Calcium is an important coagulation factor and hypocalcemia is related to progression and poor prognosis of many cardiopulmonary diseases. However, influence of hypocalcemia on pulmonary thromboembolism (PTE) prognosis has never been reported. This study aimed to explore its prognostic value and optimize the pulmonary embolism severity index (PESI), the widely used prognosis assessment model, based on the value.PTE patients’ variables in PESI and other related clinical characteristics including admission serum calcium were collected. Associations between these variables and PTE mortality were assessed by logistic regression and cox analysis. Variables significantly associated with 30-day PTE mortality were included to develop a new prognosis prediction rule and then its validity was compared with PESI and simplified PESI (sPESI).496 PTE patients were included and 49.48% patients had hypocalcemia  in admission, showing higher 7-day (P = 0.021), 14-day (P = 0.002), 30-day  mortalities than patients without hypocalcemia. Adjusting for variables in PESI, hypocalcemia was further revealed to be an independent predictor of 30-day mortality (P = 0.014).The optimal prediction rule contained hypocalcemia and 5 variables in PESI and sPESI, showing higher predictive validity  than PESI  and sPESI .Hypocalcemia is an independent predictor of the mortality following acute PTE. Based on hypocalcemia, the optimal prediction rule showed higher validity than PESI and sPESI. Acute pulmonary thromboembolism (PTE) is a life-threatening disease with high morbidity and mortality, which may cause an annual incidence rates ranging from 39 to 115 per 100,000 population and a 14-day mortality of 11.4% . PrognosThe pulmonary embolism severity index (PESI), which includes 11 clinical parameters, is an extensively validated score in the prognostic assessment of PTE patients –5. OwingCalcium as the coagulation factor IV, participates in the coagulation process. Hypocalcemia, as a common electrolyte disorder in hospitalized patients, is related to the progression and poor prognosis of many cardiopulmonary diseases, such as heart failure, acute myocardial infarction, and acute exacerbations of chronic obstructive pulmonary disease –13. Our This is a single-center, retrospective, observational study. Consecutive inpatients enrolled met the inclusion criteria: aged 18 years or older, diagnosed with PTE in Peking Union Medical College Hospital (PUMCH) from January 1, 2012 to January 18, 2019. Patients were excluded if they were diagnosed and transferred from other health care facility due to lack of initial clinical data. Patients without important follow-up data were also excluded for the relevant mortality analysis. The diagnosis of PTE required to be confirmed with computed tomographic pulmonary angiography (CTPA), enhanced computed tomography of chest, scintigraphic ventilation-perfusion (V/Q) scan revealing high probability of PTE or to be diagnosed clinically by qualified specialist based on patients’ typical symptoms of PTE, finding deep venous thrombosis (DVT) in extremity by venous ultrasound/phlebography and positive D-dimer.This study was approved by the Institutional Review Board of Peking Union Medical College Hospital , in accordance with the Declaration of Helsinki and also registered the clinical trial with identifiers of NCT04411888.Eligible patients were searching according to the diagnosis code of PTE (ICD-Code: 126) in the hospital electronic medical record system. Patients identification and risk factors related to the prognosis of PTE were collected by three qualified doctors through the hospital electronic medical record system and reviewed by a specialist from pneumology department. The risk factors comprised variables in PESI, that is, age, gender, body temperature, pulse rate, respiratory rate, blood pressure, cancer, chronic heart failure, chronic pulmonary disease, altered mental status and arterial oxyhaemoglobin saturation, and other clinical characteristics, admission laboratory tests, imaging examinations, including dyspnea, chest pain, hemoptysis, syncope, surgery or trauma within 3 months, immobilization state, previous history of DVT, cardiopulmonary resuscitation (CPR) in hospital, glucocorticoid therapy history, hyperlipidemia or diabetes, hypertension, white blood cell, neutrophil proportion, hemoglobin, platelet, D-dimer, alanine aminotransferase (ALT), glutamyl transferase (GGT), albumin, creatinine, creatine kinase-Mb (CKMB), cardiac troponin I (cTnI), N-terminal B-type natriuretic peptide (NT-proBNP), serum calcium, serum potassium, serum sodium, serum chlorine, blood glucose, pH value, echocardiography et al. All the patients enrolled completed at least 1-month follow-up and confirmed the survival status as of January 18, 2019. The follow-up data was ascertained by interviewing patients, families or their physicians by means of telephone.Continuous and integer variables were presented as the mean value and SD for normally distributed variables, and the median and quartile for abnormal distributed variables. Categorical variables were expressed as their counts and proportions. Univariate logistic regression analysis was performed for variables in PESI and other admission laboratory indicators to assess the association between each factor and 7-day, 14-day, and 30-day PTE mortality respectively. Besides, part of continuous variables which were statistically significantly associated with the PTE mortality, were converted into categorical variables by selecting the maximum Youden index in receiver operating characteristic (ROC) curve as the cutoff value. Then associations between the newly generated categorical variables and PTE mortalities were analyzed.t test for normally distributed variables, Mann–Whitney U test for variables obeyed abnormal distribution, and chi-square test for categorical variables. Adjusting for variables in the PESI, cox analysis was adopted to determine the contribution of hypocalcemia to 30-day PTE mortality.Especially, patients were classified into two groups according to their serum calcium levels, that is, patients with or without hypocalcemia. Then differences between two groups were compared by two-sided independent Student's Then with 30-day all-cause mortality as the outcome, risk factors significantly associated with 30-day PTE mortality were included to develop a multivariate prognosis prediction rule. Notably considering the practicability, the categorical variables generated by continuous variables were included rather than continuous variables themselves. Each variable was assigned an integral point ranging from 0 to 5, and sum of all variables points was calculated to assess patient risk of death. Multiple prediction rules were generated by modifying variable points according to their significance. The rule with maximum area under curve (AUC) value was selected as the optimal prediction rule. By analyzing the ROC curve, the cutoff level of the optimal prediction rule was determined to identify low risk patients. To guarantee the simplicity and applicability, the building process tried to remove less effective variables with relatively lower points, without affecting the sensitivity and specificity of the prediction rule. More details of the building process could be found in the Additional file https://mvansmeden.shinyapps.io/BeyondEPV/) [Sample size for multivariate prognosis prediction rule was estimated using tool from the website (ondEPV/)  recommenondEPV/) . ValiditondEPV/) . The thrThis study cohort comprised 496 patients with a median age of 61.5  years, and included 229 (46.17%) male patients. PTE was diagnosed in 440 patients (88.71%) by CTPA, V/Q scan in 35 (7.06%), enhanced computed tomography in 9 (1.81%) and clinical diagnosed in 12 (2.42%) patients. As of January 18, 2019, 361 patients survived and 135 died. The median survival time after diagnosis was 644.5  days. The follow-up period of four patients were less than 30 days .13 (2.62%) patients were excluded because of an undocumented serum calcium and a total of 483 patients were included for the following statistical analysis. Serum calcium levels ranged from 1.48 mmol/L to 2.60 mmol/L with a median value of 2.14  mmol/L. Univariate logistic regression analysis showed that serum calcium level was significantly associated with 7-day , 14-day , and 30-day mortalities . Further by selecting 2.13 mmol/L as the cutoff value which had the maximum Youden index in ROC curve  patients with hypocalcemia  showed significant higher 7-day , 14-day , 30-day  mortalities. Adjusting for variables in PESI, cox regression analysis further revealed that hypocalcemia was an independent predictor of 30-day mortality (P = 0.014).The clinical characteristics of the two groups were presented in Table 2 < 90%" was only associated with 7-day mortality. Other variables including "male sex", "temperature < 36 °C", and "chronic pulmonary disease" had no significant associations with mortalities. Among other laboratory examination variables, serum calcium, NT-proBNP, D-dimer and blood glucose had significant correlations with 7-day, 14-day, and 30-day mortalities. After converting these four variables into the categorical variables  was present in a substantial proportion of acute PTE patients (49.48%) at the time of admission and PTE mortality were higher in patients with lower serum calcium. To our knowledge, it is the first to explore the prognostic importance of hypocalcemia in patients with acute PTE. Based on its prognostic predictive value, we proposed the optimal prediction rule, showing higher sensitivities and specificities than PESI and sPESI.2+ through plasma membrane, leading to the reduction of serum calcium [2+ concentration during platelet activation, hypocalcemia may indicate the activation of platelet in PTE patients. Another possible mechanism is related to hypoxic pulmonary vasoconstriction (HPV), which may lead Ca2+ enter from extracellular environment by activating channels like voltage-dependent Ca2+ channels (VDCCs), store-operated channels (SOC), receptor-operated channels (ROC), and acid-sensing ion channel 1a (ASIC1a) [2+ influx can further activate vasoconstriction and lead to pulmonary hypertension [Calcium is an important cofactor of the coagulation cascade and might therefore participates in the pathophysiology of severe thromboembolic and hemorrhagic events. Hypocalcemia has been reported in patients with ST-segment elevation myocardial infarction, intracerebral hemorrhage, and infants with hypoxic-ischemic encephalopathy –22. Neve calcium , is a ma(ASIC1a) –29. Ca2+Our optimal prediction rule showed certain consistency with PESI and sPESI. Four variables associated with PTE prognosis, age > 80 years, pulse rate, heart failure, and cancer, were all included in these three rules, which indicated the prediction rule's reasonability. Besides, our prediction rule differed from PESI and sPESI in some aspects. Comparing with sPESI, the prediction rule comprised "altered mental status" as an important variable and also assigned different points to different variables in order to reflect the diagnostic values of different variables better. Variable points in our prediction rule were relatively consistent with PESI, including assigning higher points to "altered mental status", "cancer", "pulse rate ≥ 110b.p.m" and "age > 80 years". Comparing with PESI, our prediction rule was more simplified and meanwhile kept high predictive ability. Further, as a common clinical indicator and the newly added variable, hypocalcemia showed high prognostic value and helped to improve the rule's predictive validity. Meanwhile, it is also economic and easy to get even in the emergency room, showing high health economics value.Several clinical and research implications could be practiced based on our findings. More intensive surveillance of serum calcium for PTE patients should be adopted in admission. Further studies are expected to explore the mechanism of hypocalcemia and whether PTE patients with low serum calcium levels could benefit from calcium supplement. Additionally, the optimal prediction rule proposed in this study may be helpful to assess the prognosis of patients with acute PTE, but still needs to be validated in larger datasets.Our work has several limitations. First, 13 (2.62%) patients were excluded because serum calcium was not measured at admission. Second, our data can only analysis the correlation between hypocalcemia and the prognosis of PTE, not the causal relationship. Thus, we cannot determine the specific role that serum calcium plays in the pathophysiology of PTE. Third, multi-center studies with larger sample size are also needed to verify the rule's validity.Hypocalcemia is widespread in patients with acute PTE. Our study presented for the first time that admission hypocalcemia was an independent predictor of the 30-day mortality following acute PTE. Based on PESI and hypocalcemia, our optimal prediction rule showed better prognostic predictive performance than PESI and sPESI.Additional file 1: Figure S1. ROC curves for 30-day mortality for the serum calcium, NT-proBNP, D-dimer, and blood glucose.Additional file 2: Figure S2. Comparison of ROC curves of PESI, sPESI and the prediction rule using 12 variables.Additional file 3. Detailed process of derivation and validation of the prediction rule.


Considering the enormous risk of fractures in the course of osteoporosis in the area of the feet, an important aspect of prophylaxis is periodic and, in special cases, ongoing monitoring of defects and deformations as well as pressure distribution. The purpose of this article is to indicate the role of the examination of posture and pressure distribution during standing, postural balance, and gait, in the prevention of fatigue fractures in the course of osteoporosis, based on the literature review and examples of patients.  The manuscript consists of two parts; it has a review-analytical character. The first part reviews the literature. The data were obtained using the MEDLINE (PubMed), as well as Cochrane and Embase databases. The database review was carried out focusing mainly on English-language publications, while taking into account the topicality of scientific and research works in the area of osteoporosis. The problem of multiaspects in the area of bone density was pointed out. Considering the above, in the second part, the authors analyzed 11 exemplary patients with osteoporosis, referring to the assessment of foot and lower limb defects using traditional posturological methods and including pedobarography to diagnostic procedures that are used in the assessment of pressure distribution, standing and moving, and an attempt to balance.  Analysis of the research and scientific literature proved the lack of unambiguous diagnostic procedures of the locomotor system recommended for the prevention of fatigue fractures in the course of osteoporosis. The main diagnostic recommendations are imaging tests (most often X-ray), which are recommended in the case of specific clinical symptoms. The analysis of exemplary patients with osteoporosis showed numerous disorders in the distribution of pressure in the plantar part of the feet, which are related, among other things, with their individual defects and lower limbs.  Detailed posture diagnostics and gait estimation, along with the analysis of pressure distribution within the feet are a very important aspect of the prevention of structural degradation and fatigue fractures within the feet. An important postulate for further research and scientific work is the elaboration of the procedures that will serve the preventive diagnostics of the locomotor system, aimed at early detection of threats of fatigue fractures. Osteoporosis is defined by the World Health Organization (WHO) as a reduction in the bone density index, which affects about 30% of women and 12% of men . The anaBone fragility and, as a result, fractures of the distal part of the foot, pelvic bone, sacral bone, head of the proximal tibial bone, and ribs may be a manifestation of osteomalacia, with a deficiency of vitamin D3 and an equally abnormal absorption of calcium ions and phosphates. These issues should be differentiated from fractures due to osteoporosis in which there is a rupture of the femoral neck, spine vertebrae, or spondylopathy by reducing bone mineral density, which are determined by densitometric examination. The fracture risk increases with age , 14, 15.Since 2001, osteoporosis has been ultimately defined as a disorder within the skeletal system, in which the risk of bone fracture increases, not only due to their reduced density, but also in the course of their fragility, which rises with age . The lacOsteoporosis is more common in women, and an additional factor determining its occurrence is menopause and the postmenopausal period , which is related to the impact of oestrogen on osteoclasts –29. It hOsteoporosis is a significant issue in diabetic patients, especially in terms of the prevention of diabetic foot syndrome and defragmentation, as well as bone fractures in the course of Charcot neuroosteoarthropathy. In the course of type I diabetes mellitus, a mild reduction of bone mineral density is noticed, whereas in type II diabetes mellitus, which is more frequent in older people, a regular or increased BMD index is observed. An enhanced risk of fractures in individuals with diabetes is associated with peripheral neuropathy and weakened muscle capacity, which in consequence affects local structural instability caused by hyperglycaemia, particularly glycosylation in collagen fibres . PermaneFurthermore, it should be noted that the relationship between diabetes mellitus and osteoporosis is imprecise, while bone density studies in the course of diabetes often do not present clear outcomes . NeverthOn the internal level, the function of mechanical load detection is carried out by osteocytes –52. BiomOn the external level, the key issue in the elimination of biomechanical abnormalities will be the diagnosis of body posture, including diagnostic methods aimed at the early detection of defective pressure distribution during standing, body balancing, and locomotion. As a consequence, these actions are aimed at defect correction, relief, and amortization. As a part of the prevention of fractures, pharmacological treatment, supplementation of vitamin D and calcium, and diet therapy are mainly recommended –57. An iHowever, research and the scientific literature do not indicate detailed noninvasive diagnostic procedures. There are also no scientific and research reports in the area of foot assessment, including in particular the procedures for assessing the distribution of pressure within the feet.From the authors' experience, the diagnosis of postural and functional defects of structures allows the early detection of the risk of fatigue fractures in patients with osteoporosis. Consequently, periodic tests allow the early implementation of effective measures to prevent fatigue fractures. Such activities are of particular importance in the prevention of foot fractures, mainly due to the significant gravitational overloads arising during locomotion. Considering the above, the authors made a detailed diagnosis of posture in 11 exemplary patients with osteoporosis, indicating at the same time diagnostic methods for the assessment of foot defects and deformities, and the analysis of pressure distribution during standing, walking, and body balancing.The effects of the analysis of exemplary patients.All figures and images have been prepared by the authors and are their property.The analysis of patients included 11 exemplary patients with osteoporosis, aged 27–86, including eight men and 3 women with pain in the feet, ankle joint, and/or shin, with a limited range of mobility. Two patients additionally suffer from diabetes; four of them have a history of fatigue fractures. In all these patients, postural diagnostics was performed, with particular emphasis on the assessment of foot and lower limb defects using traditional posturological methods, including pedobarography in diagnostic procedures, which is used to assess the distribution of pressure in the standing and locomotion position and the balance test.  