural changes and often produces alterations in consciousness or other such bothersome symptoms as fainting. PPH is diagnosed by measuring the blood pressure changes associated with ingesting high carbohydrate test meals. Because of the time lag between food ingestion and absorption, PPH is often not reported as symptomatic and, therefore, not diagnosed as PPH. OH and PPH are independent predictors for all causes of mortality. Relative underdiagnosis may qualify PPH as a “silent killer” disease. This review is aimed at providing updates on the epidemiology, pathophysiology, and clinical aspects associated with the diagnosis and treatment of PPH. Highlighting the current gaps in knowledge and research about PPH is expected to make medical practitioners more cognizant of the dangers of underdiagnosis and motivate future research to identify individuals and populations at high risk for PPH and its sequelae. History, definition, and epidemiology of postprandial hypotensionIn 1935, Gladstone identified and described a rare condition he observed in a hypertensive patient whose blood pressure had decreased from 185/120 mmHg to 140/80 mmHg after a meal [In recent years, the diagnosis of PPH is increasing among nursing home residents  likely bPPH is prevalent in approximately 24-33% of elderly populations receiving care in nursing homes, about 67% of geriatric patients, and approximately 50% of individuals suffering from unexplainable syncope [Pathophysiology of PPH: causes and associationsThe pathophysiology of PPH is multifactorial, mainly involving sympathetic dysfunction associated with autonomic neuropathy . PatientInsulin is implicated in the pathogenesis of PPH by the mechanism of vasodilation and hypotension reported in diabetic patients after an acute administration of insulin . The genPPH state associated with youth, aging, and autonomic failure Studies have shown that young healthy subjects have modest cardiovascular vasodepressor responses to eating . IngestiIn elderly healthy subjects, hemodynamic responses to eating are generally more pronounced compared to young healthy subjects. There appears to be an age-related increase in the release of NE, which causes spillover from the sympathetic nerve terminals into the blood plasma. The heart rate response is shown to be blunted due to an age-related decline in beta-adrenergic responsiveness . Thus, mTable In contrast to young and elderly healthy subjects, elderly patients with autonomic insufficiency have difficulty maintaining postprandial BP, which is thought to result from inadequate sympathetic nerve activity and/or synaptic release of NE. Elderly patients with previously mentioned conditions associated with varying degrees of autonomic failure  exhibit inappropriate vascular responses to NE release after eating. This is evidenced by impaired peripheral vasoconstriction leading to reduced systemic vascular resistance, cardiac index, and a profound decrease in BP . It is nSymptoms and clinical presentationMuch about PPH is speculative because there is a paucity of research, and the scientific literature describing PPH suffers from small sizes of cohorts, the absence of appropriate control subjects, the lack of longitudinal assessments, and the presence of numerous potential cofounders. Hence, a more in-depth, larger-scale approach to research will probably be needed to derive a valid instrument for diagnosing and assessing patients suspected of having PPH.Although many patients may be asymptomatic, the most common signs and symptoms of PPH include motor weakness, dizziness, light-headedness, syncope, falls, angina pectoris, nausea, and visual disturbances such as black spots in the visual field (“floaters”). Patients may also be unable to walk or stand after meal consumption . Case reDiagnosis of PPHClinicians should suspect PPH specifically in the elderly with diabetes, Parkinson's disease, end-stage renal disease, and heart failure patients . InquiriThe diagnosis of PPH is preferably done by using home monitoring BP devices. While an argument could be made for the use of ambulatory BP monitoring, the cost and patient tolerance for home monitoring BP devices are far more advantageous. For the purposes of diagnosis, the test can be done in a nursing home facility or clinic setting by placing the patient in a supine position. Check the baseline BP and heart rate after five minutes of rest before administering the test meal or food or beverage  . Once thThe intraindividual reproducibility of PPH appears to be relatively high; therefore, a single test is often sufficient for correctly diagnosing the condition . The diuMedical management strategies for PPHThe complex epidemiology and pathogenesis of PPH create difficulties in achieving satisfactory results with pharmacological treatment alone. Hence, clinicians need to be cognizant of both the pharmacological and the nonpharmacological options for the treatment of patients diagnosed with PPH.Nonpharmacologic InterventionsOne of the primary treatment strategies is to reduce gastric activity to delay exposure of the products of digestion to the small intestine. Delayed emptying with moderate gastric distension is shown to result in a 200% increase in sympathetic nerve activity ,4. Such Drinking water before meals may help reduce the drop in postprandial BP that characterizes the condition. Drinking 350-480 mL of water is reported to result in a 20 mmHg gain in BP in patients experiencing autonomic failure ,17. ImprTen minutes of postprandial walking , commencing about 20 mins after breakfast was shown to be temporarily effective in about 14 feeble elderly patients. Mean arterial pressure increased by 18±4 mmHg during post-prandial exercise but dropped to pre-exercise levels 10 mins after exercise ceased . This suStudies have shown that cold glucose loading caused an increase in mean arterial pressure by a maximum of 3.9±1.3 mmHg (p<0.01), while warm glucose loading decreased BP by a maximum of 8.0±1.1 mmHg (p<0.001); indicating that the modification of the meal temperature may be adopted as a form of non-pharmacologic interventions to control PPH .Pharmacologic InterventionsStudies related to treating the condition with pharmaceuticals involve a variety of approaches. Somatostatin analogs, vasopressin, non-steroidal anti-inflammatory drugs (NSAIDs), and other agents like caffeine have been used.Caffeine, an adenosine receptor antagonist has been used for stimulation of the sympathetic nervous system. Caffeine maintains BP by constricting arterial blood vessels . CaffeinThe administration of somatostatin analogs such as octreotide may be used for local vasoconstriction to reduce splanchnic blood flow, thereby redistributing blood flow from the splanchnic to the central circulation for maintaining postprandial BP . OctreotAcarbose is an alpha-glucosidase inhibitor that may be useful for delaying gastric emptying. Acarbose functions by inhibiting the enzymes required for carbohydrate digestion, thereby decreasing the number of particles created as products of digestion transported into the duodenum after a meal . AcarbosThe mechanism of the blood pressure increase by NSAIDs is not fully understood, and NSAIDs should typically be avoided in the elderly due to an increased risk of accidental falls. NSAIDs have also been shown to be associated with gastric ulcers and many other side effects common to the elderly. Many elderly patients also have comorbid conditions and are therefore on medications that may exhibit drug interactions with NSAIDs. Prophylactic use of NSAIDs for the prevention and control of PPH is therefore not advisable for most geriatric patients. NSAID use for PPH is not fully understood; however, by implication, the outcome is most likely due to its effect on prostaglandin metabolism. Prostaglandin increases renal blood flow and the glomerular filtration rate (GFR). NSAIDs, which inhibit the production of prostaglandin, can prevent PPH likely by such renal mechanisms that decrease renal blood flow, increase sodium retention, circulating blood volume, cardiac preload, and, therefore, systemic BP .Calcitonin gene-related peptide (CGRP) is shown to play a role in PPH by virtue of its strong vasodilatory activity in response to glucose loading , therebyPsychosocial and lifestyle considerations for PPHIn patients with PPH, large meals are more likely to result in a significant drop in BP and peripheral vascular resistance than small meals . It is, Complications of PPHDue to inefficient cardiovascular response, there is an increased risk for cerebrovascular disease, transient ischemic attack, syncope, falls, and coronary events. A prospective study conducted on geriatric hypertensives using magnetic resonance imaging of the brain reported that 83% of hospitalized patients with episodes of PPH have evidence of lacunae that are suggestive of cerebrovascular damage . CoronarOther considerations for clinical practice and patient educationThere are patients who may have other co-morbidities to watch out for when screening, diagnosing, and treating for PPH. These conditions can worsen the patient’s quality of life and response to treatment. Cases of patients with diabetic neuropathy may exhibit poor baroreceptor sensitivity and, therefore, autonomic unresponsiveness. This may potentially result in marked PPH. On the other hand, the administration of exogenous insulin can also exacerbate PPH. Hence, there is a need to titrate insulin to tolerable doses based on a personalized therapeutic range. And at the same time, it’s essential to counsel patients appropriately on anticipatory complications. Other drugs like ganglionic blockers, anti-parkinsonism agents (levodopa), reserpine, and clonidine may also worsen PPH. Conversely, patients with dopamine beta-hydroxylase deficiency, a metabolic disorder, do not have the ability to convert dopamine into norepinephrine and epinephrine; hence, they can present with OH, but they are able to maintain their BP after meals. The same can also be said for tetraplegic patients with complete cervical cord transection ,34. A suPPH is loosely defined as a fall in systolic BP of at least 20 mmHg within two hours after a meal. A standardized definition of PPH is yet to be established. The precise pathophysiology of PPH remains undefined and is, therefore, based largely on extrapolation of knowledge about autonomic failure and OH. PPH appears to involve sympathetic dysregulation, primarily found in patients with diabetes, Parkinson’s disease, and multiple system atrophy. PPH can also develop in patients with an attenuated ability to increase their cardiac output because of heart failure or an attenuated baroreflex. PPH is posited to be influenced by eating large amounts of food in young people, lack of salt intake in the elderly, dehydration, and hot weather. Some people may also be predisposed to PPH genetically. Common PPH symptoms include dizziness, nausea, angina pectoris, weakness, falls, black spots in the visual field, syncope, and light-headedness. During the diagnosis, healthcare providers check the BP before and after meal ingestion at intervals of about 15 minutes. The illness can be treated pharmacologically, non-pharmacologically, or both, and involves the use of drugs such as NSAIDs, somatostatin analogs, and acarbose.