Arch height measurements that have been combined with the plantar part assessment  Goniometric assessment of the walk angle and toes positionThe results of the examinations of the feet performed in patients with osteoporosis indicate that 9 out of 11 suffer from tarsal valgus. Seven patients presented hallux valgus and defects of the toes from II to V. However, the comparison of the results of the X-ray with the outcomes of the tests indicates that each patient has a different problem and, as a consequence, a different cause of pain and distortion. The clinical exemplary patients presented in this publication show asymmetrical and chaotic dysfunctions of the foot and structural instability. Given the fact that patients have individually specific changes, the diagnostic procedure indicated by the authors points to the necessity of individual determination of the needs in terms of relief, shock absorption, and correction to be performed in patients with osteoporosis.Below are photographic documentation of 9 patients, that is, X-ray, magnetic resonance imaging, and podoscopic research, which used selected elements of functional diagnostics and anthropometry.During X-ray tests, hallux valgus with an overload of the metatarsophalangeal joint in the area of MTP I and frequent subluxation of sesamoid bones was observed in five patients. Among four patients, enthesopathy of the plantar fascia was detected. In the case of 4 exemplary patients, fractures within the foot bone were observed, in one exemplary patient case tibial, and fibula bone fractures occurred. The analysis of X-rays shows numerous overload changes in the region of the foot, which is manifested by calcifications and osteophytes in the joints and defective trabeculation.The assessment of the pressure on the arch of the foot when standing and walking will be crucial in the early detection of increased pressure. For this purpose, a pedobarographic test was carried out under both static and dynamic conditions . It is noteworthy that the compensatory processes that reduce pain while standing do not activate while walking (despite persistent pain), while standing the foot is stabilized by the tarsometatarsal joints (TMTJ), which consequently makes the second and third metatarsal bones susceptible to fractures as a result of stress –71.  Increased pressure on the heel in the MH area .  Increasing pressure on the head of the 1st (M1) to the 5th (M2) metatarsal bone. This may be due to the fact that metatarsal bones, including the arch of the foot, are exposed to fatigue fractures.Patient no. 10 presented adduction and varus deformity of the forefoot at the level of the line of Lisfranc joints. This is also illustrated by the result 10a, in the left foot:The pedobarographic examination also allowed the assessment of spatial and temporal parameters during foot shunting. The pressure distribution curve is repeatable, an increased pressure is observed on the forefoot of both feet, and this may be associated with a significant dispersion of the values of forces in individual footprints. This result may indicate instability of the structures of the upper and lower ankle.The functionality of the longitudinal arch is assessed using pedobarography. A degree of arch arcing while standing is determined using the Biomech Studio software and the AI (Arch Index). The results presented in Figures Comparative analysis of the results of foot arch examinations during standing and walking is used to assess the functionality of the feet. Six patients who are presented in this publication have overpronation of the foot, which allows a conclusion of planovalgus foot during walking to be drawn . The push off curve was also observed by pedobarography, as illustrated in The ability to maintain balance, which is also assessed during a pedobarographic examination, is also important in assessing the distribution of pressure on the feet. The pedobarography has a very wide diagnostic spectrum, while both standing and walking. Therefore, it is widely used in the prevention of fractures resulting from overloads. These include, in particular, osteoporosis.Elimination of improper pressure, through depreciation and reliefTargeting of its accurate distributionIn the prophylaxis of secondary fractures, which occur during the curing process, it is essential to create the appropriate conditions through two factors:These factors are strategic goals in the process of reducing clinically visible changes , 72. In Reduced bone density and weakened mechanisms of its reconstruction, repair of microdamage, defects in the microarchitecture of the trabeculae, and the porosity and thinning of the cortical layer require rapid prophylactic actions, starting at the level of loads arising in the course of everyday life –77. HoweIn the assessment of the foot's condition, and especially in the activities focused on the prevention of overload changes, the diagnosis of its dynamic parameters and support function has a significant role. Adjusting the pressure distribution, carried out in the process of microdamage prophylaxis, should, therefore, be a process of balancing between the motor activity and simultaneous elimination of excessive load, arising during everyday life activities –91. In aThe recommended treatment, as a component of fracture prophylaxis, mainly involves the initiation of pharmacological treatment, after prior bone density diagnosis and/or X-ray examination. Diet therapy, healthy lifestyle, and vitamin D and calcium supplementation reduces the fracture risk; nevertheless, it is suggested to estimate the intake of calcium due to controversies related to its supply and risk of cardiovascular diseases –57. In tThe research and scientific literature indicates that, in the area of locomotor system diagnostics, as well as in the investigation of fractures in the course of osteoporosis, a highly specialised imaging diagnostic examination remains the golden means . This is performed in the majority of cases when the patient already reports specific clinical symptoms, such as pain during normal life functions . This siThe scientific and research literature does not indicate specific diagnostic procedures. The studies of patients with osteoporosis, reviewed in this publication, showed a chaotic and asymmetrical and highly individualized course of dysfunctions in the area of defects and diseases of the lower extremities. According to the authors, individual differences are closely related to coexisting diseases, in particular to postural defects, with a very individualized course. This is an important postulate for further research aimed at the creation of diagnostic procedures, which are procedures applicable in the prevention of fractures in the course of osteoporosis. The imaging diagnostics recommended so far, due to its intended use, obviously do not constitute preventive procedures for the early detection of fatigue fracture threats. According to the authors, early detection of defects, distortions, gait disturbances, and mobility of structures  will be an important aspect of preventing osteoporotic (and other fractures arising in the course of low bone density) fractures.In the course of prophylaxis, screening is recommended, including women aged over 65 and men aged over 75, among patients at risk. Recommendations are population studies of older people; younger ones should be routinely assessed  and all Preventive actions in the area of fractures in the course of osteoporosis should be focused on precise feet screening diagnostics and, also, due to the fact of a close relationship between the action of forces during everyday life activities and the formation of microfractures, breakages, and a lack of adhesions, in patients with reduced bone density (BMD) , 101. ItAccording to the researchers, the diagnosis of pressure distribution through pedobarography is crucial for the prevention of tissue destruction within the foot. The assessment of defects and functions of the feet, especially during locomotion, serves for the precise detection of the causes of faulty distribution of the tensions. The essence is to differentiate the pressure that occurs while standing and walking, mainly due to the compensatory processes that maintain balance –107. PedThe balance test is an important aspect of functional diagnostics of the musculoskeletal system; combined in one device , it significantly reduces the cost of biomechanical diagnostics –118. Als  Initial assessment of foot defects, for example, valgus/varus deformity of the tarsus, height of the vault, and deformations of the toes   Reliable estimation of pressure distribution under static conditions  Evaluation of foot progression during walking, running, and other types of locomotion  Disturbances of the gait determination in terms of defective pressure distribution, including particularly the relationship of increased tension during prolonged contact of the foot with the ground  The importance of patient education in the field of foot observation and fast intervention in case of local pain, redness, and local body temperature increase –121It seems evident that deformities in the feet and lower limbs, and generally defects in posture, will encourage the formation of defective pressure distribution and a point increase in its value. At the same time, whereas the structural instability induced by osteoporosis will favour the occurrence of defects, structural inefficiencies, and balance disorders, we may speak of a kind of “vicious circle” of events. Therefore, according to the authors, the screening of patients with osteoporosis will also be crucial within the following:Screening tests of feet should consist of the assessment of skin condition for hyperkeratosis, since the first symptoms of increased pressure within the feet are calluses and blisters, formed in the soles of the feet , 123. ThThe lack of ability to relieve the feet and no autocorrection during gait (supination/pronation) is one of the most important problems of patients with diabetes and its complications, for example, Charcot neuroosteoarthropathy . This isThe analysis of the literature showed that, apart from the diagnosis of bone density and the assessment of vitamin D levels, calcium levels, and so on, highly specialised imaging tests (mainly X-ray), used in the event of clinical symptoms, are the recommended diagnostic procedures in the area of the musculoskeletal system.Patients with osteoporosis show numerous individual deformities (defects), dysfunctions, and structural changes in the feet, which results in various disorders of pressure distribution. Extending diagnostics by periodic and screening tests, focused on assessing foot defects, balance disorders, and monitoring time-space parameters during gait will be an important aspect in the prevention of fractures in the course of osteoporosis.Pedobarography has a wide range of uses in periodic screening and ongoing foot diagnostics when the first symptoms of overload  have appeared.Instability and locally increased pressure are observed especially during locomotion; therefore, it is an important aspect to conduct a detailed analysis of patients while walking.In addition to supplementation and pharmacotherapy, the prevention of osteoporotic fractures should include the use of orthopaedic insoles, taking into account the patient-tailored design of elements to relieve and absorb shocks and correct deformations and defects.