Falls among older adults have become a global concern. While previous studies have established associations between autonomic function indicator; heart rate variability (HRV) and blood pressure variability (BPV) with fall recurrence, as well as physical inactivity and psychological disorders as risk factors for falls, the influence of physical activity and psychological status on autonomic dysfunction observed among older fallers has not been adequately investigated. The aim of this study was to evaluate the relationship between psychological disorder and physical performance on the autonomic nervous system (ANS) in older fallers. We hypothesised that older fallers have poorer autonomic function, greater dependency on others and were associated with psychological disorders. Furthermore, we hypothesised that both physical performance and psychological status can contribute to the worsening of the autonomic function among the elderly.In this cross-sectional survey, adults aged ≥ 60 years were recruited. Continuous non-invasive BP was monitored over 5 min of supine and 3 min of standing. Psychological status was assessed in terms of depression, anxiety, stress, and concern about falling, while functional status was measured using time-up-and-go, functional reach, handgrip and Lawton’s Instrumental Activities of Daily Life (IADL) scale.r2 = 0.080, p = 0.025; DBPV: r2 = 0.064, p = 0.046) and standing , while anxiety score was independently associated with SBPV and DBPV during standing  as compared to the other parameters.A total of 62 participants were recruited consisting of 37 fallers and 25 non-fallers. Multivariate analysis revealed that Lawton IADL was independently associated with systolic blood pressure variability (SBPV) and diastolic blood pressure variability (DBPV) during both supine (SBPV: Our findings suggest that fallers had poorer ANS, greater dependence in IADLs, and were more anxious. IADL dependency and anxiety were the most predictive of autonomic dysfunction, and can be used in practice to identify poor autonomic function for the prevention of falls and cardiovascular diseases among older adults. Falls among older adults is a major public health concern due to an increased risk of death and serious injuries . Fall-re. [The occurrence of falls in older adults is associated with disorders within the autonomic nervous system . Heart r.  observed. .The occurrence of falls in older adults is associated with psychological factors. Fallers may avoid physical activity as a result of fear of falling , 9, withPhysical inactivity and psychological disorders are also both associated with changes in the autonomic nervous system. Studies in older adults have reported that exercise training  and physWhile previous studies have established associations between HRV and BPV with fall recurrence, as well as physical inactivity and psychological disorders as risk factors for falls, the influence of physical activity and psychological status on autonomic dysfunction observed among older fallers has not been adequately investigated. Furthermore, we are not aware of any study which investigated the association between physical performance and autonomic dysfunction. Identification of measures of physical activity, physical performance and psychological status which best predict changes in autonomic function among older fallers would help identify patients with increased risk of recurrent falls and cardiovascular diseases. Therefore, our study aims are twofold: (i) to compare the psychological function, physical activity and physical performance between fallers and non-fallers among older adults, and (ii) to determine the associations between psychological function, physical activity and physical performance with the autonomic nervous system.A total of 62 participants were recruited in the study. Of those, 37 (59.68%) had at least one fall in the past 2 months and 25 (40.32%) had no history of falls in the past year Table .Table 1CThere were significant differences between fallers and non-fallers, with fallers having worse scores in physical performance , depression and anxiety (DASS-21), concern about falling (FES-1), and supine rest systolic blood pressure (SBP).Tables Table At the standing position (refer Table Factors associated with autonomic nervous system (ANS) function were tested using variables that showed significant differences between the fallers and non-fallers groups Table . These iR2 = 6.5%) and Lawton IADL scores (R2 = 8.0%) were found to be independently associated with systolic BPV during supine rest, but not DASS-21 depression and DASS-21 anxiety scores, FES-1, as well as TUG. Standing systolic blood pressure variability (SBPV)-CV was independently associated with DASS-21 anxiety score (R2 = 11.2%) and Lawton IADL score (R2 = 11.2%), but not history of falls, DASS-21 depression, FES-1 and TUG. Supine diastolic blood pressure variability (DBPV)-CV was independently associated with Lawton IADL score (R2 = 6.4%), while the remaining variables were no longer significant. Standing diastolic blood pressure variability (DBPV)-CV was independently associated with DASS-21 anxiety (R2 = 10.5%) and Lawton IADL scores (R2 = 10.5%), but not history of falls, DASS-21 depression, FES-1 and TUG. According to the percentage of R-squared between two variables, Lawton IADL has a better correlation in predicting autonomic dysfunction during supine rest and standing, while anxiety score has a better correlation with autonomic dysfunction during standing. To summarise, a higher R2 value indicates a stronger predictive value between two variables. Generally, the adjusted R2 values were relatively small although significant associations were observed between DASS-21 anxiety, Lawton IADL and BPV.Overall, Table Our study found that community-dwelling older adults who experienced a fall in the past 2 months had poorer ANS function, anxiety, and were more dependent in instrumental activities of daily living.Previous studies have also reported fear-related activity avoidance and increased feelings of anxiety and symptoms of depression among older fallers , 10, 28.In the supine position, significantly higher time and frequency domain were observed among fallers. These observations reflected an impairment in sympathetic and parasympathetic branches  as well as blunted baroreflex sensitivity –37 among. [To date, we are not aware of any other study which has investigated the relationship between the psychological system and ANS function among fallers at different postures. Our multivariate analysis results showed that anxiety is an independent predictor for ANS function in the standing position. Several studies have highlighted that higher anxiety scores were associated with higher sympathetic reaction, as represented by both beat-to-beat BPV , 40 and .  