To review the results of studies of the effects of dialysis and kidney transplantation on the autonomic nervous system alterations that occur in chronic kidney disease.Vagal control of the heart mediated by arterial baroreceptors is altered early in the course of the renal disease. Sympathetic activation occurs, with increases in resting heart rate, venous plasma norepinephrine levels, muscle sympathetic nerve traffic, and other indirect indices of adrenergic drive. The magnitude of the changes reflects the clinical severity of the kidney disease. Both the sympathetic and parasympathetic alterations have a reflex origin, depending on the impairment in baroreflex and cardiopulmonary reflex control of the cardiovascular system. These alterations are partially reversed during acute hemodialysis, but the responses are variable depending on the specific type of dialytic treatment that is employed. Renal transplantation improves reflex cardiovascular control, resulting in sympathoinhibition following renal transplantation if the native kidneys are removed. Sympathoinhibitory effects have been also reported in renal failure patients after bilateral renal denervation.Assessment of autonomic nervous system responses to dialysis and renal transplantation provides information of clinical interest, given the evidence that autonomic alterations are involved in the development and progression of cardiovascular complications, as well as in the prognosis of chronic kidney disease. Autonomic control of the circulation undergoes profound alterations in chronic kidney disease, with important effects on the parasympathetic and sympathetic regulation of the heart and the peripheral circulation •, 2•. ThWe begin this review by describing alterations in sympathetic and parasympathetic cardiovascular control that occur in the presence of chronic kidney disease and discussing the results of the studies performed by our group and others on this issue. We then describe the mechanisms responsible for these alterations, focusing in particular on the impaired reflex modulation of vagal and adrenergic cardiovascular drive. This is followed by an in-depth evaluation of a debated issue, the reversibility of autonomic dysfunction by the hemodialysis procedure, with specific emphasis on the data collected by our group. The modifications in autonomic cardiovascular regulation exerted by renal transplantation will be then discussed. Finally, emphasis will be given to the autonomic impact of renal denervation when used in the treatment of chronic kidney disease-related resistant hypertension.The first evidence that chronic kidney disease is characterized by cardiovascular autonomic dysfunction dates back 50 years, when Goldberger and coworkers and Soriano and collegue , 4 reporAlong with the parasympathetic alterations noted above, chronic kidney disease is also characterized by profound abnormalities in sympathetic cardiovascular control. These were originally described based on measurement of venous plasma norepinephrine concentrations –12. ThisDuring the past 30 years, evaluation of human adrenergic cardiovascular drive has received renewed interest from investigators and clinicians due to the availability of new analytic techniques that can overcome the limitations of the plasma norepinephrine assay. These include the radiolabeled norepinephrine spillover technique, power spectral analysis of the heart rate signal, neuroimaging, and direct microneurographic recording of efferent postganglionic sympathetic nerve traffic in peripheral  nerves •. The noAnother approach to the investigation of autonomic function is the power spectral analysis of heart rate variability •. This aIn contrast, direct recording of efferent postganglionic muscle sympathetic nerve traffic provides direct information on the behavior of central sympathetic outflow in chronic kidney disease •. These 123metaiodobenzoguanidine) to image the sympathetic innervation of a given organ, in particular the heart [Another approach to assess sympathetic function is the neuroimaging technique, which makes use of very small amount of radiolabeled sympathetic amine  depend on increased adrenergic drive to the heart and, to a lesser extent, on reduced parasympathetic tone  depend o, and (3)There is conclusive evidence that the impaired vagal control of heart rate and the enhanced sympathetic drive seen in chronic kidney disease have a reflex origin. The evidence for impaired vagal control of heart rate dates back to the observation that the bradycardic response to arterial baroreceptor stimulation via intravenous bolus injection of phenylephrine was significantly reduced in patients on chronic hemodialysis compared to age-matched healthy controls . This fiOur group investigated autonomic reflex cardiovascular control in 25 young  uremic patients maintained on hemodialysis three times a week over an average of 4 years of follow-up 34). We evaluated baroreceptor and cardiopulmonary receptor control of the circulation before and after hemodialysis in all patients and in a selected group of patients, following kidney transplantation , 34. The. We evalWe also evaluated cardiopulmonary receptor control of the forearm vascular resistance, venous plasma norepinephrine concentration, and plasma renin activity in these patients. We used the classic lower body negative pressure technique, which, by reducing venous return to the heart, deactivates the volume-sensitive receptors in the cardiac chambers and the pulmonary vascular bed . As showMany studies have examined the impact of long-term hemodialysis on autonomic cardiovascular control , 36, 37.The evidence reported above does not clarify a crucial issue, whether and to what extent the autonomic and reflex abnormalities that occur in chronic kidney disease have a functional rather than a structural nature and whether they can be reversed by treatment. This question received a clearcut answer from the results of the studies that assessed the potential impact of kidney transplantation on autonomic and reflex function. These studies showed that parasympathetic control of the heart clearly improves after renal transplantation. This was documented years ago by evaluating heart rate responses to the Valsalva maneuver and the expiration/inspiration ratio and more recently via the power spectral analysis of the heart rate signal , 15, 42.Similarly to the arterial baroreflex, the cardiopulmonary reflex undergoes significant improvement after kidney transplantation. We found that the increase in forearm vascular resistance, venous plasma norepinephrine, and plasma renin activity triggered by the cardiopulmonary receptor deactivation induced by a mild degree of lower body negative pressure was significantly potentiated after kidney transplantation, the reflex responses becoming almost indistinguishable from those seen in heathy persons .123metaiodobenzoguanidine imaging was employed [Using venous plasma norepinephrine as marker of adrenergic drive, we and others found a significant reduction following renal transplantation •, 2•, 33employed . Howeveremployed . This fiemployed , 44. Retemployed . This fiemployed .Recent clinical studies have shown that bilateral ablation of the renal nerves may result in sustained benefits for renal function in patients with chronic kidney disease •, 47. MaThis review raises a question should be advanced, namely, why we should assess and define the autonomic cardiovascular profile in patients with chronic kidney disease. The answer is based on evidence that autonomic function has independent prognostic relevance in these patients. This has been shown for venous plasma norepinephrine, where elevated circulating levels of this adrenergic neurotransmitter (and thus likely greater levels of sympathetic activation) have been associated with lower survival rate, even after data were adjusted for confounders . This ha


In studies including the general population, the presence of non-malignant monoclonal gammopathy (MG) can be causally associated with kidney damage and shorter survival. We assessed whether the presence of an MG is associated with a higher risk of kidney failure or death in individuals with chronic kidney disease (CKD).N = 878), (2) Salford Kidney Study , and (3) Renal Risk in Derby . Participants were excluded if they had multiple myeloma or any other B cell lymphoproliferative disorder with end-organ damage. Median age was 71.0 years, 50.6% were male, median estimated glomerular filtration rate was 42.3 ml/min/1.73 m2, and median urine albumin-to-creatinine ratio was 3.4 mg/mmol. All non-malignant MG was identified in the baseline serum of participants of RIISC. Further, light chain MG (LC-MG) was identified and studied in participants of RIISC, SKS, and RRID. Participants were followed up for kidney failure  and death. Associations with the risk of kidney failure were estimated by competing-risks regression (handling death as a competing risk), and associations with death were estimated by Cox proportional hazards regression. In total, 102 (11.6%) of the 878 RIISC participants had an MG. During a median follow-up time of 74.0 months, there were 327 kidney failure events and 202 deaths. The presence of MG was not associated with risk of kidney failure , and although there was a higher risk of death in univariable analysis , this was not significant in multivariable analysis . Fifty-five (1.6%) of the 3,478 participants from all 3 studies had LC-MG. During a median follow-up time of 62.5 months, 564 of the 3,478 participants progressed to kidney failure, and 803 died. LC-MG was not associated with risk of kidney failure . There was a higher risk of death in those with LC-MG in the univariable model , but not in the multivariable model . An important limitation of this work was that only LC-MG, rather than any MG, could be identified in participants from SKS and RRID.Data were used from 3 prospective cohorts of individuals with CKD : (1) Renal Impairment in Secondary Care  is a common pre-malignant condition that can be associated with kidney damage and a higher risk of death.Chronic kidney disease (CKD) is also common, affecting approximately 10% of adults, and people with CKD may be more likely to have an MG.It is unknown whether having an MG is associated with higher risk of kidney failure or death in people with CKD.We examined how common an MG is in patients with CKD, and also examined the associations between MG and kidney failure and death using data from 3 cohort studies of patients with CKD in the UK.An MG was present in 11.6% of patients with CKD.Patients with an MG did not have a higher risk of kidney failure or death.Our results are consistent with a previous study that suggested that MG is more common in patients with CKD.However, the presence of an MG was not associated with a higher risk of kidney failure or death.Although this is reassuring for patients with CKD and their healthcare providers, we did not examine