showed t. . This ma. [Numerous studies have been performed to investigate the bidirectional relationship between physical inactivity and cardiac autonomic modulation –44. Howe. , an actiNonetheless, our results showed that physical performance tests, such as time-up-and-go, functional reach and handgrip strength, were not independent predictors of autonomic function indices. Physical performance tests only provide snapshots measures of the performance of specific body parts, such as muscle strength, walking speed and dynamic balance, and therefore are not reliable indicators of overall functional ability.The ageing population is growing, and the potential problems associated with ageing include cardiovascular diseases and injuries caused by falls. As these complications are closely related to autonomic function, clinicians have frequently adopted the tilt-table test (i.e. an autonomic function test) to detect any abnormality in the autonomic function by observing blood pressure and heart rate changes in the patients during the test. However, this requires the use of non-invasive, beat-to-beat haemodynamic monitoring technologies, which are not widely available in all clinical centres. In addition, it requires the patients to travel to the designated clinical centres, which may cause weariness and stress among older adults and their caregivers. In the tilt table/sit-to-stand assessment, the patients are required to stand upright after lying down for several minutes, which may be challenging for frail older adults.A pre-screening assessment which could help identify patients with an increased risk of autonomic dysfunction is therefore useful for early intervention. Our findings suggest that validated questionnaires such as DASS-21 and LAWTON could serve as pre-screening tools to identify patients with autonomic dysfunction. As these questionnaires are freely available online, virtual communication between physicians and patients can be conducted, thus reducing the time taken for travel to clinical centres for autonomic function tests. This could aid in the diagnosis of autonomic dysfunction severity and reduce the risk of future falls and cardiovascular diseases.2 values suggested that the haemodynamic parameters evaluated only accounted for a small amount of the variability in the above outcomes. However, using the rule of thumb of multivariate regression, with an absolute minimum of 10 participants per predictor variables, the current study had sufficient sample for the number of parameters input into the multivariate regression. The autonomic parameters have the potential to detect psychological problems in the older population, which currently remains underdiagnosed. Future studies should involve larger sample sizes to ascertain the usefulness of these parameters. Furthermore, the processing length for the standing signals is only 3 min, which is known to be shorter for the analysis of cardiac diseases. However, the limitation of the length is due to the active standing protocol where the current study needs to observe the heart rate and blood pressure changes within 3-min standing. Although a significant correlation was observed between mental state and shorter ECG recordings (< 1 min) in previously published studies, further work should take into account the length of the signals carried out to determine the potential role of ANS function as a biomarker of psychological issues related to falls as well as interventions which enhance ANS to modify falls risk, or ANS as biofeedback for fall prevention interventions.As available data only studied the cross-sectional relationship between autonomic function and psychological and functional status, we are unable to establish causation or define any temporal relationship. In addition, many factors which may influence the variability in postural changes in blood pressure and heart rate remain unaccounted for as potential factors such as medication use had not been considered in this study. While DASS-21 and LAWTON were shown to be predictive of autonomic dysfunction, the small adjusted ROur findings revealed that CV-SBPV at supine rest was independently associated with falls in the preceding two months, with differences in CV-DBPV at the standing position accounted for by functional ability. Particularly in fallers, significant correlations existed between stress and anxiety with BPV. By knowing the association between these modifiable risk factors and autonomic function, early identification could be done of patients at risk of recurrent falls and cardiovascular diseases and thus timely intervention can be performed.This was an exploratory cross-sectional study involving 37 fallers and 25 non-fallers, recruited between October 2019 and October 2020. Falls were defined as “unintentionally coming to rest on the ground, floor or other lower level” . Adults Characteristics including age, gender, characteristics of falls, past medical history, medication review, anthropometric measurements  and continuous blood pressure (BP) and heart rate (HR) assessments were obtained from all participants.The outcome measures used in this study include measures on physical performance, physical activity and psychological function.We conducted three types of tests to assess the individual’s physical performance: timed-up-and-go test, functional reach and handgrip strength. Timed-up-and-go test evaluated the time taken to rise from the sitting position on a standard armchair, walk for 3 m, turn back, and sit down again. Longer durations taken by the participants to complete the task indicate poorer physical performance . FunctioInstrumental activities of daily living were assessed using the Lawton’s Instrumental Activities of Daily Life (IADL) scale . This scDepression, anxiety and stress were measured with the 21-item Depression, Anxiety, Stress Scale (DASS-21). Participants were required to self-report the frequency and severity of the negative emotions of depression, anxiety and stress over the previous week. The frequency and severity ratings are based on a 4-point Likert scale, with 0 indicating “did not apply to me at all” and 3 indicating “applied to me very much, or most of the time”. The scores were calculated individually for the three components of depression, anxiety and stress . In addiEach participant was required to undergo a supine-to-standing orthostatic test with non-invasive beat-to-beat heart rate (HR) and blood pressure (BP) monitoring obtained using the vascular unloading technique . R–R intervals were derived based on the electrocardiogram (ECG) signal (sampling rate = 1 kHz), while beat-to-beat blood pressure values were derived from the fingertip photoplethysmographic (PPG) signal (sampling rate = 100 Hz), with the signal processing details described in the following section. Participants were required to lie in the supine position for at least 10 min before the 3-min active stand test was started, with the appropriately sized finger cuff attached on the middle and index fingers . All parThe continuous HR and BP signals for each participant were exported to MATLAB software to be processed . The ECG and finger blood pressure waveforms were pre-processed using custom written algorithms, where filtering, tracing, and denoising were performed to remove any unwanted artefacts. The QRS peaks of the ECG as well as the peaks/troughs of the cyclical blood pressure waveform within every cardiac cycle were then detected using standard derivative or threshold algorithms for the purpose of estimating heart rate and systolic or diastolic blood pressure. Beat-to-beat HR and BP readings were identified and separated into three different segments: supine rest, interval and standing. Blood pressure variability (BPV) and heart rate variability (HRV) were computed as time domain indices and power spectral indices.Time domain analysis measures dispersion of blood pressure values over a given time window, while frequency domain analysis measures blood pressure fluctuation as a function of frequency. Time domain indices are divided into two categories: (1) measures of dispersion of average values over a given time window of 10-min supine rest and 3-min standing, which include standard deviation (SD) and coefficient of variation (CV); (2) estimation that accounts for the sequence of measurements over time, which include average real variability (ARV) and root mean square of real variability (RMSRV). On the other hand, frequency domain indices are obtained through spectral analysis techniques, in which we measured fluctuations in beat-to-beat blood pressure as a function of frequency. Linear detrending technique was first performed, followed by the application of fast Fourier transform (FFT) algorithms on the extracted beat-to-beat heart rate and systolic/diastolic blood pressure data to obtain the frequency domain HRV and BPV indices: low-frequency normalised unit , high-frequency normalised unit , total power (TP), and ratio of low-frequency and high-frequency (LF/HF) , 7. The t-test for normally distributed continuous variables. For non-normally distributed data, continuous variables were expressed as median with quartile 1 to quartile 3 in parenthesis and the differences between groups were analysed with the Mann–Whitney U test. Then, correlation between psychological disorder and autonomic response was measured using the Pearson’s correlation coefficient. Finally, multivariable linear regression was used to adjust for potential confounding variables and to determine potential predictors for autonomic dysfunction. The assumptions of linear regression were checked, and all met for normality, linearity and homoscedasticity. A p-value < 0.05 was considered statistically significant.A priori sample size calculations were performed using G*Power statistical software , and wit


Elderly patients exhibit a higher incidence of chronic heart failure (CHF). Patients with CHF can develop acute kidney injury (AKI) during follow-up, which can result in poor prognosis. This relationship between kidney dysfunction and levels of N-terminal pro-brain natriuretic peptides (NT-proBNP), with regard to prognosis, is complicated and has rarely been analyzed in elderly patients with CHF.We conducted a retrospective cohort study involving patients with a CHF history aged ≥ 65 years, who experienced an episode of AKI. Kaplan–Meier curves and Cox or logistic proportional hazards regression models were used to evaluate the association between serum NT-proBNP concentrations and mortality or renal recovery by day 90.A total of 1,160 eligible patients with AKI were available for the study. Of this sample, 41.5% of patients died within 90 days of the onset of AKI. Patients with a decreased change in NT-proBNP accompanying the episode of AKI had a lower risk  of more severe AKI (stage 2 and 3 vs. stage 1). The more severe AKI were associated with higher mortality and non-recovery of renal function in elderly patients with CHF, independent of NT-proBNP levels. Elevated levels of baseline lnNT-proBNP  predicted mortality in elderly patients with CHF within 90 days of AKI onset. Patients with a decrease in NT-proBNP accompanying AKI had a lower risk of mortality . However, a decrease in NT-proBNP is a risk factor  for the non-recovery of renal function following AKI–especially in elderly survivors with low baseline NT-proBNP levels.A decreased change in NT-proBNP maybe protective for elderly patients with CHF by improving survival outcomes and preventing severe AKI. However, an excessive decrease in NT-proBNP is a risk factor for the non-recovery of renal function following AKI. Avoiding excessive changes in NT-proBNP may be protective for survival and renal injury prognosis. The prevalence of chronic heart failure (CHF) is high and increasing in aging populations worldwide. The higher incidence of CHF in elderly persons can be attributed to aging and the high frequency of comorbidities, particularly coronary heart disease and hypertension. CHF with preserved ejection fraction is particularly prevalent in geriatric patients. The aging-related changes in the diastolic properties of the myocardium predispose older adults to develop CHF with preserved ejection fraction and atrial