whether having an MG is associated with the risk of other adverse outcomes. Monoclonal gammopathy (MG) is a prevalent condition  that canSeveral studies in general populations have shown that the presence of MGUS is associated with shorter survival ,6, and tThis study was performed to determine the prevalence of non-malignant MG in a CKD population and to evaluate whether the presence of a non-malignant MG adds to the risk of adverse outcomes in CKD. We tested the pre-specified hypotheses that the presence of a non-malignant MG is independently associated with a higher risk of kidney failure and shorter survival in patients with CKD.A prospective analysis plan was written . This stPatients from 3 prospective UK cohorts of individuals with CKD who had not received kidney replacement therapy  were included: Renal Impairment in Secondary Care , the Salford Kidney Study , and Renal Risk in Derby .Each study had research ethics committee (REC) approval . All participants in all 3 studies provided written informed consent, and all studies were conducted in accordance with the Declaration of Helsinki.Complete details of these cohorts have been reported elsewhere –11, and Although the majority of included participants with MG will have had MGUS, we have used the more general term non-malignant MG to reflect the fact that only a minority of participants had kidney biopsies to exclude MGRS definitively. Two forms of non-malignant MG were assessed: (1) any non-malignant MG (assessed in the RIISC cohort only), defined as (a) a monoclonal protein on serum protein electrophoresis (SPEP) confirmed by serum immunofixation or (b) a serum κ/λ free light chain (FLC) ratio < 0.37 or >3.10 with an increased level of the involved light chain, or (2) light chain MG (LC-MG) , defined as a serum κ/λ FLC ratio < 0.37 or >3.10 with an increased level of the involved light chain.The Freelite assay  was used to measure κ and λ FLC concentration in all 3 cohorts. The serum κ/λ FLC ratio reference range of 0.37 to 3.10 has been recommended in patients with kidney impairment to account for the associated change in FLC clearance ,13. For Patients were recruited prospectively in all 3 cohorts, and data and biological samples collected at baseline visits were used for this analysis. Years of recruitment, end of follow-up, and median follow-up time for each study are given in The following variables were available for analysis: age, sex, ethnicity , smoking status , co-morbidities , cause of CKD , mean arterial pressure (MAP), estimated glomerular filtration rate , and urine albumin-to-creatinine ratio (ACR).No formal sample size calculations were carried out for these analyses, which were performed using the available specimen collections and datasets.Missing data were assumed to be missing at random, and multiple imputation using chained equations was performed. Results of complete case analyses were similar and are provided in Continuous variables all had skewed distributions as assessed by histograms. The relationships of MG or LC-MG status with other categorical baseline variables were assessed using Fisher’s exact test, and relationships with continuous variables were assessed using the Wilcoxon rank-sum test.The prognostic significance of an MG or LC-MG for risk of kidney failure was estimated by competing-risks regression (the Fine and Gray method ) to accoAll variables included in multivariable models were pre-specified, based on established prognostic factors for kidney failure and death in patients with CKD. Dummy variables were created for categorical variables with more than 2 categories, and fractional polynomials were used to explore the presence of non-linear relationships between continuous predictors and each outcome. Where fractional polynomials provided a better model fit, plots of risk against the variable on its original scale are presented to aid appreciation of the non-linear relationship.P < 0.001), and a higher proportion had a history of malignancy (P = 0.037). For all other baseline variables, there were no statistically significant differences between those with and those without an MG.In total, 878 participants from the RIISC cohort were included, and 102 (11.6%) of these had an MG. Types of MG were as follows: 63 (61.8%) were IgG, 8 (7.8%) were IgM, 5 (4.9%) were IgA, 1 (1.0%) was biclonal (IgG and IgM), and 25 (24.5%) were LC-MG. Study population characteristics and the relationship between MG status and other baseline variables are shown in P = 0.85; In total, 327 (37.2%) participants progressed to kidney failure, with rates per 100 person-years of 10.5 and 9.3 for those with and without MG, respectively. The univariable associations between baseline variables and the risk of kidney failure are shown in P = 0.43). Younger age, female sex, black ethnicity, a cystic or congenital cause of CKD, a lower eGFR, and a higher urine ACR were all associated with a higher risk of kidney failure. In this multivariable model, age, eGFR, and urine ACR had non-linear associations with risk of kidney failure (The multivariable model for kidney failure is shown in  failure .P < 0.001), as shown in P = 0.11; In total, 202 (23.0%) participants died. The death rates per 100 person-years were 10.8 and 5.3 for those with and without MG, respectively. The presence of an MG was associated with a higher risk of death in the univariable model , a higher proportion were male (P = 0.006) and of black ethnicity (P = 0.004), and a lower proportion had a history of IHD (P = 0.001) or PAD (P = 0.004). There were no statistically significant differences between those with and those without LC-MG with respect to all other baseline variables.In total, 3,478 participants from the 3 cohorts were included, and 55 (1.6%) of these had an LC-MG. P = 0.82; In total, 564 (16.2%) patients progressed to kidney failure, with rates per 100 person-years of 4.9 and 3.2 for those with and without an LC-MG, respectively. The univariable associations between baseline variables and the risk of kidney failure are shown in P = 0.26). In this multivariable model, a younger age, black ethnicity, a lower eGFR, and a higher urine ACR were associated with a higher risk of kidney failure, and the non-linear associations with age, eGFR, and urine ACR are shown in The multivariable model for kidney failure is shown in P < 0.001), and P = 0.10). In this multivariable model, older age; male sex; a history of DM, IHD, or cerebrovascular disease; being a previous or current smoker, a lower eGFR, and a higher urine ACR  participants died. Death rates were 9.3 and 4.5 per 100 person-years for those with and without an LC-MG, respectively. The univariable associations between baseline factors and death are shown in We evaluated the prognostic significance of non-malignant MG in patients with CKD. We found the prevalence of non-malignant MG to be higher in our CKD population compared to reported estimates of prevalence for the general population . HoweverTo the best of our knowledge, only 1 other study, by Haynes et al. , has assThe results of our study and the study by Haynes et al. suggest that the shorter survival associated with MGUS in the general population is not seen in patients with CKD. It is possible that neither study was large enough to detect a small increase in the risk of death. However, it may be that the already significantly increased rate of death in individuals with CKD compared to individuals without CKD renders any risk associated with an MG, which is primarily due to malignant transformation over time, negligible.Our finding of a higher prevalence of MG in CKD is also consistent with the study by Haynes et al. and appears attributable to an increased prevalence of both intact immunoglobulin MG and LC-MG. The prevalence of total MGUS in the Olmsted County cohort in individuals aged 70–79 was 5.9%, and the prevalence of light chain MGUS was 1.1% ; in our A significant strength of this study was the inclusion of participants from multiple cohorts from both primary and secondary care and that it is the largest cohort to date of patients with MGUS and CKD. A significant limitation was the absence of SPEP and immunofixation data from the SKS and RRID cohorts. We could, therefore, detect only LC-MG in these cohorts, and many patients with an intact Ig MG would not have been identified. However, in the RIISC study, where SPEP and immunofixation were performed on serum from all participants, the presence of any non-malignant MG was not associated with a higher risk of kidney failure or death.Further, we did not assess the association of MGUS in this CKD population with other clinically important outcomes that are associated with MGUS in those without CKD, such as cardiovascular events, infections, or the evolution of an MG to multiple myeloma or other paraprotein-related diseases. We also did not examine CKD progression (via change in eGFR) with time, which would be a more sensitive marker for MG-associated kidney damage than the outcome of kidney failure.Further research is required concerning the prognostic implications of non-malignant MG in patients with CKD. However, based on the results of our study, these patients and their healthcare providers may be reassured that the presence of an MG does not significantly increase the risk of kidney failure or death that is associated with CKD.In conclusion, the prevalence of non-malignant MG appears to be higher in patients with CKD than in the general population. However, its presence is not independently associated with a significantly higher risk of kidney failure or death.S1 STROBE Checklist(DOCX)Click here for additional data file.S1 Protocol(DOCX)Click here for additional data file.S1 Tablex3; (b) x−2; (c) x-2ln(x); (d) ln(x); (e) x−1; (f) x0.5. ACR, albumin-to-creatinine ratio; CI, confidence interval; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HR, hazard ratio; IHD, ischaemic heart disease; MAP, mean arterial pressure; MG, monoclonal gammopathy; PAD, peripheral artery disease; RIISC, Renal Impairment in Secondary Care; SHR, subhazard ratio.Continuous variables are linear per 1 standard deviation unless otherwise indicated. Transformed continuous variables are indicated by the following footnotes: (a) (DOCX)Click here for additional data file.S2 Tablex3; (b) x-2; (c) x−2ln(x); (d) x0.5; (e) x2; (f) x−1; (g) ln(x); (h) [ln(x)]2; (i) x0.5ln(x). ACR, albumin-to-creatinine ratio; CI, confidence interval; CKD, chronic kidney disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HR, hazard ratio; IHD, ischaemic heart disease; LC-MG, light chain monoclonal gammopathy; MAP, mean arterial pressure; PAD, peripheral artery disease; SHR, subhazard ratio.Continuous variables are linear per 1 standard deviation unless otherwise indicated. Transformed continuous variables are indicated by the following footnotes: (a) (DOCX)Click here for additional data file. 15 Nov 2019Dear Dr. Fenton,Thank you very much for submitting your manuscript "Association between non-malignant monoclonal gammopathy and adverse outcomes in chronic kidney disease" (PMEDICINE-D-19-03271) for consideration at PLOS Medicine. Your paper was evaluated by a senior editor and discussed among all the editors here. 