fibrillation . ElderlyB-type natriuretic peptide (BNP) and the precursor of BNP, N-terminal pro-brain natriuretic peptide (NT-proBNP), are produced mainly by cardiomyocytes in response to stretch from volume overload and myocardial ischemia. Circulating natriuretic peptides are widely used biomarkers that are indicative of HF and volume overload. In elderly patients with heart disease, elevated NT-proBNP levels are associated with a greater risk of cardiovascular mortality . In eldePatients with CHF are often characterized by impaired renal function, also referred to as cardiorenal syndrome (CRS). Cardiorenal syndrome is prevalent in the elderly, and a dynamic interplay between the heart and kidneys exists . PatientSince most of the randomized clinical trials for CHF and AKI were designed to exclude elderly patients, only limited data on elderly patients with cardiorenal syndrome are available. In the current analysis, we conducted a retrospective observational study to investigate the relationships between change in NT-proBNP, renal function and adverse outcomes in elderly patients with AKI in CHF.2) or incomplete medical histories were excluded from the study. Patients were also excluded if they lacked serum creatinine (SCr) or NT-proBNP data, either at baseline or at AKI onset. We followed all patients for 90 days after the initial AKI episode, to determine clinical outcomes relating to mortality and renal function.We conducted a retrospective cohort study at the Second Medical Center (Geriatric Department) of the Chinese PLA General Hospital to assess AKI outcomes in older patients with CHF. Patients 65 years of age or older, with a history of CHF with preserved and mildly reduced ejection fraction [left ventricular ejection fraction (LVEF) > 40%], were enrolled if they experienced an episode of AKI between 1 January 2008 and 31 December 2018. Patients with end-stage renal disease , and the requirement for informed consent was waived.The ICD10 codes I50.22 and I50.32 were used to retrieve data on patients with CHF history. The diagnosis of CHF was based on clinical findings, symptoms, abnormal electrocardiogram, elevation of brain natriuretic peptide level (NT-proBNP > 125 pg/mL), and structural cardiac abnormalities identified on echocardiography according to 2021 ESC guidelines . AKI is The secondary outcome of the study was non-recovery from AKI, defined as the last available SCr measurement (during the follow-up of 90 days) where SCr remained at more than 150% of the baseline value (thus still meeting the criteria for AKI).at AKI to NT-proBNP at baseline. The change in NT-proBNP was also analyzed as a binary variable. A decreased change in NT-proBNP was defined by the ratio of NT-proBNP at AKI to NT-proBNP at baseline < 1.All data were obtained from hospital electronic health records. Demographic characteristics (age and sex), medical history , accompanying conditions , and laboratory test results  were recorded. SCr levels were routinely measured in our clinical laboratory, using the Cobas c 501 analyzer (Roche Diagnostics). The serum NT-proBNP concentration was measured using Dimension EXL with an LM Integrated Chemistry System (Siemens). Within 3 months before AKI onset, the NT-proBNP level at baseline (NT-proBNP at baseline) was measured together with the baseline SCr value in a stable state. The NT-proBNP at AKI diagnosis (NT-proBNP at AKI) was measured together with the increased SCr value, which contributed to the diagnosis of AKI. The change in NT-proBNP (continuous) accompanying the episode of AKI was expressed as the ratio of NT-proBNP U test (continuous variables), or Pearson’s χ2 test . NT-proBNP concentrations were log-transformed to reduce skew, modeled as continuous variables, and divided into quartiles. Kaplan–Meier, log rank, and univariate and multivariate Cox regression analyses were used for the outcomes of 90-day mortality. Univariate and multivariate logistic regression models were used to evaluate the associations between NT-proBNP concentrations and the severity of AKI and the 90-day renal recovery. Multivariable models were constructed including NT-proBNP levels, severe AKI and confounding factors that were significantly associated with outcomes in the univariate analyses (P < 0.05). Interaction testing was performed between the direction of change in NT-proBNP, before and after AKI, and the quartiles of baseline NT-proBNP levels, with renal outcomes. The association between the change in NT-proBNP levels and non-recovery from AKI was further examined within different quartiles of baseline NT-proBNP levels. P-values of < 0.05 were considered statistically significant for all analyses, including interaction terms.Continuous variables were presented as mean ± standard deviation for normally distributed data or median [25−75% interquartile ranges (IQR)] for non-normal distributions. Discrete variables were presented as percentages. Patient characteristics were compared by the Student’s t-test, the Mann–Whitney at AKI/NT-proBNP at baseline) were found in the non-survivors. Stage 1 AKI occurred in 746 patients (64.3%), stage 2 in 245 patients (21.1%), and stage 3 in 169 patients (14.6%). In the non-surviving group, the percentage of patients with more severe AKI was higher than that in the surviving group . Moreover, non-survivors experienced a higher incidence of comorbidities including prior myocardial infarction, atrial fibrillation, COPD, and malignant tumors, as well as abnormal conditions including lower LVEF, proteinuria, extremity edema, infection, higher blood glucose, electrolyte disturbance, lower blood pressure, lower hemoglobin and higher cTnI. Additionally, survivors were more often treated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), and non-survivors were more often treated with loop diuretics.A total of 1,160 eligible patients with CHF and AKI were enrolled and assessed in this study. Clinical characteristics and survival outcomes of the enrolled geriatric patients are shown in As shown in Severe AKI may result from several associated risk factors. P < 0.001; P < 0.001) and stage 3 (log rank P < 0.001) compared to stage 1.Kaplan–Meier curves for 90-day mortality showed that patients with higher NT-proBNP levels at baseline  survivors did not recover from AKI. Significant variables  from univariate logistic regression analyses and retained adjustors (NT-proBNP levels and AKI stages) were analyzed in multivariate models  as covarat AKI to NT-proBNP at baseline for non-recovery of renal function was not statistically significant. However, interaction testing was significant (adjusted P = 0.026) for the interaction between the direction of change in NT-proBNP and the quartiles of baseline NT-proBNP levels. In the lowest quartile of baseline NT-proBNP , patients with decongestion accompanied by an episode of AKI had significantly worse renal outcomes , which could contribute to the decline in heart and renal function, leading to the deterioration of systemic functions and worse outcomes . ElderlyElderly patients have the highest prevalence of HF, and a positive correlation between natriuretic peptides and age has been found . NatriurCardiorenal syndrome is a common clinical condition in the elderly. Cardiorenal syndrome occurs when dysfunction of either the heart or kidneys progresses to the other organ, leading to both cardiac and renal failure. Patients with CHF can develop AKI during follow-up . Pre-renThe role of kidney dysfunction in mortality has been frequently observed in patients with HF, especially acute decompensated HF. Improving renal function was previously reported to be paradoxically associated with worse outcomes in acute HF, but outcomes may differ based on the response to decongestion (decrease in NT-proBNP) . The relIn this study, 18% of survivors did not fully recover from AKI. Compared with non-elderly patients, impaired recovery of kidney function after AKI is more common in elderly patients . Non-recThere were several limitations of our study. This was a retrospective study in a single center that was restricted to a former member of the armed forces. Identified or unidentified confounders may have influenced the result. We lacked adequate data on the history of CHF  and the etiology of HF was difficult to precisely determine. We also lacked detailed data at AKI onset. In addition to BNP and extremity edema, lung congestion, liver congestion, and other indicators of volume and congestion status were unavailable and not included in our analyses. The causes of AKI and mortality in elderly patients with CHF are diverse and may have influenced the result. Subgroup analysis based on different causes is further required.In conclusion, a decreased change in NT-proBNP was associated with a lower risk of more severe AKI in elderly patients with CHF. Elevated levels of baseline NT-proBNP and increased change in NT-proBNP accompanying the episode of AKI predicted a higher 90-day mortality in elderly patients with a CHF history. However, an excessive decrease in NT-proBNP is a risk factor for the non-recovery of renal function following AKI–especially in elderly CHF patients with low baseline NT-proBNP levels. Continuous monitoring of NT-proBNP is recommended in elderly patients with CHF and avoiding excessive changes in NT-proBNP may be protective for survival and renal injury prognosis.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of Chinese People’s Liberation Army General Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.JH and XZ contributed to the data analysis and drafting the manuscript. ZW contributed to the data collection and data analysis. YL, YZ, JZ, XW, HC, GY, and QM contributed to the data collection of the study. QC and QA contributed to the design of the study and data analysis. All authors reviewed the manuscript.


The study was performed in a retrospective and observational manner. All adult (age 18 years or older) in-hospital subjects treated from January until December 2019 were included. CKD was diagnosed according to the KDIGO 2012 CKD Guideline. The following variables were assessed: CKD stage, quantification/analysis (yes/no) of blood pressure, proteinuria, serum phosphate, serum 25-OH-D3, ferritin and transferrin saturation, and blood gas analysis. In addition, recommendations of the following medicines were analyzed (given/not given): ACE inhibitor or sartan, phosphate binder, vitamin D3 (activated or native), iron, erythropoietin, and bicarbonate. It was also evaluated whether discharge letters contained CKD-related diagnoses or not.  In total, 581 individuals were included in the study. The majority of aspects related to the monitoring and therapeutic management of CKD were either considered in only a small proportion of affected individuals  or avoided nearly at all . A reasonable quality of care was identified concerning the blood pressure monitoring (performed in 100%) and blood gas analysis . Serum phosphate was measured in 12.9%, particularly in subjects at higher CKD stages.  The current investigation revealed poor quality of care in CKD patients treated at the Brandenburg University Hospital over the period of one year. Quality improvement must be achieved, most likely via a standardized educational program for physicians and a directer access to CKD management guidelines. Chronic kidney disease (CKD)  is an emIn the current investigation, we evaluated the CKD-associated health care quality in all in-hospital subjects that were treated during the year 2019. The study focused on quality of blood pressure and proteinuria control, renal anemia, bone metabolism, and renal acidosis.In 2014, the Brandenburg Medical School was founded as the first university of medicine in the whole federal state of Brandenburg (Germany). Its fundamental mission is to improve the quality of health care in rural communities. In summer 2017, a new department of nephrology was opened as part of the University Hospital Brandenburg. It was the first time in more than 20 years that a nephrologist became responsible for managing patients with various types of kidney disease. Currently, the Brandenburg university hospital is the only hospital localized in the city of Brandenburg. Patients with kidney disease receive in-hospital treatment if necessary, and extracorporeal therapies are performed on a dialysis unit if mandatory. In addition, an outpatient unit provides health care for ambulatory patients. Besides the university hospital, only one additional outpatient unit provides diagnostics and treatment for subjects with kidney disease. Most patients receive health care coverage from statutory health insurance companies.The study was retrospective and observational. The