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For instructions see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it. Please ensure that the paper adheres to the PLOS Data Availability Policy  in the subtitle .Abstract- please clarify if a causal association can be inferred from population studies? Please consider toning down or removingAbstract-please provide population demographics, ie where the cohorts are from including names of hospitals or countries as appropriateAbstract Please introduce FLC ratio on first viewAbstract background- please rephrase the first sentence to “In studies including the general population..” or similar for clarityAbstract methods and findings-please include a limitation of your work as the last sentence of this sectionAbstract methods section requires clarification. Please simplify the text in the abstract to explain the FLC ratio/LC MG measurement. In line 31-33 you say “Further, to assess the32 association between a light-chain (LC) MG  two other cohorts were34 also studied…”. Could you clarify what association is being referred to here?At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Pleasehttps://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summarysee our author guidelines for more information: Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section. a) If a prospective analysis plan  was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript. b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place. c) In either case, changes in the analysis—including those made in response to peer review comments—should be identified as such in the Methods section of the paper, with rationale.For all observational studies, in the manuscript text, please indicate: (1) the specific hypotheses you intended to test, (2) the analytical methods by which you planned to test them, (3) the analyses you actually performed, and (4) when reported analyses differ from those that were planned, transparent explanations for differences that affect the reliability of the study's results. If a reported analysis was performed based on an interesting but unanticipated pattern in the data, please be clear that the analysis was data-driven.Line 100- Please introduce MGRS at first viewPlease provide p values along with 95% CI where appropriateLines 164-165 require clarification- please can you explain what is meant by “more had a history of …” etc? Please ensure that the study is reported according to the STROBE guideline, and include the completed STROBE checklist as Supporting Information. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)."http://www.equator-network.org/reporting-guidelines/strobe/The STROBE guideline can be found here: When completing the checklist, please use section and paragraph numbers, rather than page numbers.Please present and organize the Discussion as follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion.Comments from the reviewers:Reviewer #1: This is a retrospective analysis of data collected prospectively for other causes from 3 different sources, used to analyze if there is a correlation between CKD progression and MG (prognostic significance of MGUS in CKD patients). Hypotheses are well defined by the authors. First, as they are using data collected for other purposes, adding many variables to the statistical analysis limits the researchers' ability to determine cause and effect. It is difficult to assess correlation using a retrospective study (RS) design, as RS are subject to numerous threats to validity : the results should be considered as preliminary. Thus, the authors should be very cautious in their conclusions.Also, data collection comes from 3 differents sources, with different inclusion criteria, data collected, etc... Define if MG was detected by serum protein electrophoresis, if then patients underwent serum immunosubtraction and/or immunofixation (Immunofixation of a 24 h urine specimen performed to test for Bence Jones protein?). The diagnostic criteria for MGUS also should be included in this article and not referred for readers to the 3 studies used for it : it would be great if authors could clarify eGFR formula used  and include the definition of MG/MGUS. Specify type of Ig related MG if possible.There is a low proportion of events , which limits statistical power to detect associations: authors should write about their study SUGGESTING X or Y are/aren't risk factors, but that further prospective studies are neccessary to clarify. It would be interesting to know some serologies in these patients, as MG has been related to them : Babel N, Schwarzmann F, Pruss A, et al. Monoclonal gammopathy of undetermined significance (MGUS) is associated with an increased frequency of Epstein‐Barr Virus (EBV) - Latently infected B lymphocytes in long‐term renal transplant patients. Transplant Proc 2004; 36: 2679; Regamey N, Hess V, Passweg J, et al. Infection with human herpesvirus 8 and transplant‐associated gammopathy. Transplantation 2004; 77: 1551.Include Monoclonal gammopathy after liver transplantation: a risk factor for long‐term medical complications other than malignancies (DOI 10.1111/j.1432-2277.2011.01362.x), as they refer to CKD and MG .Overall, the results indeed suggested that there might be no association between CKD and MG, but no clear cut conclusion should be drawn from this (I would change their strong conclusion phrasing).I believe it is an interesting topic for nephrologists, as nowadays the number of patients with MG that reach our clinics is growing.Reviewer #2: I confine my remarks to statistical aspects of this paper. The general approach is fine, but I do have some issues to resolve before I can recommend publication.One general thing is that I would move the supplemental figures into the text.Line 55-56: This is too strong. This accepts the null. If you want to make this statement, you would have to do tests of equivalence. Line 130-131: In general, this is not a reason to not do power analysis. If the authors had done power analysis and found that they needed a larger N, then they would have had to either find more data or do a different analysis. In this specific case, since N is so large, it's not a problem.Line 137-140 How many extreme points were there? Also, why not use robust Cox regression? Line 141-143 Why was this done? Here, statistical significance is not the issue. Also, the authors don't seem to use the results of these analyses (unless I missed something)Line 148-149 Good!Line 150 "Stratified" usually means "separate" I'm not sure that this is what is meant here. Was each cohort analyzed separately? It doesn't look like that was done, from the results. Please clarify. .Line 154: GoodTables: Why are some sections blank?Peter FlomReviewer #3: Fenton et al. reported the association between MGUS and CKD and found that no association with the progression of CKD. The statistical analyses wee well performed. However, it is difficult to find the role of MGUS for the progression of CKD. The presented data is very limited and it is very difficult to understand the the meaning of the statistical analyses.  Among MGUS, amyloidosis is a rare but an important disease for the progression of CKD. In general, patients with amyloidosis has large amount of urinary protein excretion witch has some association with the progression of CKD. However, there is no description about amyloidosis. If the authors investigate the association between amyloidosis and the progression of CKD, the results would be useful for nephrologist. Just the definition of MGUS is too wide to consider the role for the progression of CKD. There is no information on CRP. Since the infection has a key role for the progression of MGUS, the lack of such information should be avoided.  The data are collected at baseline visits. Although the authors described higher HR of ACR, urinary protein excretion may increase with time. So, it may be inadequate to investigate the role of urinary protein excretion by the baseline value. Reviewer #4: I have several comments:* In addition to renal transplantation or dialysis, do the authors have data to consider other endpoints, such as acute kidney injury, or rapid CKD progression?* The confidence intervals in the abstract are quite wide, so it is not inconceivable that the study did not have enough power to detect significance at the conventional 5% levels. Could the authors also discuss the possibly of over-adjusting in the multivariable model, for example, adjusting for common confounders between the exposures & the outcomes?* Could the authors provide more detail on the process of dealing with the extreme values. Was the truncation process applied to the creatinine measurements as well? Also, am I right that the measurements were not excluded, but rather it is their truncated values were used? How many measurements were truncated in the end?Minor comments* How was eGFR calculated from creatinine?* Table 1: Inclusion criteria for RIISC: what does "with eGFR decline" mean?Any attachments provided with reviews can be seen via the following link:[LINK] 19 Dec 2019AttachmentResponse_to_reviewers.docxSubmitted filename: Click here for additional data file. 21 Jan 2020Dear Dr. Fenton,Thank you very much for re-submitting your manuscript "Association between non-malignant monoclonal gammopathy and adverse outcomes in chronic kidney disease: a cohort study" (PMEDICINE-D-19-03271R1) for review by PLOS Medicine.I have discussed the paper with my colleagues and the academic editor and it was also seen again by xxx reviewers. 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Please email us , which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.Please ensure that the paper adheres to the PLOS Data Availability Policy :873-881, Ren Fail. 2015 ;37(1):45-9.). Since the authors investigated the progression of CKD by non-malignant monoclonal gammopathy, the role of CRP has to be evaluated. Reviewer #4: The authors have addressed all my comments, thank you. Study limitations have been acknowledged appropriately, together with the need for future research and suggestions and suggestions on which direction this research could take place in.Any attachments provided with reviews can be seen via the following link:[LINK] 30 Jan 2020AttachmentResponse_to_reviewers.docxSubmitted filename: Click here for additional data file. 3 Feb 2020Dear Dr Fenton, On behalf of my colleagues and the academic editor, Dr. Guiseppe Remuzzi, I am delighted to inform you that your manuscript entitled "Association between non-malignant monoclonal gammopathy and adverse outcomes in chronic kidney disease: a cohort study" (PMEDICINE-D-19-03271R2) has been accepted for publication in PLOS Medicine. PRODUCTION PROCESSBefore publication you will see the copyedited word document (in around 1-2 weeks from now) and a PDF galley proof shortly after that. The copyeditor will be in touch shortly before sending you the copyedited Word document. 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Hypotension following endotracheal intubation in the ICU is associated with poor outcomes. There is no formal prediction tool to help estimate the onset of this hemodynamic compromise. Our objective was to derive and validate a prediction model for immediate hypotension following endotracheal intubation.A multicenter, prospective, cohort study enrolling 934 adults who underwent endotracheal intubation across 16 medical/surgical ICUs in the United States from July 2015-January 2017 was conducted to derive and validate a prediction model for immediate hypotension following endotracheal intubation. We defined hypotension as: 1) mean arterial pressure <65 mmHg; 2) systolic blood pressure <80 mmHg and/or decrease in systolic blood pressure of 40% from baseline; 3) or the initiation or increase in any vasopressor in the 30 minutes following endotracheal intubation.Post-intubation hypotension developed in 344 (36.8%) patients. In the full cohort, 11 variables were independently associated with hypotension: increasing illness severity; increasing age; sepsis diagnosis; endotracheal intubation in the setting of cardiac arrest, mean arterial pressure <65 mmHg, and acute respiratory failure; diuretic use 24 hours preceding endotracheal intubation; decreasing systolic blood pressure from 130 mmHg; catecholamine and phenylephrine use immediately prior to endotracheal intubation; and use of etomidate during endotracheal intubation. A model excluding unstable patients’ pre-intubation (those receiving catecholamine vasopressors and/or who were intubated in the setting of cardiac arrest) was also developed and included the above variables with the exception of sepsis and etomidate. In the full cohort, the 11 variable model had a C-statistic of 0.75 . In the stable cohort, the 7 variable model C-statistic was 0.71 . In both cohorts, a clinical risk score was developed stratifying patients’ risk of hypotension.A novel multivariable risk score predicted post-intubation hypotension with accuracy in both unstable and stable critically ill patients.NCT02508948 and Registered Report Identifier: RR2-10.2196/11101.Clinicaltrials.gov identifier:  Hypotension in critically ill patients in the intensive care unit (ICU) is associated with an increasing risk of myocardial injury, mortality, and acute kidney injury (AKI). Recent work has seen that for every unit increase in time weighted average of mean arterial pressure (MAP) <65 mmHg, the odds of in-hospital mortality increased 11.4% and the odds of AKI increased 7.0% .Respiratory failure requiring endotracheal intubation (ETI) occurs commonly . UnfortuCertain risk factors are known to be associated with immediate hypotension surrounding ETIs. These including, increasing age, higher illness severity, ETI for acute respiratory failure, emergent ETI, use of paralytics, and pre-existing renal failure and chronic obstructive pulmonary disease have all been associated with PIH –9. IntubGiven the lack of predictability and harm associated with PIH in critically ill patients, the HEModynamic and AIRway (HEMAIR) study aimed to examine the current state of ETI in ICUs throughout the United States to derive and validate a prediction model for immediate hypotension in this environment.The HEMAIR study was approved by the Institutional Review Boards at participating centers , with Mayo Clinic Rochester Institutional Review Board serving as the primary regulatory body. The study was conducted under a waiver of consent. All sites were responsible for entering ETI data at their institutions. The study was registered at Clinicaltrials.gov (identifier-NCT02508948) (Registered Report Identifier RR2-10.2196/11101).The current study was a prospective, multicenter, cohort study of critically ill adult (≥18 years) patients who underwent ETI in 16 ICUs throughout the United States from July 2015 to January 2017. The study included general, cardiac, and trauma surgery ICUs and medical ICU patients with various diagnoses including neurological patients across 7 Health & Human Services (HHS) regions in the United States. Endotracheal intubations performed outside the ICU, centers with ≤5 enrollments, and patients with unavailable pre/post- blood pressure data were excluded.https://www.haemair.com/) and monthly HEMAIR investigator meetings were established. Regarding airway management, rapid sequence intubation was defined a priori . The analysis cohort for the present study included patients who had blood pressure measurements available at baseline and 15 minutes post-intubation. As a secondary analysis, we excluded patients who were receiving pre-intubation catecholamine vasopressors and/or who were intubated in the setting of cardiac arrest to arrive at a cohort of stable patients. Candidate predictor variables were selected e review   vs. Stable: 402 [55.1%]) .The primary outcome was experienced in 344 (36.8%) patients of the full cohort and in 216 (29.6%) patients of the stable cohort . Thus, we utilized SBP in the calculation of the HYpotension Prediction Score (HYPS—Full Cohort) and the (s)table HYpotension Prediction Score ([s] HYPS—Stable Cohort). The calibration plots and receiver operating characteristic curves are shown in The potential bedside clinical utility of HYPS and (s) HYPS are shown in Tables The HEMAIR multicenter study retrieved data on ETIs performed in the critically ill to derive and validate a predictive model for immediate hypotension following ETI. We identified 11 variables  that were independently associated with the primary outcome. Of these 11 variables, etomidate use was found to lower the risk of PIH. We combined these predictors into a risk scoring system that we named HYpotension Prediction Score (HYPS) and stable (s) HYPS to stratify patients’ risk for PIH in both all-comers and stable patients. Both the HYPS and (s) HYPS were acceptable with a validation cohort C-statistic higher than 0.70 with stable calibration plots .Post-intubation hypotension is common in the ICU patient with reported incidences ranging between 20–52% , 20, 21.in extremis, we excluded those who were receiving pre-intubation catecholamine vasopressors and/or who were intubated in the setting of cardiac arrest ([s] HYPS). We found similar risk factors in this group of patients as in the full cohort with the exception of etomidate use and sepsis.Age, ETI for acute respiratory failure, pre-intubation hypotension, APACHE, history of obstructive lung disease and renal disease are variables that have been implicated in the pathway to PIH , 26, 27.Traditional blood pressure thresholds of 65 mmHg in the ICU have recently been questioned. A cohort of nearly 9,000 patients demonstrated that the earliest association of myocardial injury, AKI, and mortality occurred at a MAP of 85 mmHg. For mortality and AKI, this harm increased in a progressive manner down to a MAP of 55 mmHg . Our resOur study has several strengths. We enrolled a clinically diverse set of patients from around the country representing 7 regions of the United States. Based on our sample-size analysis, we had a robust sample for our primary outcome. Second, data were collected prospectively and in real-time, allowing for bedside validation of documented blood pressure both before and after ETI. Third, we present a novel score, called the HYpotension Prediction Score (HYPS), that is also clinically useful in more stable patients (stable [s] HYPS) and therefore, may aid the clinician in quickly and efficiently predicting immediate hypotension following ETI. This, in theory, would allow for preemptive adjustment of treatment plans to avoid this immediate complication. For example, implementation of an ETI bundle consisting of fluid loading in the setting of diuretics, choice of etomidate for sedation, and early use of vasopressors with decreasing SBP may reduce immediate hypotension following ETI as demonstrated in one study . FinallyFirst, we did not capture ETIs outside the ICU and thus our results may not be generalizable to non-ICU settings. These patients may be even more vulnerable to untoward physiologic outcomes than the ICU population (and certainly further afield from rescue with vasopressors). However, our intent was to develop a scoring system that would be beneficial in the most severely ill patients, i.e., the critically ill. Second, the providers performing ETI were aware of the study and may have taken precautions to limit complications  thereby introducing bias. Third, we had a large amount of missing data for some variables such as APACHE and lactate. However, we used multiple imputations when appropriate and with data from same HHS region. Fourth, although we used LASSO regression with the penalty parameter (λ) chosen using 10-fold cross-validation, we did not validate our model using an external dataset. Fifth, we may not have captured every ICU ETI. Nonetheless, our study did not exclude any ICU ETI and thus, likely represented random sampling. Sixth, there may be multiple other variables related to PIH not included in the analysis. Our dataset was fairly extensive and thus we feel the majority of variables related to PIH were captured. Finally, the upper risk cut-off could have been extended. However, we chose the upper risk cut-off in both cohorts based on the reasoning that differentiating those at lower risk was felt to be more relevant than those at higher risk as most clinicians would have likely altered their plans if the risk for PIH was already high.in extremis. The utility of both scores in the ICU—including its additive efficacy compared with unassisted clinical decision making—requires further research.The HYPS and (s) HYPS are practical, validated tools that can be calculated using clinically available information. These scores effectively identify those individuals who are at increased risk for PIH in all-comers and in those not S1 TableHEMAIR: HEModynamic and AIRway collaborators, HHS: Health & Human Services.(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 TableHHS: Health & Human Services.(DOCX)Click here for additional data file.S4 TableSBP: systolic blood pressure, MAP: mean arterial pressure.(DOCX)Click here for additional data file.S5 TableThe observed rate is plotted against the mean predicted risk score for the given decile. For the lowest decile, the mean score was ~20%, but there were individuals with scores below this.).(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.S7 TableReference lines separating the 4 risk categories in HYpotension Prediction Score, Reference lines separating the 3 risk categories in (s)table HYpotension Prediction Score.(DOCX)Click here for additional data file.S8 Table(CSV)Click here for additional data file.