ethics committee of the Medical School of Brandenburg approved the study (No. E-02-20200602). It was not mandatory to obtain written consent to participate due to the retrospective and observational character of the investigation. All patients treated at the University Hospital Brandenburg from January until the end of December 2019 were screened. Data were extracted from the central database of the hospital (MEDICO® by CGM). All patient's histories and treatment-associated clinical data are stored in the database. The same applies to all laboratory findings and the medication prescribed before hospital admission and then after. Information about follow-up recommendations was extracted from individual discharge letters.Two inclusion criteria were defined: (I) age of at least 18 years or older and (II) the diagnosis of CKD was according to the KDIGO 2012 CKD Guideline : (I) redThree general quality categories were defined as follows: (I) blood testing for CKD-related surrogate markers, (II) recommendation of antiprogressive medications, and (III) documentation of CKD-related diagnoses in the discharge letter. Quality category I: quantification/analysis (yes/no) of proteinuria, serum phosphate, serum 25-OH-D3, ferritin, and transferrin saturation, and blood gas analysis. Quality category II: recommendations of one or more of the following substances (yes/no): ACE inhibitor or angiotensin II type 1 receptor blocker (termed as “sartan(s)” throughout the article), phosphate binder, vitamin D3 (activated or native), iron, erythropoietin, and oral bicarbonate. Quality category III: documentation of one or more of the following diagnoses (yes/no): CKD, CKD stage, arterial hypertension, “CKD-MBD” or “renal osteopathy” or “renal osteodystrophia,” renal anemia, and renal acidosis. The respective CKD stage was defined according to KDIGO , based ot-test if normality was fulfilled or with the Mann–Whitney test if the results were not distributed normally. Three or more groups were compared with ANOVA if the data were distributed normally or with the Kruskal–Wallis test if the normal distribution was not given. Results are either given as percentages or as mean ± SEM. Statistical significance was postulated if the p value was below 0.05. All analyses were performed with the following application: Wizard® for Mac OS .Before any analysis, all data were checked for normality using the Kolmogorov–Smirnov test. Two groups were compared with the Student's In total, 581 individuals were included in the study . The mean age was 81.2±10.1 years . The age distribution is shown in The mean systolic blood pressure at the time of discharge was 127±21 mmHg, and the diastolic pressure was 70±12 mmHg. On the day of discharge, blood pressure was evaluated in all subjects. The diagnosis of hypertension was documented in 59.2% of all discharge letters. A recommendation for RAAS inhibition was not given at all in 26.5%. An ACE inhibitor was recommended in 38.9%, and an angiotensin II inhibitor was recommended in 34.6% .It was analyzed whether the following parameters of bone metabolism were measured at least once during the hospital stay: serum phosphate, serum parathormone (PTH), and serum 25-OH-D3. Also, it was evaluated whether the discharge letter contained recommendations for the administration of phosphate binders and/or any vitamin D preparation and whether a bone-related diagnosis  was listed. Serum quantifications were performed in the following percentages of all subjects: phosphate 12.9, PTH 5.5, and 25-OH-D3 6. Phosphate binder administration was recommended in 3.6%, and the usage of any vitamin D preparation in 23.1%. A bone-related diagnosis was listed in 0.3% .Among the parameters for monitoring renal anemia, our study evaluated serum ferritin and transferrin saturation. Serum ferritin was measured in 14.6%, and the transferrin saturation in 13.6%. Recommendations for iron and erythropoietin supplementation were given in 12.7% and 1%. Finally, the diagnosis of renal anemia was documented in 3.8% .Proteinuria was assessed in only 10.3% of all subjects. (Venous) blood gas analysis was performed in at least 55.1% of the patients, and a recommendation for regular bicarbonate supplementation was given in 5% .p=0.005) , gender, duration of in-hospital stay (days±SD), systolic and diastolic blood pressure (mmHg±SD), quantification of serum phosphate, PTH, ferritin, transferrin saturation , assessment of proteinuria (%), RAAS inhibition , and recommendation of oral bicarbonate (%). Three variables were distributed heterogeneously: age, systolic blood pressure, and quantification of serum phosphate. The latter was measured with increasing frequency from stage IIIa to V  .The current retrospective and observational investigation reveals a poor health care quality in CKD subjects, treated at an emerging university hospital for a period of one year. The majority of aspects related to the monitoring and therapeutic management of CKD were either considered in only a small proportion of affected individuals  or avoided at all . Reasonable quality of care was identified concerning blood pressure monitoring, blood gas analysis , and serum phosphate quantification. The latter, although performed in only 12.5% of all individuals, was at least initiated more frequently in higher CKD stages according to KDIGO.In recent years, several studies reported on the quality of care for CKD. In 2019, Tummalapalli and colleagues  publisheThe current study has limitations. On one hand, we were not able to reliably identify subjects that were in definite need of receiving a certain type of medicine. The reason is, at least in part, the limited accessibility to individual patients via the central database. Another reason is the retrospective nature of the study. Prospective study designs usually ensure the documentation of more complete data sets. Finally, we did not apply standardized tools for assessing the health care quality but exclusively documented frequencies of diagnostic and therapeutic measures related to the diagnosis of CKD. In summary, the current retrospective investigation nevertheless revealed a poor quality of care in CKD patients treated at the Brandenburg University Hospital for the period of one year. Quality improvement must be achieved, most likely via a standardized educational program for physicians.