Our study is to explore the association between thiamine and cognitive impairment after acute ischemic stroke.Reduced thiamine  and non‐PSCI according to the score of MMSE and the degree of education.p = .045) after adjusting for potential confounding factors. Advanced age, lower education, diabetes mellitus, left hemisphere infarction, and higher National Institute of Health Stroke Scale (NIHSS) were also independent risk factors for PSCI.Reduced thiamine (<1.0 ng/ml) was independently associated with PSCI  of patients suffered with PSCI. Reduced serum thiamine was associated with early cognitive impairment in patients with acute infarction after adjusting for potential confounding factors. Advanced age, lower education, diabetes mellitus, left hemisphere infarction, and higher NIHSS were also independent risk factors for PSCI. Incidence of PSCI ranges from about one‐third to a half within 3 months after stroke  an age range from 18 to 90 years old; (b) acute cerebral infarction occurring within 7 days; (c) diagnosed by computerized tomography (CT) or/and magnetic resonance imaging (MRI); (d) the modified Rankin Score (mRS) ≤2 before stroke; and (e) with complete information of regular auxiliary examinations. And the exclusive criteria were listed as follows: (a) transient ischemic attacks (TIA); (b) a history of depression  or/ and PSD, or other psychiatric disorders; (c) unconscious, severe aphasia and dysarthria; (d) with chronic neurological disease, such as dementia, Parkinson's disease (PD), or Parkinson syndrome; (e) with severe underlying diseases; (f) had a history of cancer whether cured or not; (g) failed to complete the measurement of cognition or mood; (h) diagnosed as infratentorial infarction by the neuroimaging; and (i) carrying one or more large old lesions (diameter more than 20 mm) in the imaging.2.2Standardized questionnaires were used in this study and conducted by trained physicians. Demographic data, lifestyle characteristics, and health status of the subjects were collected by the questionnaires within a week after admission. Hypertension was defined if patients had a history of hypertension or were using antihypertensive medication or systolic pressure > 140 mmHg and/or diastolic pressure > 90 mmHg during subject's hospitalization; hyperlipidemia was defined when triglyceride > 1.7 mmol/L, and/or total cholesterol > 5.2 mmol/L, and/or low‐density lipoprotein cholesterol >3.1 mmol/L, or the use of lipid‐lowering drugs. Diabetes mellitus (DM) was defined by a history of DM were using oral hypoglycemic agents/insulin, or/and fasting serum glucose level of 7.0 mmol/L or more, a postprandial serum glucose level of 11.1 mmol/L or more, or/and HbA1c level of 6.5% or more. Ischemic heart disease was defined as a history of myocardial infarction. Atrial fibrillation was diagnosed on a history or the results of electrocardiogram obtained during hospitalization. Anemia was diagnosed according the standard that hemoglobin was <115 g/L for female and 130 g/L for male; hyperuricemia was defined as the level of uric acid above 357 μmol/L for female and 428 μmol/L for male; smoking was defined as current smoking; drinking means drinking regularly (at least once a week), no less than one standard drink  a day; and all the patients who had a drinking history were divided into two subgroups according to the amount of drinking: moderate drinking (≤2 standard drink/d) and heavy drinking (>2 standard drink/day). Results within 24 hr after admission of fasting serum glucose (FBG), thyroid hormone (TH), thyrotropin‐releasing hormone (TSH), and homocysteine were also recorded (Table 2.3Brain imaging (CT and/or MRI) after stroke was obtained. An acute infarct was defined by the presence of a hyperintense MRI DWI lesion or/and hypodense lesions on CT that were relevant to the acute neurological symptoms. A radiologist and a neurologist both viewed the neuroimagings, and results were got with agreement. The following informations were recorded: size, location, and laterality of lesions. Infarcts were categorized as small if the diameter ≤20 mm (divided as single or multiple) or large if the diameter >20 mm. Locations of infarct were classified into cortical, subcortical white matter, and deep . The lesion was labeled as left or right hemisphere of the brain. White matter lesion was evaluated with Fazekas scale (from 0 to 3 point) according to the degree , which was performed by trained physicians who in charge of the patients at admission; the Chinese version of Mini‐Mental State Examination (MMSE),17‐item Hamilton Depression Rating Scale (HAMD); and the 17‐item Hamilton Anxiety Rating Scale (HAMA), which were performed by only one fixed psychiatrist blind to all the clinical massages of the patients. Poststroke depression (PSD) was defined when HAMD score > 7 points, and those with PSD were finally excluded in this study; anxiety symptoms were screened by HAMA, and poststroke anxiety (PSA) was defined when HAMA score > 7 points. The PSCI was diagnosed by the MMSE scores and adjusted according to education years. Patients who were illiterate according the level ≤17 points, and a primary school education were according the level ≤ 20 points, postsecondary education or above were according the level ≤ 24 points  were measured using a kind of liquid chromatography–tandem mass spectrometer . A laboratory technician blinded to all clinical data processed the samples. The normal reference values of vitamin Bs were listed as follows: Thiamine was 1.0–10.10 ng/ml, vitamin B2 was 2.30–14.60 ng/ml, vitamin B3 was 5.2–72.10 ng/ml, vitamin B5 was12.90–253.10 ng/ml, and vitamin B9 was above 3.0 ng/ml. For results of blood tests, see Table 3.Serum samples were obtained by centrifugation in the next morning after admission. Samples for the determination of vitamin Bs were stored at −80°C before being assayed. Thiamine and other vitamin Bs (vitamins B2.6SD) and compared using Student's t test; while data on normal distribution, variables were exhibited as median (interquartile range) and compared using the Mann–Whitney U test. Categorical variables were listed as number (percentage) and compared using the chi‐squared test. The significant variables including thiamine were further taken into logistic regression analysis and adjusted for the potential confounding factors. In logistic regression analysis, education was dichotomized as lower education , and NIHSS was dichotomized as severity ; drinking was divided into three groups . The results of logistic regression analysis were expressed as adjusted odds ratios (OR) with the corresponding 95% confidence intervals (CI). Software of SPSS19.0 was adopted for statistical analysis. Values of p < .05 were considered to be statistically significant in all tests.To continuous variables on normal distribution, results were expressed as the mean ± standard deviation (3p = .001) and had higher NIHSS (p = .001), lower education (p = .001), and higher proportion of diabetes mellitus (p = .006) (Table p = .005) (Table p = .011) (Table p = .015) and drinking history (p = .039) were also considered to be statistically significant in analysis of single factor . Advanced age , lower education , diabetes mellitus , infarction in left hemisphere , and higher NIHSS  were also independent risk factors of PSCI in this study , after adjusted for confounding factors. To the best of our knowledge, this is the first research to explore the relationship between thiamine and PSCI on acute stage.In our study, among 182 patients, more than a half (54.4%) were diagnosed with PSCI on the acute stage of cerebral infarction. Low level of thiamine is independently associated with early cognitive impairment , which also named thiamine pyrophosphate (TPP), is the biologically active form of thiamine. The brain uses 25% of the glucose with only 2% of body weight in awake state , and our future study will be conducted to measure thiamine dynamically. Last, the sample size of this study is not so large.5Poststroke cognitive impairment shows a high incidence on acute stage, and more than a half (54.4%) of patients suffered with PSCI. Reduced serum thiamine was associated with early cognitive impairment in patients with acute infarction after adjusting for potential confounding factors. Advanced age, lower education, diabetes mellitus, left hemisphere infarction, and higher NIHSS were also independent risk factors for PSCI.All the authors declare that there are no conflicts of interest.Yiming Liu and Jincai He conceived and designed the experiments. Liang Feng drafted and revised the article and analyzed and interpreted the data. Weilei He nd Guiqian Huang screened the subjects and collected the basic data. Shasha Lin, Chengxiang Yuan, and Haoran Cheng collected and stored the blood samples.All authors read and approved the final manuscript.https://publons.com/publon/10.1002/brb3.1709.The peer review history for this article is available at